Clinical Practice Companion

CLINICAL PRACTICE COMPANION An NEJM Special Collection

Limited Time Free Clinical Practice Companion We are pleased to present you with a collection of recent articles relevant to today’s practicing physician. NEJM is committed to helping physicians improve patient care by providing the best current information in an understandable and clinically useful format . These regular features, Clinical Practice, Clinical Therapeutics, and Current Concepts, demonstrate how to diagnose and manage diseases, keep you up to date with the latest in clinical care, and highlight the best treatments and management options. This collection will only be available for a limited time, with free access available by clicking through from the Special Collections tab in My NEJM.

Table of Contents

Table of Contents

CLINICAL 4 PRACTICE CLINICAL PRACTICE

5 Gout T. Neogi

51 52

February 3, 2011

and F.L. Coe

September 2, 2010

S.C. Lazarus

August 19, 2010

Iron-Chelating Therapy for Transfusional Iron Overload G.M. Brittenham

63

72

CLINICAL PRACTICE

Alzheimer’s Disease 35 Early R. Mayeux

CLINICAL THERAPEUTICS

Bisphosphonates for Osteoporosis M.J. Favus

43

Helicobacter pylori Infection K.E.L. McCol

C.L. Moore and J.A. Copel February 24, 2011

80

Coronary Intervention A. Prasad and J. Herrmann

CLINICAL THERAPEUTICS

REVIEW ARTICLE

Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration J.C. Folk and E.M. Stone

CLINICAL THERAPEUTICS

Dietary Therapy in Hypertension F.M. Sacks and H. Campos June 3, 2010

91

Infarction 110 Myocardial Due to Percutaneous February 3, 2011

October 21, 2010

April 29, 2010

CLINICAL THERAPEUTICS

Mitral-Valve Repair for Mitral-Valve Prolapse S. Verma and T.G. Mesana December 3, 2009

BACK to TOC

101 Point-of-Care Ultrasonography

November 18, 2010

June 10, 2010 CLINICAL PRACTICE

REVIEW ARTICLE

REVIEW ARTICLE

CLINICAL PRACTICE

Treatment 25 Emergency of Asthma

CLINICAL THERAPEUTICS

100

CURRENT CONCEPTS

January 13, 2011

CLINICAL PRACTICE

Kidney Stones 15 Calcium E.M. Worcester

CLINICAL THERAPEUTICS

Tuberculosis — 122 MDR Critical Steps for

Prevention and Control E. Nathanson and others September 9, 2010

131

OTHER CLINICAL RESOURCES VIDEOS IN CLINICAL MEDICINE

Evaluation 132 Clinical of the Knee

T.L. Schraeder and others July 22, 2010 INTERACTIVE MEDICAL CASE

Low 137 Lying J.J. Ross and others February 10, 2011

Clinical Practice Clinical Practice articles begin with the presentation of a single case and continue to provide a complete description of diagnostic and treatment strategies, therapeutic options, areas of uncertainty, treatment guidelines — everything you need to know about the current state of knowledge about a common condition. These articles are also available in audio format, so you can listen at your computer or download articles for transfer to any iPod or MP3 player.

BACK to TOC

4

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical practice

Gout Tuhina Neogi, M.D., Ph.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.

A 54-year-old man with crystal-proven gout has a history of four attacks during the previous year. Despite receiving 300 mg of allopurinol daily, his serum urate level is 7.2 mg per deciliter (428 μmol per liter). He is moderately obese and has hypertension, for which he receives hydrochlorothiazide, and his serum creatinine level is 1.0 mg per deciliter (88 μmol per liter). How should his case be managed?

The Cl inic a l Probl em Symptoms and Prevalence

Gout is a type of inflammatory arthritis induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. It is associated with hyperuricemia, which is defined as a serum urate level of 6.8 mg per deciliter (404 μmol per liter) or more, the limit of urate solubility at physiologic temperature and pH.1 Humans lack uricase and thus cannot convert urate to soluble allantoin as the end product of purine metabolism. Hyperuricemia that is caused by the overproduction of urate or, more commonly, by renal urate underexcretion is necessary but not sufficient to cause gout. In one cohort study, gout developed in only 22% of subjects with urate levels of more than 9.0 mg per deciliter (535 μmol per liter) during a 5-year period.2 Gout has two clinical phases. The first phase is characterized by intermittent acute attacks that spontaneously resolve, typically over a period of 7 to 10 days, with asymptomatic periods between attacks. With inadequately treated hyperuricemia, transition to the second phase can occur, manifested as chronic tophaceous gout, which often involves polyarticular attacks, symptoms between attacks, and crystal deposition (tophi) in soft tissues or joints. Although the prevalence of tophaceous gout varies among populations, in one study, tophi were detected in three quarters of patients who had had untreated gout for 20 years or more.3 Recurrent attacks are common. In one study, approximately two thirds of patients with at least one gout attack in the previous year had recurrent attacks.4 An estimated 6.1 million adults in the United States have had gout.5 The prevalence increases with age and is higher among men than among women, with a ratio of 3 or 4 to 1 overall.5-7 However, this sex disparity decreases at older ages, at least in part because of declining levels of estrogen, which has uricosuric effects in women. The rising incidence and prevalence of gout are probably related to the aging of the population, increasing levels of obesity, and dietary changes.6,7

From the Section of Clinical Epidemiology Research and Training Unit, Boston University School of Medicine; and the Department of Epidemiology, Boston University School of Public Health — both in Boston. Address reprint requests to Dr. Neogi at the Clinical Epidemiology Unit, Boston University School of Medicine, 650 Albany St., Suite X-200, Boston, MA 02118, or at [email protected]. N Engl J Med 2011;364:443-52. Copyright © 2011 Massachusetts Medical Society.

An audio version Click here to of this article access audio is available at version. NEJM.org

Risk Factors

The use of thiazide diuretics, cyclosporine, and low-dose aspirin (<1 g per day) can cause hyperuricemia, whereas high-dose aspirin (≥3 g per day) is uricosuric. Factors n engl j med 364;5 BACK to TOC

nejm.org

february 3, 2011

443

5

The

n e w e ng l a n d j o u r na l

that are associated with hyperuricemia and gout include insulin resistance, the metabolic syndrome, obesity, renal insufficiency, hypertension, congestive heart failure, and organ transplantation.8,9 The uricosuric effects of glycosuria in diabetes may reduce the risk of gout.10 Rare X-linked inborn errors of metabolism can cause gout.8 Genomewide association studies have identified common polymorphisms in several genes involved in renal urate transport that are associated with gout, including SLC2A9, ABCG2, SLC17A3, and SLC22A12.11,12 The risk of incident gout is increased in persons with an increased intake of dietary purines (particularly meat and seafood), ethanol (particularly beer and spirits), soft drinks, and fructose13-16 and is decreased in those with an increased intake of coffee, dairy products, and vitamin C (which lower urate levels).15,17,18 Triggers for recurrent flares include recent diuretic use, alcohol intake, hospitalization, and surgery.19,20 Urate-lowering therapy, which reduces the risk of gout attacks in the long term, can trigger attacks in the early period after its initiation, presumably as a result of mobilization of bodily urate stores.21,22

S t r ategie s a nd E v idence The diagnostic standard remains synovial fluid or tophus aspiration with identification of negatively birefringent monosodium urate crystals under polarizing microscopy. Crystals are detectable during attacks and also potentially between attacks, primarily in previously inflamed joints in patients with hyperuricemia.23 However, crystal evaluation is not performed routinely in clinical practice.15 Hyperuricemia may not be present during acute gout attacks and therefore may not be a helpful criterion for diagnosis. A typical presentation that is strongly suggestive of the diagnosis includes rapid development of severe pain (i.e., within 24 hours), erythema, and swelling in a characteristic joint distribution — for example, in the first metatarsophalangeal joint (podagra). In a population with a 0.5% prevalence of gout overall, a patient with hyperuricemia and this presentation has an 82% chance of having gout.23 The differential diagnosis of acute gout includes other crystal-induced arthritides (e.g., calcium pyrophosphate dihydrate) and a septic joint. Joint aspiration with Gram’s staining and culture must be performed if a septic joint is suspected, 444 BACK to TOC

n engl j med 364;5

of

m e dic i n e

even if monosodium urate crystals are identified. Older adults, particularly women, may present with polyarticular involvement, which may be mistaken for rheumatoid arthritis; a tophus may be mistaken for a rheumatoid nodule. Tophaceous deposits that are not clinically apparent may be visualized by plain radiography or another imaging method. A diagnosis of gout should prompt evaluation for potentially modifiable risk factors (e.g., dietary habits) and associated coexisting illnesses (e.g., hypertension and hyperlipidemia) that may require intervention.

T r e atmen t Op t ions Acute Gout

The main aim of therapy for acute gout is rapid relief of pain and disability caused by intense inflammation. Options for managing acute attacks include the use of nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, glucocorticoids, and possibly corticotropin.24 The choice of agent, dose, and duration of therapy is guided by consideration of coexisting illnesses that preclude the safe use of a particular regimen, as well as the severity of the gout. Adjunctive measures include applying ice to and resting the affected joint.25 NSAIDs and colchicine are first-line agents for acute attacks (Table 1).24 Oral colchicine has long been used, although it has only recently (in 2009) been approved by the Food and Drug Administration (FDA) for use in patients with acute gout. In a randomized trial, colchicine (at a dose of 1.2 mg at the onset of a flare, followed by 0.6 mg 1 hour later) was significantly more likely than placebo to result in a reduction in pain of 50% or more 24 hours later (rates, 37.8% and 15.5%, respectively).26 This regimen had efficacy similar to that of a high-dose regimen (1.2 mg, then 0.6 mg per hour for 6 hours), with fewer gastrointestinal side effects. This study did not address treatment after the first 24 hours. The relative efficacy of colchicine as compared with NSAIDs is unknown. In head-to-head studies, various NSAIDs have had similar benefits for acute gout, and a controlled trial showed the efficacy of tenoxicam over placebo.24,27 When the use of NSAIDs or colchicine is poorly tolerated or contraindicated, glucocorticoids or corticotropin may be used, although evidence for the use of intraarticular and intramuscular glucocorticoids and corticotropin is limited by a lack

nejm.org

february 3, 2011

6

BACK to TOC

n engl j med 364;5

nejm.org

february 3, 2011

375–500 mg orally twice daily for 3 days, then 250–375 mg orally twice daily for 4–7 days or until attack resolves

Alternative Regimens for Complete Attack Resolution* Precautions

Consider additional acute gout regimen Avoid (or use lower dose) in older adults and those with renal to continue managing attack insufficiency, hepatic dysfunction, or known gastrointestinal 12–24 hr after colchicine regimen symptoms; adjust dose (and avoid in patients with renal (e.g., 0.6 mg of colchicine twice daily, or hepatic impairment) if used in conjunction with a nonsteroidal antiinflammatory P-glycoprotein or CYP3A4 inhibitors (e.g., cyclosporine, clardrug regimen, or an oral glucocortiithromycin, certain antiretroviral agents, certain antifungal coid regimen until attack resolves) agents, certain calcium-channel blockers, and grapefruit juice); avoid for gout-flare therapy in patients with renal or hepatic impairment who are already receiving colchicine prophylaxis; monitor for gastrointestinal symptoms, myotoxicity, and blood dyscrasias (details are available at www.fda.gov).

Avoid in patients with renal or hepatic insufficiency, bleeding disorder, congestive heart failure, or allergy; associated with an increased risk of adverse thrombotic and gastrointestinal events; may be administered with a proton-pump inhibitor in patients at risk for gastrointestinal events.

Prednisolone, 30–35 mg daily for 5 days Prednisone, 30–60 mg daily for 2 days Use caution in patients with hyperglycemia or congestive heart (depending on severity of attack), failure; may be used in patients with moderate-to-severe renal then reduce by 5–10 mg every 2 days impairment. (depending on starting dose) in 10-day taper

1.2 mg orally at first sign of gout flare, followed by 0.6 mg orally 1 hr later

50 mg orally three times daily for 2 days, 50 mg orally three times daily for 3 days, then 25 mg orally three times daily then 25 mg orally three times daily for 3 days for 4–7 days or until attack resolves

500 mg orally twice daily for 5 days

Examples of Regimens from Randomized Clinical Trials

* Longer durations of therapy may be necessary for patients with long-standing disease and severe flares. † There are no published trials establishing the efficacy of celecoxib, the only selective cyclooxygenase-2 inhibitor available in the United States, for use in acute gout. ‡ Although there are insufficient data to recommend the use of intraarticular glucocorticoid injection, it may be a useful alternative for attacks that are limited to one or two joints and amenable to aspiration and in the absence of joint sepsis.

Oral glucocorticoids (prednisone or prednisolone)‡

Colchicine

Indomethacin

Naproxen

Nonsteroidal antiinflammatory drug†

Drug

Table 1. Pharmacologic Management Options for Acute Gout Attacks.

clinical pr actice

445

7

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

hyperuricemia, and antihyperuricemic therapies are not without risk. Recommendations that are based on both consensus and evidence support the consideration of urate-lowering therapy in patients with hyperuricemia who have at least two gout attacks per year or tophi (as determined by either clinical or radiographic methods).38 However, the severity and frequency of flares, the presence of coexisting illnesses (including nephrolithiasis), and patient preference are additional considerations.24 Urate-lowering therapy should not be initiated during acute attacks but rather started 2 to 4 weeks after flare resolution, with a low initial dose that is increased as needed over a period of weeks to months, and with close monitoring of urate levels, renal function, and adverse effects. The dose should be adjusted as necessary to maintain a serum urate level below 6 mg per deciliter (357 μmol per liter), which is associated with a reduced risk of recurrent attacks and tophi.22,39,40 It is uncertain whether a more stringent target of less than 5 mg per deciliter (297 μmol per liter) results in greater disease control.41,42 Therapy is generally continued indefinitely. Three classes of drugs are approved for lowering urate levels: xanthine oxidase inhibitors, uricosuric agents, and uricase agents (Table 2 and Fig. 2). Xanthine oxidase inhibitors block the synthesis of uric acid and can be used regardless of whether there is overproduction of urate. In this class of drugs, the one most commonly prescribed to lower urate levels is allopurinol, which is effective in decreasing flares and tophi, particularly among patients in whom target urate levels are achieved.22,39 Although allopurinol has an acceptable side-effect profile in most patients, a mild rash develops in approximately 2%.22,39,43 Severe allopurinol hypersensitivity is much less common but can be life-threatening. Allopurinol desensitization can be attempted in patients with mild cutaneous reactions, but its safety in those with more serious reactions is unknown.44 The majority of patients receive 300 mg of allopurinol daily, but this dose is often inadequate to achieve target urate levels. Daily doses up to 800 mg may be used in patients with normal renal function. The dose is typically reduced in patients with renal impairHyperuricemia ment, owing to concerns about an increased risk Pharmacologic Approaches of hypersensitivity in such patients. However, studThe purpose of lowering serum urate levels is to ies have not shown an association between dose prevent acute flares and development of tophi. and risk of hypersensitivity, and a reduced dose However, gout does not develop in all patients with may contribute to suboptimal gout control.43

of data from blinded, randomized, placebocontrolled trials24,27-29 (Table 1). Monoarticular attacks are often managed with the use of intraarticular glucocorticoids. In two randomized, placebo-controlled trials of a 5-day course of oral prednisolone (one evaluating a dose of 30 mg daily and the other a dose of 35 mg daily), the efficacy of prednisolone was equivalent to that of standard regimens of indomethacin (vs. the 30-mg dose of prednisolone) and naproxen (vs. the 35-mg dose).30,31 The dose and duration of therapy for acute gout should be sufficient to eradicate the profound inflammatory response. Although randomized trials have generally studied the effects of short courses of treatment on pain reduction, clinical experience suggests that 7 to 10 days of treatment may be necessary to ensure the resolution of symptoms. Increased doses of antiinflammatory drugs are typically prescribed for the first few days, with a reduction in the dose once symptoms begin to improve.32 Flares should be treated without interruption of urate-lowering therapy. A “medications in the pocket” strategy should be considered for patients with established gout so that therapy can be started promptly at the onset of symptoms that are consistent with typical attacks. There is evidence that attacks of gout are caused by the activation of the NLRP3 inflammasome by urate crystals, leading to the release of interleukin-1β33 (Fig. 1). For this reason, interleukin-1 antagonists are being studied as potential options for patients in whom other treatments are not feasible.34 In a randomized trial, the fully human monoclonal antibody canakinumab significantly reduced pain from acute gout, as compared with 40 mg of intramuscular triamcinolone acetonide, 72 hours after administration of the study drug.35 Anakinra and rilonacept improved acute and chronic gout symptoms, respectively, in two small, uncontrolled pilot studies; however, rilonacept did not significantly reduce pain, as compared with indomethacin, in a randomized trial.34,36,37 More data are needed to assess the potential role of these agents.

446 BACK to TOC

n engl j med 364;5

nejm.org

february 3, 2011

8

clinical pr actice

In 2009, another xanthine oxidase inhibitor, febuxostat, was approved by the FDA for the treatment of hyperuricemia in patients with gout. As compared with a daily dose of 300 mg of allopurinol, febuxostat at daily doses of 80 mg and 120 mg was 2.5 and 3 times as likely, respectively, to achieve serum urate levels of less than 6 mg per deciliter in a 52-week trial.22 During the initial 8 weeks of the study, the frequency of gout attacks was higher among patients receiving 120 mg of febuxostat than among those receiving either 80 mg of febuxostat or 300 mg of allopurinol, but there was no significant difference among the three groups for the remainder of the trial. In another study involving patients with renal impairment (defined as a creatinine clearance of 30 to 89 ml per minute), daily doses of 80 mg and 40 mg of febuxostat were superior to 300 mg of allopurinol (or 200 mg in patients with moderate renal impairment) for lowering serum urate to a level below 6 mg per deciliter.39 There was no increase in cardiovascular risk or hypersensitivity associated with the use of either dose of febuxostat, as compared with allopurinol, although the trial was not powered for such comparisons. Postmarketing surveillance is needed to better understand the risks and benefits of febuxostat. Its efficacy as compared with increased doses of allopurinol is not known, nor is its safety in persons with allopurinol hypersensitivity. Uricosuric drugs (including probenecid, sulfinpyrazone, and benzbromarone) block renal tubular urate reabsorption. Although these drugs can be used in patients with underexcretion of urate (accounting for up to 90% of patients with gout), they are used less frequently than xanthine oxidase inhibitors and are contraindicated in patients with a history of nephrolithiasis. Benzbromarone (not available in the United States) may be used in patients with mild-to-moderate renal insufficiency but is potentially hepatotoxic, whereas the other two drugs are generally ineffective in patients with renal impairment. In two openlabel, randomized trials, benzbromarone was equivalent to allopurinol (the latter at a daily dose of as much as 600 mg) and superior to probenecid (among patients in whom target urate levels were not achieved with 300 mg of allopurinol) in lowering serum urate to 5 mg per deciliter or less.41,45 Uricase converts uric acid into soluble allantoin. Pegloticase, a polyethylene glycolated (pegn engl j med 364;5 BACK to TOC

Monosodium urate crystals Resident macrophage lineage cells + NLRP3 inflammasome Pro–interleukin-1β

+ C5b-9

Other mediators (e.g., TNF-α, interleukin-6 and 8, leukotrienes, alarmins)

Interleukin-1β

Endothelial or synovial cell

Interleukin-1 receptor

Adhesion molecules, chemokines

Neutrophil recruitment, activation, and release of additional inflammatory mediators

Figure 1. Mechanisms of Inflammation in Gout. In acute gout, monosodium urate crystals that have undergone phagocytosis activate the NLRP3 inflammasome, leading to secretion of interleukin1β. In turn, this secretion can induce further production of interleukin-1β and other inflammatory mediators and further the activation of synovial lining cells and phagocytes. Monosodium urate crystals also induce many other inflammatory cytokines (e.g., tumor necrosis factor α [TNF-α], interleukin-6 and 8, leukotrienes, and alarmins) by mechanisms that are both dependent on and independent of interleukin-1. Experimental models of gout have demonstrated a role for the activation of the terminal complement pathway (C5b-9 membrane attack complex) induced by monosodium urate crystals. Binding of interleukin-1β to the interleukin-1 receptor results in signal transduction, leading to altered expression of adhesion molecules and chemokines, which together with the other inflammatory events results in the neutrophil recruitment that is a major driver of the intense inflammation in gout. In chronic gout, with low-grade synovitis and frequently recurring or nonresolving flares, these inflammatory processes are probably ongoing with potentially continued release of inflammatory mediators, including interleukin-1β, in the presence of persistent monosodium urate crystals.

ylated) modified porcine recombinant uricase, was approved by the FDA in 2010 for chronic gout that is refractory to conventional treatments. The approval was based on data from two doubleblind, randomized, placebo-controlled, 6-month trials showing the drug’s urate-lowering and tophus-reducing effects. However, pegloticase must be administered intravenously, and infusion reactions were common.46 Rasburicase, which is approved for use in preventing the tumor lysis syn-

nejm.org

february 3, 2011

447

9

448

BACK to TOC

n engl j med 364;5

Starting dose: 40 mg orally daily; increase to 80 mg orally daily after 2–4 wk to achieve serum urate target, if necessary†

Starting dose: 50–100 mg orally daily; increase dose every 2–4 wk to achieve serum urate target, with dose based on creatinine clearance; average daily dose, 300 mg, although many patients require higher doses

nejm.org

of

Avoid in patients with a history of nephrolithiasis and a creatinine clearance of <30 ml per minute. Adequate hydration is required to reduce risk of nephrolithiasis. The use of this drug can increase serum penicillin levels. Evaluate for renal uric acid excretion in patients with a family history of early onset of gout, onset of gout at <25 yr, or a history of nephrolithiasis, since this may identify patients with an overproduction of urate in whom uricosuric therapy should be avoided because of the risk of nephrolithiasis.

Use as a second-line agent for patients who have contraindications or an inadequate response to allopurinol or uricosuric therapy. Although no dose adjustment is required for patients with mild-to-moderate renal or hepatic insufficiency, there are insufficient data for use in patients with a creatinine clearance of <30 ml per minute or severe hepatic impairment. Currently contraindicated for use with theophylline. Febuxostat has a higher cost than allopurinol.

Use with caution in patients with renal insufficiency (based on creatinine clearance). The maximal dose may be as high as 800 mg daily, but there are limited data for doses above 300 mg daily. A mild rash occurs in approximately 2% of patients, and the risk is potentially increased by coadministration of ampicillin, amoxicillin, thiazide diuretics, or ACE inhibitors. Allopurinol hypersensitivity is rare, occurring in approximately 0.1% of patients, but can be fatal (rate of death, 20%). If the target serum urate level is not achieved, consider dose escalation beyond the level suggested by guidelines in patients with renal impairment (with close monitoring) or consider the use of an alternative therapy (e.g., febuxostat). Allopurinol can increase the anticoagulant effect of warfarin.

n e w e ng l a n d j o u r na l

Uricosuric agent (probenecid)‡ Starting dose: 250 mg orally daily; increase by 500 mg per mo to a maximal dose of 2–3 g per day (2 divided doses) in patients with normal renal function to achieve serum urate target

Febuxostat

Allopurinol

Use in patients with urate overproduction or underexcretion. Avoid use (or monitor closely) in patients receiving azathioprine or 6-mercaptopurine because these drugs are metabolized by xanthine oxidase.

Xanthine oxidase inhibitor

Considerations or Precautions Aim to maintain serum urate levels below 6 mg per deciliter, which requires regular monitoring and may require dose adjustments. Accompany the initiation of therapy with flare prophylaxis.

Example of Regimen

Urate-lowering therapy

Drug

Table 2. Pharmacologic Options for Hyperuricemia Therapy in Gout.*

The

m e dic i n e

february 3, 2011

10

n engl j med 364;5 BACK to TOC

drome, is not appropriate for use in patients with gout because of its immunogenicity and short half-life. Lifestyle, Nutrition, and Adjunctive Therapies

* ACE denotes angiotensin-converting enzyme, and NSAID nonsteroidal antiinflammatory drug. † Febuxostat at a dose of 120 mg is available in Europe. ‡ Benzbromarone and sulfinpyrazone are available in a limited number of countries but not in the United States.

See Table 1 for precautions, particularly taking into account potential for increased toxic effects with prolonged therapy. This drug has not been formally tested but has been used for prophylaxis in trials of urate-lowering therapies. Naproxen, 250 mg twice daily NSAID

See Table 1 for precautions, particularly taking into account potential for increased toxic effects with prolonged therapy. 0.6 mg orally once or twice daily as tolerated Colchicine

Aim to reduce the risk of flare during initial decrease in urate levels, presumably related to rapid mobilization of bodily urate stores. The duration of therapy is not well defined but treatment for at least 6 mo or until tophi resolve is recommended. Flare prophylaxis during initiation of urate-lowering therapy

Uricase (pegloticase)

Intravenous infusion of 8 mg every 2 wk; requires premedication with antihistamines and glucocorticoids; start gout-flare prophylaxis ≥7 days before initiating treatment

Use for chronic gout in adults whose disease is refractory to conventional therapy (e.g., lack of normalization of serum urate, inadequate control of signs and symptoms with the use of a xanthine oxidase inhibitor at maximum medically appropriate dose, or other contraindication). There is a risk of infusion reactions (26%, vs. 5% in placebo group) even with premedication, particularly in patients without a therapeutic response (in whom serum urate levels increase to above 6 mg per deciliter, particularly on two consecutive occasions) or with antibodies against pegloticase. Anaphylaxis occurs in 5% of patients (vs. 0% in placebo group). No data are available regarding retreatment after stopping treatment for longer than 4 weeks. Do not use in patients with G6PD deficiency, and use caution in patients with congestive heart failure (insufficient safety data; some exacerbations in clinical trials). Cost is higher than for other therapies.

clinical pr actice

nejm.org

Observational data indicate that nonpharmacologic approaches, such as avoiding alcohol or modifying one’s diet, can reduce serum urate levels but may not be sufficient to control established gout.24 In one randomized trial involving persons without gout, 500 mg of vitamin C per day for 2 months resulted in serum urate levels that were 0.5 mg per deciliter (30 μmol per liter) lower than in those receiving placebo.47 The intake of dairy milk reduced serum urate levels by approximately 10% during a 3-hour period in a small, randomized, crossover trial involving healthy volunteers.48 Whether these approaches would have similar effects in persons with gout, or with a longer duration of therapy, is not known. Losartan and fenofibrate, which have uricosuric effects, may be considered in patients with gout who have hypertension or hypertriglyceridemia, respectively,49 although it is not known whether their use reduces the frequency of gout attacks. Flare Prophylaxis during Initiation of Urate-Lowering Therapy

Because rapid lowering of urate levels is associated with gout flares, with an increased risk associated with therapies that more effectively lower urate levels,22,46 prophylaxis against acute flares is advised during the initiation of urate-lowering therapy (Table 2).24 In a study of patients with normal renal function who were starting allopurinol therapy, oral colchicine (at a dose of 0.6 mg twice daily for an average of 5.2 months) significantly reduced the likelihood of gout attacks and lessened the severity of flares that did occur, as compared with placebo.21 Diarrhea was common, resulting in a once-daily regimen of colchicine for many patients. Thus, the general recommendation for flare prophylaxis is to use colchicine at a dose of 0.6 mg once or twice daily, with dose adjustments as needed for renal impairment, potential drug interactions, or intolerance. Although NSAIDs are also used for prophylaxis, there are few studies that support their use.24 For patients without tophi, prophylaxis should be continued for 6 months. The optimal duration for those with tophi is uncertain; ongoing prophylaxis until tophus resolution may be necessary.

february 3, 2011

449

11

The

n e w e ng l a n d j o u r na l

Exogenous purines Dietary restriction Endogenous purines Xanthine oxidase inhibitors

Body urate pool

Recombinant uricase

Renal tubules

Uricosuric agents

Renal insufficiency or failure

Figure 2. Management Strategies in Patients with Hyperuricemia. Hyperuricemia can be targeted at many levels. Restriction of exogenous purine intake through dietary modifications or the use of xanthine oxidase inhibitors to block uric acid synthesis from endogenous purine metabolism can reduce the amount of urate that contributes to the total-body urate pool. Modified uricase agents reduce the total-body urate pool by converting uric acid into soluble allantoin. In patients with normal renal function, uricosuric agents can promote renal elimination of urate, thereby reducing total-body urate pools. However, decreased renal urate excretion in patients with renal impairment leads to increased totalbody urate stores.

A r e a s of Uncer ta in t y Data are limited regarding the safety and efficacy of combination therapies for the treatment of gout (e.g., the use of a xanthine oxidase inhibitor and a uricosuric agent for hyperuricemia or the use of multiple drugs for acute gout attacks). The safety and cost-effectiveness of new agents for gout, including inhibitors of urate transporter 1 and purine nucleoside phosphorylase, which are under development, and interleukin-1 antagonists, require further study. Preliminary data have suggested the potential efficacy of the interleukin-1 antagonists canakinumab and rilonacept for flare prophylaxis.34 450 BACK to TOC

n engl j med 364;5

of

m e dic i n e

Risk factors for recurrent gout flares may differ from those that predispose patients to the initial attack. Whether factors that lower serum urate levels over the long term in persons without gout would have similar effects with short-term or episodic exposure in persons with gout requires clarification. It is not known to what level urate can be safely lowered. Observational data have suggested associations between low urate levels and an increased risk of Parkinson’s disease,50 but it is unclear whether the low levels are a cause or consequence of disease. The optimal duration of urate-lowering therapy is also uncertain, and such therapy is recommended indefinitely at this time. In one study, the withdrawal of urate-lowering therapy was associated with prolonged symptomfree intervals (3 to 4 years) in a cohort of 89 patients after long-term control of urate levels (<7 mg per deciliter), flares, and tophi resolution,51 but further study is needed. Finally, the concept of asymptomatic hyperuricemia as a benign condition is being challenged. Experimental data suggest that urate may contribute to vascular remodeling and hypertension, although it remains uncertain whether urate plays a causal role in cardiovascular disease.9

Guidel ine s The American College of Rheumatology is currently developing guidelines for the management of gout. The European League against Rheumatism and the British Society for Rheumatology have published guidelines for the evaluation and management of gout on the basis of trial data (when available) and expert consensus.23,24,42 The present recommendations are largely consistent with these guidelines.

C onclusions a nd R ec om mendat ions In patients presenting with suspected gout, the diagnosis should be confirmed by examination of synovial fluid or tophus aspirate for monosodium urate crystals. Management should be tailored to the stage of disease and coexisting illnesses. The patient who is described in the vignette has crystalproven gout, with multiple attacks and a serum urate level of more than 6 mg per deciliter despite receipt of allopurinol at a dose of 300 mg per day.

nejm.org

february 3, 2011

12

clinical pr actice

Since his renal function is normal, the allopurinol dose should be increased (e.g., 100-mg increments every 2 to 4 weeks until the target urate level is reached), with monitoring of renal function and serum urate levels and assessment for potential adverse reactions. Colchicine prophylaxis (0.6 mg once or twice daily) is reasonable while the dose of allopurinol is escalated. If target serum urate levels cannot be achieved or if the patient has serious side effects at higher allopurinol doses, the use of either febuxostat or a uricosuric agent is another option, given his normal renal function. The patient should understand that the intake of alcohol and an excessive amount of meat or seafood and sugar-sweetened drinks may contribute to elevated urate levels and should be minimized. He should be advised to keep well hydrated and to lose weight. Associated cardiovascular risk factors should be identified and treated. Although the use of hydrochlorothiazide may contribute to

the increased urate level, I would not necessarily change that medication if it is effectively controlling his blood pressure, and I would advise him to take the diuretic consistently, since intermittent use may precipitate flares. The addition of losartan for the hypertension might be considered. He should be advised to maintain his urate-lowering regimen during flares, which can be managed with colchicine. Follow-up is necessary to ensure that appropriate serum urate levels are achieved and maintained and to monitor the patient for adverse effects. Dr. Neogi reports serving as a core expert panel leader for the American College of Rheumatology Gout Treatment Guidelines. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. I thank Drs. Saralynn Allaire, Hyon Choi, and Yuqing Zhang for their review of the first draft of the manuscript and Dr. Robert Terkeltaub for his review of an earlier version of Figure 1.

References 1. Loeb JN. The influence of temperature

on the solubility of monosodium urate. Arthritis Rheum 1972;15:189-92. 2. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia: risks and consequences in the Normative Aging Study. Am J Med 1987;82:421-6. 3. Gutman AB. The past four decades of progress in the knowledge of gout, with an assessment of the present status. Arthritis Rheum 1973;16:431-45. 4. Neogi T, Hunter DJ, Chaisson CE, Allensworth-Davies D, Zhang YQ. Frequency and predictors of inappropriate management of recurrent gout attacks in a longitudinal study. J Rheumatol 2006;33:104-9. 5. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part II. Arthritis Rheum 2008;58:26-35. 6. Arromdee E, Michet CJ, Crowson CS, O’Fallon WM, Gabriel SE. Epidemiology of gout: is the incidence rising? J Rheumatol 2002;29:2403-6. 7. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol 2004;31:1582-7. 8. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499-516. 9. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21. [Erratum, N Engl J Med 2010;362:2235.] 10. Rodríguez G, Soriano LC, Choi HK. Impact of diabetes against the future risk

of developing gout. Ann Rheum Dis 2010;69:2090-4. 11. Dehghan A, Kottgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 2008; 372:1953-61. 12. Taniguchi A, Urano W, Yamanaka M, et al. A common mutation in an organic anion transporter gene, SLC22A12, is a suppressing factor for the development of gout. Arthritis Rheum 2005;52:2576-7. 13. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004;363:1277-81. 14. Choi HK, Willett W, Curhan G. Fructose-rich beverages and risk of gout in women. JAMA 2010;304:2270-8. 15. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004;350:1093103. 16. Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ 2008; 336:309-12. 17. Choi HK, Gao X, Curhan G. Vitamin C intake and the risk of gout in men: a prospective study. Arch Intern Med 2009; 169:502-7. 18. Choi HK, Willett W, Curhan G. Coffee consumption and risk of incident gout in men: a prospective study. Arthritis Rheum 2007;56:2049-55. 19. Hunter DJ, York M, Chaisson CE, Woods R, Niu J, Zhang Y. Recent diuretic use and the risk of recurrent gout attacks:

n engl j med 364;5 BACK to TOC

nejm.org

the online case-crossover gout study. J Rheumatol 2006;33:1341-5. [Erratum, J Rheumatol 2006;33:1714.] 20. Zhang Y, Woods R, Chaisson CE, et al. Alcohol consumption as a trigger of recurrent gout attacks. Am J Med 2006; 119(9):800.e13-800.e18. 21. Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;31: 2429-32. 22. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353: 2450-61. 23. Zhang W, Doherty M, Pascual E, et al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1301-11. 24. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1312-24. 25. Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty arthritis. J Rheumatol 2002; 29:331-4. 26. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for

february 3, 2011

451

13

clinical pr actice early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallelgroup, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060-8. 27. Sutaria S, Katbamna R, Underwood M. Effectiveness of interventions for the treatment of acute and prevention of recurrent gout — a systematic review. Rheumatology (Oxford) 2006;45:1422-31. 28. Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum 1988;31: 803-5. 29. Janssens HJ, Lucassen PL, Van de Laar FA, Janssen M, Van de Lisdonk EH. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev 2008;2:CD005521. 30. Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a doubleblind, randomised equivalence trial. Lancet 2008;371:1854-60. 31. Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/ paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med 2007;49:670-7. 32. Mandell BF, Edwards NL, Sundy JS, Simkin PA, Pile JC. Preventing and treating acute gout attacks across the clinical spectrum: a roundtable discussion. Cleve Clin J Med 2010;77:Suppl 2:S2-S25. 33. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237-41. 34. Neogi T. Interleukin-1 antagonism in acute gout: is targeting a single cytokine the answer? Arthritis Rheum 2010;62: 2845-9.

35. So A, De Meulemeester M, Pikhlak A,

et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: results of a multicenter, phase II, dose-ranging study. Arthritis Rheum 2010; 62:3064-76. 36. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9:R28. 37. Terkeltaub R, Sundy JS, Schumacher HR, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis 2009;68:1613-7. 38. Mikuls TR, MacLean CH, Olivieri J, et al. Quality of care indicators for gout management. Arthritis Rheum 2004;50:937-43. 39. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12:R63. 40. Perez-Ruiz F, Lioté F. Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arthritis Rheum 2007;57:1324-8. 41. Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout. Ann Rheum Dis 2009;68:892-7. 42. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007;46: 1372-4. 43. Dalbeth N, Kumar S, Stamp L, Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in pa-

tients with gout. J Rheumatol 2006;33: 1646-50. 44. Fam AG, Dunne SM, Iazzetta J, Paton TW. Efficacy and safety of desensitization to allopurinol following cutaneous reactions. Arthritis Rheum 2001;44:231-8. 45. Reinders MK, van Roon EN, Jansen TL, et al. Efficacy and tolerability of uratelowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis 2009;68:51-6. 46. Sundy JS, Becker MA, Baraf HS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum 2008;58:2882-91. 47. Huang HY, Appel LJ, Choi MJ, et al. The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum 2005;52:1843-7. 48. Dalbeth N, Wong S, Gamble GD, et al. Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial. Ann Rheum Dis 2010;69:167782. 49. Takahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Effects of combination treatment using anti-hyperuricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis 2003;62:572-5. 50. Kutzing MK, Firestein BL. Altered uric acid levels and disease states. J Pharmacol Exp Ther 2008;324:1-7. 51. Perez-Ruiz F, Atxotegi J, Hernando I, Calabozo M, Nolla JM. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of longterm urate-lowering therapy: a prospective study. Arthritis Rheum 2006;55:786-90. Copyright © 2011 Massachusetts Medical Society.

CLINICAL TRIAL REGISTRATION

The Journal requires investigators to register their clinical trials in a public trials registry. The members of the International Committee of Medical Journal Editors (ICMJE) will consider most reports of clinical trials for publication only if the trials have been registered. Current information on requirements and appropriate registries is available at www.icmje.org/faq_clinical.html.

452 BACK to TOC

n engl j med 364;5

nejm.org

february 3, 2011

14

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical practice

Calcium Kidney Stones Elaine M. Worcester, M.D., and Fredric L. Coe, M.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors’ clinical recommendations.

A 43-year-old man presents for evaluation of recurrent kidney stones. He passed his first stone 9 years earlier and has had two additional symptomatic stones. Analysis of the first and the last stones showed that they contained 80% calcium oxalate and 20% calcium phosphate. Analysis of a 24-hour urine collection while the patient was not receiving medications revealed a calcium level of 408 mg (10.2 mmol), an oxalate level of 33 mg (367 μmol), and a volume of 1.54 liters; the urine pH was 5.6. The patient had been treated with 20 to 40 mmol of potassium citrate daily since he passed his first stone. How should he be further evaluated and treated?

The Cl inic a l Probl em From the Nephrology Section, Department of Medicine, University of Chicago, Chicago. Address reprint requests to Dr. Worcester at the Nephrology Section, MC 5100, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, or at [email protected]. N Engl J Med 2010;363:954-63. Copyright © 2010 Massachusetts Medical Society.

Click here to access audio version.

An audio version of this article is available at NEJM.org

In the United States, the prevalence of kidney stones has risen over the past 30 years.1 By 70 years of age, 11.0% of men and 5.6% of women will have a symptomatic kidney stone. The risk among white persons is approximately three times that among black persons. About 80% of stones are composed of calcium oxalate with variable amounts of calcium phosphate. Diagnosis of a calcium stone requires analysis after passage or removal of the stone. After passage of a first stone, the risk of recurrence is 40% at 5 years and 75% at 20 years. Among patients with recurrent calcium stones who have served as control subjects in randomized, controlled trials of interventions, new stones formed in 43 to 80% of subjects within 3 years.2-9 Hospitalizations, surgery, and lost work time that are associated with kidney stones cost more than $5 billion annually in the United States.10 Stone formation is associated with increased rates of chronic kidney disease and hypertension,11,12 increases that are not completely explained by obesity, which is a risk factor for each of these conditions.13 Although many inherited and systemic diseases are associated with calcium kidney stones,14 most such stones are idiopathic. The majority of patients with idiopathic stones have at least one metabolic abnormality, as identified by 24-hour urine testing. Prevention requires evaluation to identify systemic disease and modifiable factors.

Patho gene sis Physicochemical Factors

Supersaturation, often expressed as the ratio of urinary calcium oxalate or calcium phosphate concentration to its solubility, is the driving force in stone formation. At levels of supersaturation below 1, crystals dissolve, whereas at supersaturation levels above 1, crystals can nucleate and grow, promoting stone formation. Supersaturation is generally higher in patients with recurrent kidney stones than in those without the condition, and the type of stone that is formed correlates with urinary 954 BACK to TOC

n engl j med 363;10

nejm.org

september 2, 2010

15

clinical pr actice

supersaturation. Calcium oxalate supersaturation is independent of urine pH, but calcium phosphate supersaturation increases rapidly as urine pH rises from 6 to 7. Since calcium oxalate stones form over an initial calcium phosphate layer,15 treatment optimally should lower the supersaturation of both types. Most 24-hour analyses of kidneystone risk that are performed at specialized laboratories include calculated supersaturation values. Urine also contains substances that can accelerate or retard urinary crystallization.16 The only such substance that can be modified in practice at this time is citrate, which can slow the growth of calcium crystals.17 Anatomic abnormalities, in particular those that result in urinary stasis (such as ureteropelvic junction obstruction, horseshoe kidney, or polycystic kidney), may precipitate or worsen stone formation.18 Patients with a single functioning kidney are at particular risk, since stone passage with ureteral obstruction can result in acute kidney failure. Metabolic Factors

Imbalances between excretions of calcium, oxalate, and water create supersaturation. Hypercalciuria, the most common metabolic abnormality found in patients with recurrent calcium stones, is most often familial and idiopathic19 and is strongly influenced by diet. Gut calcium absorption is increased in persons with idiopathic hypercalciuria, but serum calcium values remain unchanged, since absorbed calcium is promptly excreted.20 On a low-calcium diet, such persons often excrete more calcium than they eat,21 and urinary calcium excretion also rises markedly after the intake of calcium-free nutrients such as simple oral glucose; in such cases, the only source possible is bone. Although hypercalciuria is sometimes divided into subtypes (absorptive, resorptive, and renal leak), this classification is not helpful in guiding treatment. However, measurement of serum calcium is indicated to identify patients with primary hyperparathyroidism. The level of oxalate excretion is modestly higher among patients with recurrent calcium stones than among those without the condition, possibly because of increased oxalate absorption in the gut.22 The intake of ascorbic acid and a high level of protein may increase oxalate production.23 Because calcium binds with oxalate in the gut and hinders its absorption, oxalate is n engl j med 363;10 BACK to TOC

more readily absorbed when dietary calcium is low.23 This may be why a low-calcium diet does not successfully prevent stone recurrence.24 Citrate chelates calcium in the urine, decreasing supersaturation and reducing the growth of crystals17; hypocitraturia is a risk factor for stone formation. Distal renal tubular acidosis, hypokalemia, and the use of carbonic anhydrase inhibitors (e.g., topiramate) lead to hypocitraturia, but the cause of this condition in most patients with recurrent kidney stones is unknown.25 Hyperuricosuria, often from high dietary intake of purines, is thought to promote the formation of calcium stones by reducing the solubility of calcium oxalate.26 Histopathology

Intraoperative papillary biopsy specimens obtained from patients with recurrent kidney stones show that the pattern of crystal deposition differs according to the type of stone. Idiopathic calcium oxalate stones form over regions of interstitial calcium phosphate deposits (Randall’s plaque) on the papillary surface,27 whereas idiopathic calcium phosphate stones are associated with crystal deposits in inner medullary collecting ducts that contain mainly apatite,28,29 sometimes mixed with other crystals. (For additional details, see the Supplementary Appendix, available with the full text of this article at NEJM.org.)

S t r ategie s a nd E v idence Patients with recurrent calcium stones should be evaluated to rule out systemic disease and guide preventive therapy. Evaluation includes history taking directed at detecting potential causes of stones (Table 1). All stones should be analyzed to classify the type and to detect conversion from one stone type to another — for example, from calcium oxalate to struvite in the presence of infection or to calcium phosphate if the urinary pH rises in response to treatment.30 Computed tomography (CT) without the use of contrast material provides information regarding the presence, size, and location of stones, as well as ruling out anatomic abnormalities and providing a baseline for assessing whether subsequent stones that are passed are old or new (with the latter indicating a need for improved preventive treatment). Given the expense and radiation exposure of CT, renal ultrasonography

nejm.org

september 2, 2010

955

16

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 1. Key Coexisting Medical Conditions, Medication Use, Diet, and Other Factors Associated with Calcium Kidney Stones. Variable

Features

Type of Kidney Stone Calcium Oxalate

Calcium Phosphate

Medical or surgical history Bowel disease

Chronic diarrhea, malabsorption

Yes

Intestinal surgery

Small-bowel resection, ileostomy

Yes

Bariatric surgery

Duodenal switch, Roux-en-Y gastric bypass

Yes

Sarcoidosis

Yes

Gout

Yes

Renal tubular acidosis

Yes Yes

Bone disease or fracture

Primary hyperparathyroidism, idiopathic hypercalciuria, myeloma

Yes

Yes

Immobilization

Trauma, prolonged illness

Yes

Yes

Hyperthyroidism

Untreated, iatrogenic

Yes

Yes

Renal anomaly

Urinary stasis

Yes

Yes

Medications Topiramate

Seizures, migraine

Yes

Calcium supplements

Antacids, dietary supplement

Carbonic anhydrase inhibitor

Glaucoma

Yes

Yes

Alkali

Bicarbonate, citrate

Yes

Vitamin D

Yes

Yes

Yes

Yes

Yes

Occupational or recreational factor Dehydration

Hot environment, inability to drink

Dietary factor Oxalate loads

Nuts, spinach, ascorbic acid

Yes

Excess salt

Prepared foods, snack foods

Yes

Yes

Eating disorders

Vomiting, use of laxatives

Yes

Yes

Strange diets*

Protein powder, sugar loads

Yes

Yes

Idiopathic hypercalciuria, primary hyperoxaluria

Yes

Yes

Family history History of kidney stones in a firstdegree relative

* Strange diets include very restrictive choices of food or the use of a large number or amount of supplements.

or abdominal plain radiography may be used in follow-up imaging of known stones, although these methods are less sensitive than CT. Metabolic testing should be done after the resolution of the acute episode of stone passage, when patients have resumed their usual diet and activity. Evaluation includes a blood test to screen for hypercalcemia, chronic kidney disease, and renal tubular acidosis. Analysis of a 24-hour urine collection to detect metabolic abnormalities should preferably be performed twice, since mineral excretions may vary from day to day.31 Tables 2 and 3 provide a suggested framework 956 BACK to TOC

n engl j med 363;10

for testing and interpretation. Whether to evaluate patients after a single kidney-stone episode is controversial, although it seems prudent to rule out systemic disease, especially in patients with a first stone before adulthood.

T r e atmen t Management of Symptomatic Stones

Stones that have formed in kidneys do not require removal or fragmentation unless they cause obstruction, infection, serious bleeding, or persistent pain. Ureteral stones of less than 10 mm in

nejm.org

september 2, 2010

17

clinical pr actice

Table 2. Diagnostic Testing for Patients with Recurrent Kidney Stones.* Measurement

Normal Value or Range for Adults

Purpose

Blood testing Calcium

8.8–10.3 mg/dl

Detection of primary hyperparathyroidism, excessive vitamin D intake, sarcoidosis

Phosphate

2.5–5.0 mg/dl

Detection of primary hyperparathyroidism

Creatinine

0.6–1.2 mg/dl

Detection of chronic kidney disease

Bicarbonate

20–28 mmol/liter

Detection of renal tubular acidosis

Chloride

95–105 mmol/liter

Detection of renal tubular acidosis

Potassium

3.5–4.8 mmol/liter

Detection of renal tubular acidosis, eating disorders, gastrointestinal disease

Urine collection over 24-hour period Volume

>1.5 liter/day

Calcium

<300 mg/day for men, <250 mg/day for women; <140 mg/g creatinine/day

Detection of hypercalciuria

Oxalate

<40 mg/day

Detection of hyperoxaluria

pH

Detection of low volume as cause of stones

5.8–6.2

Phosphate

Calculation of calcium phosphate and uric acid supersaturation, diagnosis of renal tubular acidosis

500–1500 mg/day

Calculation of calcium phosphate supersaturation

Citrate

>450 mg/day for men, >550 mg/day for women

Detection of low citrate level and diagnosis of renal tubular acidosis; calculation of calcium phosphate supersaturation

Uric acid

<800 mg/day for men, <750 mg/day for women

Detection of hyperuricosuria as cause of stones; calculation of uric acid supersaturation

Sodium

50–150 mmol/day

Diet counseling; calculation of supersaturation

Potassium

20–100 mmol/day

Use of potassium salts; calculation of supersaturation

Magnesium

50–150 mg/day

Detection of malabsorption; calculation of supersaturation

Sulfate

20–80 mmol/day

Calculation of supersaturation; measure of net acid production

Ammonium

15–60 mmol/day

Calculation of supersaturation

Creatinine Protein catabolic rate†

20–24 mg/kg/day for men, 15–19 mg/kg/day for women 0.8–1.0 g/kg/day

Comparison of actual with predicted creatinine to assess the completeness of the urine collection Estimation of protein intake

Calculated supersaturation‡ Calcium oxalate

6–10

Guidance of treatment

Calcium phosphate

0.5–2

Guidance of treatment

Negative

Detection of cystinuria

Other screening tests Urinary cystine screening§ Stone analysis

Basic classification of condition

* Blood testing for renal tubular acidosis, chronic kidney disease, and hypercalcemia, along with urinary cystine screening and kidney-stone analysis, are appropriate for all patients with recurrent kidney stones. Collection of urine over a 24-hour period is appropriate if medical prevention of kidney-stone formation is planned. To convert the values for calcium to millimoles per day, multiply by 0.025. To convert the values for phosphate to millimoles per day, multiply by 0.0323. To convert the values for creatinine to micromoles per day multiply by 0.00884. To convert the values for urinary oxalate to micromoles per day, multiply by 11.11. To convert the values for urinary citrate to mmol per day, multiply by 0.0052. To convert the values for urinary uric acid to millimoles per day, multiply by 0.00595. To convert the values for urinary magnesium to mmol per day, multiply by 0.0411. To convert the values for urinary urea nitrogen to moles per day, multiply by 0.0357. † The protein catabolic rate is calculated by multiplying the urea nitrogen excretion in grams per day by 6.25 and dividing by body weight in kilograms. ‡ Supersaturation is expressed as the ratio of urinary calcium oxalate or calcium phosphate concentration to its solubility. § Urinary cystine was tested with the use of the cyanide nitroprusside test. A negative test means that the cystine concentration is less than 75 mg per liter.

n engl j med 363;10 BACK to TOC

nejm.org

september 2, 2010

957

18

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 3. Primary Causes of Calcium Kidney Stones and Their Treatments.* Cause

Key Abnormality Serum Calcium

Serum Parathyroid Hormone

Urine Calcium

Urine pH

Urine Citrate

Urine Oxalate

Idiopathic calcium oxalate

Normal

Normal

Normal or increased

Normal

Normal or decreased

Normal or increased

Idiopathic calcium phosphate

Normal

Normal

Normal or increased

Increased

Normal or decreased

Normal

Primary hyperparathyroidism

Increased

Increased

Increased

Increased

Normal

Normal

Sarcoidosis

Increased

Decreased

Increased

Normal

Normal

Normal

Lithium use

Increased

Increased

Increased

Increased

Normal

Normal

Oral supplementation with calcium or vitamin D

Normal or increased

Normal

Increased

Normal

Normal

Normal

Ileostomy

Normal or decreased

Normal

Decreased

Decreased

Decreased

Normal

Short-bowel syndrome

Normal or decreased

Normal

Decreased

Decreased

Decreased

Increased

Bariatric surgery

Normal or decreased

Normal

Decreased

Normal

Decreased

Increased

Normal

Normal

Normal or increased

Increased

Decreased

Normal

Renal tubular acidosis

* NA denotes not available because histologic analyses have not been reported for patients with the listed conditions.

diameter may be followed with conservative treatment in the absence of fever, infection, or renal failure, if pain is controlled. Opioid analgesics and nonsteroidal antiinflammatory agents are both effective for pain control in acute colic. Therapy with drugs that block α1-adrenergic receptors or calcium-channel blockers may facilitate passage of ureteral stones.32 In general, stones larger than 10 mm in diameter will not pass, and those smaller than 5 mm will; stones from 5 mm to 10 mm have variable outcomes. Stones in the distal ureter are more likely to pass than those located more proximally. If stones do not pass, there are several surgical options for removal.33 Data to guide surgical recommendations are derived largely from metaanalyses of small trials. For ureteral stones, the treatment of choice is either shock-wave lithotripsy or ureteroscopy with laser lithotripsy. Stonefree rates are better with ureteroscopy, but complication rates are higher, including sepsis and ureteral injury. For stones lodged in the kidney, the size, location, and presumed composition play a role in determining treatment. Not all stone types fragment equally well; for example, 958 BACK to TOC

n engl j med 363;10

calcium oxalate monohydrate and brushite stones are more resistant to fragmentation than calcium oxalate dihydrate or apatite stones. Shockwave lithotripsy and ureteroscopy are frequently used for smaller stones. Percutaneous nephrolithotomy may be used for single large stones (above 2 cm) or a large or obstructing stone burden. This procedure requires general anesthesia and hospitalization and carries more risk of complications, including bleeding and infection, than other techniques but can result in a stone-free kidney.34 Open or laparoscopic procedures are occasionally used for stone removal in challenging cases. Prevention of Idiopathic Calcium Oxalate Stones

Prevention of recurrent stones requires decreasing urinary supersaturation, which is generally achieved by raising urine volume and lowering calcium and oxalate excretion. It should be recognized that urinary abnormalities are graded risk factors, and thresholds for the definition of normal urinary function are not absolute cutoffs.35 Table 4 summarizes treatment strategies.

nejm.org

september 2, 2010

19

clinical pr actice

Supersaturation Urine Uric Acid

Urine Volume

Calcium Calcium Oxalate Phosphate

Normal or increased

Normal or decreased

High

Normal

Normal

High

Tissue Changes Uric Acid

Interstitial Plaque

Collecting-Duct Plugging

Normal or high

Normal or high

Increased

Not present

High

Normal

Normal

Increased

Treatment

� � � �

� � � Normal

Normal

High

High

Low

Increased

Increased

Normal

Normal

High

High

Normal

NA

NA

Glucocorticoids, possible ketoconazole

Normal

Normal

High

High

Normal

NA

NA

Discontinuation of lithium

Normal

Normal

High

High

Low

NA

NA

Discontinuation of supplements

Normal

Decreased

High

Low

High

Increased

Increased

Normal

Decreased

High

Low

High

Normal

Increased

Normal

Normal

High

Normal

Normal

Normal

Increased

Normal

Increased

Normal

High

Low

Normal

Increased

(For additional details regarding treatment trials, see Table 1 in the Supplementary Appendix.) A randomized trial of increased fluid intake that was targeted to maintain a daily urine volume of more than 2 liters showed a significant reduction in recurrent stone passage among patients with first-time kidney stones.36 A target urine volume of 2 to 2.5 liters is reasonable and can be achieved by an increased intake of fluids, especially water, although most low-sodium, lowcarbohydrate fluids are acceptable in moderation for this purpose. In a randomized, controlled trial involving Italian men with hypercalciuria,24 a diet that was low in animal protein (52 g per day), sodium (50 mmol per day), and oxalate (200 mg per day) with normal calcium intake (1200 mg per day) was associated with a reduction in stone formation of almost 50% over a period of 5 years, as compared with a diet that was low in calcium (400 mg per day) and oxalate. In contrast, in a U.S. trial, a low-protein diet did not reduce stone recurrence during a 4.5-year period, but compliance with the diet was poor and dietary sodium was not restricted.37 A low-sodium diet can significantly decrease excretion of both calcium and n engl j med 363;10 BACK to TOC

Thiazide for idiopathic hypercalciuria; potassium citrate for calcium oxalate (and perhaps calcium phosphate) stones; allopurinol for hyperuricosuria; sodium restriction and possible protein or oxalate restriction; increased fluid intake Parathyroid surgery

� � � � � � �

Fluids, alkali; supplements to reduce urine oxalate excretion for the shortbowel syndrome and bariatric surgery

Alkali, possible thiazides

oxalate,38 but data on the effect of a sodiumrestricted diet alone on stone recurrence are lacking. Calcium restriction should be avoided in patients with hypercalciuria, since it may result in a reduction in bone mineral density39 and an increased rate of fracture.40 Thiazide-type diuretics decrease urine calcium excretion, and in randomized, controlled trials, these medications significantly reduced recurrence rates of calcium stones by more than 50% during a 3-year period, as compared with placebo.2,4,6,9 Long-acting agents like chlorthalidone and indapamide are effective with once-daily doses, whereas twice-daily doses are recommended for hydrochlorothiazide. Hyperoxaluria may occur when dietary calcium is low or oxalate intake is unusually high or (less commonly) when oxalate is overproduced. Dietary oxalate restriction to less than 100 mg per day and the avoidance of an intake of ascorbic acid above 100 mg per day are prudent if hyperoxaluria is present. Foods that are very high in oxalate include spinach, rhubarb, wheat bran, chocolate, beets, miso, tahini, and most nuts. (A list of the oxalate content of various foods is available at www.ohf.org under Resources.) Marked

nejm.org

september 2, 2010

959

20

Allergy (may be severe) Patients with hyperuricosuria and calcium stones Lowers urinary uric acid concentration, which may improve solubility of calcium salts Allopurinol

100–300 mg/day (may be taken once daily)

Need to monitor urine pH and calcium phosphate supersaturation; avoid supersaturation of >1 Patients with hypocitraturia Lowers supersaturation by chelating calcium; inhibits growth of calcium crystals Potassium alkali

Potassium citrate, 10–20 mmol two or three times daily

Hypokalemia, reduced blood pressure (may be desirable); allergy and sun sensitivity Patients with hypercalciuria; may be useful for some with normocalciuria Lowers supersaturation by decreasing calcium excretion Thiazide-type diuretic

Chlorthalidone, 12.5–50 mg/day; indapamide, 1.25–2.5 mg/day; hydrochlorothiazide, 12.5–25 mg twice daily

Difficulty in maintaining diet; should obtain calcium from dietary sources and avoid supplements Recommendations for sodium and protein especially useful in patients with hypercalciuria or hyperuricosuria; for oxalate in patients with hyperoxaluria; and for calcium in all patients with calcium stones Sodium, <100 mmol/day; protein, <0.8–1 g of animal protein/kg/day; oxalate, <100 mg/day; calcium, 800–1000 mg/day Lowers supersaturation by decreasing calcium and oxalate excretion; maintains bone mineral, prevents hyperoxaluria Diet

Potential Complications Selection Criteria

Useful for all patients; possible sole treatment for patients with a single stone episode

Dose

Adequate to maintain urine volume >2 liters daily Lowers supersaturation by dilution of solutes

Mechanism of Action

BACK to TOC

n e w e ng l a n d j o u r na l

Fluids

Treatment

Table 4. Treatment Recommendations for the Prevention of Idiopathic Calcium Kidney Stones in Adults.

960

Need to avoid fluids containing excess salt or carbohydrates

The

n engl j med 363;10

of

m e dic i n e

hyperoxaluria should prompt consideration of malabsorption or one of the primary hyperoxaluria syndromes.41 Two randomized trials have shown substantial reductions in stone recurrence among patients with hypocitraturia who were treated with potassium alkali three times daily.3,7 One trial of sodium–potassium citrate had negative results.8 Potassium alkali may be safely combined with thiazide9,42 when indicated, but no trials have compared the combination against either agent alone for the prevention of stone recurrence. Hyperuricosuria can decrease the solubility of calcium oxalate and increase the incidence of calcium oxalate stones. Allopurinol (at a dose of 300 mg daily) decreased stone recurrence in a randomized trial involving patients with idiopathic calcium oxalate stones who had hyperuricosuria.5 A reduction in the intake of protein (and therefore purine) is also prudent but has not been explicitly tested among patients with hyperuricosuria and recurrent kidney stones. In long-term clinical follow-up, preventive treatment resulted in persistent reductions in stone recurrence during a period of 20 years or more.43 However, compliance tended to wane over time, with rates of nonadherence approaching 20% per year.44 Prevention of Calcium Phosphate Stones

Most calcium stones consist of more than 90% calcium oxalate with trace amounts of calcium phosphate, but the proportion of calcium phosphate in stones has increased over time.45,46 Idiopathic calcium phosphate stones (more than 50% calcium phosphate) are more common among women and are associated with alkaline urine pH, a condition whose cause is not well understood. Mild abnormalities in urine acidification may be present, although metabolic acidosis is uncommon.46,47 Some patients convert from the formation of calcium oxalate stones to the formation of calcium phosphate stones. In one study, such patients had a urine pH that was more alkaline (>6.2) at baseline than those who continued to produce calcium oxalate stones.30 Calcium phosphate stones are associated with poorer stone-free rates after percutaneous nephrolithotomy and with more shock-wave lithotripsy treatments than are calcium oxalate stones.46,48 Among patients with calcium phosphate stones, treatment is similar to that of patients with calcium oxalate stones except that potassium alnejm.org

september 2, 2010

21

clinical pr actice

kali should be used cautiously because it raises urine pH, potentially worsening calcium phosphate supersaturation. Levels of urine pH and citrate and the degree of supersaturation should be assessed after starting therapy. If the citrate level does not rise and the degree of supersaturation worsens, the medication is unlikely to be of benefit.

A r e a s of Uncer ta in t y Treatment trials for calcium stones have not looked specifically at outcomes in patients with calcium phosphate stones. Dietary recommendations to increase fluids, lower salt and protein intake, and maintain a normal intake of calcium are supported by an Italian randomized trial,24 but no women were included in this study, and it is unclear whether many Americans can comply with the necessary dietary pattern sufficiently to successfully prevent stones. The Dietary Approaches to Stop Hypertension (DASH)–Sodium diet, when modified to remove high-oxalate foods, replicates many of the features of the study diet and may provide a model to follow, but its effects on stone recurrence have not been explicitly studied.49 Stone formation is associated with an increased risk of bone disease, chronic kidney disease, and hypertension, but it is not known whether effective stone prevention decreases these risks.

Guidel ine s Guidelines of the American Urological Association (www.auanet.org) recommend that patients who require surgery for ureteral stones should be informed about benefits and risks of all current treatment approaches. Shock-wave lithotripsy and ureteroscopy with laser lithotripsy are both considered acceptable first-line treatments, although ureteroscopy achieves greater stone-free rates. Percutaneous access and open or laparoscopic surgery are used as needed for selected cases. The guidelines do not address evaluation or treatment to prevent recurrent stones.

C onclusions a nd R ec om mendat ions Preventive treatment to decrease stone recurrence is indicated for patients with recurrent calcium stones, such as the patient in the vignette. n engl j med 363;10 BACK to TOC

If systemic disease is not present, treatment should focus on metabolic abnormalities uncovered during the workup, such as hypercalciuria, hypocitraturia, hyperuricosuria, or hyperoxaluria. Although data comparing specific supersaturation targets are lacking, a logical strategy is to lower calcium oxalate and calcium phosphate supersaturation to the low end of the normal range. Patients should be advised to increase fluid intake to at least 2 liters daily and reduce sodium intake to 2300 mg and protein intake to 0.8 to 1 g per kilogram of body weight per day, since these dietary interventions have reduced stone recurrence in randomized trials. Calcium intake should not be reduced below the recommended intake for sex and age and should be supplied by food rather than by supplements, which may increase the risk of stone formation. In many patients, medication is also needed; the choice of medication is influenced by the metabolic abnormalities identified, the type of stone, and the preference of patients. The stones of the patient in the vignette contain 20% phosphate, despite a low urine pH while the patient was not receiving medications; the increased phosphate level may reflect his previous treatment with citrate. Both hypocitraturia and hypercalciuria may contribute to his stone formation. In addition to the recommendations above, we would initiate therapy with a thiazide-type diuretic (e.g., 25 mg of chlorthalidone daily) to lower the urinary calcium level. A reduction in sodium intake will also reduce a thiazide-induced loss of potassium. A follow-up 24-hour urine collection and serum chemical analysis should be performed in 4 to 6 weeks to assess the efficacy of treatment and possible side effects, particularly hypokalemia, which can worsen hypocitraturia. If potassium supplementation is needed, it may be added as potassium alkali, but the urine pH level and the level of calcium phosphate supersaturation should be monitored. If the level of calcium phosphate supersaturation rises and is consistently above 1, potassium chloride should be substituted. Primary treatment with potassium alkali would be an alternative to a thiazide but may not lower the level of urinary calcium phosphate supersaturation as effectively. Ongoing attention is warranted at follow-up visits to monitor whether the patient is adhering to preventive recommendations.

nejm.org

september 2, 2010

961

22

The

n e w e ng l a n d j o u r na l

Drs. Worcester and Coe report receiving consulting fees from LabCorp. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. References 1. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kidney Int 2003;63:1817-23. 2. Borghi L, Meschi T, Guerra A, Novarini A. Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol 1993;22:Suppl 6: S78-S86. 3. Ettinger B, Pak CY, Citron JT, Thomas C, Adams-Huet B, Vangessel A. Potassiummagnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol 1997;158:2069-73. 4. Ettinger B, Citron JT, Livermore B, Dolman LI. Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol 1988; 139:679-84. 5. Ettinger B, Tang A, Citron JT, Livermore B, Williams T. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 1986;315: 1386-9. 6. Laerum E, Larsen S. Thiazide prophylaxis of urolithiasis: a double-blind study in general practice. Acta Med Scand 1984; 215:383-9. 7. Barcelo P, Wuhl O, Servitge E, Rousaud A, Pak CYC. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 1993;150:1761-4. 8. Hofbauer J, Höbarth K, Szabo N, Marberger M. Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis — a prospective randomized study. Br J Urol 1994;73:362-5. 9. Fernández-Rodríguez A, Arrabal-Martín M, García-Ruiz MJ, Arrabal-Polo MA, Pichardo-Pichardo S, Zuluaga-Gómez A. Papel de las tiazidas en la profilaxis de la litiasis calcica recidivante. Actas Urol Esp 2006;30:305-9. 10. Saigal CS, Joyce G, Timilsina AR. Direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int 2005; 68:1808-14. 11. Rule AD, Bergstralh EJ, Melton LJ III, Li X, Weaver AL, Lieske JC. Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol 2009;4:804-11. 12. Madore F, Stampfer MJ, Rimm EB, Curhan GC. Nephrolithiasis and risk of hypertension. Am J Hypertens 1998;11: 46-53. 13. Taylor EN, Stampfer MJ, Curhan GC.

962 BACK to TOC

of

m e dic i n e

We thank Andrew Evan, Ph.D., for providing original versions of the figures in the Supplementary Appendix and guidance in the preparation of the manuscript.

Obesity, weight gain, and the risk of kidney stones. JAMA 2005;293:455-62. 14. Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest 2005;115:2598608. 15. Evan AP, Coe FL, Lingeman JE, et al. Mechanism of formation of human calcium oxalate renal stones on Randall’s plaque. Anat Rec (Hoboken) 2007;290: 1315-23. 16. De Yoreo JJ, Qiu SR, Hoyer JR. Molecular modulation of calcium oxalate crystallization. Am J Physiol Renal Physiol 2006;291:F1123-F1131. 17. Tiselius HG, Berg C, Fornander AM, Nilsson MA. Effects of citrate on the different phases of calcium oxalate crystallization. Scanning Microsc 1993;7:381-9. 18. Gambaro G, Fabris A, Puliatta D, Lupo A. Lithiasis in cystic kidney disease and malformations of the urinary tract. Urol Res 2006;34:102-7. 19. Worcester EM, Coe FL. New insights into the pathogenesis of idiopathic hypercalciuria. Semin Nephrol 2008;28:120-32. 20. Worcester EM, Gillen DL, Evan AP, et al. Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis. Am J Physiol Renal Physiol 2007;292:F66-F75. 21. Coe FL, Favus MJ, Crockett T, et al. Effects of low-calcium diet on urine calcium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in normal subjects. Am J Med 1982;72:25-32. 22. Voss S, Hesse A, Zimmermann DJ, Sauerbruch T, von Unruh GE. Intestinal oxalate absorption is higher in idiopathic calcium oxalate stone formers than in healthy controls: measurements with the [(13)C2]oxalate absorption test. J Urol 2006;175:1711-5. 23. Taylor EN, Curhan GC. Determinants of 24-hour urinary oxalate excretion. Clin J Am Soc Nephrol 2008;3:1453-60. 24. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002;346:7784. 25. Hamm LL, Hering-Smith KS. Pathophysiology of hypocitraturic nephrolithiasis. Endocrinol Metab Clin North Am 2002; 31:885-93. 26. Coe FL, Kavalach AG. Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. N Engl J Med 1974; 291:1344-50.

n engl j med 363;10

nejm.org

27. Miller NL, Gillen DL, Williams JC Jr,

et al. A formal test of the hypothesis that idiopathic calcium oxalate stones grow on Randall’s plaque. BJU Int 2009;103:96671. 28. Evan AP, Lingeman JE, Coe FL, et al. Crystal-associated nephropathy in patients with brushite nephrolithiasis. Kidney Int 2005;67:576-91. 29. Evan AE, Lingeman JE, Coe FL, et al. Histopathology and surgical anatomy of patients with primary hyperparathyroidism and calcium phosphate stones. Kidney Int 2008;74:223-9. 30. Parks JH, Coe FL, Evan AP, Worcester EM. Urine pH in renal calcium stone formers who do and do not increase stone phosphate content with time. Nephrol Dial Transplant 2009;24:130-6. 31. Parks JH, Goldfisher E, Asplin JR, Coe FL. A single 24-hour urine collection is inadequate for the medical evaluation of nephrolithiasis. J Urol 2002;167:1607-12. 32. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006;368:1171-9. 33. Wignall GR, Canales BK, Denstedt JD, Monga M. Minimally invasive approaches to upper urinary tract urolithiasis. Urol Clin North Am 2008;35:441-54. 34. Keeley FX Jr, Assimos DG. Clinical trials of the surgical management of urolithiasis: current status and future needs. Adv Chronic Kidney Dis 2009;16:65-9. 35. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int 2001; 59:2290-8. 36. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urinary volume, water and recurrences of idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 1996;155: 839-43. 37. Hiatt RA, Ettinger B, Caan B, Quesenberry CP Jr, Duncan D, Citron JT. Randomized controlled trial of low animal protein, high fiber diet in the prevention of recurrent calcium oxalate kidney stones. Am J Epidemiol 1996;144:25-33. 38. Nouvenne A, Meschi T, Prati B, et al. Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial. Am J Clin Nutr 2010;91:565-70. 39. Heilberg IP, Weisinger JR. Bone disease in idiopathic hypercalciuria. Curr Opin Nephrol Hypertens 2006;15:394-402.

september 2, 2010

23

clinical pr actice 40. Lauderdale DS, Thisted RA, Wen M,

Favus MJ. Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey. J Bone Miner Res 2001;16:1893-8. 41. Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int 2009; 75:1264-71. 42. Odvina CV, Preminger GM, Lindberg JS, Moe OW, Pak CY. Long-term combined treatment with thiazide and potassium citrate in nephrolithiasis does not lead to hypokalemia or hypochloremic metabolic alkalosis. Kidney Int 2003;63:240-7.

43. Parks JH, Coe FL. Evidence for durable

kidney stone prevention over several decades. BJU Int 2009;103:1238-46. 44. Parks JH, Asplin JR, Coe FL. Patient adherence to long-term medical treatment of kidney stones. J Urol 2001;166:205760. 45. Mandel N, Mandel I, Fryjoff K, Rejniak T, Mandel G. Conversion of calcium oxalate to calcium phosphate with recurrent stone episodes. J Urol 2003;169:20269. 46. Parks JH, Worcester EM, Coe FL, Evan AP, Lingeman JE. Clinical implications of abundant calcium phosphate in routinely

analyzed kidney stones. Kidney Int 2004; 66:777-85. 47. Gault MH, Parfrey PS, Robertson WG. Idiopathic calcium phosphate nephrolithiasis. Nephron 1988;48:265-73. 48. Kacker R, Meeks JJ, Zhao L, Nadler RB. Decreased stone-free rates after percutaneous nephrolithotomy for high calcium phosphate composition kidney stones. J Urol 2008;180:958-60. 49. Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol 2009;20:2253-9. Copyright © 2010 Massachusetts Medical Society.

Fox

Robert Raichelson, M.D.

n engl j med 363;10 BACK to TOC

nejm.org

september 2, 2010

963

24

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical practice

Emergency Treatment of Asthma Stephen C. Lazarus, M.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.

A 46-year-old woman who has had two admissions to the intensive care unit (ICU) for asthma during the past year presents with a 4-day history of upper respiratory illness and a 6-hour history of shortness of breath and wheezing. An inhaled corticosteroid has been prescribed, but she takes it only when she has symptoms, which is rarely. She generally uses albuterol twice per day but has increased its use to six to eight times per day for the past 3 days. How should this case be managed in the emergency department?

The Cl inic a l Probl em Asthma is one of the most common diseases in developed countries and has a worldwide prevalence of 7 to 10%.1 It is also a common reason for urgent care and emergency department visits. From 2001 through 2003 in the United States, asthma accounted for an average 4210 deaths annually and an average annual total of approximately 504,000 hospitalizations and 1.8 million emergency department visits.2 The average annual rate of emergency department visits for asthma was 8.8 per 100 persons with current asthma. Rates were higher among children than among adults (11.2 vs. 7.8 visits per 100 persons), among blacks than among whites (21 vs. 7 visits per 100 persons), and among Hispanics than among non-Hispanics (12.4 vs. 8.4 visits per 100 persons). Women made twice the number of emergency department visits as men.2 Approximately 10% of visits result in hospitalization.1 Asthma is a heterogeneous disease, with varied triggers, manifestations, and responsiveness to treatment. Some patients with acute severe asthma presenting to the emergency department have asthma that responds rapidly to aggressive therapy, and they can be discharged quickly; others require admission to the hospital for more prolonged treatment. The reasons for this difference in responsiveness to treatment include the degree of airway inflammation, presence or absence of mucus plugging, and individual responsiveness to β2-adrenergic and corticosteroid medications. The major challenge in the emergency department is determining which patients can be discharged quickly and which need to be hospitalized.

From the Division of Pulmonary and Critical Care Medicine and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco. Address reprint requests to Dr. Lazarus at the University of California, San Francisco, 505 Parnassus Ave., San Francisco, CA 94143-0111, or at [email protected]. N Engl J Med 2010;363:755-64. Copyright © 2010 Massachusetts Medical Society.

An audio version Click here to of this article access audio is available at version. NEJM.org

S t r ategie s a nd E v idence Initial Assessment in the Emergency Department

Patients presenting to the emergency department with asthma should be evaluated and triaged quickly to assess the severity of the exacerbation and the need for urgent intervention (Fig. 1). A brief history should be obtained, and a limited physical examination performed. This assessment should not delay treatment; it can be performed while patients receive initial treatment. Clinicians should search for signs

n engl j med 363;8 BACK to TOC

nejm.org

august 19, 2010

755

25

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Triage patient immediately Take brief history to ascertain risk factors Previous intubation or ICU admission ≥2 Hospitalizations or ≥3 emergency department visits in past yr >2 Canisters of short-acting β2-adrenergic agonist per mo Coexisting conditions Assess vital signs and perform brief physical examination Observe for breathlessness Measure respiratory rate and heart rate, check for pulsus paradoxus Note whether accessory muscles of respiration used Perform chest examination

Initiate treatment with oxygen to achieve SaO2 ≥90%

Assess for mild-to-moderate exacerbation FEV1 or PEF ≥40% Patient talks in sentences Pulse ≤120 beats/min Minimal or no pulsus paradoxus SaO2 ≥90%

Assess for severe exacerbation FEV1 or PEF <40% Patient talks in words or phrases but not sentences Pulse >120 beats/min, respiratory rate >30 breaths per min Pulsus paradoxus (decrease in systolic arterial pressure by >25 mm Hg on inspiration) Loud wheezes or silent chest SaO2 <90% or PaO2 <60 mm Hg

Initiate treatment Short-acting β2-adrenergic agonist administered by means of a metereddose inhaler with valved holding chamber or a nebulizer, up to 3 doses in first hr Oral corticosteroids if no immediate response or if patient recently received systemic corticosteroids

Initiate treatment High-dose short-acting β2-adrenergic agonist plus ipratropium bromide administered by means of a metereddose inhaler with valved holding chamber or a nebulizer every 20 min or continuously for 1 hr Oral corticosteroids

Reassess history, symptoms, vital signs, results of physical examination, PEF, and SaO2 after 60–90 min of treatment

Figure 1. Initial Assessment of a Patient Presenting to the Emergency Department with Asthma. Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3.3 FEV1 denotes forced expiratory volume in 1 second, ICU intensive care unit, PaCO2 partial pressure of arterial carbon dioxide, PaO2 partial pressure of arterial oxygen, PEF peak expiratory flow, and SaO2 arterial oxygen saturation.

of life-threatening asthma (e.g., altered mental status, paradoxical chest or abdominal movement, or absence of wheezing), which necessitate admission. Attention should be paid to factors that are associated with an increased risk of death from asthma, such as previous intubation or ad-

756 BACK to TOC

n engl j med 363;8

mission to an ICU, two or more hospitalizations for asthma during the past year, low socioeconomic status, and various coexisting illnesses.3 The measurement of lung function (e.g., forced expiratory volume in 1 second [FEV1] or peak expiratory flow [PEF]) can be helpful for assessing

nejm.org

august 19, 2010

26

clinical pr actice

the severity of an exacerbation and the response to treatment but should not delay the initiation of treatment. Laboratory and imaging studies should be performed selectively, to assess patients for impending respiratory failure (e.g., by measuring the partial pressure of arterial carbon dioxide [PaCO2]), suspected pneumonia (e.g., by obtaining a complete blood count or a chest radiograph), or certain coexisting conditions such as heart disease (e.g., by obtaining an electrocardiogram). Treatment in the Emergency Department

All patients should be treated initially with supplementary oxygen to achieve an arterial oxygen saturation of 90% or greater, inhaled short-acting β2-adrenergic agonists, and systemic corticosteroids (Fig. 1). The dose and timing of these agents and the use of additional pharmacologic therapy depend on the severity of the exacerbation. β2-Adrenergic Agonists

Inhaled short-acting β2-adrenergic agonists should be administered immediately on presentation, and administration can be repeated up to three times within the first hour after presentation. The use of a metered-dose inhaler with a valved holding chamber is as effective as the use of a pressurized nebulizer in randomized trials,4,5 but proper technique is often difficult to ensure in ill patients. Most guidelines recommend the use of nebulizers for patients with severe exacerbations; metered-dose inhalers with holding chambers can be used for patients with mild-to-moderate exacerbations, ideally with supervision from trained respiratory therapists or nursing personnel (see the Supplementary Appendix and a Video, both available at NEJM.org, for descriptions of how to use inhalers with and inhalers without a holding chamber, respectively). The dose administered by means of metered-dose inhalers for exacerbations is substantially greater than that used for routine relief: four to eight puffs of albuterol can be administered every 20 minutes for up to 4 hours and then every 1 to 4 hours as needed (Table 1). Albuterol can be delivered by means of a nebulizer either intermittently or continuously. A meta-analysis of results from six randomized trials indicated that intermittent administration and continuous administration have similar effects on both lung function and the overall rate of hospitalization,6

n engl j med 363;8 BACK to TOC

whereas a Cochrane review of findings from eight trials suggested that continuous administration resulted in greater improvement in PEF and FEV1 and a greater reduction in hospital admissions, particularly among patients with severe asthma.7 Albuterol is the inhaled β2-adrenergic agonist most widely used for emergency management. Levalbuterol, the R-enantiomer of albuterol, has been shown to be effective at half the dose of albuterol, but randomized trials conducted in the emergency department have not consistently shown a clinical advantage of levalbuterol over racemic albuterol.8,9 Pirbuterol and bitolterol are effective for mild or moderate exacerbations, but a higher dose is required than with albuterol or levalbuterol, and their use for severe exacerbations has not been studied. Oral or parenteral administration of β2adrenergic agonists is not recommended, since neither has been shown to be more effective than inhaled β2-adrenergic agonists, and both are associated with an increased frequency of side effects. The long-acting inhaled β2-adrenergic salmeterol has not been studied for the treatment of exacerbations, though trials with formoterol (ClinicalTrials.gov numbers, NCT00819637 and NCT00900874) are under way. Anticholinergic Agents

Because of its relatively slow onset of action, inhaled ipratropium is not recommended as monotherapy in the emergency department but can be added to a short-acting β2-adrenergic agonist for a greater and longer-lasting bronchodilator effect.10,11 In patients with severe airflow obstruction, the use of ipratropium together with a β2adrenergic agonist in the emergency department, as compared with a β2-adrenergic agonist alone, has been shown to reduce rates of hospitalization by approximately 25%,12,13 although there is no apparent benefit of continuing ipratropium after hospitalization. Systemic Corticosteroids

In most patients with exacerbations that necessitate treatment in the emergency department, systemic corticosteroids are warranted. The exception is the patient who has a rapid response to initial therapy with an inhaled β2-adrenergic agonist. Although most randomized, controlled

nejm.org

august 19, 2010

757

27

758

BACK to TOC

n engl j med 363;8

1.25–2.5 mg every 20 min over the first hr, then 1.25–5 mg every 1–4 hr as needed; levalbuterol administered at half the milligram dose of albuterol has similar efficacy and safety; continuous nebulization has not been evaluated

Nebulizer solution (0.63 mg/3 ml, 1.25 mg/0.5 ml, or 1.25 mg/3 ml)

nejm.org

8 puffs every 20 min as needed, for up to 3 hr 0.5 mg every 20 min for 1 hr (three doses), then as needed; can be used with albuterol in one nebulizer

Nebulizer solution (0.25 mg/ml)

Should not be used as first-line therapy; should be added to short-acting β2-adrenergic agonist therapy for severe exacerbations. The addition of ipratropium to a short-acting β2-adrenergic agonist has not been shown to provide further benefit once the patient is hospitalized.

Ipratropium bromide

Metered-dose inhaler (18 μg/puff)

Adverse effects include dry mouth, cough, and blurred vision.

Anticholinergic agents

of

Has not been studied in patients with severe asthma exacerbations.

Same as for albuterol, nebulizer solution; bitolterol thought to be half as potent as albuterol on a milligram basis

Nebulizer solution (2 mg/ml)

n e w e ng l a n d j o u r na l

Pirbuterol, metered-dose inhaler (200 μg/puff) Same as for albuterol, metered-dose inhaler; pirbuterol thought to be half as potent as albuterol on a milligram basis

Same as for albuterol, metered-dose inhaler; bitolterol thought to be half as potent as albuterol on a milligram basis

Metered-dose inhaler (370 μg/puff)

Bitolterol

Same as for albuterol, metered-dose inhaler; levalbuterol administered in half the milligram dose of albuterol has similar efficacy and safety

Metered-dose inhaler (45 μg/puff)

Has not been studied in patients with severe asthma exacerbations. Not available in the United States.

2.5–5 mg every 20 min over the first hr, then 2.5–10 mg every For optimal delivery, dilute solution to a minimum of 3 ml at a gas flow 1–4 hr as needed or 10–15 mg/hr continuously of 6–8 liters/min. Use large-volume nebulizers for continuous administration.

Levalbuterol†

4–8 puffs every 20 min up to 4 hr, then every 1–4 hr as needed

Adverse effects include tachycardia, palpitations, tremor, and hypokalemia.

Comments

Nebulizer solution (0.63 mg/3 ml, 1.25 mg/3 ml, 2.5 mg/3 ml, or 5.0 mg/ml)

Dose

Metered-dose inhaler (90 μg/puff)

Albuterol

Short-acting β2-adrenergic agonists

Drug and Available Formulation

Table 1. Medications for Treatment of Asthma Exacerbation in the Emergency Department.*

The

m e dic i n e

august 19, 2010

28

n engl j med 363;8 BACK to TOC

Adverse effects include adrenal suppression, growth suppression, osteoporosis, muscle weakness, hypertension, weight gain, diabetes, cataracts, Cushing’s syndrome, and dermal thinning. * Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3.3 † Levalbuterol is the R-enantiomer of albuterol.

40–80 mg/day in one dose or two divided doses, given until peak expiratory flow reaches 70% of predicted value or a personal best value Systemic corticosteroids: prednisone, prednisolone, and methylprednisolone

Nebulizer solution (each 3-ml vial contains 3 ml every 20 min for 3 doses, then as needed 0.5 mg of ipratropium bromide and 2.5 mg of albuterol)

Metered-dose inhaler (each puff containing 18 μg of ipratropium and 90 μg of albuterol)

Ipratropium bromide and albuterol

8 puffs every 20 min as needed, up to 3 hr

May be used for up to 3 hr during initial management of severe exacerbations. The addition of ipratropium to albuterol has not been shown to provide further benefit once the patient is hospitalized.

There is no known advantage of higher doses of corticosteroids to treat severe asthma exacerbations or of intravenous administration over oral therapy, provided that gastrointestinal absorption is not impaired. The total course of systemic corticosteroids for an asthma exacerbation necessitating an emergency department visit or hospitalization may be 3 to 10 days. For corticosteroid courses of <1 wk, there is no need to taper the dose; for courses of 7–10 days, there probably is no need to taper, especially if patients are concurrently receiving inhaled corticosteroids.

clinical pr actice

nejm.org

trials of corticosteroids in patients seen in the emergency department and those admitted to the hospital have been small, these studies individually14,15 and collectively16-18 show that the use, as compared with nonuse, of systemic corticosteroids is associated with a more rapid improvement in lung function, fewer hospitalizations, and a lower rate of relapse after discharge from the emergency department. Because comparisons of oral prednisone and intravenous corticosteroids have not shown differences in the rate of improvement of lung function or in the length of the hospital stay,19-21 the oral route is preferred for patients with normal mental status and without conditions expected to interfere with gastrointestinal absorption. Although the optimal dose of corticosteroid is not known, pooled data from controlled trials involving patients seen in the emergency department or admitted to the hospital have shown no significant advantage of doses greater than 100 mg per day of prednisone equivalent.19,20,22-25 The most recent guidelines from the National Asthma Education and Prevention Program (NAEPP) (Expert Panel Report 3) recommend the use of 40 to 80 mg per day in one dose or two divided doses.3 Inhaled Corticosteroids

Although high-dose inhaled corticosteroids are often used to treat worsening of asthma control and to try to prevent exacerbations, the evidence does not support the use of inhaled corticosteroids as a substitute for systemic corticosteroids in the emergency department.26 Inhaled corticosteroids are, however, preferred for long-term asthma control. At the time of discharge from the emergency department, these agents should be continued in patients who have been taking them for long-term control and should be prescribed for patients who have not previously taken them. In a randomized, controlled trial of 1006 consecutively enrolled patients with acute asthma treated in a Canadian emergency department, the addition at discharge of inhaled budesonide (for 21 days) to treatment with oral corticosteroids (for 5 to 10 days) was associated with a 48% reduction in the rate of relapse at 21 days and with improvement in the quality of life with respect to asthma (as measured by the Asthma Quality of Life Questionnaire) and symptoms, as compared with treatment with oral corticosteroids alone.27

august 19, 2010

759

29

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Reassess history, symptoms, vital signs, results of physical examination, PEF, and SaO2 after 60–90 min of treatment

Patient has continued mild-to-moderate exacerbation

Patient has continued severe exacerbation

Continue treatment Oxygen to achieve SaO2 ≥90% Short-acting β2-adrenergic agonist administered by means of a metered-dose inhaler with valved holding chamber or a nebulizer, every 60 min Oral corticosteroids Continue treatment 1–3 hr, provided there is improvement

Continue treatment Oxygen to achieve SaO2 ≥90% Short-acting β2-adrenergic agonist plus ipratropium bromide administered by means of a metered-dose inhaler with valved holding chamber or a nebulizer, every hr or continuously Oral corticosteroids Consider magnesium sulfate or heliox

Within <4 hr, make decision to admit or discharge

Patient has good response FEV1 or PEF ≥70% sustained for 60 min No distress Normal examination

Patient has incomplete response FEV1 or PEF 40–69% Mild-to-moderate symptoms

Patient has poor response FEV1 or PEF <40% PaCO2 ≥42 mm Hg Severe symptoms Drowsiness, confusion

Discharge

Discharge or admit, on the basis of risk factors, likelihood of adherence, and home environment

Admit

Figure 2. Continued Management of Asthma in the Emergency Department. Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3.3 Heliox is a mixture of helium and oxygen, usually 79% and 21%, respectively, whose density is about one third that of air. FEV1 denotes forced expiratory volume in 1 second, PaCO2 partial pressure of arterial carbon dioxide, PEF peak expiratory flow, and SaO2 arterial oxygen saturation.

760 BACK to TOC

Treatments That Are Not Recommended

Assessment of Response to Treatment

Although methylxanthines were once a standard treatment for asthma in the emergency department, it is now clear that their use increases the risk of adverse events without improving outcomes.28 Antibiotics should not be used routinely but rather should be reserved for patients in whom bacterial infection (e.g., pneumonia or sinusitis) seems likely. Similarly, neither aggressive hydration nor administration of mucolytic agents is recommended for acute exacerbations.3

Patients should be reassessed after the first treatment with an inhaled bronchodilator and again at 60 to 90 minutes (i.e., after three treatments).3 This assessment should include a survey of symptoms, a physical examination, and measurement of FEV1 or PEF (Fig. 2). For the most severe exacerbations, this repeat assessment should probably include the measurement of arterial blood gases. Most patients will have clinically significant improvement after one dose of an inhaled

n engl j med 363;8

nejm.org

august 19, 2010

30

clinical pr actice

bronchodilator, and 60 to 70% will meet the criteria for discharge from the emergency department (see below) after three doses.29-31 The degree of subjective and objective improvement that occurs in response to treatment predicts the need for hospitalization.32-38 In a study of 720 patients treated in 36 Australian emergency departments, the need for hospital admission among patients assessed as having moderate asthma, as well as the need for ICU care of patients assessed as having severe asthma, was better predicted by the assessment of asthma severity after 1 hour of treatment than by the initial assessment in the emergency department.38 Indications for Admission

After treatment in the emergency department for 1 to 3 hours, patients who have an incomplete or poor response, defined as an FEV1 or PEF of less than 70% of the personal best or predicted value, should be evaluated for admission to the hospital. Patients who have an FEV1 of less than 40%, persistent moderate-to-severe symptoms, drowsiness, confusion, or a PaCO2 of 42 mm Hg or greater should be admitted. Patients who have an FEV1 of 40 to 69% and mild symptoms should be assessed individually for risk factors for death, ability to adhere to a prescribed regimen, and the presence of asthma triggers in the home. The NAEPP Expert Panel Report 3 suggests that the decision to admit or discharge a patient should be made within 4 hours after presentation to the emergency department.3 Management of Respiratory Insufficiency

Patients with altered mental status, exhaustion, or hypercapnia should be considered for immediate intubation and ventilatory support. Because of high positive intrathoracic pressures, intubation and ventilation may lead to hypotension and barotrauma. Care should be taken to ensure adequate intravascular volume, and to avoid high airway pressures. A strategy of “permissive hypercapnia,” achieved by adjusting the ventilator to correct hypoxemia while avoiding high airway pressures, was associated in an observational study with decreased mortality among patients with status asthmaticus,39 and this approach has become standard. Guidelines suggest that once a decision has been made in the emergency department to intubate a patient, the procedure should be semielective and performed under controlled condin engl j med 363;8 BACK to TOC

tions (vs. performed as an emergency procedure by the first available staff). Randomized trials have shown a benefit from noninvasive positivepressure ventilation for acute exacerbations of chronic obstructive pulmonary disease, but most information used to guide the ventilation strategy for treating acute asthma comes from case reports or noncontrolled studies. A randomized crossover study that compared the use of bilevel positive airway pressure for 2 hours with standard care in children with acute asthma showed a significantly lower respiratory rate and improved scores on a questionnaire regarding asthma symptoms with bilevel positive airway pressure but no significant difference in arterial oxygen saturation, transcutaneous carbon dioxide levels, or other outcomes.40 In a randomized, shamcontrolled trial of the use of bilevel positive airway pressure in 30 adults with acute asthma, bilevel positive airway pressure was associated with a higher FEV1 value at 4 hours and a lower rate of hospitalization (17.6%, vs. 62.5% with sham treatment).41 These data suggest that noninvasive positive-pressure ventilation could be considered for patients who decline intubation and for selected patients who are likely to cooperate with mask therapy, but more data are needed to recommend this approach. Discharge from the Emergency Department

Patients may be discharged if the FEV1 or PEF after treatment is 70% or more of the personal best or predicted value and if the improvements in lung function and symptoms are sustained for at least 60 minutes.3 After discharge, patients should continue to use inhaled short-acting β2adrenergic agonists as needed and should be given oral corticosteroids for 3 to 10 days3 (Table 2). Inhaled corticosteroids can be started at any time during treatment of the exacerbation, but initiation at the time of discharge, if not before, is prudent to reduce the risk of relapse.27,42,43 Education of Patients

The need for treatment in the emergency department often reflects inadequate maintenance therapy and insufficient knowledge of how to deal with a worsening of asthma control. Presentation to the emergency department provides a unique opportunity to educate patients about medications, inhaler technique, and steps that can reduce exposure to household triggers of allergic reaction and to ensure that discharged

nejm.org

august 19, 2010

761

31

The

n e w e ng l a n d j o u r na l

Table 2. Recommendations for Discharge from the Emergency Department.* Medications Continue inhaled short-acting β2-adrenergic agonists every 1–2 hr, as needed Continue oral corticosteroids at a dose of 40–80 mg/day for 3–10 days If course is <1 wk, no need to taper the dose If course is 7–10 days, probably no need to taper, especially if patients are concurrently receiving inhaled corticosteroids Continue or start an inhaled corticosteroid at a “medium dose” (e.g., beclomethasone [HFA], 240–480 μg/day; budesonide [DPI], 600–1200 μg/day; or fluticasone [DPI], 300–500 μg/day) Education Review purposes and doses of asthma medications with patient Review inhaler technique with patient Teach patient to monitor for signs and symptoms of poor asthma control Provide patient with an asthma action plan Follow-up Advise patient to call primary care provider within 3–5 days after discharge Schedule a follow-up appointment with provider to occur within 1–4 wk * DPI denotes dry-powder inhaler, and HFA hydrofluoroalkane formulation.

patients have an asthma action plan and instructions for monitoring their symptoms and implementing their plan. A follow-up appointment should be scheduled with the patient’s primary care provider or with an asthma specialist to occur 1 to 4 weeks after discharge. Guidelines also recommend that patients be encouraged to contact their asthma care provider within 3 to 5 days after discharge, when the risk of relapse is greatest,3 although data are lacking to show that this action improves outcomes.

A r e a s of Uncer ta in t y In patients with severe asthma that is refractory to standard treatment, intravenous magnesium sulfate is widely used,44 but there is controversy regarding its efficacy. A meta-analysis of 1669 patients in 24 studies who received either intravenous magnesium sulfate (used in 15 studies) or nebulized magnesium sulfate (used in 9 studies) showed that intravenous treatment was weakly associated with improved lung function in adults but had no significant effect on hospital admissions; in children, the use of intravenous magnesium sulfate significantly improved lung function and reduced rates of hospital admission. The effect of nebulized magnesium sulfate is less 762 BACK to TOC

n engl j med 363;8

of

m e dic i n e

substantiated.45 Expert opinion46 and guidelines3 suggest that clinicians consider the use of intravenous magnesium sulfate in patients who have severe exacerbations and whose FEV1 or PEF remains less than 40% of the personal best or predicted value after initial treatments. The results of a large multicenter trial in the United Kingdom47 (Current Controlled Trials number, ISRCTN04417063) comparing treatment with intravenous or nebulized magnesium sulfate and standard treatment in patients with severe asthma are expected in 2011. Heliox is a mixture of helium and oxygen, usually 79% and 21%, respectively, with a density about one third that of air, that reduces airflow resistance within regions of the bronchial tree where turbulent flow predominates. It is thought to reduce the work of breathing and to improve delivery of aerosolized medications. However, its role in the management of acute severe asthma is unclear. A Cochrane analysis of 544 patients in 10 trials led to the conclusion that heliox might be beneficial in patients with severe airflow obstruction who have not had a response to initial treatment,48 and current guidelines reflect this conclusion.3 Since the administration of oral leukotriene inhibitors results in increases in the FEV1 within 1 to 2 hours,49,50 there has been interest in using these agents in the emergency department, but their usefulness in that setting is unclear. In a randomized, placebo-controlled trial of intravenous montelukast in 583 adults whose FEV1 remained at 50% or less of the predicted value after 60 minutes of standard care, the use of montelukast significantly improved the FEV1 at 60 minutes but did not reduce the rate of hospitalization.51

Guidel ine s The NAEPP and the Global Initiative for Asthma have developed and updated evidence-based guidelines for the diagnosis and management of asthma.3,52 The recommendations in this article are consistent with these guidelines.

C onclusions a nd R ec om mendat ions The patient described in the vignette has chronic uncontrolled asthma necessitating daily rescue use of albuterol, but she has not been receiving

nejm.org

august 19, 2010

32

clinical pr actice

daily controller therapy. Her history of ICU admissions and excessive albuterol use indicate that she is at increased risk for death related to asthma. Treatment with oxygen, aerosolized albuterol and ipratropium, and systemic corticosteroids should be initiated. The patient should be monitored closely and her signs and symptoms reassessed frequently, and a decision to admit or discharge her should be made within 4 hours after presentation. If she is discharged from the emergency department, she should be educated about medications, inhaler technique, and steps

for monitoring symptoms and for managing exacerbations. Emergency department staff should provide her with a discharge plan, schedule a follow-up appointment, and ensure that she has adequate medications or prescriptions to last until that appointment. Because of her previous admissions to the ICU and her history of consistently poor asthma control, referral to an asthma specialist would be prudent.

No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

References 1. Rowe BH, Voaklander DC, Wang D,

et al. Asthma presentations by adults to emergency departments in Alberta, Canada: a large population-based study. Chest 2009;135:57-65. 2. Moorman JE, Rudd RA, Johnson CA, et al. National surveillance for asthma — United States, 1980–2004. MMWR Surveill Summ 2007;56:1-54. 3. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma: full report 2007. (Accessed July 23, 2010, at http://www.nhlbi .nih.gov/guidelines/asthma/asthgdln.pdf.) 4. Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev 2006;2: CD000052. 5. Dhuper S, Chandra A, Ahmed A, et al. Efficacy and cost comparisons of bronchodilatator administration between metered dose inhalers with disposable spacers and nebulizers for acute asthma in an inner-city adult population. J Emerg Med 2008 December 10 (Epub ahead of print). 6. Rodrigo GJ, Rodrigo C. Continuous vs intermittent beta-agonists in the treatment of acute adult asthma: a systematic review with meta-analysis. Chest 2002;122:160-5. 7. Camargo CA Jr, Spooner CH, Rowe BH. Continuous versus intermittent betaagonists in the treatment of acute asthma. Cochrane Database Syst Rev 2003;4: CD001115. 8. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr 2003;143:731-6. 9. Qureshi F, Zaritsky A, Welch C, Meadows T, Burke BL. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005;46:29-36. 10. Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the

emergency department. Am J Respir Crit Care Med 2000;161:1862-8. 11. Gelb AF, Karpel J, Wise RA, Cassino C, Johnson P, Conoscenti CS. Bronchodilator efficacy of the fixed combination of ipratropium and albuterol compared to albuterol alone in moderate-to-severe persistent asthma. Pulm Pharmacol Ther 2008; 21:630-6. 12. Plotnick LH, Ducharme FM. Combined inhaled anticholinergics and beta2agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev 2000;4:CD000060. 13. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax 2005;60:740-6. [Errata, Thorax 2008;63: 1029, 2006;61:274, 458.] 14. Fanta CH, Rossing TH, McFadden ER Jr. Glucocorticoids in acute asthma: a critical controlled trial. Am J Med 1983;74: 845-51. 15. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med 1986;314:150-2. 16. Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of acute adult asthma: an evidence-based evaluation. Chest 1999;116:285-95. 17. Rowe BH, Edmonds ML, Spooner CH, Diner B, Camargo CA Jr. Corticosteroid therapy for acute asthma. Respir Med 2004;98:275-84. 18. Krishnan JA, Davis SQ, Naureckas ET, Gibson P, Rowe BH. An umbrella review: corticosteroid therapy for adults with acute asthma. Am J Med 2009;122:977-91. 19. Harrison BD, Stokes TC, Hart GJ, Vaughan DA, Ali NJ, Robinson AA. Need for intravenous hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet 1986;1:181-4. 20. Ratto D, Alfaro C, Sipsey J, Glovsky MM, Sharma OP. Are intravenous corticosteroids required in status asthmaticus? JAMA 1988;260:527-9.

n engl j med 363;8 BACK to TOC

nejm.org

21. Jónsson S, Kjartansson G, Gíslason D,

Helgason H. Comparison of the oral and intravenous routes for treating asthma with methylprednisolone and theophylline. Chest 1988;94:723-6. 22. Engel T, Dirksen A, Frølund L, et al. Methylprednisolone pulse therapy in acute severe asthma: a randomized, double-blind study. Allergy 1990;45:224-30. 23. Bowler SD, Mitchell CA, Armstrong JG. Corticosteroids in acute severe asthma: effectiveness of low doses. Thorax 1992; 47:584-7. 24. Emerman CL, Cydulka RK. A randomized comparison of 100-mg vs 500-mg dose of methylprednisolone in the treatment of acute asthma. Chest 1995;107: 1559-63. 25. Marquette CH, Stach B, Cardot E, et al. High-dose and low-dose systemic corticosteroids are equally efficient in acute severe asthma. Eur Respir J 1995;8:22-7. [Erratum, Eur Respir J 1995;8:1435.] 26. Edmonds ML, Camargo CA Jr, Pollack CV Jr, Rowe BH. Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev 2003;3:CD002308. 27. Rowe BH, Bota GW, Fabris L, Therrien SA, Milner RA, Jacono J. Inhaled budesonide in addition to oral corticosteroids to prevent asthma relapse following discharge from the emergency department: a randomized controlled trial. JAMA 1999;281:2119-26. 28. Parameswaran K, Belda J, Rowe BH. Addition of intravenous aminophylline to beta2-agonists in adults with acute asthma. Cochrane Database Syst Rev 2000;4: CD002742. 29. Karpel JP, Aldrich TK, Prezant DJ, Guguchev K, Gaitan-Salas A, Pathiparti R. Emergency treatment of acute asthma with albuterol metered-dose inhaler plus holding chamber: how often should treatments be administered? Chest 1997;112: 348-56. 30. Strauss L, Hejal R, Galan G, Dixon L, McFadden ER Jr. Observations on the effects of aerosolized albuterol in acute

august 19, 2010

763

33

clinical pr actice asthma. Am J Respir Crit Care Med 1997; 155:454-8. 31. Rodrigo C, Rodrigo G. Therapeutic response patterns to high and cumulative doses of salbutamol in acute severe asthma. Chest 1998;113:593-8. 32. Rodrigo G, Rodrigo C. Early prediction of poor response in acute asthma patients in the emergency department. Chest 1998;114:1016-21. 33. Chey T, Jalaludin B, Hanson R, Leeder S. Validation of a predictive model for asthma admission in children: how accurate is it for predicting admissions? J Clin Epidemiol 1999;52:1157-63. 34. McCarren M, Zalenski RJ, McDermott M, Kaur K. Predicting recovery from acute asthma in an emergency diagnostic and treatment unit. Acad Emerg Med 2000;7: 28-35. 35. Karras DJ, Sammon ME, Terregino CA, Lopez BL, Griswold SK, Arnold GK. Clinically meaningful changes in quantitative measures of asthma severity. Acad Emerg Med 2000;7:327-34. 36. Smith SR, Baty JD, Hodge D III. Validation of the pulmonary score: an asthma severity score for children. Acad Emerg Med 2002;9:99-104. 37. Gorelick MH, Stevens MW, Schultz TR, Scribano PV. Performance of a novel clinical score, the Pediatric Asthma Severity Score (PASS), in the evaluation of acute asthma. Acad Emerg Med 2004;11: 10-8. 38. Kelly AM, Kerr D, Powell C. Is severity

assessment after one hour of treatment better for predicting the need for admission in acute asthma? Respir Med 2004;98: 777-81. 39. Darioli R, Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respir Dis 1984;129:385-7. 40. Thill PJ, McGuire JK, Baden HP, Green TP, Checchia PA. Noninvasive positivepressure ventilation in children with lower airway obstruction. Pediatr Crit Care Med 2004;5:337-42. [Erratum, Pediatr Crit Care Med 2004;5:590.] 41. Soroksky A, Stav D, Shpirer I. A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest 2003; 123:1018-25. 42. Blais L, Ernst P, Boivin JF, Suissa S. Inhaled corticosteroids and the prevention of readmission to hospital for asthma. Am J Respir Crit Care Med 1998;158:126-32. 43. Sin DD, Man SF. Low-dose inhaled corticosteroid therapy and risk of emergency department visits for asthma. Arch Intern Med 2002;162:1591-5. 44. Jones LA, Goodacre S. Magnesium sulphate in the treatment of acute asthma: evaluation of current practice in adult emergency departments. Emerg Med J 2009;26:783-5. 45. Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J 2007;24:82330.

46. Rowe BH, Camargo CA Jr. The role of

magnesium sulfate in the acute and chronic management of asthma. Curr Opin Pulm Med 2008;14:70-6. 47. NIHR Health Technology Assessment Program. The 3Mg Trial: randomised controlled trial of intravenous or nebulised magnesium sulphate or standard therapy for acute severe asthma. 2010. (Accessed July 23, 2010, at http://www.hta.ac.uk/ project/1619.asp.) 48. Rodrigo G, Pollack C, Rodrigo C, Rowe BH. Heliox for nonintubated acute asthma patients. Cochrane Database Syst Rev 2006;4:CD002884. 49. Liu MC, Dubé LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. J Allergy Clin Immunol 1996;98:859-71. 50. Dockhorn RJ, Baumgartner RA, Leff JA, et al. Comparison of the effects of intravenous and oral montelukast on airway function: a double blind, placebo controlled, three period, crossover study in asthmatic patients. Thorax 2000;55:260-5. 51. Camargo CA Jr, Gurner DM, Smithline HA, et al. A randomized placebocontrolled study of intravenous montelukast for the treatment of acute asthma. J Allergy Clin Immunol 2010;125:374-80. 52. Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008;31:143-78. Copyright © 2010 Massachusetts Medical Society.

COLLECTIONS OF ARTICLES ON THE JOURNAL’S WEB SITE

The Journal’s Web site (NEJM.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.

764 BACK to TOC

n engl j med 363;8

nejm.org

august 19, 2010

34

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical practice

Early Alzheimer’s Disease Richard Mayeux, M.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.

A 72-year-old man who is still managing investments at a brokerage firm seeks consultation at the urging of his wife for increasing difficulty with memory over the past 2 years. Clients have expressed concern about his occasional lapses in memory. His wife reports that he frequently repeats questions about social appointments and becomes angry when she points this out. The physical examination is normal, but the patient has difficulty remembering elements of a brief story and adding a small amount of change. He has a score of 28 out of 30 on the Mini–Mental State Examination, indicating slightly impaired cognitive function.1 Early Alzheimer’s disease is suspected. How should the patient be further evaluated and treated?

The Cl inic a l Probl em From the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center, Columbia University, New York. Address reprint requests to Dr. Mayeux at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center, Columbia University, 630 W. 168th St., New York, NY 10032, or at [email protected]. This article (10.1056/NEJMcp0910236) was updated on September 15, 2010, at NEJM .org. N Engl J Med 2010;362:2194-201. Copyright © 2010 Massachusetts Medical Society.

Click here to access audio version.

2194 BACK to TOC

An audio version of this article is available at NEJM.org

Alzheimer’s disease is the most frequent cause of dementia in Western societies, affecting an estimated 5 million people in the United States and 17 million worldwide.2 The annual incidence worldwide increases from 1% between the ages of 60 and 70 years to 6 to 8% at the age of 85 years or older.3 In countries in which survival to the age of 80 years or older is not uncommon, the proportion of persons in this age group with Alzheimer’s disease now approaches 30% and is expected to continue to increase substantially.4 The disease onset is insidious, and manifestations evolve over a period of years from mildly impaired memory to severe cognitive loss. A transitional state, referred to as mild cognitive impairment, often precedes the earliest manifestations of Alzheimer’s disease.5 The course of Alzheimer’s disease is inevitably progressive and terminates in mental and functional incapacity and death. Plateaus sometimes occur in which the degree of cognitive impairment is stable for 1 or 2 years, but progression usually resumes thereafter. An inability to retain recently acquired information is typically the initial symptom, whereas memory for remote events is relatively spared until later. With disease progression, impairment in other areas of cognition (e.g., language, abstract reasoning, and executive function or decision making) occurs to varying degrees and typically coincides with difficulty at work or in social situations or household activities. Changes in mood and affect often accompany the decline in memory.6 Delusions and psychotic behavior are not typically presenting signs but can occur at any time during the disease course.7 The occurrence of psychosis during the initial stages of dementia suggests other diagnoses, such as dementia with Lewy bodies. At autopsy, the most frequent pathological features in the brains of patients with Alzheimer’s disease include extracellular beta-amyloid protein in diffuse plaques and in plaques containing elements of degenerating neurons, termed neuritic plaques.8 Intracellular changes include deposits of hyperphosphorylated tau protein, a microtubule assembly protein, in the form of neurofibrillary tangles. These pathological lesions first appear in the entorhinal regions of the hippocampus and n engl j med 362;23

nejm.org

june 10, 2010

35

clinical pr actice

then become widespread. Over time, there is widespread loss of neurons and synapses. The pathogenic mechanisms that are responsible for the development of these changes are unknown. A family history of dementia is one of the most consistently reported risk factors for Alzheimer’s disease.3 There are rare cases of families with autosomal dominant inheritance of Alzheimer’s disease that develops between the ages of 30 and 50 years; about half these cases result from mutations in genes encoding amyloid precursor protein, presenilin 1, or presenilin 2.9 Studies of these mutated genes have led to the assertion that Alzheimer’s disease is caused by the generation and aggregation of beta-amyloid peptide, which then forms neuritic plaques. Although several hundred families carry these mutations, they account for less than 1% of cases. First-degree relatives of patients with late-onset disease have approximately twice the expected lifetime risk of the disease. The disease is also more often concordant among monozygotic twins than among dizygotic twins.10 Individuals from families that have many members with late-onset Alzheimer’s disease are at increased risk for dementia, but the distribution of cases is rarely consistent with mendelian inheritance. The genetic variant encoding apolipoprotein (APOE) ε4 is the only well-established mutation associated with the late-onset form of Alzheimer’s disease.11 Risks that are associated with the APOE ε4 allele peak between the ages of 60 and 80 years. As compared with the absence of the APOE ε4 allele, the presence of one such allele is associated with a doubling or tripling of the lifetime risk of disease, and the presence of two copies is associated with an increase in risk by a factor of five or more. Associations between Alzheimer’s disease and variants in sortilin-related receptor 1 (SORL1),12 clusterin, phosphatidylinositol-binding clathrin assembly protein, and a complement component (3b/4b) receptor have been reported,13,14 but mechanisms underlying these associations remain uncertain.

S t r ategie s a nd E v idence Impaired memory is typically one of the first signs of Alzheimer’s disease, but difficulty recalling the names of friends or recent events is also common among normal elderly persons. The clinician is thus faced with the difficulty of distinguishing between normal aging and the early stages of n engl j med 362;23 BACK to TOC

Alzheimer’s disease. Mild cognitive impairment is an intermediate state in which persons have more memory problems than would be considered normal for their age, but their symptoms are not as severe as the symptoms of Alzheimer disease and they do not have functional impairment.5 Alzheimer’s disease develops at a much higher frequency among persons with mild cognitive impairment than among those with normal aging. Determining when patients have reached the very early stage of Alzheimer’s disease is not easy, particularly because it is likely that a preclinical stage of Alzheimer’s disease exists in which senile plaques, neuritic plaques, and neurofibrillary tangles occur in sufficient numbers to meet standard neuropathological criteria for Alzheimer’s disease in the absence of overt symptoms or signs of dementia.15 Other causes of memory impairment must also be considered, such as cerebrovascular disease, hydrocephalus, hypothyroidism, vitamin B12 deficiency, central nervous system infection, a cognitive disorder related to human immunodeficiency virus infection, adverse effects of prescribed medications, substance abuse, and cancer. A substantial decline in verbal memory and executive function (e.g., the ability to perform sequential tasks) typically occurs at the onset of Alzheimer’s disease but may be difficult to document without formal neuropsychological testing (Fig. 1). Reduced independence in daily activities (often recognized by the patient’s family) is one of the strongest predictors of disease.16 Functional status can be measured by the Clinical Dementia Rating (CDR) scale, which evaluates cognitive and functional performance on a scale ranging from 0 to 3, with higher scores indicating a greater severity of impairment.17 This assessment requires a collateral source of information gathering concerning the patient’s ability to function independently but can be performed in the primary care setting and is particularly useful for clinicians who do not have ready access to formal neuropsychological testing. The assessment requires 30 to 45 minutes to administer, and training is provided online. (Additional details are available in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The CDR score was the strongest predictor of Alzheimer’s disease in a study involving community volunteers without dementia, and scores on a functional rating scale that is based on the CDR effectively identified patients in the early stages of Alzheimer’s disease in a clinical setting.18 Formal neuropsychological

nejm.org

june 10, 2010

2195

36

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

CDR = 0

CDR = 0.5

CDR = 1.0

Normal Aging

Preclinical Alzheimer’s Disease MIld Cognitive Impairment

Early Alzheimer’s Disease

CSF tau and phosphorylated tau

Increases with time

Dependence on assistance in daily activities

FDG-PET parietal metabolism CSF beta-amyloid peptide

Decreases with time

Increasing amyloid and l id plaques l d neurofibrillary tangles

Hippocampal size on MRI Neuropsychological test performance

Time Figure 1. Sequence of Pathological, Clinical, Physiological, and Radiologic Changes from Normal Aging to Early Alzheimer’s Disease. Changes from normal aging to preclinical Alzheimer’s disease to early Alzheimer’s disease (yellow to green) are shown. The most frequent pathological feature of Alzheimer’s disease is the presence of extracellular beta-amyloid protein in diffuse plaques, along with intracellular changes that include deposits of hyperphosphorylated tau protein in the form of neurofibrillary tangles. These changes correspond to scores on the Clinical Dementia Rating (CDR) scale, which ranges from 0 to 3, with 0 indicating no impairment, 0.5 very mild impairment, 1.0 mild impairment, 2.0 moderate impairment, and 3.0 severe impairment. CSF denotes cerebrospinal fluid, FDG-PET 18F-fluorodeoxyglucose–positron-emission tomography, and MRI magnetic resonance imaging.

testing that shows a substantial decline in verbal memory and executive function supports the diagnosis of Alzheimer’s disease18,19 but requires a trained professional for administration and interpretation. Occasionally, patients with early Alzheimer’s disease present with impaired language or perceptual dysfunction rather than memory loss.20 Over time, both memory impairment and functional decline become apparent in such patients. Patients with early disease are at increased risk for motor vehicle accidents. The American Academy of Neurology21 recommends that clinicians perform a careful assessment of driving ability, including asking the caregiver to rate the patient’s driving ability and reviewing any traffic citations and accidents. Cognitive assessments that include visual perception and sequential-task performance may also be helpful in assessing the capacity to 2196 BACK to TOC

n engl j med 362;23

drive.22 Many state motor vehicle agencies have simulated driving laboratories or are willing to assess driving ability for a nominal fee. Information regarding resources for evaluating potentially impaired drivers is available through the National Highway Traffic Safety Administration (www.nhtsa.dot.gov).

T r e atmen t Op t ions Drug Therapies

Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the N-methyl-d-aspartate receptor antagonist memantine are the only treatments for Alzheimer’s disease that have been approved by the Food and Drug Administration23 (Table 1). Randomized, placebo-controlled clinical trials of cholinesterase inhibitors have included patients with mainly mild-to-moderate Alz-

nejm.org

june 10, 2010

37

clinical pr actice

Table 1. Drug Therapy for Alzheimer’s Disease. Medication

Common Adverse Side Effects

Dose 5 mg/day at bedtime with or without food for 4 to 6 weeks; 10 mg/day there-after, if tolerated

Nausea, vomiting, loss of appetite, weight loss, diarrhea, dizziness, muscle cramps, insomnia and vivid dreams

Available in a single daily dose

Rivastigmine (Exelon)

3 mg daily, split into morning and evening doses with meals; dose increased by 3 mg/day every 4 weeks as tolerated, with a maximum daily dose of 12 mg

Nausea, vomiting, loss of appetite, weight loss, diarrhea, indigestion, dizziness, drowsiness, headache, diaphoresis, weakness

Available as a patch

Galantamine (Razadyne)

8 mg daily, split into morning and evening doses with meals; dose increased by 4 mg every 4 weeks, as tolerated, with a maximum daily dose of 16 to 24 mg

Nausea, vomiting, loss of appetite, weight loss, diarrhea, dizziness, headache, fatigue

Available as an extendedrelease capsule

Memantine (Namenda)

5 mg/day with or without food; dose increased by 5 mg every week, with a maximum daily dose of 20 mg

Constipation, dizziness, headache, pain (nonspecific)

Often used as an adjunct to cholinesterase inhibitors; not recommended alone for treatment of early disease

heimer’s disease and have shown significant but clinically marginal benefits with respect to cognition, daily function, and behavior.24-26 The condition of patients who are taking these drugs remains stable for a year or more and then may decline, though at a rate that is slower than that among untreated patients. Although there are few studies directly comparing the three cholinesterase inhibitors, a systematic review and meta-analysis of data from 27 randomized trials concluded that there were no significant differences in effects on cognitive performance among these medications.27 During the study period (usually, 3 to 6 months), the use of each of these drugs as prescribed at a standard dose resulted in a mean improvement of 2 to 3 points on the Alzheimer’s Disease Assessment Scale for cognition (a scale ranging from 0 to 70, with higher scores indicating worse cognition) or a decreased rate of decline, as compared with the placebo group (approximately a 3-point difference, with a minimal clinically important difference of 4 points). On the basis of 14 studies that measured daily function, donepezil was modestly but significantly more effective than rivastigmine. Donepezil was likewise modestly but significantly better than rivastigmine and galantamine with regard to behavior, as measured by the Neuropsychiatric Inn engl j med 362;23 BACK to TOC

Comments

Donepezil (Aricept)

ventory (on a scale ranging from 1 to 144, with higher scores indicating a greater severity of disease). Patients receiving donepezil had a mean reduction of 4.3 points in the baseline score, as compared with a reduction of 1.4 for those receiving the other agents. The likelihood of an overall improvement in score was 1.9 times as great with donepezil as with placebo, 1.2 times as great with rivastigmine as with placebo, and 1.6 times as great with galantamine as with placebo. Adverse effects (including nausea, vomiting, diarrhea, dizziness, and weight loss) were frequent with all three medications, although slightly less frequent with donepezil than with the other medications. Initial randomized trials of memantine involving patients with moderate-to-severe disease showed a small but significant reduction in cognitive deterioration.28 Subsequent randomized trials involving patients with mild-to-moderate disease showed that memantine resulted in marginal benefits over a period of 6 months, with absolute changes in cognitive and functional measures of 1 percentage point.29 However, studies that were limited to patients with mild or early-stage disease have shown no significant benefit of memantine therapy.30 Memantine has also been used in patients with late-stage disease in combination with cholinesterase inhibitors, such as donepezil,

nejm.org

june 10, 2010

2197

38

The

n e w e ng l a n d j o u r na l

with modest improvements (a relative change in score of 2 to 5%) on the Severe Impairment Battery and the activities of daily living inventory of the Alzheimer’s Disease Cooperative Study.31 More data are needed to guide the optimal timing of treatment of early Alzheimer’s disease. In a small, randomized, placebo-controlled trial of donepezil, patients in whom Alzheimer’s disease had been diagnosed within the preceding year showed improvement in cognitive performance over a period of 24 weeks.32 In an openlabel study, patients who were treated early in the disease course had improvement that was only slightly greater than that of patients who began treatment later.26 In another observational study, a duration of treatment with cholinesterase inhibitors or memantine of at least 3 years was associated with a significantly slower rate of decline in cognitive ability and daily function.33 In practice, subjective reports of improvement in patients receiving cholinesterase inhibitors or memantine are common, but objective improvements are modest, if detectable at all. A rational approach is to try a cholinesterase inhibitor first, switching to another agent in the same class if the initial agent is ineffective or if intolerable side effects emerge.23 Memantine may be added to any of the cholinesterase inhibitors in patients who have little or no improvement with cholinesterase inhibitor monotherapy.

of

m e dic i n e

stage of Alzheimer’s disease. In one study, 25% of patients with Alzheimer’s disease were reported to have received the diagnosis of depression at the time of or just before the onset of symptoms of the disease.40 In patients in whom pharmacotherapy is considered appropriate, selective serotonin-reuptake inhibitors are commonly used; tricyclic antidepressants are generally avoided, since their anticholinergic effects can cause or exacerbate confusion.41 Psychosis that is characterized by hallucinations and delusions may occur infrequently in patients with early Alzheimer’s disease. The occurrence of agitation, delusions, hallucinations, and irritability early in the disease course also raises the possibility of an alternative diagnosis, such as dementia with Lewy bodies. Treatment with conventional or atypical antipsychotic agents may be helpful, but such drugs should be used with caution because of the potential adverse effects (e.g., parkinsonism, extrapyramidal signs, sedation, and confusion).42 Caregiver Support

Persons who live with and provide care for patients with Alzheimer’s disease, even in the early phases of the disease, often report emotional stress, in part related to the need to give up vacations, hobbies, or even work to care for the patient. Caregivers should routinely be offered counseling and support. Resources for caregivers and Other Strategies patients are available through the Alzheimer’s AsThe use of nonsteroidal antiinflammatory drugs, sociation (www.alz.org). estrogen therapy, antioxidant vitamins, or statins has been proposed for the prevention of AlzheiA r e a s of Uncer ta in t y mer’s disease, but the results of randomized trials have been inconsistent or negative.34-37 Similarly, Further study of brain-imaging methods and biothe efficacy of commonly used complementary markers that may facilitate the identification of therapies (e.g., ginkgo biloba, acetyl-L-carnitine, patients with early Alzheimer’s disease is needed. lecithin, huperzine A, piracetam, curcumin, peri- Focal atrophy on magnetic resonance imaging winkle, and phosphatidylserine) has not been (MRI) of the inferior temporal region, particularly shown in randomized trials.38 A review of nine the hippocampus, has been shown to predict the randomized clinical trials of cognitive training conversion from mild cognitive impairment to and rehabilitation therapies that were used to ad- Alzheimer’s disease.43 However, there is no standress loss of memory and other intellectual func- dard technique to quantify atrophy in the clinical tions showed no significant effects.39 setting, and the diagnostic sensitivity and specificity of MRI are unclear. Management of Psychiatric Symptoms Studies have shown that evidence of decreased Behavioral and psychiatric symptoms typically in- metabolism and perfusion in the parietal lobes crease with disease progression. However, depres- on 18F-fluorodeoxyglucose–positron-emission tosion and anxiety are frequent even in the early mography (FDG–PET) is as accurate as evidence

2198 BACK to TOC

n engl j med 362;23

nejm.org

june 10, 2010

39

clinical pr actice

of focal atrophy on MRI in predicting progression from mild cognitive impairment to Alzheimer’s disease.43,44 However, PET scanning is costly and not widely available at present, and its role in diagnosis remains uncertain. PET imaging with the use of amyloid-binding compounds, such as carbon 11–labeled Pittsburgh compound B (PIB),45 has been reported to identify patients with early Alzheimer’s disease.46 Some normal elderly persons without dementia have PIB retention similar to that observed in patients with Alzheimer’s disease, but progression to Alzheimer’s disease occurs more rapidly in persons with mild cognitive impairment who have PIB retention than in those without retention, indicating that amyloid deposition may be an early biomarker of incipient disease.47,48 Measurement of markers in cerebrospinal fluid has also been proposed to identify early Alzheimer’s disease. Among persons with mild cognitive impairment, reduced levels of beta-amyloid peptide and increased levels of total tau and tau phosphorylated at threonine 181 have predicted the diagnosis of Alzheimer’s disease.49,50 Assessment requires lumbar puncture, and the threshold diagnostic levels of these markers have varied across studies.51,52 These measures are now commercially available with clinical interpretation, but their role in practice remains unclear.

Guidel ine s The European Federation of Neurological Societies has published recommendations for the diagnosis and management of Alzheimer’s disease.53 On the basis of available randomized trials, treatment with cholinesterase inhibitors is recommended even for mild or early disease; no specific cholinesterase inhibitor is recommended over another. The American Academy of Neurology published practice recommendations in 200154 that have not yet been updated. In 2006, the American Association for Geriatric Psychiatry published

practice recommendations that also emphasize treatment with approved medications for cognitive symptoms, as well as symptomatic treatment for neuropsychiatric manifestations, such as depression and psychosis, and attention to issues related to safety, such as driving, living alone, and medication administration.55

C onclusions a nd R ec om mendat ions The 72-year-old patient who is described in the vignette has a history of memory and functional impairment, with a relatively high Mini–Mental State Examination1 score and a normal neurologic examination. Basic blood chemical analysis and measures of thyrotropin should be performed, along with additional laboratory studies as deemed clinically relevant. Brain MRI to rule out other brain diseases and assess atrophy and a detailed neuropsychological assessment are warranted to make a preliminary diagnosis. If the diagnosis of Alzheimer’s disease is established, I would discuss with the patient and caregiver potential safety issues, including the current living situation and driving, and I would initiate treatment with one of the cholinesterase inhibitors, probably donepezil (starting at 5 mg each night at bedtime). I would plan a follow-up visit in 4 to 6 weeks to assess the side effects and efficacy of the medication (both subjective and objective) by repeating the Mini– Mental State Examination. At that time, the dose of the cholinesterase inhibitor could be increased to 10 mg daily if the drug has been well tolerated. The patient should be closely followed clinically, with repeated neuropsychological assessment within 2 years. Dr. Mayeux reports receiving an honorarium from Quintiles for serving on a data and safety monitoring board for a trial of a product manufactured by Eli Lilly. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

References 1. Folstein MF, Folstein SE, McHugh PR.

“Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-98. 2. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-7.

3. Mayeux R. Epidemiology of neurode-

generation. Annu Rev Neurosci 2003;26: 81-104. 4. Ziegler-Graham K, Brookmeyer R, Johnson E, Arrighi HM. Worldwide variation in the doubling time of Alzheimer’s disease incidence rates. Alzheimers Dement 2008;4:316-23.

n engl j med 362;23 BACK to TOC

nejm.org

5. Petersen RC, Smith GE, Waring SC,

Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303-8. [Erratum, Arch Neurol 1999;56: 760.] 6. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for

june 10, 2010

2199

40

The

n e w e ng l a n d j o u r na l

Alzheimer disease: systematic review, metaanalysis, and metaregression analysis. Arch Gen Psychiatry 2006;63:530-8. 7. Lopez OL, Becker JT, Sweet RA, et al. Psychiatric symptoms vary with the severity of dementia in probable Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 2003;15:346-53. 8. Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol 2009; 118:5-36. 9. Rogaeva E, Kawarai T, George-Hyslop PS. Genetic complexity of Alzheimer’s disease: successes and challenges. J Alzheimers Dis 2006;9:Suppl:381-7. 10. Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006;63:168-74. 11. Mucke L. Neuroscience: Alzheimer’s disease. Nature 2009;461:895-7. 12. Rogaeva E, Meng Y, Lee JH, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007;39:168-77. 13. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 2009;41:1088-93. 14. Lambert JC, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 2009;41: 1094-9. 15. Price JL, McKeel DW Jr, Buckles VD, et al. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 2009; 30:1026-36. 16. Hsiung GY, Alipour S, Jacova C, et al. Transition from cognitively impaired not demented to Alzheimer’s disease: an analysis of changes in functional abilities in a dementia clinic cohort. Dement Geriatr Cogn Disord 2008;25:483-90. 17. Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9:Suppl 1: 173-8. 18. Dickerson BC, Sperling RA, Hyman BT, Albert MS, Blacker D. Clinical prediction of Alzheimer disease dementia across the spectrum of mild cognitive impairment. Arch Gen Psychiatry 2007;64:1443-50. 19. Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Bennett DA. Mild cognitive impairment in different functional domains and incident Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2005;76:1479-84. 20. Alladi S, Xuereb J, Bak T, et al. Focal cortical presentations of Alzheimer’s disease. Brain 2007;130:2636-45. 21. Iverson DJ, Gronseth GS, Reger MA, Classen S, Dubinsky RM, Rizzo M. Prac-

2200 BACK to TOC

of

m e dic i n e

tice parameter update: evaluation and management of driving risk in dementia: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2010;74:1316-24. 22. Dawson JD, Anderson SW, Uc EY, Dastrup E, Rizzo M. Predictors of driving safety in early Alzheimer disease. Neurology 2009;72:521-7. 23. Farlow MR, Cummings JL. Effective pharmacologic management of Alzheimer’s disease. Am J Med 2007;120:388-97. 24. Rösler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 1999;318:633-8. 25. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. BMJ 2000;321:1445-9. 26. Winblad B, Wimo A, Engedal K, et al. 3-Year study of donepezil therapy in Alzheimer’s disease: effects of early and continuous therapy. Dement Geriatr Cogn Disord 2006;21:353-63. 27. Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin Interv Aging 2008;3: 211-25. 28. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333-41. 29. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev 2006;2: CD003154. 30. Bakchine S, Loft H. Memantine treatment in patients with mild to moderate Alzheimer’s disease: results of a randomised, double-blind, placebo-controlled 6-month study. J Alzheimers Dis 2008;13: 97-107. 31. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317-24. 32. Seltzer B, Zolnouni P, Nunez M, et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol 2004;61:1852-6. 33. Rountree SD, Chan W, Pavlik VN, Darby EJ, Siddiqui S, Doody RS. Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimers Res Ther 2009;1:7. 34. Aisen PS, Thal LJ, Ferris SH, et al. Rofecoxib in patients with mild cognitive impairment: further analyses of data

n engl j med 362;23

nejm.org

from a randomized, double-blind, trial. Curr Alzheimer Res 2008;5:73-82. 35. Feldman HH, Doody RS, Kivipelto M, et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010;74:956-64. 36. Hogervorst E, Yaffe K, Richards M, Huppert FA. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database Syst Rev 2009;1:CD003799. 37. Isaac MG, Quinn R, Tabet N. Vitamin E for Alzheimer’s disease and mild cognitive impairment. Cochrane Database Syst Rev 2008;3:CD002854. 38. Kelley BJ, Knopman DS. Alternative medicine and Alzheimer disease. Neurologist 2008;14:299-306. 39. Clare L, Woods RT, Moniz Cook ED, Orrell M, Spector A. Cognitive rehabilitation and cognitive training for early-stage Alzheimer’s disease and vascular dementia. Cochrane Database Syst Rev 2003;4: CD003260. 40. Panza F, Frisardi V, Capurso C, et al. Late-life depression, mild cognitive impairment, and dementia: possible continuum? Am J Geriatr Psychiatry 2010;18:98116. 41. Starkstein SE, Mizrahi R, Power BD. Depression in Alzheimer’s disease: phenomenology, clinical correlates and treatment. Int Rev Psychiatry 2008;20:382-8. 42. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355:1525-38. 43. Schroeter ML, Stein T, Maslowski N, Neumann J. Neural correlates of Alzheimer’s disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients. Neuroimage 2009;47:1196-206. 44. Yuan Y, Gu ZX, Wei WS. Fluorodeoxyglucose-positron-emission tomography, single-photon emission tomography, and structural MR imaging for prediction of rapid conversion to Alzheimer disease in patients with mild cognitive impairment: a meta-analysis. AJNR Am J Neuroradiol 2009;30:404-10. 45. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-19. 46. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature 2009;461:916-22. 47. Fripp J, Bourgeat P, Acosta O, et al. Appearance modeling of 11C PiB PET images: characterizing amyloid deposition in Alzheimer’s disease, mild cognitive impairment and healthy aging. Neuroimage 2008;43:430-9. 48. Okello A, Koivunen J, Edison P, et al. Conversion of amyloid positive and nega-

june 10, 2010

41

clinical pr actice tive MCI to AD over 3 years: an 11C-PIB PET study. Neurology 2009;73:754-60. 49. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228-34. 50. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302:385-93. 51. Smach MA, Charfeddine B, Ben Othman L, et al. Evaluation of cerebrospinal

fluid tau/beta-amyloid(42) ratio as diagnostic markers for Alzheimer disease. Eur Neurol 2009;62:349-55. 52. Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimination and cognitive correlations. Neurology 2009;73:287-93. 53. Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 2007;14(1): e1-e26.

54. Knopman DS, DeKosky ST, Cummings

JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1143-53. 55. Lyketsos CG, Colenda CC, Beck C, et al. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. Am J Geriatr Psychiatry 2006;14:561-72. Copyright © 2010 Massachusetts Medical Society.

POSTING PRESENTATIONS AT MEDICAL MEETINGS ON THE INTERNET

Posting an audio recording of an oral presentation at a medical meeting on the Internet, with selected slides from the presentation, will not be considered prior publication. This will allow students and physicians who are unable to attend the meeting to hear the presentation and view the slides. If there are any questions about this policy, authors should feel free to call the Journal’s Editorial Offices.

n engl j med 362;23 BACK to TOC

nejm.org

june 10, 2010

2201

42

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical practice

Helicobacter pylori Infection Kenneth E.L. McColl, M.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.

A 29-year-old man presents with intermittent epigastric discomfort, without weight loss or evidence of gastrointestinal bleeding. He reports no use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs). Abdominal examination reveals epigastric tenderness. A serologic test for Helicobacter pylori is positive, and he receives a 10-day course of triple therapy (omeprazole, amoxicillin, and clarithromycin). Six weeks later, he returns with the same symptoms. How should his case be further evaluated and managed?

The Cl inic a l Probl em Helicobacter pylori, a gram-negative bacterium found on the luminal surface of the gastric epithelium, was first isolated by Warren and Marshall in 19831 (Fig. 1). It induces chronic inflammation of the underlying mucosa (Fig. 2). The infection is usually contracted in the first few years of life and tends to persist indefinitely unless treated.2 Its prevalence increases with older age and with lower socioeconomic status during childhood and thus varies markedly around the world.3 The higher prevalence in older age groups is thought to reflect a cohort effect related to poorer living conditions of children in previous decades. At least 50% of the world’s human population has H. pylori infection.2 The organism can survive in the acidic environment of the stomach partly owing to its remarkably high urease activity; urease converts the urea present in gastric juice to alkaline ammonia and carbon dioxide.4 Infection with H. pylori is a cofactor in the development of three important upper gastrointestinal diseases: duodenal or gastric ulcers (reported to develop in 1 to 10% of infected patients), gastric cancer (in 0.1 to 3%), and gastric mucosa-associated lymphoid-tissue (MALT) lymphoma (in <0.01%). The risk of these disease outcomes in infected patients varies widely among populations. The great majority of patients with H. pylori infection will not have any clinically significant complications. Gastric and Duodenal Ulcers

From the Division of Cardiovascular and Medical Sciences, University of Glasgow, Gardiner Institute, Glasgow, United Kingdom. Address reprint requests to Dr. McColl at the Division of Cardiovascular and Medical Sciences, University of Glasgow, Gardiner Institute, 44 Church St., Glasgow G11 6NT, United Kingdom, or at [email protected]. This article (10.1056/NEJMcp1001110) was updated on August 4, 2010, at NEJM.org. N Engl J Med 2010;362:1597-604. Copyright © 2010 Massachusetts Medical Society.

An audio version Click here to access audio of this article is available at version. NEJM.org

In patients with duodenal ulcers, the inflammation of the gastric mucosa induced by the infection is most pronounced in the non–acid-secreting antral region of the stomach and stimulates the increased release of gastrin.5 The increased gastrin levels in turn stimulate excess acid secretion from the more proximal acid-secreting fundic mucosa, which is relatively free of inflammation.5,6 The increased duodenal acid load damages the duodenal mucosa, causing ulceration and gastric metaplasia. The metaplastic mucosa can then become colonized by H. pylori, which may contribute to the ulcerative process. Eradication of the infection provides a long-term cure of duodenal ulcers in more than 80% of patients whose ulcers are not associated with the use of NSAIDs.7 NSAIDs are the main cause of H. pylori–negative ulcers.

n engl j med 362;17 BACK to TOC

nejm.org

april 29, 2010

1597

43

The

n e w e ng l a n d j o u r na l

Figure 1. Helicobacter pylori. H. pylori is a gram-negative bacterium with a helical rod shape. It has prominent flagellae, facilitating its penetration of the thick mucous layer in the stomach.

of

m e dic i n e

Figure 2. Gastric-Biopsy Specimen Showing Helicobacter pylori Adhering to Gastric Epithelium and Underlying Inflammation. H. pylori is visible as small black rods (arrows) on the epithelial surface and within the glands. The underlying mucosa shows inflammatory-cell infiltrates.

Ulceration of the gastric mucosa is believed to be due to the damage to the mucosa caused by H. pylori. As with duodenal ulcers, eradicating the infection usually cures the disease, provided that specimens of the gastric mucosa often reveal the presence of H. pylori and associated inflammation, the gastric ulcer is not due to NSAIDs.8 although this finding is also common in persons Gastric Cancer without upper gastrointestinal symptoms. Most Extensive epidemiologic data suggest strong asso- randomized trials of therapy for H. pylori eradicaciations between H. pylori infection and noncar- tion in patients with nonulcer dyspepsia have dia gastric cancers (i.e., those distal to the gastro- shown no significant benefit regarding sympesophageal junction).9 The infection is classified toms; a few have shown a marginal benefit,16,17 as a human carcinogen by the World Health Or- but this can be explained by the presence of unganization.10 The risk of cancer is highest among recognized ulceration.18 There is thus little evipatients in whom the infection induces inflam- dence that chronic H. pylori infection in the abmation of both the antral and fundic mucosa and sence of gastric or duodenal ulceration causes causes mucosal atrophy and intestinal metapla- upper gastrointestinal symptoms. The prevalence of H. pylori infection is lower sia.11 Eradication of H. pylori infection reduces the progression of atrophic gastritis, but there is little among patients with gastroesophageal reflux disevidence of reversal of atrophy or intestinal meta- ease (GERD)19 and those with esophageal adenoplasia,12 and it remains unclear whether eradica- carcinoma (which may arise as a complication of GERD) than among healthy controls.20 H. pylori– tion reduces the risk of gastric cancer.13 associated atrophic gastritis, which reduces acid Gastric MALT Lymphoma secretion, may provide protection against these Epidemiologic studies have also shown strong as- diseases. A recent meta-analysis showed no sigsociations between H. pylori infection and the pres- nificant association between H. pylori eradication ence of gastric MALT lymphomas.14 Furthermore, and an increased risk of GERD.21 eradication of the infection causes regression of most localized gastric MALT lymphomas.15 S t r ategie s a nd E v idence Other Gastrointestinal Conditions

At least 50% of persons who undergo endoscopy for upper gastrointestinal symptoms have no evidence of esophagitis or gastric or duodenal ulceration and are considered to have nonulcer or functional dyspepsia. In such patients, biopsy 1598 BACK to TOC

n engl j med 362;17

Candidates for Testing for H. pylori Infection

Since the vast majority of patients with H. pylori infection do not have any related clinical disease, routine testing is not considered appropriate.22,23 Definite indications for identifying and treating

nejm.org

april 29, 2010

44

clinical pr actice

the infection are confirmed gastric or duodenal ulcers and gastric MALT lymphoma.22,23 Testing for infection, and subsequent eradication, also seems prudent after resection of early gastric cancers.24 In addition, European guidelines recommend eradicating H. pylori infection in first-degree relatives of patients with gastric cancer and in patients with atrophic gastritis, unexplained irondeficiency anemia, or chronic idiopathic thrombocytopenic purpura, although the data in support of these recommendations are scant.23 Patients with uninvestigated, uncomplicated dyspepsia may also undergo testing for H. pylori infection by means of a nonendoscopic (noninvasive) method22,23,25; eradication therapy is prescribed for patients with positive test results. The rationale for this strategy is that in some patients with dyspepsia, underlying H. pylori–induced ulcer disease is causing their symptoms. This nonendoscopic strategy is not appropriate for patients with accompanying alarm symptoms (e.g., weight loss, persistent vomiting, or gastrointestinal bleeding) or for older patients (≥45 or ≥55 years of age, depending on the specific set of guidelines) with new-onset dyspepsia, in whom endoscopy is warranted.22,23,25 The nonendoscopic strategy is also not generally recommended for patients with NSAID-associated dyspepsia, since NSAIDs can cause ulcers in the absence of H. pylori infection. An attraction of the test-and-treat strategy is that it avoids the discomfort and costs of endoscopy. However, because only a minority of patients with dyspepsia who have a positive H. pylori test have underlying ulcer disease,26,27 most patients treated by means of the test-and-treat strategy incur the inconvenience, costs, and potential side effects of therapy without a benefit. In a placebo-controlled trial of empirical treatment involving 294 patients with uninvestigated dyspepsia and a positive H. pylori breath test, the 1-year rate of symptom resolution was 50% in those receiving H. pylori–eradication therapy, as compared with 36% of those receiving placebo (P = 0.02)28; 7 patients would need to receive eradication therapy for 1 patient to have a benefit. A greater benefit would be expected if treatment were limited to patients with an increased probability of having an ulcer. However, neither the characteristics of the symptoms nor the presence of other risk factors for ulcer (e.g., male sex, smoking, and family history of ulcer disease) are n engl j med 362;17 BACK to TOC

particularly useful in clinical practice for identifying patients with ulcer dyspepsia and those with nonulcer dyspepsia.29 In randomized trials comparing a noninvasive test-and-treat strategy with early endoscopy26,27 or with proton-pump–inhibitor therapy,30,31 the three strategies resulted in a similar degree of symptom improvement, but early endoscopy was more expensive than the other two strategies.32 However, the test-and-treat strategy is unlikely to be cost-effective in populations with a prevalence of H. pylori infection below 20%.33 Information is lacking on the longer-term outcomes of these strategies. Tests for H. pylori Infection

Table 1 summarizes the various tests for H. pylori infection. Nonendoscopic Tests

Serologic testing for IgG antibodies to H. pylori is often used to detect infection. However, a metaanalysis of studies of several commercially available quantitative serologic assays showed an overall sensitivity and specificity of only 85% and 79%, respectively.34 The appropriate cutoff values vary among populations, and the test results are often reported as positive, negative, or equivocal. Also, this test has little value in confirming eradication of the infection, because the antibodies persist for many months, if not longer, after eradication. The urea breath test involves drinking 13Clabeled or 14C-labeled urea, which is converted to labeled carbon dioxide by the urease in H. pylori. The labeled gas is measured in a breath sample. The test has a sensitivity and a specificity of 95%.35 The infection can also be detected by identifying H. pylori–specific antigens in a stool sample with the use of polyclonal or monoclonal antibodies (the fecal antigen test).36 The monoclonal-antibody test (which also has a specificity and a sensitivity of 95%36) is more accurate than the polyclonal-antibody test. For both the breath test and the fecal antigen test, the patient should stop taking proton-pump inhibitors 2 weeks before testing, should stop taking H2 receptor antagonists for 24 hours before testing, and should avoid taking antimicrobial agents for 4 weeks before testing, since these medications may suppress the infection and reduce the sensitivity of testing.

nejm.org

april 29, 2010

1599

45

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 1. Tests for Helicobacter pylori Infection.* Test

Advantages

Disadvantages

Nonendoscopic Serologic test

Widely available; the least expensive of available tests

Positive result may reflect previous rather than current infection; not recommended for confirming eradication

Urea breath test

High negative and positive predictive values; useful before and after treatment

False negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations; considerable resources and personnel required to perform test

Fecal antigen test

High negative and positive predictive values with monoclonal-antibody test; useful before and after treatment

Process of stool collection may be distasteful to patient; false negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations

Urease-based tests

Rapid, inexpensive, and accurate in selected patients

False negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations

Histologic assessment

Good sensitivity and specificity

Requires trained personnel

Culture

Excellent specificity; provides opportunity to test for antibiotic sensitivity

Variable sensitivity; requires trained staff and properly equipped facilities

Endoscopic

* PPI denotes proton-pump inhibitor.

1600 BACK to TOC

Endoscopic Tests

Treatment of H. pylori Infection

H. pylori infection can be detected on endoscopic biopsy of the gastric mucosa, by means of several techniques. The biopsy specimens are usually taken from the prepyloric region, but an additional biopsy specimen obtained from the fundic mucosa may increase the test’s sensitivity, especially if the patient has recently been treated with a proton-pump inhibitor. The urease-based method involves placement of the endoscopic biopsy specimen in a solution of urea and pH-sensitive dye. If H. pylori is present, its urease converts the urea to ammonia, increasing the pH and changing the color of the dye. Recommendations for avoiding proton-pump inhibitors, H2 receptor antagonists, and antimicrobial therapy before testing apply to this test as well, to minimize the chance of false negative results.37 The test has a sensitivity of more than 90% and a specificity of more than 95%.35 Another means of diagnosis involves routine histologic testing of a biopsy specimen; if there is H. pylori infection, the organism and associated gastritis are apparent on sections stained with hematoxylin and eosin or Giemsa. Although culturing of the organism is also possible and permits testing for sensitivity to antimicrobial agents, facilities for the culture of H. pylori are not widely available and the method is relatively insensitive.

Various drug regimens are used to treat H. pylori infection (Table 2). Most include two antibiotics plus a proton-pump inhibitor or a bismuth preparation (or both). The most commonly used initial treatment is triple therapy consisting of a proton-pump inhibitor plus clarithromycin and amoxicillin, each given twice per day for 7 to 14 days. Metronidazole is used in place of amoxicillin in patients with a penicillin allergy. The recommended duration of triple therapy is typically 10 to 14 days in the United States and 7 days in Europe.22,23 A recent meta-analysis of 21 randomized trials showed that the rate of eradication was increased by 4 percentage points with the use of triple therapy for 10 days as compared with 7 days and by 5 percentage points with the use of triple therapy for 14 days as compared with 7 days38 — absolute differences that are statistically significant but of marginal clinical significance. Another possible initial therapy in areas with a high prevalence of clarithromycin-resistant H. pylori infection (i.e., >20%) is quadruple therapy comprising the use of a proton-pump inhibitor, tetracycline, metronidazole, and a bismuth salt for 10 to 14 days23; however, bismuth salts are not available in some countries. A recent metaanalysis of 93 studies showed a higher rate of eradication with quadruple therapy that included

n engl j med 362;17

nejm.org

april 29, 2010

46

clinical pr actice

both clarithromycin and metronidazole than with triple therapy that included both these agents in populations with either clarithromycin or metronidazole resistance.39 An alternative initial regimen is 10-day sequential therapy, involving a proton-pump inhibitor plus amoxicillin for 5 days followed by a proton-pump inhibitor plus clarithromycin and tinidazole for 5 more days. This regimen was reported to achieve an eradication rate of 93%, as compared with a rate of 77% with standard triple therapy, in a meta-analysis of 10 randomized trials in Italy.40 However, in a trial in Spain, the eradication rate among patients randomly assigned to receive sequential therapy was only 84%, indicating a need to confirm its efficacy before it is used widely.41

Table 2. Regimens Used to Treat Helicobacter pylori Infection. Standard initial treatment (use one of the following three options) Triple therapy for 7–14 days PPI, healing dose twice/day* Amoxicillin, 1 g twice/day† Clarithromycin, 500 mg twice/day Quadruple therapy for 10–14 days‡ PPI, healing dose twice/day* Tripotassium dicitratobismuthate, 120 mg four times/day Tetracycline, 500 mg four times/day Metronidazole, 250 mg four times/day§ Sequential therapy Days 1–5 PPI, healing dose twice/day* Amoxicillin, 1 g twice/day Days 6–10

Confirmation of Eradication

It is important to confirm the eradication of H. pylori infection in patients who have had an H. pylori–associated ulcer or gastric MALT lymphoma or who have undergone resection for early gastric cancer.22,23 In addition, to avoid repeated treatment of patients whose symptoms are not attributable to H. pylori, follow-up testing is indicated in patients whose symptoms persist after H. pylori eradication treatment for dyspepsia. Eradication may be confirmed by means of a urea breath test or fecal antigen test; these are performed 4 weeks or longer after completion of therapy, to avoid false negative results due to suppression of H. pylori.22 Eradication can also be confirmed by testing during repeat endoscopy (Table 1) for patients in whom endoscopy is required. Management of Persistent Infection after Treatment

Before prescribing a second course of therapy, it is important to confirm that the infection is still present and consider whether additional antimicrobial treatment is appropriate. Further attempts at eradication are indicated in patients with confirmed ulcer or gastric MALT lymphoma or after resection for early gastric cancer. However, if the initial therapy was for uninvestigated dyspepsia, which is associated with a low likelihood of underlying ulcer and symptomatic benefit from eradication, the appropriateness of further eradication therapy is unclear; data from studies designed to determine the optimal management of such cases are lacking. Options for treatment include emn engl j med 362;17 BACK to TOC

PPI, healing dose twice/day* Clarithromycin, 500 mg twice/day Tinidazole, 500 mg twice/day§ Second-line therapy, if triple therapy involving clarithromycin was used initially (use one or the other) Triple therapy for 7–14 days PPI, healing dose once/day* Amoxicillin, 1 g twice/day Metronidazole, 500 mg (or 400 mg) twice/day§ Quadruple therapy, as recommended for initial therapy * Examples of healing doses of proton-pump inhibitors (PPIs) include the following regimens, all twice per day: omeprazole at a dose of 20 mg, esomeprazole at a dose of 20 mg, rabeprazole at a dose of 20 mg, pantoprazole at a dose of 40 mg, and lansoprazole at a dose of 30 mg. In some studies, esomeprazole has been given at a dose of 40 mg once per day. † If the patient has an allergy to amoxicillin, substitute metronidazole (at a dose of 500 mg or 400 mg) twice per day and (in initial triple therapy only) use clarithromycin at reduced dose of 250 mg twice per day. ‡ Quadruple therapy is appropriate as first-line treatment in areas in which the prevalence of resistance to clarithromycin or metronidazole is high (>20%) or in patients with recent or repeated exposure to clarithromycin or metronidazole. § Alcohol should be avoided during treatment with metronidazole or tinidazole, owing to the potential for a reaction resembling the reaction to disulfiram with alcohol use.

pirical acid-inhibitory therapy, endoscopy to check for underlying ulcer or another cause of symptoms, and repeat use of the noninvasive test-andtreat strategy. The possibility that symptoms may be due to a different cause (e.g., biliary tract, pancreatic, musculoskeletal, or cardiac disease or psychosocial stress) should routinely be considered. If another course of therapy is administered to eradicate H. pylori infection, the importance of adherence to the treatment regimen should be

nejm.org

april 29, 2010

1601

47

The

n e w e ng l a n d j o u r na l

Table 3. Guidelines for Evaluation and Management of Helicobacter pylori Infection.* American College of Gastroenterology

Maastricht III Consensus Report

Criteria for testing Active gastric or duodenal ulcer, his- Same as American College of Gastrotory of active gastric or duodenal enterology criteria, with the followulcer not previously treated for ing additional criteria: gastric canH. pylori infection, gastric MALT cer in first-degree relative, atrophic lymphoma, history of endoscopgastritis, unexplained iron-deficienic resection of early gastric cancy anemia, or chronic idiopathic cer, or uninvestigated dyspepsia thrombocytopenic purpura† Criteria for test-and-treat strategy Age <55 yr and no alarm symptoms§

Age <45 yr and no alarm symptomsठ7 Days

* The American College of Gastroenterology guidelines are reported by Chey, Wong, and the Practice Parameters Committee of the American College of Gastroenterology22; the Maastricht III consensus report guidelines are reported by Malfertheiner and colleagues.23 MALT denotes mucosa-associated lymphoid tissue. † Eradication of H. pylori in patients with chronic idiopathic thrombocytopenic purpura has been reported to increase the platelet count, although the data are limited. ‡ The age cutoff varies among countries, depending on the prevalence of upper gastrointestinal cancer. § Alarm symptoms include dysphagia, weight loss, evidence of gastrointestinal bleeding, and persistent vomiting.

m e dic i n e

for culturing H. pylori and performing sensitivity testing and experience with alternative treatments for the infection. Several regimens have been reported to be effective as salvage therapy in case series. For example, retreatment after treatment failure with a triple regimen consisting of levofloxacin or rifabutin, along with a proton-pump inhibitor and amoxicillin, has been associated with high rates of eradication.45-47 However, caution is warranted in the use of rifabutin, which may lead to resistance of mycobacteria in patients with preexisting mycobacterial infection.

A r e a s of Uncer ta in t y

Duration of therapy 10–14 Days

of

Data from randomized trials are lacking to guide the care of patients whose symptoms persist after completion of H. pylori eradication therapy for uninvestigated dyspepsia. The effect of eradication of H. pylori infection on the risk of gastric cancer is unclear but is currently under study.

Guidel ine s

The American College of Gastroenterology guidelines22 and the Maastricht guidelines23 differ slightly in their recommendations for testing and emphasized, since poor adherence may underlie treatment of H. pylori infection (Table 3). the failure of initial therapy. The choice of second-line treatment is influC onclusions a nd enced by the initial treatment (Table 2). Treatment R ec om mendat ions failure is often related to H. pylori resistance to clarithromycin or metronidazole (or both agents). The noninvasive test-and-treat strategy for H. pyIf initial therapy did not include a bismuth salt, lori infection is reasonable for younger patients bismuth-based quadruple therapy is commonly who have upper gastrointestinal symptoms but used as second-line therapy, with eradication not alarm symptoms, like the patient in the virates in case series ranging from 57 to 95%.42 gnette. Noninvasive testing can be performed Triple therapies have also been tested as second- with the use of the urea breath test, fecal antigen line therapies in patients in whom initial therapy test, or serologic test; the serologic test is the failed. A proton-pump inhibitor used in combina- least accurate. Triple therapy with a proton-pump tion with metronidazole and either amoxicillin inhibitor, clarithromycin, and amoxicillin or or tetracycline is recommended in patients previ- metronidazole remains an appropriate first-line ously treated with a proton-pump inhibitor, therapy, provided that there is not a high local amoxicillin, and clarithromycin.23,43 Clarithro- rate of clarithromycin resistance. Recurrence or mycin should be avoided as part of second-line persistence of symptoms after eradication therapy therapy unless resistance testing confirms that for uninvestigated dyspepsia is much less likely the H. pylori strain is susceptible to the drug.44 to indicate that treatment has failed than to indiPatients in whom H. pylori infection persists cate that the symptoms are unrelated to H. pylori after a second course of treatment and for whom infection. Further eradication therapy should not eradication is considered appropriate should be be considered unless persistent H. pylori infection referred to a specialist with access to facilities is confirmed. Data are lacking to inform the op-

1602 BACK to TOC

n engl j med 362;17

nejm.org

april 29, 2010

48

clinical pr actice

timal management of recurrent or persistent dys- other potential reasons for the symptoms should pepsia after noninvasive testing and treatment of also be reconsidered. H. pylori infection. Options include symptomatic Dr. McColl reports receiving lecture fees from AstraZeneca acid-inhibitory therapy, endoscopy to check for and Nycomed and consulting fees from Sacoor. No other potential conflict of interest relevant to this article was reported. underlying ulcer or another cause of symptoms, Disclosure forms provided by the author are available with the and repeat of the H. pylori test-and-treat strategy; full text of this article at NEJM.org. References 1. Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983;1:1273-5. 2. Everhart JE. Recent developments in the epidemiology of Helicobacter pylori. Gastroenterol Clin North Am 2000;29: 559-79. 3. Woodward M, Morrison C, McColl K. An investigation into factors associated with Helicobacter pylori infection. J Clin Epidemiol 2000;53:175-81. 4. Marshall BJ, Barrett LJ, Prakash C, McCallum RW, Guerrant RL. Urea protects Helicobacter (Campylobacter) pylori from the bactericidal effect of acid. Gastroenterology 1990;99:697-702. 5. el-Omar EM, Penman ID, Ardill JES, Chittajallu RS, Howie C, McColl KEL. Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 1995;109:681-91. 6. Gillen D, el-Omar EM, Wirz AA, Ardill JES, McColl KEL. The acid response to gastrin distinguishes duodenal ulcer patients from Helicobacter pylori-infected healthy subjects. Gastroenterology 1998; 114:50-7. 7. Hentschel E, Brandstätter G, Dragosics B, et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med 1993;328:308-12. 8. Axon ATR, O’Moráin CA, Bardhan KD, et al. Randomised double blind controlled study of recurrence of gastric ulcer after treatment for eradication of Helicobacter pylori infection. BMJ 1997;314: 565-8. 9. Hansen S, Melby KK, Aase S, Jellum E, Vollset SE. Helicobacter pylori infection and risk of cardia cancer and non-cardia gastric cancer: a nested case-control study. Scand J Gastroenterol 1999;34:353-60. 10. Infection with Helicobacter pylori. In: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 61. Schistosomes, liver flukes and Helicobacter pylori. Lyon, France: International Agency for Research on Cancer, 1994:177-240. 11. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:784-9.

12. Leung WK, Lin SR, Ching JY, et al.

Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 2004;53:1244-9. 13. Malfertheiner P, Sipponen P, Naumann M, et al. Helicobacter pylori eradication has the potential to prevent gastric cancer: a state-of-the-art critique. Am J Gastroenterol 2005;100:2100-15. 14. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori and gastric lymphoma. N Engl J Med 1994;330:1267-71. 15. Fischbach W, Goebeler-Kolve ME, Dragosics B, Greiner A, Stolte M. Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: experience from a large prospective series. Gut 2004;53: 34-7. 16. Moayyedi P, Soo S, Deeks J, et al. Systematic review and economic evaluation of Helicobacter pylori eradication treatment for non-ulcer dyspepsia. BMJ 2000; 321:659-64. 17. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia: a meta-analysis of randomized, controlled trials. Ann Intern Med 2001;134:361-9. 18. McColl KEL. Absence of benefit of eradicating Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med 2000;342:589. 19. Raghunath A, Hungin AP, Wooff D, Childs S. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ 2003;326:737-9. 20. de Martel C, Llosa AE, Farr SM, et al. Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma. J Infect Dis 2005;191:761-7. 21. Yaghoobi M, Farrokhyar F, Yuan Y, Hunt RH. Is there an increased risk of GERD after Helicobacter pylori eradication? A meta-analysis. Am J Gastroenterol 2010 January 19 (Epub ahead of print). 22. Chey WD, Wong BCY, Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007;102:1808-25. 23. Malfertheiner P, Megraud F, O’Morain

n engl j med 362;17 BACK to TOC

nejm.org

C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III consensus report. Gut 2007; 56:772-81. 24. Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008;372: 392-7. 25. Talley NJ, Vakil N, Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005;100:2324-37. 26. McColl KEL, Murray LS, Gillen D, et al. Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H pylori testing alone in the management of dyspepsia. BMJ 2002;324:999-1002. [Errata, BMJ 2002;325: 479, 580.] 27. Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455-60. 28. Chiba N, Van Zanten SJO, Sinclair P, Ferguson RA, Escobedo S, Grace E. Treating Helicobacter pylori infection in primary care patients with uninvestigated dyspepsia: the Canadian adult dyspepsia empiric treatment–Helicobacter pylori positive (CADET-Hp) randomised controlled trial. BMJ 2002;324:1012-6. 29. The Danish Dyspepsia Study Group. Value of the unaided clinical diagnosis in dyspepsia patients in primary care. Am J Gastroenterol 2001;96:1417-21. 30. Jarbol DE, Kragstrup J, Stovring H, Havelund T, Schaffalitzky de Muckadell OB. Proton pump inhibitor or testing for Helicobacter pylori as the first step for patients presenting with dyspepsia? A clusterrandomized trial. Am J Gastroenterol 2006;101:1200-8. 31. Manes G, Menchise A, de Nucci C, Balzano A. Empirical prescribing for dyspepsia: randomised controlled trial of test and treat versus omeprazole treatment. BMJ 2003;326:1118. 32. Delaney BC, Innes MA, Deeks J, et al. Initial management strategies for dyspepsia. Cochrane Database Syst Rev 2001;3: CD001961.

april 29, 2010

1603

49

clinical pr actice 33. Delaney BC, Moayyedi P, Forman D.

Initial management strategies for dyspepsia. Cochrane Database Syst Rev 2003;2: CD001961. 34. Loy CT, Irwig LM, Katelaris PH, Talley NJ. Do commercial serological kits for Helicobacter pylori infection differ in accuracy? A meta-analysis. Am J Gastroenterol 1996;91:1138-44. 35. Vaira D, Vakil N. Blood, urine, stool, breath, money, and Helicobacter pylori. Gut 2001;48:287-9. 36. Gisbert JP, Pajares JM. Stool antigen test for the diagnosis of Helicobacter pylori infection: a systematic review. Helicobacter 2004;9:347-68. 37. Midolo P, Marshall BJ. Accurate diagnosis of Helicobacter pylori: urease tests. Gastroenterol Clin North Am 2000;29: 871-8. 38. Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F. Meta-analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication. Ann Intern Med 2007;147:553-62.

39. Fischbach L, Evans EL. Meta-analysis:

the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori. Aliment Pharmacol Ther 2007;26:343-57. 40. Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment. Ann Intern Med 2008;148:92331. [Erratum, Ann Intern Med 2008;149: 439.] 41. Sánchez-Delgade J, Calvet X, Bujanda L, Gisbert JP, Titó L, Castro M. Ten-day sequential treatment for Helicobacter pylori eradication in clinical practice. Am J Gastroenterol 2008;103:2220-3. 42. Gisbert JP, Pajares JM. Helicobacter pylori “rescue” regimen when proton pump inhibitor-based triple therapies fail. Aliment Pharmacol Ther 2002;16:1047-57. 43. Realdi G, Dore MP, Piana A, et al. Pretreatment antibiotic resistance in Helicobacter pylori infection: results of three randomized controlled studies. Helicobacter 1999;4:106-12.

44. Lamouliatte H, Mégraud F, Delchier

JC, et al. Second-line treatment for failure to eradicate Helicobacter pylori: a randomized trial comparing four treatment strategies. Aliment Pharmacol Ther 2003;18: 791-7. 45. Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther 2006;23:35-44. 46. Saad RJ, Schoenfeld P, Kim HM, Chey WD. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol 2006;101:488-96. 47. Qasim A, Sebastian S, Thornton O, et al. Rifabutin- and furazolidone-based Helicobacter pylori eradication therapies after failure on standard first- and secondline eradication attempts in dyspepsia patients. Aliment Pharmacol Ther 2005;21: 91-6. Copyright © 2010 Massachusetts Medical Society.

FULL TEXT OF ALL JOURNAL ARTICLES ON THE WORLD WIDE WEB

Access to the complete contents of the Journal on the Internet is free to all subscribers. To use this Web site, subscribers should go to the Journal’s home page (NEJM.org) and register by entering their names and subscriber numbers as they appear on their mailing labels. After this one-time registration, subscribers can use their passwords to log on for electronic access to the entire Journal from any computer that is connected to the Internet. Features include a library of all issues since January 1993 and abstracts since January 1975, a full-text search capacity, and a personal archive for saving articles and search results of interest. All articles can be printed in a format that is virtually identical to that of the typeset pages. Beginning 6 months after publication, the full text of all Original Articles and Special Articles is available free to nonsubscribers.

1604 BACK to TOC

n engl j med 362;17

nejm.org

april 29, 2010

50

Clinical Therapeutics Clinical Therapeutics articles provide practical guidance for the use of specific medications, devices, and procedures in patient care. Topics include: how the therapy is used, evidence that supports (or fails to support) its use, adverse effects and areas of uncertainty, guidelines from major professional societies, and author recommendations.

BACK to TOC

51

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical therapeutics

Iron-Chelating Therapy for Transfusional Iron Overload Gary M. Brittenham, M.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

A 16-year-old boy with sickle cell anemia undergoes routine screening with transcranial Doppler ultrasonography to assess the risk of stroke. This examination shows an abnormally elevated blood-flow velocity in the middle cerebral artery. The hemoglobin level is 7.2 g per deciliter, the reticulocyte count is 12.5%, and the fetal hemoglobin level is 8.0%. Long-term treatment with red-cell transfusion is initiated to prevent stroke. A hematologist recommends prophylactic iron-chelating therapy.

The Cl inic a l Probl em From the Division of Pediatric Hematology, Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York. Address reprint requests to Dr. Brittenham at the Division of Pediatric Hematology, Department of Pediatrics, Columbia University Medical Center, Rm. CHN 10-08, 3959 Broadway, New York, NY 10032, or at gmb31@ columbia.edu. N Engl J Med 2011;364:146-56. Copyright © 2011 Massachusetts Medical Society.

Long-term treatment with red-cell transfusion effectively prevents stroke and other complications of sickle cell anemia1 and can sustain patients with chronic congenital and acquired refractory anemia, including thalassemia major, Diamond– Blackfan anemia, myelodysplastic syndromes, myelofibrosis, aplastic anemia, and other disorders. In the United States, 10,000 to 20,000 patients with sickling disorders receive repeated transfusions. An estimated 4000 to 5000 patients with myelodysplastic syndromes and other forms of acquired refractory anemia require redcell transfusions. The number of patients with transfusion-dependent thalassemia in the United States is smaller — probably less than 1000.2 However, globally, almost 100,000 patients with thalassemia syndromes undergo transfusions. The majority of these patients are in low- and middle-income countries.3 Because humans lack any effective means to excrete excess iron, long-term transfusion alone inexorably produces the clinical problem of iron overload. In patients with thalassemia who undergo transfusion from infancy, iron-induced liver disease and endocrine disorders develop during childhood and are almost inevitably followed in adolescence by death from iron-induced cardiomyopathy.4 In patients with sickle cell anemia, although iron-induced complications appear to develop later, eventually, liver disease with cirrhosis as well as cardiac and pancreatic iron deposition can develop.5,6 The annual per-patient costs of care for complications of iron overload are estimated at $15,000 to $20,000.7,8

PATHOPH YSIOL O GY A ND EFFEC T OF THER A PY At the end of their life span, transfused red cells are phagocytosed by reticuloendothelial macrophages in the liver, bone marrow, and spleen (Fig. 1). Their hemoglobin is digested, and the iron is freed from heme and released into the cytosol. Early in the course of long-term transfusion, most of this additional iron can be stored within reticuloendothelial macrophages. Gradually, limits on the capacity of macrophages to retain iron result in the release of excess iron into plasma.9 Transferrin 146 BACK to TOC

n engl j med 364;2

nejm.org

january 13, 2011

52

clinical ther apeutics

binds the released iron, with an increase in the plasma iron concentration and transferrin saturation. As the transferrin saturation increases, hepatocytes are recruited to serve as storage sites for the excess iron. With continued transfusion, macrophages and hepatocytes can no longer retain all the surplus iron. Iron then enters plasma in amounts that exceed the transport capacity of circulating transferrin. As a consequence, non–transferrin-bound iron appears in the plasma (Fig. 1) as a heterogeneous assortment of iron complexes that appear to be the major mediators of extrahepatic tissue damage in transfusional iron overload.10 Non–transferrin-bound plasma iron enters specific cells, particularly hepatocytes, cardiomyocytes, anterior pituitary cells, and pancreatic betacells. In these cells, iron accumulation leads to the generation of reactive oxygen species, resulting in damage to lipids, proteins, DNA, and subcellular organelles, including lysosomes and mitochondria. This injury may result in cellular dysfunction, apoptosis, and necrosis. Therapy with chelating agents that form a complex with iron and promote its excretion can clear plasma non–transferrin-bound iron, remove excess iron from cells, and maintain or return body iron to safe levels (Fig. 1). (An interactive graphic depicting iron supply and storage in sickle cell anemia with long-term red-cell transfusion and iron-chelating therapy is available with the full text of this article at NEJM.org.) Two iron-chelating agents are approved for use in North America (Table 1): parenteral deferoxamine mesylate (Desferal, Novartis) and oral deferasirox (Exjade, Novartis). Deferoxamine is a siderophore (an iron-binding compound) produced by the bacterium Streptomyces pilosus. It is poorly absorbed after oral administration and is rapidly cleared; consequently, subcutaneous or intravenous administration is necessary. One molecule of deferoxamine binds a single atom of iron, forming a feroxamine complex that is virtually inert metabolically. Plasma iron chelated with deferoxamine is eliminated predominantly by the kidneys. Hepatocytes efficiently take up deferoxamine, which then chelates hepatocellular iron, with the feroxamine excreted in the bile. Within cells, deferoxamine is localized to lysosomes, where it induces autophagy of cytosolic ferritin. Lysosomal degradation of cytosolic ferritin releases iron that is bound by deferoxamine, and the chelated iron is then cleared from the cell.14 n engl j med 364;2 BACK to TOC

In contrast to deferoxamine, the synthetic chelator deferasirox is well absorbed from the gastrointestinal tract and is cleared from the circulation slowly.13,15 Two molecules of deferasirox are needed to bind a single atom of iron. Like deferoxamine, deferasirox forms complexes with plasma iron, but deferasirox–iron complexes are eliminated predominantly through a hepatobiliary route. Hepatocytes readily take up deferasirox, which chelates hepatocellular iron. The deferasirox–iron complexes are then excreted in the bile.15 Within cells, deferasirox chelates cytosolic iron, leading to ferritin degradation by the proteasome.14 A third iron chelator, the synthetic oral agent deferiprone (Ferriprox, Apotex; Kelfer, Cipla), is not approved for use in the United States or Canada. In the European Union and some other countries, it is approved specifically for patients with thalassemia major when deferoxamine is contraindicated or inadequate (Table 1).

CL INIC A L E V IDENCE The use of deferoxamine therapy antedates the common use of randomized, controlled trials to establish the efficacy of medical treatments. Only one small, randomized trial has compared chelation plus deferoxamine with no therapy; this trial enrolled 20 children with β-thalassemia. After a mean of 5.8 years of treatment with intramuscu-

An interactive graphic is available at NEJM.org

Click here to access interactive graphic.

Figure 1 (see next two pages). Iron Supply and Storage in Sickle Cell Anemia with Long-Term Red-Cell Transfusion and Iron-Chelating Therapy. In all four panels, the area of the red and blue circles is roughly proportional to the amount of iron in each pool, and the width of the arrows is roughly proportional to the daily magnitude of the iron flux. Panel A shows normal iron supply and storage in a healthy person without sickle cell disease (i.e., with hemoglobin A). The major pathway of internal iron exchange is a unidirectional flow from plasma transferrin to the erythroid marrow to circulating red cells to reticuloendothelial macrophages and back to plasma transferrin (orange arrows). In the circulating plasma, virtually all iron is bound to transferrin. Panel B shows that in sickle cell anemia, hemolysis shortens the average life span of the red cell from about 4 months to 5 or 6 weeks, increasing red-cell catabolism by reticuloendothelial macrophages and increasing iron delivery to the erythroid marrow by 6 to 8 times the normal rate. There is little ineffective erythropoiesis, and iron absorption from the gastrointestinal tract is not increased. Panel C shows that long-term red-cell transfusion decreases erythroid marrow activity to 2 to 3 times the normal rate but results in accumulation of iron in reticuloendothelial macrophages and hepatocytes. Eventually, the capacity for safe storage is exceeded, with the appearance of plasma non–transferrin-bound iron (dashed arrow) and its progressive deposition in the heart and endocrine organs. In Panel D, the green arrows show that iron-chelating therapy with deferasirox can clear plasma non–transferrinbound iron and remove excess iron from the liver, heart, and other organs, with subsequent excretion through the bile into the stool.

nejm.org

january 13, 2011

147

53

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

A Normal Iron Supply and Storage Functional iron

Reticuloendothelial macrophages

Storage iron

Muscle and other parenchymal cells

Heart and endocrine organs

Transferrinbound iron Gastrointestinal tract

Ci l tii Circulating red cells

Hepatocytes

Erythroid marrow

B Sickle Cell Anemia Reticuloendothelial macrophages Muscle and other parenchymal cells

Heart and endocrine organs

Transferrinbound iron

Circulating red cells

Gastrointestinal tract

Hepatocytes

Erythroid marrow

148 BACK to TOC

n engl j med 364;2

nejm.org

january 13, 2011

54

clinical ther apeutics

C Sickle Cell Anemia with Long-Term

Non–transferrin-bound iron

Red-Cell Transfusion Reticuloendothelial macrophages Heart and endocrine organs

Transfusion

Muscle and other parenchymal cells

Transferrinbound iron Gastrointestinal tract

Circullating Circulating ti red cells

Hepatocytes

Erythroid marrow

D Sickle Cell Anemia with Transfusion

Chelator-bound iron

and Iron-Chelating Therapy Reticuloendothelial macrophages Heart and endocrine organs

Transfusion

Muscle and other parenchymal cells

Transferrinbound iron Circulating ti red cells

Gastrointestinal tract

Hepatocytes

Erythroid marrow

n engl j med 364;2 BACK to TOC

nejm.org

january 13, 2011

149

55

Agranulocytosis and neutropenia; gastrointestinal disturbances, arthropathy, increased liver-enzyme levels, low plasma zinc level, progression of hepatic fibrosis associated with increase in iron overload or hepatitis C11 Gastrointestinal disturbances, rash, increase in serum creatinine level; potentially fatal renal and hepatic impairment or failure, gastrointestinal hemorrhage13 Irritation at the infusion site, ocular and auditory disturbances, growth retardation and skeletal changes, allergy, respiratory distress syndrome with higher-than-recommended doses12

Transfusional iron overload in patients with thalassemia major, when deferoxamine therapy is contraindicated or inadequate Transfusional iron overload Transfusional iron overload

Predominantly urinary Predominantly biliary

Approved in United States, Canada, Europe, and other countries Approved in United States, Canada, Europe, and other countries

Not approved in United States or Canada; approved in Europe11 and other countries

n e w e ng l a n d j o u r na l

Biliary and urinary

of

m e dic i n e

lar deferoxamine, the mean hepatic iron concentration was 25.9 mg per gram of liver tissue (dry weight) in the deferoxamine group and 42.2 mg per gram in the control group.16 At 14 years, one death had occurred in the deferoxamine group and six deaths had occurred in the control group.17 In lieu of randomized trials, observational studies have investigated the effects of deferoxamine in the management of transfusion-related iron overload. One study involved 977 children with transfusion-dependent thalassemia major who survived beyond the first decade of life.18 Subsequent survival was examined according to 5-year birth cohorts beginning in 1960; deferoxamine was introduced in 1975. The survival rate increased progressively in each 5-year cohort (see Fig. 1 in the Supplementary Appendix, available at NEJM.org). The survival rate was significantly higher among children born after 1975 than among those in previous cohorts. Deferasirox has been compared with deferoxamine in a few short-term trials sponsored by Novartis.19-23 In the largest of these trials, 586 children with β-thalassemia were randomly assigned to either agent, with dosing according to the baseline hepatic iron concentration.19 The primary end point was the percentage of subjects with either a maintained or reduced hepatic iron concentration at 1 year; this end point was reached in 52.9% of patients assigned to deferasirox and in 66.4% of patients assigned to deferoxamine. This result, which did not meet a prespecified noninferiority target, was attributed to the relative underdosing of deferasirox. The total hepatic iron concentration decreased by a mean of 2.4 mg per gram (dry weight) in the deferasirox group and by 2.9 mg per gram in the deferoxamine group. No trial has established the long-term effectiveness of deferasirox in preventing organ toxicity or improving survival. Deferiprone has also been compared with deferoxamine in several small, randomized trials.24 As is the case with deferasirox, no long-term trials have been performed to evaluate the effect of deferiprone on organ function or survival.

Adverse effects

CL INIC A L USE

Indication

Regulatory approval

Route of elimination

2–3 hr 8–16 hr Plasma half-life

20–30 min

Oral, three times daily Oral, once daily Subcutaneous or intravenous, 8–10 hr/day, 5–7 days/wk Administration

25–50 mg/kg/day

Bidentate, 3:1 complex Tridentate, 2:1 complex

20–40 mg/kg/day

Hexadentate, 1:1 complex

Usual dose

Chelator-iron complex

Deferoxamine

Deferasirox BACK to TOC

Variable

Table 1. Iron-Chelating Agents in Clinical Use.

150

75–100 mg/kg/day

Deferiprone

The

n engl j med 364;2

Iron-chelating therapy should be considered in all patients who require long-term red-cell transfusion. Such patients include those with sickle cell disease, myelodysplastic syndromes, thalassemia major, Diamond–Blackfan anemia, aplastic nejm.org

january 13, 2011

56

clinical ther apeutics

anemia, and other congenital and acquired forms of refractory anemia. There are alternatives to chelation in some patients. Some of the underlying disorders requiring transfusion may be cured by hematopoietic stem-cell transplantation. In some patients with sickle cell disease, exchange transfusion may reduce or obviate the need for iron chelation. Infrequently, phlebotomy may be an option for the removal of excess iron in the event of cure or remission of a refractory anemia. Iron-chelating therapy itself may sometimes decrease or eliminate the need for transfusion in patients with myelodysplasia25 or myelofibrosis. Chelation therapy may not be needed in patients with myelodysplasia or other acquired refractory anemias who have an estimated survival of less than 1 year.26 With the exception of these groups, ironchelating therapy is indicated in almost all patients requiring long-term red-cell transfusion. Iron chelation is contraindicated in patients who are hypersensitive to the chelating agent or excipients in the chelator formulation, and it requires specialized management in patients with several renal disease or anuria. Chelators should be avoided or used with great caution in patients who are pregnant or breast-feeding. Ideally, iron-chelating therapy should be initiated prophylactically, before clinically significant iron accumulation has occurred. Treatment should begin when patients have received between 10 and 20 red-cell transfusions. Patients who have already undergone repeated transfusion without sufficient chelation can also be successfully treated, but they may require more intensive regimens (see below). Evaluation of the patient before the initiation or adjustment of iron-chelating therapy includes a detailed characterization of the underlying disorder, with thorough documentation of the history of transfusion and chelation; determination of the body iron load by measurement of the hepatic iron and serum ferritin concentrations; estimation of the rate of transfusional iron loading; and assessment of cardiac iron deposition. The techniques for assessing cardiac iron overload, transfusional iron loading, and body iron burden are described in the Supplementary Appendix. The extent of any existing iron-induced hepatic, cardiac, or endocrine dysfunction should be established, and in children and adolescents, growth and maturation should be assessed. Nutritional evaluation with correction of deficiencies is recommended.27 n engl j med 364;2 BACK to TOC

In the United States and Canada, the choice of an iron chelator for transfusional iron overload is either parenteral deferoxamine or oral deferasirox. The decision is best made with the patient and, if the patient is a child, with his or her parents. Despite the lack of data on longterm effectiveness, most patients now opt for deferasirox because of the ease of oral administration. Deferasirox is preferred for prophylactic or maintenance therapy. Deferoxamine, which has been proved to reverse iron-induced heart disease and increase long-term survival,28 may be indicated if deferasirox is ineffective in a particular patient, and it may be favored for severe iron overload, especially with cardiac involvement. Conversely, deferasirox may be the better choice in patients who are unable to tolerate subcutaneous infusions of deferoxamine. Deferasirox also may be substituted for deferoxamine after successful clearance of cardiac iron. Deferiprone is available in the United States on a compassionate-use basis, usually in combination with deferoxamine, in patients in whom iron-induced heart failure has developed or who are at high risk for the development of heart failure.29,30 Deferoxamine is administered subcutaneously or intravenously, usually with a portable pump, for 8 to 10 hours each day, 5 to 7 days per week. Subcutaneous administration is preferred except in patients with severe cardiac iron deposition, for whom continuous intravenous deferoxamine therapy is recommended.28,31 Deferasirox is administered orally once daily, and deferiprone is administered orally three times daily. The dose of an iron-chelating agent is determined by three principal factors: the presence or absence of cardiac iron overload, the rate of transfusional iron loading, and the body iron burden (see the Supplementary Appendix and Table 2). In brief, if cardiac iron overload is present, ridding the heart of the excess iron becomes the critical therapeutic goal. In the absence of cardiac iron overload, the long-term objective is to maintain the body iron at a level that permits safe storage while avoiding chelator toxicity. The greater the rate of transfusional iron loading, the greater the dose of an iron chelator that will be needed to control the accumulation of iron. During treatment, tests to monitor chelatorassociated toxicity should be performed, depending on the potential adverse effects of the specific agent to be used (see Table 1 and the Adverse Effects section below). In patients who receive

nejm.org

january 13, 2011

151

57

152

BACK to TOC

Deferoxamine: suspend thera- Deferoxamine: suspend thera- Deferoxamine: suspend thera- Deferoxamine: adjust intrave- Deferoxamine: adjust intravepy; deferasirox: suspend py; deferasirox: suspend py; deferasirox: suspend nous or subcutaneous dose nous or subcutaneous dose therapy therapy therapy according to therapeutic according to therapeutic index32; deferasirox: adjust index32; deferasirox: adjust oral dose, monitoring renal oral dose, monitoring renal and hepatic function and and hepatic function and blood count blood count

<3 mg/g, dry weight

n e w e ng l a n d j o u r na l

n engl j med 364;2

nejm.org

of

* To minimize interference with growth and skeletal development, the dose of deferoxamine in young children should not exceed 25 to 30 mg per kilogram of body weight. The dose should be adjusted according to the therapeutic index.32 The bioavailability of deferasirox may affect the response. T2* denotes the cardiac effective transverse relaxation time on magnetic resonance imaging.

Deferoxamine: 30–40 mg/kg/ Deferoxamine: 30–40 mg/kg/ Deferoxamine: 30–40 mg/kg/ Deferoxamine: 40–50 mg/kg/ Deferoxamine: 40–50 mg/kg/ day, 8 to 10 hr/day, 5 days/ day, 8 to 10 hr/day, 5 days/ day, 8 to 10 hr/day, 5 days/ day, 8 to 10 hr/day, 6 or 7 day by continuous infuwk, by subcutaneous infuwk, by subcutaneous infuwk, by subcutaneous infudays/wk, by subcutaneous sion28; deferasirox: oral sion; deferasirox: oral dose sion; deferasirox: oral dose sion; deferasirox: oral dose infusion; deferasirox: oral dose of 30–40 mg/kg daily of 20–30 mg/kg daily of 20–30 mg/kg daily of 20–30 mg/kg daily dose of 30–40 mg/kg daily

3 to <7 mg/g, dry weight

T2*, <10 msec

T2*, 10 to <20 msec

Deferoxamine: 30–40 mg/kg/ Deferoxamine: 40–50 mg/kg/ Deferoxamine: 40–50 mg/kg/ Deferoxamine: 40–50 mg/kg/ Deferoxamine: 40–50 mg/kg/ day, 8 to 10 hr/day, 5 days/ day, 8 to 10 hr/day, 6 or 7 day, 8 to 10 hr/day, 6 or 7 day, 8 to 10 hr/day, 6 or 7 day by continuous infuwk, by subcutaneous infudays/wk, by subcutaneous days/wk, by subcutaneous days/wk, by subcutaneous sion28; deferasirox: oral sion; deferasirox: oral dose infusion; deferasirox: oral infusion; deferasirox: oral infusion; deferasirox: oral dose of 30–40 mg/kg daily of 20–30 mg/kg daily dose of 30–40 mg/kg daily dose of 30–40 mg/kg daily dose of 30–40 mg/kg daily

>0.5 mg/kg of body weight

7 to <15 mg/g, dry weight

0.3 to 0.5 mg/kg of body weight

Severe

Mild to Moderate

Cardiac Iron Overload (T2*, <20 msec)

Deferoxamine: 40–50 mg/kg/ Deferoxamine: 40–50 mg/kg/ Deferoxamine: 40–50 mg/kg/ Deferoxamine: 50 mg/kg/day Deferoxamine: 50 mg/kg/day day, 8 to 10 hr/day, 6 or 7 day, 8 to 10 hr/day, 6 or 7 day, 8 to 10 hr/day, 6 or 7 by continuous intravenous by continuous intravenous days/wk, by subcutaneous days/wk, by subcutaneous days/wk, by subcutaneous infusion28; deferasirox: oral infusion28; deferasirox: oral infusion; deferasirox: oral infusion; deferasirox: oral infusion; deferasirox: oral dose of 40 mg/kg daily, but dose of 40 mg/kg daily, but dose of 30–40 mg/kg daily dose of 30–40 mg/kg daily dose of 30–40 mg/kg daily uncertain efficacy in reducuncertain efficacy in reducing cardiac iron ing cardiac iron

<0.3 mg/kg of body weight

Daily Transfusional Iron Intake

No Cardiac Iron Overload (T2*, ≥20 msec)

≥15 mg/g, dry weight

Hepatic Iron Concentration

Table 2. Usual Doses of Deferoxamine or Deferasirox for Transfusional Iron Overload.*

The

m e dic i n e

january 13, 2011

58

clinical ther apeutics

deferoxamine, these tests include annual assessments of auditory function and vision. In patients who receive deferasirox, serum creatinine, serum aminotransferases, and bilirubin levels and complete blood counts should be assessed monthly. In patients who receive deferiprone, weekly assessment of complete blood counts and monthly assessments of serum aminotransferases should be performed. The effectiveness of iron-chelating therapy is best monitored by periodic measurements of cardiac iron concentrations by magnetic resonance imaging (MRI), of cardiac function, and of hepatic iron concentrations and by review of the actual rate of transfusional iron loading once or twice a year, depending on the severity of the iron overload (see the Supplementary Appendix). Dose adjustments can be made according to the guidelines in Table 2. Serum ferritin concentrations are usually measured at least quarterly. As at baseline, hepatic, cardiac, and endocrine function should be assessed periodically along with nutritional status, and, in children and adolescents, growth and maturation should be monitored. In the United States, on the basis of 2006 wholesale acquisition prices, the annual costs of deferoxamine for iron-chelating therapy have been estimated to range from $6,824 to $29,209, plus $9,286 for infusion, and the estimated annual costs of deferasirox range from $24,404 to $53,095, with the actual cost depending on dose and body weight.7 Administration of a chelator will be needed as long as transfusion is continued and will be lifelong in most patients.

the dose as the hepatic iron concentration approaches normal levels. Although treatment with deferoxamine may reduce endocrine complications of iron overload, such as a delay of puberty, the chelator itself can interfere with growth,35 apparently as a result of skeletal dysplasia.36 To minimize this effect, the dose of deferoxamine in young children should not exceed 25 to 30 mg per kilogram.37 In the registration trial of deferasirox described above,19 gastrointestinal disturbances occurred in approximately 15% of patients, rash in 11%, and increases in serum creatinine levels in 38%. Similar rates have been observed in subsequent trials.20-22 In January 2010, on the basis of postmarketing studies, the Food and Drug Administration required a change in the prescribing information for deferasirox. The new information states that the drug could cause potentially fatal renal and hepatic impairment or failure as well as gastrointestinal hemorrhage.13 These adverse effects were reported to occur more frequently in older patients and in patients with high-risk myelodysplastic syndromes, thrombocytopenia, or underlying renal or hepatic impairment. The most common adverse effects of deferiprone are diarrhea and gastrointestinal effects, arthropathy (including severe arthritis with clinically significant disability), increased levels of serum liver enzymes, and progression of hepatic fibrosis associated with an increase in iron overload or hepatitis C.11 The most serious adverse effects are agranulocytosis (incidence, 1.1%) and neutropenia (incidence, 4.9%); weekly monitoring of the neutrophil count is recommended. Neurologic abnormalities have been reported A DV ER SE EFFEC T S with higher-than-recommended doses of deferiDiscomfort or pain at the site of subcutaneous prone.38 infusion develops in almost all patients treated with subcutaneous deferoxamine, and induration A r e a s of Uncer ta in t y or erythema develops in some patients. These symptoms can often be mitigated with topical Several areas of uncertainty exist with regard to anesthetic or glucocorticoid creams. Visual and the optimal approach to iron-chelating therapy. auditory toxicity associated with deferoxamine First, a variety of binary combinations of chelathas been reported, and in one series involving 89 ing agents are being examined in off-label uses, patients treated with this agent, 13 presented with with either synchronous or sequential adminisvision loss, deafness, or both.33 Subsequent stud- tration. The clinical usefulness of such combinaies suggest a much lower incidence of toxicity,34 tion therapies is unclear at present, in the aband these risks can be minimized by not exceed- sence of unequivocal evidence of the superiority ing doses of 50 mg per kilogram of body weight of any specific combination over treatment with in patients with iron overload and by decreasing a single agent.24 n engl j med 364;2 BACK to TOC

nejm.org

january 13, 2011

153

59

The

n e w e ng l a n d j o u r na l

Second, MRI performed to evaluate the iron content of the liver, heart, and other organs has become the method of choice for guiding ironchelating therapy, but calibrated methods are not available for all patients. A 1-year study of deferasirox involving patients with various types of anemias used an alternative approach; the investigators based the initial dose on the rate of transfusional iron loading and subsequently adjusted the dose according to measurements of serum ferritin levels and safety markers.23 The long-term efficacy and safety of this strategy are uncertain. Third, in patients with myelodysplastic syndromes who have undergone long-term transfusion and for whom prolonged survival is anticipated, iron-chelating therapy may be appropriate. In individual patients, the benefit of such treatment may vary, given the morbidity associated with chelation, the variable prognosis for the underlying disorder, and the latency period between the onset of the transfusion and the development of clinical manifestations of iron overload. Data are lacking from prospective, randomized trials examining the clinical circumstances in which morbidity and mortality improve with iron-chelating therapy in these patients39; one such trial is currently recruiting patients.40 Fourth, there is evidence to suggest that iron overload is associated with lower rates of cardiomyopathy, endocrinopathy, and other conditions among patients with sickle cell disease than among patients with thalassemia.41 The effects of the systemic inflammatory state on iron handling in patients with sickle cell disease,42 as well as differences in the rate and duration of transfusion and in the age of the patient at the initiation of long-term transfusion, the extent of ineffective erythropoiesis, and gastrointestinal iron absorption, may be involved. It is unclear whether these data provide sufficient grounds to recommend a higher body iron threshold for chelation therapy in patients with sickle cell disease, especially given the potential risks of iron-induced liver disease. Finally, there is a lack of certainty with respect to the optimal hepatic iron concentrations (Table 2) for minimizing the risk that hepatic fibrosis will progress to cirrhosis and its ultimate complication, hepatocellular carcinoma.43,44

154 BACK to TOC

n engl j med 364;2

of

m e dic i n e

Guidel ine s Guidelines and consensus statements on the management of sickle cell disease,45,46 thalassemia,32,47 Diamond–Blackfan anemia,48 aplastic anemia,49 and myelodysplastic syndromes26,50 all include recommendations for iron-chelating therapy for transfusional iron overload. All these guidelines are generally consistent with the approach outlined in this review, although there are variations in the individual recommendations, depending in part on the year of publication and the specific underlying disorder. For example, the guidelines for iron chelation in thalassemia32,47 generally endorse measurement of serum ferritin levels as a useful way to monitor iron overload, whereas the guidelines for the management of sickle cell disease45,46 emphasize that ferritin levels can be altered by liver disease and inflammation. The guidelines on the management of thalassemia by the Italian Society of Hematology47 endorse deferoxamine as first-line therapy over the oral chelators, whereas most of the other guidelines do not state an explicit preference in this regard.

R ec om mendat ions After discussing the need for iron-chelating therapy with the patient and his family, I would describe the advantages and disadvantages of subcutaneous deferoxamine and oral deferasirox so that a genuinely informed decision can be made. At present, the most frequent choice is oral deferasirox. Before the initiation of treatment, I would obtain information about the number of previous transfusions and the rate of ongoing transfusion and would arrange for cardiac T2* and hepatic transverse relaxation rate (R2) measurements, an MRI evaluation of cardiac function, and echocardiographic and electrocardiographic studies. Auditory and ophthalmic testing, including slit-lamp examination and dilated-fundus examination, should be performed. Laboratory tests should include a complete blood count with a differential count and measurement of serum creatinine, serum aminotransferases, bilirubin levels, and iron indexes. After transfusion of a total of 10 to 20 units of blood, or with the hepatic iron concentration between 3 and 7 mg per gram, I would administer once-daily oral therapy

nejm.org

january 13, 2011

60

clinical ther apeutics

with deferasirox at a dose of 20 mg per kilogram. With good support and careful monitoring, this regimen, adjusted as needed, should provide long-term protection against the complications of transfusional iron overload in this patient. Supported by grants from the St. Giles Foundation, the Food

and Drug Administration (R01 FD003702), and the National Institutes of Health (R37 DK049108; R01 DK066251). Dr. Brittenham reports that his institution filed a patent application in April 2010 for a rapid MRI method. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

References 1. Adams RJ, McKie VC, Hsu L, et al.

Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11. 2. Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF. Changes in the epidemiology of thalassemia in North America: a new minority disease. Pediatrics 2005;116(6):e818-e825. 3. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010;115:4331-6. 4. Weatherall DJ, Clegg JB. The thalassemia syndromes. 4th ed. Oxford, England: Blackwell Science, 2001. 5. Darbari DS, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O. Circumstances of death in adult sickle cell disease patients. Am J Hematol 2006;81:858-63. 6. Finch CA, Lee MY, Leonard JM. Continuous RBC transfusions in a patient with sickle cell disease. Arch Intern Med 1982;142:279-82. 7. Delea TE, Sofrygin O, Thomas SK, Baladi JF, Phatak PD, Coates TD. Cost effectiveness of once-daily oral chelation therapy with deferasirox versus infusional deferoxamine in transfusion-dependent thalassaemia patients: US healthcare system perspective. Pharmacoeconomics 2007;25:329-42. 8. Delea TE, Edelsberg J, Sofrygin O, et al. Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion-dependent thalassemia: a literature review. Transfusion 2007;47:1919-29. 9. Fillet G, Beguin Y, Baldelli L. Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation. Blood 1989;74:844-51. 10. Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci 2000;23:185-92. 11. European Medicines Agency. Ferriprox (deferiprone): summary of product characteristics. European public assessment report 2009, rev. ed. 14. (http://www.ema .europa.eu/humandocs/Humans/EPAR/ ferriprox/ferriprox.htm.) 12. Novartis Pharmaceuticals. Desferal (deferoxamine mesylate) prescribing information. 2010. (http://www.desferal.com.) 13. Novartis Pharmaceuticals. Exjade (de-

ferasirox) prescribing information. 2010. (http://www.exjade.com.) 14. De Domenico I, Ward DM, Kaplan J. Specific iron chelators determine the route of ferritin degradation. Blood 2009; 114:4546-51. 15. Waldmeier F, Bruin GJ, Glaenzel U, et al. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug Metab Dispos 2010;38:808-16. 16. Barry M, Flynn DM, Letsky EA, Risdon RA. Long-term chelation therapy in thalassaemia major: effect on liver iron concentration, liver histology, and clinical progress. BMJ 1974;2:16-20. 17. Modell B, Letsky EA, Flynn DM, Peto R, Weatherall DJ. Survival and desferrioxamine in thalassaemia major. Br Med J (Clin Res Ed) 1982;284:1081-4. 18. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004;89:1187-93. 19. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 2006;107: 3455-62. 20. Piga A, Galanello R, Forni GL, et al. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orallyadministered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 2006;91:873-80. 21. Porter J, Galanello R, Saglio G, et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 2008;80:168-76. 22. Vichinsky E, Onyekwere O, Porter J, et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007; 136:501-8. 23. Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica 2010;95:557-66. 24. Roberts DJ, Brunskill SJ, Doree C,

n engl j med 364;2 BACK to TOC

nejm.org

Williams S, Howard J, Hyde CJ. Oral deferiprone for iron chelation in people with thalassaemia. Cochrane Database Syst Rev 2007;3:CD004839. 25. Jensen PD, Heickendorff L, Pedersen B, et al. The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol 1996;94:288-99. 26. Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol 2008;88:24-9. 27. Claster S, Wood JC, Noetzli L, et al. Nutritional deficiencies in iron overloaded patients with hemoglobinopathies. Am J Hematol 2009;84:344-8. 28. Davis BA, Porter JB. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia. Blood 2000;95:1229-36. 29. Cohen AR. Compassionate use of deferiprone for patients with thalassemia and iron-induced heart disease. (ClinicalTrials .gov identifier no. NCT00293098.) (http:// www.clinicaltrials.gov/ct2/show/ NCT00293098?term=deferiprone+ thalassemia&rank=2.) 30. Borgna-Pignatti C, Cappellini MD, De Stefano P, et al. Cardiac morbidity and mortality in deferoxamine- or deferipronetreated patients with thalassemia major. Blood 2006;107:3733-7. 31. Anderson LJ, Westwood MA, Holden S, et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Haematol 2004;127: 348-55. 32. Iron overload. In: Cappellini MD, Cohen A, Eleftheriou A, Piga A, Porter J, Taher A. Guidelines for the clinical management of thalassemia. 2nd ed. rev. Nicosia, Cyprus: Thalassaemia International Federation, November 2008:33-63. 33. Olivieri NF, Buncic JR, Chew E, et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med 1986;314: 869-73. 34. Cohen A, Martin M, Mizanin J, Konkle DF, Schwartz E. Vision and hearing during deferoxamine therapy. J Pediatr 1990;117:326-30. 35. De Sanctis V, Roos M, Gasser T, et al.

january 13, 2011

155

61

clinical ther apeutics Impact of long-term iron chelation therapy on growth and endocrine functions in thalassemia. J Pediatr Endocrinol Metab 2006;19:471-80. 36. Chan YL, Pang LM, Chik KW, et al. Patterns of bone diseases in transfusiondependent homozygous thalassemia major: predominance of osteoporosis and desferrioxamine-induced bone dysplasia. Pediatr Radiol 2002;32:492-7. 37. Olivieri NF, Brittenham GM. Ironchelating therapy and the treatment of thalassemia. Blood 1997;89:739-61. [Erratum, Blood 1997;89:2621.] 38. Beau-Salinas F, Guitteny MA, Donadieu J, Jonville-Bera AP, Autret-Leca E. High doses of deferiprone may be associated with cerebellar syndrome. BMJ 2009; 338:a2319. 39. Leitch HA. Controversies surrounding iron chelation therapy for MDS. Blood Rev 2010 October 26 (Epub ahead of print). 40. Novartis Pharmaceuticals. Myelodysplastic syndromes (MDS) event free survival with iron chelation therapy study

(TELESTO). (ClinicalTrials.gov identifier no. NCT00940602.) (http://www.clinicaltrials .gov/ct2/show/NCT00940602?term=telesto &rank=1.) 41. Vichinsky E, Butensky E, Fung E, et al. Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia. Am J Hematol 2005;80:70-4. 42. Walter PB, Fung EB, Killilea DW, et al. Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. Br J Haematol 2006;135:254-63. 43. Borgna-Pignatti C, Vergine G, Lombardo T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol 2004;124:114-7. 44. Ko C, Siddaiah N, Berger J, et al. Prevalence of hepatic iron overload and association with hepatocellular cancer in endstage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 2007;27:1394-401. 45. Division of Blood Diseases and Resources NHLBI. The management of sickle cell disease. Bethesda, MD: National

Heart, Lung, and Blood Institute, 2002. (http://www.nhlbi.nih.gov/health/prof/ blood/sickle/sc_mngt.pdf.) 46. Standards for the clinical care of adults with sickle cell disease in the UK. London: Sickle Cell Society, 2008. (http://www .sicklecellsociety.org/pdf/CareBook.pdf.) 47. Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica 2008; 93:741-52. 48. Vlachos A, Ball S, Dahl N, et al. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol 2008;142:859-76. 49. Marsh JC, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2009;147:43-70. 50. Bennett JM. Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol 2008;83:858-61. Copyright © 2011 Massachusetts Medical Society.

SPECIALTIES AND TOPICS AT NEJM.ORG

Specialty pages at the Journal’s Web site (NEJM.org) feature articles in cardiology, endocrinology, genetics, infectious disease, nephrology, pediatrics, and many other medical specialties. These pages, along with collections of articles on clinical and nonclinical topics, offer links to interactive and multimedia content and feature recently published articles as well as material from the NEJM archive (1812–1989).

156 BACK to TOC

n engl j med 364;2

nejm.org

january 13, 2011

62

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical therapeutics

Bisphosphonates for Osteoporosis Murray J. Favus, M.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

A 67-year-old woman was referred by her primary care physician for treatment of osteoporosis and progressive bone loss. One year before the visit, the patient had discontinued hormone-replacement therapy. She had subsequently begun to experience midback pain and lost 3.8 cm (1.5 in.) in height. A dual-energy x-ray absorptiometry (DXA) scan showed bone mineral density T scores of −3.1 at the lumbar spine and −2.8 at the femoral neck, which are consistent with a diagnosis of osteoporosis. One year later, a second scan showed a further decrease of 5.4% in bone mineral density at the lumbar spine (Fig. 1), as well as a compression fracture of the 11th thoracic vertebra (Fig. 2). Results of blood and urine tests ruled out the common secondary causes of osteoporosis. To prevent additional vertebral fractures, oral bisphosphonate therapy was recommended.

The Cl inic a l Probl em Osteoporosis is a systemic skeletal disorder that is characterized by the loss of bone tissue, disruption of bone architecture, and bone fragility, leading to an increased risk of fractures.1 Bone loss and low bone mass are asymptomatic until fractures occur. Estrogen deficiency after menopause is the most common cause of osteoporosis, but secondary causes2 must be ruled out before treatment is undertaken (Table 1). Osteoporosis is the most common metabolic bone disease and the most common cause of fractures in older adults in the United States. Ten million people in the United States have osteoporosis, and an additional 33 million people have low bone mass (osteopenia) and are at increased risk for fractures.4,5 More than 2 million fractures occur each year as a result of osteoporosis or osteopenia, including 300,000 hip fractures, 547,000 vertebral fractures, and 135,000 pelvic fractures. Postmenopausal white women have a 40% lifetime risk of at least one osteoporotic fracture.4 Osteoporotic hip fractures are associated with the highest morbidity and mortality. Up to 50% of patients with such fractures have permanently impaired mobility, and 25% lose the skills necessary to live independently.6,7 A recent meta-analysis showed that among older men and women, the rate of death from any cause is increased by a factor of 5 to 8 during the first 3 months after a hip fracture.8

From the Department of Medicine, University of Chicago, Chicago. Address reprint requests to Dr. Favus at the Department of Medicine, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, or at [email protected]. N Engl J Med 2010;363:2027-35. Copyright © 2010 Massachusetts Medical Society.

Pathoph ysiol o gy a nd Effec t of Ther a py Estrogen deficiency due to either spontaneous or surgical menopause9 increases the production by bone marrow stromal cells and osteoblasts of the receptor activator of nuclear factor κB ligand (RANKL), which, in turn, increases the binding of RANKL10 to the osteoclast cell-surface receptor nuclear factor κB (RANK). Increased n engl j med 363;21 BACK to TOC

nejm.org

november 18, 2010

2027

63

n e w e ng l a n d j o u r na l

The

binding of RANKL to RANK initiates the proliferation of osteoclast precursors and their differentiation into mature osteoclasts.10-12 The expanded osteoclast population increases bone turnover and the depth and number of resorption pits (Fig. 3). Later in the course of menopause, agerelated bone loss and accompanying changes in the properties of bone material exacerbate the bone loss and fragility associated with estrogen deficiency.10 At the microscopical level, the increased number and activity of osteoclasts disrupt trabecular connectivity and increase cortical porosity.9,11 Resorption pits are incompletely filled, since osteoblastic new bone formation does not keep pace with rates of bone resorption.10 Reduced bone density and bone quality compromise the mechanical weight-bearing properties of the skeleton and confer a predisposition to fractures occurring either spontaneously or when falls cause mechanical overload.11 Bisphosphonates reduce fractures by suppressing bone resorption.12,13 The molecular structure of the bisphosphonates (P-C-P) is analogous to that of the naturally occurring pyrophosphates (P-O-P), with two short side chains (R1 and R2) attached to the C core. Bisphosphonates

Pyrophosphates

R1 O OH

P

O C

OH

P OH

O OH

OH

P OH

O O

P

OH

OH

R2

The R1 side chain determines bone-binding affinity, and the R2 side chain determines antiresorption potency. Bisphosphonates that are approved for use in the United States (alendronate, ibandronate, risedronate, and zoledronate) have nitrogen-containing R2 side chains14 that enhance antiresorptive and antifracture potency. Variations in the structure of the side chains determine the strength with which the biphosphonate binds to bone, the distribution through bone, and the amount of time it remains in the bone after treatment is discontinued.15 In bone, bisphosphonates accumulate in the hydroxyapatite mineral phase, and the concentration of the bisphosphonates is increased by a factor of 8 at sites of active bone resorption.14,16,17 The bound nitrogen-containing bisphosphonates enter osteoclasts and reduce resorption through inhi2028 BACK to TOC

n engl j med 363;21

of

m e dic i n e

bition of farnesyl pyrophosphate synthase (FPPS), an enzyme in the mevalonate-to-cholesterol pathway.18,19 Inhibition of FPPS interferes with isoprenylation of small guanosine triphosphatases (GTPases) at the ruffled border of the osteoclasts and disrupts the attachment of osteoclasts to the bone surface, which stops resorption and promotes early cell death.16,20

Cl inic a l E v idence Three of the most important phase 3 trials of the use of bisphosphonates for the treatment of osteoporosis are described below. In these trials, a reduction in the rate of fractures was the primary end point, and increases in bone mineral density at the lumbar spine and a reduction in markers of bone turnover were secondary end points. In the Fracture Intervention Trial (FIT),21 2027 postmenopausal women at high risk for fracture, with low bone density at the femoral neck and at least one vertebral fracture, were randomly assigned to either placebo or alendronate, at a dose of 5 mg daily for 24 months, followed by 10 mg daily for the final 12 months of the trial. At 36 months, 15.0% of the women who received the placebo and 8.0% of the women who were treated with alendronate had sustained one or more new vertebral fractures, as assessed by radiography (P = 0.001). New hip fractures occurred in 2.1% of the women in the placebo group and 1.1% of the women in the alendronate group (P = 0.05). In the Vertebral Efficacy with Risedronate Therapy (VERT) trial,22 2458 postmenopausal women with at least one vertebral fracture and a T score at the lumbar spine of –2.0 or less were randomly assigned to either placebo or risedronate at a dose of 2.5 mg or 5 mg daily. During the course of the trial, data from other studies suggested that a dose of 2.5 mg was less effective than a dose of 5 mg; therefore the 2.5-mg group was discontinued. In the two remaining groups, the rate of new vertebral fractures after 3 years was 11.3% among subjects treated with 5 mg of risedronate daily, as compared with 16.3% in the placebo group (P = 0.003). In a subsequent trial, risedronate was shown to be effective in reducing the rate of hip fractures as well.23 The efficacy of zoledronic acid in the treatment of osteoporosis was evaluated in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly trial (HORIZON; ClinicalTrials .gov number, NCT00049829).24 In this trial,

nejm.org

november 18, 2010

64

clinical ther apeutics

B Reference: L1–L4

BMD (g/cm2)

1.44

2

Normal

1.32

1

1.19

0

1.07

−1

0.95 Osteopenia

−2

0.82

−3

0.70

−4 Osteoporosis

0.58 0.00

0

−5

Young-Adult T Score

A Anteroposterior Spine Bone Density

Region L1 L2 L3 L4 L1–L4

BMD

g/cm2 0.805 0.743 0.706 0.786 0.758

Young-Adult

Age-Matched

% T score 71 −2.7 61 −3.9 59 −4.1 66 −3.4 64 −3.5

% z score 81 −1.5 70 −2.7 67 −2.9 75 −2.2 73 −2.3

20 30 40 50 60 70 80 90 100

Age (yr)

C Trend: L1–L4 Change from Baseline (%)

2 1 0 −1 −2 −3 −4 −5 −6

0

65

66

Date Measured

Age

04/13/2005 05/14/2004

yr 66.7 65.8

BMD

g/cm2 0.758 0.798

Change from Baseline % %/yr −4.9 −5.4 Baseline Baseline

67

Age (yr)

Figure 1. Dual-Energy X-Ray Absorptiometry (DXA) Scan of the Lumbar Spine. Bone mineral density (BMD) was measured with the use of DXA in the 67-year-old woman described in the vignette (Panel A). The woman’s BMD is analyzed from lumbar spine L1 through L4 (Panel B). The BMD (rectangle) meets World Health Organization criteria for osteoporosis (T score of less than −2.5), as shown in the reference graph. The T score is the standard-deviation change in BMD from the theoretical peak bone mass this woman had in her mid-20s to the current BMD. The z score is the standard-deviation difference between the mean BMD of a population matched for age, race, and sex and the patient’s current BMD. The current study (Panel C) shows that her BMD (solid rectangle) is 5.4% lower than that indicated by the previous scan (open rectangle). A clinically significant change is a change of more than 2.8%.

7765 postmenopausal women with osteoporosis (T score of –2.5 or less or –1.5 or less with evidence of vertebral fracture) were randomly assigned to either zoledronic acid, at a dose of 5 mg administered at baseline, 12 months, and 24 months, or placebo. At 36 months, the absolute rate of new vertebral fractures as assessed by standard radiography was 3.3% in the zoledronic acid group, as compared with 10.9% in the placebo group (P<0.001). There were 52 new hip fractures (1.4%) in the zoledronic acid group, as compared with 88 (2.5%) in the placebo group (P<0.001). Randomized, placebo-controlled trials of other oral bisphosphonates, including ibandronate,25 clodronate,26 and etidronate,27 have shown that these drugs also have efficacy in reducing the risk of new vertebral fractures. However, because these n engl j med 363;21 BACK to TOC

trials were not powered to show efficacy for the treatment of hip fractures, the clinical usefulness of these agents for preventing hip fractures is currently unknown. Pamidronate has been used to treat a variety of bone diseases in children and adults. However, no randomized, placebo-controlled trial has been performed with sufficient power to assess the efficacy of the drug for the treatment of hip fracture in women with postmenopausal osteoporosis.

Cl inic a l Use All postmenopausal women with measurements of bone mineral density at either the spine or the hip that meet World Health Organization (WHO) criteria for osteoporosis (T score of less than −2.5)

nejm.org

november 18, 2010

2029

65

The

A

B

n e w e ng l a n d j o u r na l

T4

T6

T11 T12

L4

Figure 2. Dual-Energy X-Ray Absorptiometry (DXA) Scan of the Thoracic and Lumbar Spine. Vertebral deformation at the thoracic and lumbar spine was assessed in the patient described in the vignette, with the use of the vertebral-fracture assessment on the same DXA scanner as that used for the measurement of bone mineral density in Figure 1. Panel A shows thoracic kyphosis due to a 75% loss of height of T11. For comparison, Panel B shows a normal vertebral-fracture assessment in a 58-year-old woman without osteoporosis.

should receive long-term therapy with an agent that has been proven to prevent fractures. In contrast, it may be difficult to decide whom to treat among the large number of patients who have osteopenia (T score of −1.0 to −2.5). Many postmenopausal women in whom fractures develop have osteopenia rather than osteoporosis; in these women, the fractures may occur because of the contributions of risk factors that are independent of bone mineral density.28 I often use the WHO Fracture Risk Assessment Tool (FRAX; www.sheffield.ac .uk/FRAX/) to assist in making treatment decisions. FRAX is a calculator algorithm that incorporates risk factors with measurements of bone mineral density, generating a quantitative estimate of the 10-year probability of a major osteoporotic fracture (hip, vertebral, humerus, or fore2030 BACK to TOC

n engl j med 363;21

of

m e dic i n e

arm) or of a hip fracture alone in patients who have not yet begun therapy. In general, I initiate pharmacologic treatment in patients who have a 10-year probability of a hip fracture that exceeds 3% or a 10-year probability of a major osteoporotic fracture that exceeds 20%.29 In addition to weighing the objective evidence, I consider the patient’s lifestyle. I am more likely to initiate treatment for low bone mass in a patient who wishes to continue participating in sports or recreational activities such as cycling, tennis, skiing, and running. Such patients are likely to have a greater risk of falls and fractures than are sedentary patients. A major consideration in selecting therapy is the risk of hip fracture. All treatments that have been approved by the Food and Drug Administration (FDA) have shown efficacy in reducing the rates of vertebral fracture, but not all have been clearly shown to reduce the rate of hip fractures. If bone mineral density at the hip is low, I usually select an agent for which there are trials showing efficacy in preventing hip fractures. I recommend either alendronate or risedronate if the patient is capable of taking an oral agent. If the patient cannot tolerate oral bisphosphonates, then I may select intravenous zoledronic acid. If bone density at the hip is normal or only mildly reduced, I may select oral or intravenous ibandronate, which has not been shown to be effective in reducing the risk of hip fracture. Alternatives to bisphosphonates include the anabolic agent teriparatide (parathyroid hormone 1-34), which reduces the risk of vertebral and nonvertebral fractures but, among subjects in a large, pivotal trial, did not reduce the risk of hip fracture alone.30 Teriparatide is also more expensive than the bisphosphonates and requires daily subcutaneous injection. Estrogen is effective in decreasing the risk of vertebral and hip fractures in postmenopausal women31 but may confer increased risks of breast cancer and cardiovascular disease. Raloxifene is an oral selective estrogenreceptor modulator (SERM) that decreases the risk of vertebral fractures by 40 to 49%, but it may not reduce the risk of nonvertebral fractures.32 Calcitonin administered by means of a nasal spray is an antiresorptive agent that has limited efficacy in reducing the risk of vertebral fractures and lacks efficacy in preventing hip fracture.33 Oral bisphosphonates must be taken after an overnight fast either once weekly (alendronate at a dose of 70 mg or risedronate at a dose of 35 mg),

nejm.org

november 18, 2010

66

clinical ther apeutics

once monthly (ibandronate at a dose of 150 mg or risedronate at a dose of 150 mg), or on 2 consecutive days once monthly (risedronate at a dose of 75 mg). The tablets are taken with 6 to 8 oz of tap water. The patient should remain upright for at least 30 minutes after taking the drug to minimize gastroesophageal reflux. To optimize absorption, food, medications, and liquids other than tap or filtered water should be avoided for at least 30 to 45 minutes to allow for dissolution of the tablet and gastric emptying. Intravenous bisphosphonates include ibandronate (at a dose of 3 mg every 3 months) and zoledronic acid (at a dose of 5 mg every 12 months). They are usually administered in an outpatient facility that has the resources for administering and monitoring intravenous infusions. Oral and intravenous bisphosphonates are contraindicated in patients who have had a prior allergic reaction to a bisphosphonate or who have an estimated creatinine clearance of 35 ml per minute or less, vitamin D depletion (serum 25hydroxyvitamin D levels should be more than 30 ng per milliliter before initiating bisphosphonates), osteomalacia (vitamin D depletion or deficiency causing defective mineralization), or hypocalcemia. Oral bisphosphonates are contraindicated in patients who have impaired swallowing or esophageal disorders such as achalasia, esophageal varices, or severe gastroesophageal reflux or who are unable to sit up for at least 30 minutes after taking the medication. There are no known interactions between bisphosphonates and other medications. After initiating bisphosphonate therapy, I typically reevaluate the patient in 1 month to assess tolerance and thereafter at 3 months, 6 months, and 1 year. At 3 months and 6 months, I obtain measurements of bone-turnover markers, such as osteocalcin or serum C-terminal telopeptide of type 1 collagen (CTX). At 1 year, and every 2 years thereafter, I repeat the assessment of bone mineral density with the use of DXA. An increase in bone mineral density is not required for a therapy to be considered effective, but a substantial decline in bone mineral density requires further evaluation. Poor adherence to therapy should be suspected if the patient has an otherwise unexplained decline in bone mineral density, a new fracture, continued bone loss, or high rates of bone turnover that persist after 12 months of therapy. When I suspect poor adherence, I ask the patient whethn engl j med 363;21 BACK to TOC

Table 1. Common Secondary Causes of Osteoporosis and Laboratory Evaluations.* Possible Cause of Osteoporosis

Laboratory Test

Vitamin D deficiency

Measurement of serum 25-hydroxyvitamin D level

Primary hyperparathyroidism

Measurement of fasting serum calcium and parathyroid hormone levels

Celiac disease

Measurement of serum tissue transglutaminase, total IgA, and gliadin levels

Idiopathic hypercalciuria

Measurement of 24-hour urine calcium excretion after discontinuation of calcium supplements

Hyperthyroidism

Measurement of serum thyrotropin and total thyroxine levels

Myeloma

Serum and urine immunoelectrophoresis

* Additional information regarding secondary causes of osteoporosis can be found in Tannenbaum et al.2 and Jamal et al.3

er he or she has had any side effects and attempt to document the patient’s use of the drug by measuring markers of bone turnover. Evidence of treatment failure in a patient with good adherence to an oral bisphosphonate regimen requires a change to either intravenous zoledronic acid or another class of medications such as anabolic agents (e.g., teriparatide). The optimal duration of bisphosphonate therapy remains unresolved. However, on the basis of available data, it seems likely that discontinuing therapy after 5 years, at least for a temporary drug holiday, is not harmful and may be advantageous.34 Patients with mildly reduced bone mineral density may be the most suitable candidates for a 1-year to 2-year drug holiday, because the risk of fracture will be low if bone loss occurs while the person is not receiving therapy. Generic alendronate was introduced in 2008 and is less expensive than other agents, with cost ranging from $4 to $40 per month. The cost of risedronate ranges from $60 to $120 per month; generic risedronate will become available in the near future. The cost of oral ibandronate ranges from $90 to $130 per month. One infusion of zoledronic acid is estimated to cost $1,300; intravenous ibandronate costs about $1,300 per year.

A dv er se Effec t s An acute-phase reaction characterized by fever, myalgia, bone pain, and weakness35 occurs in 20% of patients after an initial intravenous infusion of

nejm.org

november 18, 2010

2031

67

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Figure 3. Cellular Elements Involved in Postmenopausal Trabecular Bone Turnover before and during Bisphosphonate Therapy. Panel A shows the untreated postmenopausal state, in which osteoclast-mediated bone resorption occurs at a high rate, exceeding osteoblast-driven bone formation and leading to net bone loss. Panel B shows the initial events associated with bisphosphonate therapy, including the localization and concentration of bisphosphonates in bone through binding to sites of active bone resorption. Panel C shows the effects of bisphosphonates after 6 months of therapy. The number of osteoclasts has decreased owing to early apoptosis. As a result, bone resorption is decreased, and osteoblasts and bone formation are also decreased. The bisphosphonate concentration is reduced around previous resorption pits. A lower steady-state rate of bone turnover, similar to premenopausal rates, is established.

bisphosphonates and in a very small number of patients during oral therapy. Erosive esophagitis, ulceration, and bleeding have been associated with daily oral alendronate or risedronate therapy but occur rarely with current (nondaily) regimens. Heartburn, chest pain, hoarseness, and vocal-cord irritation36 may occur with weekly (alendronate or risedronate) or monthly (ibandronate or risedronate) therapy. A relationship between esophageal cancer and oral bisphosphonates, suggested on the basis of a small number of case reports, has not been substantiated.37 Transient renal toxic effects can occur after rapid intravenous administration.38,39 Slow infusion rates (no less than 15 minutes) and lower doses minimize peak drug serum levels and the risk of renal damage. Bisphosphonates are not recommended when creatinine clearance is less than 35 ml per minute.38 Dose reductions may be required for patients with stage III chronic kidney disease (as defined by an estimated glomerular filtration rate between 59 and 30 ml per minute per 1.73 m2 of body-surface area). Mild transient hypocalcemia is a rare complication of intrave-

2032 BACK to TOC

n engl j med 363;21

nous bisphosphonate therapy that may require an interruption in treatment,40 but once the serum calcium level has returned to the normal range, therapy can be resumed. Severe hypocalcemia is a contraindication for continued administration. Osteonecrosis of the jaw is a rare but serious complication of long-term bisphosphonate therapy that may appear either spontaneously or after an oral surgical procedure. Exposed mandibular or maxillary dead bone, nonhealing mucosa, and chronic infection may persist for weeks to years.41-43 More than 95% of cases of osteonecrosis of the jaw occur in patients who are receiving zoledronic acid or pamidronate for the treatment of myeloma, breast cancer, or other bone cancers at doses 10 to 12 times as high as those used for the treatment of osteoporosis.42,44 Case reports suggest that atypical femoral fractures (in the subtrochanteric and mid-diaphyseal portions of the femur) may be more common during bisphosphonate therapy.37,45 Recent data from a cross-sectional study of femur fractures recorded in the Danish national health registry46 and a pooled post hoc analysis of the trials that

nejm.org

november 18, 2010

68

clinical ther apeutics

studied the effects of alendronate and zoledronic acid on the incidence of fractures47 showed no relationship between the use of bisphosphonates and atypical femur fractures. However, these reports are not definitive, and the possibility of a relationship continues to be investigated.

A r e a s of Uncer ta in t y The optimal duration of bisphosphonate therapy remains uncertain. Recent retrospective studies and case reports suggest that long-term bisphosphonate therapy may result in the suppression of bone turnover and confer a predisposition to increased bone fragility, with an increased risk for atypical femur fractures.37 Markers of bone turnover underestimate the extent of suppressed bone formation,12,48 and their usefulness in monitoring long-term safety may therefore be limited. An accumulation of microcracks in bone-biopsy specimens was found in one study of patients receiving alendronate therapy when the analysis was adjusted for potential confounders such as age and bone mineral density at the femoral neck49 but not in another study of long-term alendronate therapy (mean, 6.5 years).50 Prospective studies are needed to estimate the long-term risk of side effects associated with bisphosphonate therapy, including osteonecrosis of the jaw and atypical femur fractures. Until a better estimate of the risk of these complications emerges, one must balance the long-term risk of these uncommon complications against the known efficacy of the agents in reducing rates of common osteoporotic fractures. It is also not known whether these complications can be minimized by periodic rotation of treatment from one class of agents to another.

Gynecologists,54 and the North American Menopause Society6 agree that persons with osteoporosis (bone mineral density T score of less than −2.5) or low bone mass and hip or vertebral fractures should receive treatment. These guidelines also suggest that persons with T scores higher than −1.5 should not receive therapy unless there is clinical evidence of osteoporosis. Thus, controversy remains regarding the indications for treatment among people with mild reductions in bone density. The guidelines include oral bisphosphonates among the first-line therapies for osteoporosis but do not name specific FDA-approved drugs.

R ec om mendat ions

The patient described in the vignette is at high risk for additional fractures on the basis of her history of vertebral compression fracture and a bone mineral density T score in the osteoporosis range. A drug with efficacy in preventing hip and spinal fractures is required, and I would treat the patient with either alendronate or risedronate for 5 years. After 5 years of treatment, I would decide whether a drug holiday might be appropriate for this patient, taking into consideration the fact that she is at high risk for recurrent fracture. I would suggest a calcium intake of 1200 mg per day from dietary sources, with calcium supplements as a second choice. I would also measure the serum 25-hydroxyvitamin D level and select an appropriate level of vitamin D intake, encourage regular weight-bearing exercise, and emphasize the importance of adherence to procedures for taking the medication. I would use measurements of bone mineral density to monitor her response to therapy 12 months after treatment is initiated and then at 24-month intervals as needed. A decline in bone mass or another low-trauma Guidel ine s fracture would require careful review of the treatGuidelines for the management of osteoporosis ment plan and possible selection of another agent. published by the National Osteoporosis FoundaDr. Favus reports receiving honoraria and consulting fees tion,51 the American Association of Clinical En- from CVS Caremark and Amgen. No other potential conflict of interest relevant to this article was reported. docrinologists,52 the American College of PhysiDisclosure forms provided by the author are available with the cians,53 the American College of Obstetricians and full text of this article at NEJM.org. References 1. NIH Consensus Development Panel

on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-95. 2. Tannenbaum C, Clark J, Schwartzman

K, et al. Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab 2002;87:4431-7. 3. Jamal SA, Leiter RE, Bayoumi AM,

n engl j med 363;21 BACK to TOC

nejm.org

Bauer DC, Cummings SR. Clinical utility of laboratory testing in women with osteoporosis. Osteoporos Int 2005;16:534-40. 4. Bone health and osteoporosis: a report of the Surgeon General. Rockville,

november 18, 2010

2033

69

The

n e w e ng l a n d j o u r na l

MD: Department of Health and Human Services, 2004. 5. Advisory Group on Osteoporosis. Report. London: Department of Health, 1994. 6. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010;17:25-54. 7. Cooper C, Atkinson EJ, Jacobsen SJ, O’Fallon WM, Melton LJ III. Populationbased study of survival after osteoporotic fractures. Am J Epidemiol 1993;137:1001-5. 8. Haentjens P, Magaziner JS, ColónEmeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med 2010; 152:380-90. 9. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 2005;115:3318-25. 10. Khosla S. Pathogenesis of osteoporosis. In: Robertson RP, ed. Translational endocrinology & metabolism: osteoporosis update. Chevy Chase, MD: The Endocrine Society, 2010:55-86. (http://www .endojournals.org/translational/issues/ osteoporosis.pdf.) 11. Seeman E, Delmas PD. Bone quality — the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250-61. 12. Hofbauer LC, Schoppet M. Bone biology underlying therapeutic approaches. In: Robertson RP, ed. Translational endocrinology & metabolism: osteoporosis update. Chevy Chase, MD: The Endocrine Society, 2010:117-48. (http://www.endojournals.org/ translational/issues/osteoporosis.pdf.) 13. Rodan G, Reszka A, Golub E, Rizzoli R. Bone safety of long-term bisphosphonate treatment. Curr Med Res Opin 2004; 20:1291-300. 14. McClung MR. Bisphosphonates. Endocrinol Metab Clin North Am 2003;32: 253-71. 15. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008;19:73359. 16. Sato M, Grasser W, Endo N, et al. Bisphosphonate action: alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 1991; 88:2095-105. 17. Masarachia P, Weinreb M, Balena R, Rodan GA. Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat and mouse bones. Bone 1996;19: 281-90. 18. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan GA. Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys 2000;373:231-41. 19. Fisher JE, Rogers MJ, Halasy JM, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the meval-

2034 BACK to TOC

of

m e dic i n e

onate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999;96:133-8. 20. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell RG, Rogers MJ. Nitrogen-containing bisphosphonates inhibit mevalonate pathway and prevent posttranslational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 1998;13:581-9. 21. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348:1535-41. 22. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 1999;282:1344-52. 23. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:333-40. 24. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-22. 25. Chestnut CH III, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004;19:1241-9. 26. McCloskey E, Selby P, Davies M, et al. Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a doubleblind, placebo-controlled 3-year study. J Bone Miner Res 2004;19:728-36. 27. Wells GA, Cranney A, Peterson J, et al. Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008;1:CD003376. 28. Cranney A, Tugwell P, Adachi J, et al. Meta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:517-23. 29. Dawson-Hughes B, Looker AC, Tosteson AN, Johansson H, Kanis JA, Melton LJ III. The potential impact of new National Osteoporosis Foundation guidance on treatment patterns. Osteoporos Int 2010; 21:41-52. 30. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41. 31. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003;290:1729-38. 32. Cranney A, Tugwell P, Zytaruk N, et al.

n engl j med 363;21

nejm.org

Meta-analyses of therapies for postmenopausal osteoporosis. IV. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:524-8. 33. Cranney A, Tugwell P, Zytaruk N, et al. Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:540-51. 34. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006;296:2927-38. 35. Adami S, Bhalla AK, Dorizzi R, et al. The acute-phase response after bisphosphonate administration. Calcif Tissue Int 1987;41:326-31. 36. Ribeiro A, DeVault KR, Wolfe JT III, Stark ME. Alendronate-associated esophagitis: endoscopic and pathologic features. Gastrointest Endosc 1998;47:525-8. 37. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 2010;95:1555-65. 38. Lewiecki EM, Miller PD. Renal safety of intravenous bisphosphonates in the treatment of osteoporosis. Expert Opin Drug Saf 2007;6:663-72. 39. Boonen S, Sellmeyer DE, Lippuner K, et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney Int 2008;74:641-8. 40. Maalouf NM, Heller HJ, Odvina CV, Kim PJ, Sakhaee K. Bisphosphonateinduced hypocalcemia: report of 3 cases and review of the literature. Endocr Pract 2006;12:48-53. 41. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34. 42. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:147991. 43. Bilezikian JP. osteonecrosis of the jaw — do bisphosphonates pose a risk? N Engl J Med 2006;355:2278-81. 44. Woo SB, Hellstein JW, Kalmar JR. Systemic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144:753-61. [Erratum, Ann Intern Med 2006;145:235.] 45. Shane E. Evolving data about subtrochanteric fractures and bisphosphonates. N Engl J Med 2010;362:1825-7. 46. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 2009;24:1095102.

november 18, 2010

70

clinical ther apeutics 47. Black DM, Kelly MP, Genant HK, et al.

Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 2010;362:1761-71. 48. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-301. 49. Stepan JJ, Burr DB, Pavo I, et al. Low bone mineral density is associated with bone microdamage accumulation in postmenopausal women with osteoporosis. Bone 2007;41:378-85. 50. Chapurlat RD, Arlot M, Burt-Pichat B,

et al. Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res 2007; 22:1502-9. [Erratum, J Bone Miner Res 2008;23:1153.] 51. Clinician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation, 2008. 52. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporo-

sis: 2001 edition, with selected updates for 2003. Endocr Pract 2003;9:544-64. [Erratum, Endocr Pract 2004;10:90.] 53. Qaseem A, Snow V, Shekelle P, Hopkins R Jr, Forciea MA, Owens DK. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2008;149:404-15. 54. American College of Obstetricians and Gynecologists Women’s Health Care Physicians. Osteoporosis. Obstet Gynecol 2004;104:Suppl:66S-76S. Copyright © 2010 Massachusetts Medical Society.

JOURNAL ARCHIVE AT NEJM.ORG

Every issue of the Journal is now available at NEJM.org, beginning with the first article published in January 1812. The entire archive is fully searchable, and browsing of titles and tables of contents is easy and available to all. Individual subscribers are entitled to free 24-hour access to 50 archive articles per year. Access to content in the archive is available on a per-article basis and is also being provided through many institutional subscriptions.

n engl j med 363;21 BACK to TOC

nejm.org

november 18, 2010

2035

71

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical therapeutics

Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration James C. Folk, M.D., and Edwin M. Stone, M.D., Ph.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors’ clinical recommendations.

A

n ophthalmologist refers a 66-year-old man for consultation with a retinal specialist. The patient has had blurred and distorted vision in his right eye for the past 2 weeks. Examination reveals drusen beneath the retina in both eyes. His right eye also has a subretinal hemorrhage just temporal to the center of the macula, as well as subretinal fluid (Fig. 1A). A fluorescein angiogram shows subfoveal neovascularization (Fig. 1B). Optical coherence tomography reveals fluid beneath and within the layers of the retina (Fig. 1C). The retinal specialist diagnoses neovascular age-related macular degeneration (AMD) and recommends intraocular injections of ranibizumab.

The Cl inic a l Probl em From the Department of Ophthalmology and Visual Sciences (J.C.F., E.M.S.) and the Howard Hughes Medical Institute (E.M.S.), University of Iowa Carver College of Medicine, Iowa City. Address reprint requests to Dr. Stone at the Department of Ophthalmology and Visual Sciences, University of Iowa, 375 Newton Rd., 4111 MERF, Iowa City, IA 52242, or at [email protected]. N Engl J Med 2010;363:1648-55. Copyright © 2010 Massachusetts Medical Society.

AMD is the leading cause of blindness in the United States. All patients initially have a form of the disorder called dry AMD, characterized by the development and accumulation of drusen, which are localized deposits of extracellular material that appear as yellow spots in the retina on ophthalmoscopy. As dry AMD progresses, focal areas of atrophy of the retinal pigment epithelium appear. Wet, or neovascular, AMD then develops in some patients with established dry AMD. Wet AMD is characterized by the growth of abnormal vessels beneath the retinal pigment epithelium and between the retinal pigment epithelium and the overlying retina. The Eye Diseases Prevalence Research Group estimates that in the year 2000, a total of 1.2 million residents of the United States had neovascular AMD, 973,000 had dry AMD with atrophy of the retinal pigment epithelium, and 7.3 million had large drusen (≥125 μm in diameter) and were therefore at increased risk for atrophy or neovascularization. The same group estimates that these numbers will increase by more than 50% by the year 2020 as a result of aging of the population.1 Many patients with AMD have moderate vision loss, between 20/50 and 20/100 in the better eye. These patients have quality-of-life measurements that are 32% below normal, similar to those among patients with severe angina or hip fractures.2 A person with very severe neovascular disease may have 20/800 vision in the better eye and will have a reduction in quality of life of 60%, similar to that of a patient who is bedridden with a catastrophic stroke.2 AMD is estimated to cost the United States $30 billion a year.2

Pathoph ysiol o gy a nd Effec t of Ther a py Despite decades of intensive investigation, the molecular mechanisms underlying the pathogenesis of AMD are still obscure. It is likely that in most patients, a num1648 BACK to TOC

n engl j med 363;17

nejm.org

october 21, 2010

72

clinical ther apeutics

ber of genetic factors3-12 and environmental factors (e.g., smoking)13 contribute incrementally to the development of the disease. Genomewide association studies of patients with AMD and control subjects have shown that the largest single genetic factor contributing to AMD is a variant of codon 402 in the gene encoding complement factor H. This observation strongly supports the longheld belief that the immune system is an important contributor to AMD.3-5,14,15 The photoreceptor cells of the retina depend on the underlying retinal pigment epithelium for phagocytosis of their continuously renewed outer segments, as well as for reisomerization of their light-sensitive, vitamin-A–based chromophore16 (Fig. 2A). Both the photoreceptors and the retinal pigment epithelium depend on the choriocapillaris for oxygen, nutrients, and removal of metabolic waste products.17 In patients with AMD, drusen form between the retinal pigment epithelium and Bruch’s membrane. In some patients with AMD, there is apoptotic atrophy of the retinal pigment epithelium and choriocapillaris in the macula (the central region of the fundus).14,18 Neovascularization occurs in about 10% of patients with AMD for reasons that are still unknown but that may be due in part to injury or degeneration of Bruch’s membrane. This complication is responsible for most (perhaps as much as 90%) of the severe vision loss caused by this disease.19 In neovascular AMD, abnormal capillaries grow from the choroid through Bruch’s membrane and into spaces beneath the retinal pigment epithelium and retina (Fig. 2B). As these vessels proliferate, they leak serum or blood, which causes swelling beneath and within the retina and loss of visual acuity. If left unchecked, the vessels eventually cause a subretinal fibrotic scar and permanent loss of vision.20,21 Vascular endothelial growth factor A (VEGF-A) is closely associated with the growth and permeability of neovascular vessels.22-26 Ranibizumab is the Fab fragment of a recombinant, humanized, monoclonal antibody that binds to all forms of VEGF-A. The inhibition of VEGF-A reduces the permeability of the neovascular vessels, as well as their further growth.27 In tumors, long-term VEGF blockade results in vessel maturation and remodeling, decreased numbers of endothelial cells, increased coverage of the vessel wall by pericytes, and a more stable, nonleaking vessel28 (Fig. 2C). When vessel growth n engl j med 363;17 BACK to TOC

A

B

C

Figure 1. Clinical Characteristics of Neovascular Age-Related Macular Degeneration. A color photograph of the right eye at presentation shows scattered yellow drusen, multilayered hemorrhage, and serous fluid in the macula (Panel A). A latephase fluorescein angiogram of the right eye shows hyperfluorescence of occult choroidal neovascularization involving the center of the macula (Panel B). The dark area to the left is caused by hemorrhage, which blocks the underlying fluorescence. A time-domain optical coherence tomogram taken through the center of the right macula reveals fluid (arrow) within and beneath the retina (Panel C).

and leakage are stopped, the retinal swelling usually diminishes and vision can stabilize or improve. Studies in primate models have shown that when ranibizumab is injected into the eye, effective retinal concentrations are maintained for about 1 month.27

nejm.org

october 21, 2010

1649

73

The

A

n e w e ng l a n d j o u r na l

Normal Retina

Photoreceptors

Retina

Retinal pigment epithelium

Choroid

B

Choriocapillaris

Bruch’s membrane

Neovascular AMD

Cl inic a l E v idence

Fluid accumulation beneath the retina

VEGF-A VEGF-A receptor

C

New bloodvessel growth

Ranibizumab Therapy Reattachment of photoreceptors to retinal pigment epithelium

Ranibizumab

Shrinkage and maturation of vessels

1650 BACK to TOC

m e dic i n e

Figure 2. Therapeutic Action of Ranibizumab. In the normal retina, the retinal pigment epithelium is attached to Bruch’s membrane and the choroid supplies oxygen and nutrients to the outer layers of the retina (Panel A). In patients with neovascular age-related macular degeneration (AMD), new blood vessels grow from choroidal capillaries through Bruch’s membrane and proliferate beneath the retinal pigment epithelium (Panel B). Vascular endothelial growth factor A (VEGF-A) binds with its receptor and promotes vascular growth and leakage. Fluid or blood accumulates beneath the retina, detaching it from the retinal pigment epithelium. Fluid can also accumulate within the retinal layers. Ranibizumab binds to VEGF-A and prevents it from binding to its receptor (Panel C). Long-term blockade of VEGF-A causes shrinkage and maturing of the vessels so that they no longer leak. The accumulation of fluid within and beneath the retina resolves, and the photoreceptors reattach to the underlying retinal pigment epithelium.

Fluid accumulation within retinal layers

Fluid leakage from immature vessels

of

n engl j med 363;17

Two main patterns of choroidal neovascularization are seen on fluorescein angiography in patients with AMD. Classic neovascularization fluoresces brightly in the early phases of the angiogram and leaks profusely in the late phases, whereas occult neovascularization fills more slowly and leaks much less.29 Large, randomized, controlled trials have evaluated the benefit of ranibizumab for the treatment of both forms of neovascularization. In the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) trial (ClinicalTrials.gov number, NCT00056836), investigators compared monthly intraocular injections of ranibizumab with placebo in patients who had AMD with the predominantly occult type of choroidal neovascularization.30 At 1 year, only 5% of patients who were treated with either 0.3 mg or 0.5 mg of ranibizumab had lost 15 letters of vision (about three lines on a standard eye chart), as compared with 38% of control subjects. Of the patients who were treated with ranibizumab, 34% of those receiving the 0.5-mg dose and 25% of those receiving the 0.3-mg dose gained 15 letters of vision, as compared with only 5% of control subjects.30 Ranibizumab had a positive treatment effect in all subgroups of patients with neovascular AMD.31

nejm.org

october 21, 2010

74

clinical ther apeutics

In the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) study (NCT00061594), investigators compared monthly intraocular injections of ranibizumab with photodynamic therapy in patients who had AMD with the predominantly classic type of neovascularization.32 Photodynamic therapy involves the intravenous injection of verteporfin, a photosensitizing dye, followed by application of a nonthermal red laser light (at a wavelength of 689 nm) to the area of neovascularization.33 The red laser light stimulates the dye, which causes the formation of singlet oxygen and secondary damage to the vessels. Only 4% of patients who were treated with 0.5 mg of ranibizumab and 5% of those treated with 0.3 mg lost 15 letters of vision at 1 year, as compared with 36% of patients who were treated with laser-activated verteporfin. Among patients who were treated with ranibizumab, 40% of those receiving the 0.5-mg dose and 36% of those receiving the 0.3-mg dose gained 15 letters of vision, as compared with only 6% in the verteporfin group.

Cl inic a l Use In the absence of anti-VEGF therapy, neovascular AMD usually results in a substantial loss of vision. An alternative treatment is thermal laser photocoagulation, but this therapy damages the overlying and surrounding retina and is associated with a high rate of recurrent neovascularization. At 24 months after laser treatment of neovascularization that extended beneath the center of the macula, only 1% of treated eyes had better than 20/100 vision.34 Another alternative is photodynamic therapy, but the ANCHOR study showed that treatment with ranibizumab is superior.32 Bevacizumab is an agent that is commonly used as an alternative to ranibizumab. Bevacizumab is also a monoclonal antibody that binds to VEGF-A, but the Food and Drug Administration (FDA) has approved it only for the treatment of colon cancer. The similarity between the two molecules has led many clinicians to hypothesize that the two drugs might be equally effective for the treatment of neovascular AMD, although this hypothesis has not been formally confirmed. When bevacizumab is used for the treatment of AMD, a pharmacy can split a vial into small

n engl j med 363;17 BACK to TOC

doses that can be administered intraocularly. Generally, the dose that is used is 1.25 mg, which costs about $75, as compared with approximately $2,000 for a dose of ranibizumab. It should be emphasized that this use of bevacizumab for neovascular AMD is considered off-label therapy. Ranibizumab is injected into the eye in an outpatient clinic (see video, available with the full text of this article at NEJM.org). Hospitalization is not needed. We perform injections in a room specially designed for minor surgery. Informed consent should be obtained before the procedure. We begin the injection procedure by giving anesthetic drops of proparacaine hydrochloride 0.5% and tetracaine hydrochloride 0.5%, followed by an antibiotic drop. Many retinal specialists do not use subconjunctival anesthesia, but for most of our patients, we inject about 0.2 ml of 1% lidocaine without epinephrine beneath the conjunctiva in the superotemporal quadrant, 3 mm posterior to the corneal limbus. After waiting about 4 minutes, we place a lid speculum into the eye to hold the lids open and drop 5% povidone–iodine onto the conjunctiva. We use calipers to mark the injection site 3.5 mm posterior to the limbus (the outer border of the cornea). We use a 30-gauge needle on a 1-mm tuberculin syringe to inject 0.05 ml (0.5 mg of ranibizumab) into the middle of the vitreous cavity, then place a sterile cotton swab firmly over the injection site as the needle is withdrawn to prevent backflush of fluid through the injection site. We then remove the lid speculum and gently irrigate the eye to remove any residual povidone–iodine. We give an additional drop of antibiotic and instruct the patient to use the drops twice more that day and then four times per day for the next 3 days. Some retinal specialists no longer use prophylactic antibiotic drops because they believe that the drops do not reduce the risk of infectious endophthalmitis. We tell the patient to call if vision decreases or the eye becomes painful. We give the patient a sheet that contains the instructions for using the antibiotic drops, warnings, and numbers to call if there are problems. The patient makes an appointment to return in 1 month. Intraocular hemorrhage is rare after injections of ranibizumab. As noted, the needle is small (30 gauge), and the injection site is chosen to avoid major ocular blood vessels. The injection of the

nejm.org

october 21, 2010

A video showing Click here injection of to access ranibizumab video. is available at NEJM.org

1651

75

The

n e w e ng l a n d j o u r na l

drug temporarily raises the intraocular pressure to or even above the vascular perfusion pressure of the eye, which effectively tamponades any bleeding until clotting occurs. Therefore, there is no need for a patient to stop taking warfarin or antiplatelet drugs. There are no known interactions with other drugs, and no adjustments need to be made for other medical conditions. At the 1-month follow-up appointment, the patient’s vision is checked, and the eye is examined for signs of inflammation, new hemorrhage, or fluid within or under the retina. We then give a second injection and repeat the process again 1 month later, for a total of three monthly treatments. At subsequent visits, we give additional ranibizumab injections, but we carefully extend the follow-up period between the visits by 1 week if the eye remains stable, with no fluid or hemorrhage.35 Once the followup interval reaches 3 months and the eye is stable, consideration can be given to stopping the injections, but the patient should still be seen every 3 to 4 months to detect any late recurrences. Patients should be reminded frequently to call if vision loss or distortion occurs. If a patient has only a partial response or no response to serial injections, it may be appropriate to stop the treatment. This decision should be made jointly with the patient. It often depends somewhat on whether the better eye is being treated. Patients often wish to forgo injections of modest benefit if the poorer eye is being treated, whereas they may be reluctant to stop if the injections are being given in the better eye. Brown and colleagues36 calculated that the cost of treating a patient with monthly injections of ranibizumab over a 2-year period, as described in the MARINA trial, would be $52,652. Of this total (which includes incidental procedural costs), $44,812 would be the cost of the drug, and $5,981 the physician’s fees.36

A dv er se Effec t s The injection of either anesthetic or ranibizumab can cause mild subconjunctival hemorrhage. The blood is cosmetically unappealing but resolves without sequelae. Many clinicians use topical anesthetics only, but in our experience, most patients who are treated in this manner feel some pain when the needle pierces the wall of the eye.

1652 BACK to TOC

n engl j med 363;17

of

m e dic i n e

Any intraocular injection can cause bacterial endophthalmitis, a serious complication that threatens vision. In the MARINA study, the presumed rate of endophthalmitis (presumed because not all eyes showed positive cultures) was 1.0% (infection in 5 of 477 patients); the rate per injection was 0.05% (infection associated with 5 of 10,443 injections).30 Patients in whom endophthalmitis develops have vision loss or an increase in floaters, almost always within the first week after the injection. The eye is red and may be painful. Patients with such symptoms after ranibizumab injection should be seen promptly by their retinal specialist. In the MARINA and ANCHOR trials, the respective risks of nonocular hemorrhage were 9% and 6% in the treated groups versus 6% and 2% in the comparator groups, which may indicate a systemic anti-VEGF effect.30,32 In the MARINA trial, rates of stroke were 2.5% in the 0.5-mg group and 1.3% in the 0.3-mg group versus 0.8% in the sham group. Rates of myocardial infarction were 1.3% in the 0.5-mg group and 2.5% in the 0.3-mg group versus 1.7% in the sham group.30 Similar effects were seen in the 2-year results from the ANCHOR trial.37 None of these differences were statistically significant. As noted above, bevacizumab is also an anti– VEGF-A monoclonal antibody. In a meta-analysis of trials of bevacizumab in patients with metastatic cancer, arterial thromboembolic events, including cardiac ischemia and stroke, occurred in 3.3% of patients who had received the drug, as compared with 2.0% who had not.38 The totalbody dose of bevacizumab that was used in these trials was more than 1000 times the dose used in the treatment of AMD.

A r e a s of Uncer ta in t y A major area of uncertainty is whether bevacizumab is as effective as ranibizumab in the treatment of neovascular AMD. This issue has been evaluated in several small studies, with encouraging results.39-42 However, these findings are provisional. To answer the question definitively, a large, randomized clinical trial, called the Comparison of AMD Treatments Trial (CATT; NCT00593450), is currently being conducted. Results from this trial are expected in the spring of 2011.43 Since the cost of the dose of bevacizumab

nejm.org

october 21, 2010

76

clinical ther apeutics

that is commonly used in AMD is so much less than the cost of the standard dose of ranibizumab ($75 vs. $2,000), the majority of our patients choose to be treated with bevacizumab on the basis of currently available data. Another area of uncertainty is the optimal treatment schedule. Some specialists administer ranibizumab on a fixed monthly schedule, whereas others administer the agent only when fluid is present on optical coherence tomography or when leakage is seen on fluorescein angiography.44 In CATT, investigators are comparing these two approaches to treatment, as well as comparing ranibizumab with bevacizumab. If the study shows that the difference in outcome between the fixed and as-needed approaches is minimal, patients and physicians may opt for less-frequent injections. All the groups in CATT are being followed monthly, but most patients dislike having to return for a visit every month. An additional trial may be warranted in the future, comparing monthly visits with gradual extension of the follow-up interval for patients whose condition is stable. Some pharmacokinetic data, though not conclusive, support the hypothesis that bevacizumab may have a longer intraocular half-life than ranibizumab.45

Guidel ine s The American Academy of Ophthalmology included ranibizumab in its September 2008 Preferred Practice Pattern Guidelines for Age-Related Macular Degeneration, grading such therapy as level A (most important to the care process) and level I (greatest strength of evidence).46 The same guidelines also listed bevacizumab as a recommended treatment, grading it level A for importance but only level III (the lowest level) with respect to strength of evidence. The guidelines state that when using bevacizumab, “the ophthalmologist should provide appropriate informed consent with respect to the off-label status.” The guidelines committee of the European Society of Retina Specialists make similar recommendations in a statement published in August 2007.47

R ec om mendat ions The patient described in the vignette is an appropriate candidate for either ranibizumab or bevacizumab therapy. We would explain to the patient that only ranibizumab has been approved by the FDA for use in AMD. We would also explain that the efficacy of bevacizumab is thought to be similar to that of ranibizumab, although such efficacy has not been evaluated in definitive trials, and that bevacizumab is substantially less expensive. Regardless of the patient’s choice of agent, we would carry out the initial injection in our outpatient minor surgery unit, as described in the Clinical Use section. After the first injection of either bevacizumab or ranibizumab, we would ask the patient to return for another injection in 4 weeks. After the second injection, we would ask him to return in 4 weeks if he received ranibizumab and in 6 weeks if he received bevacizumab. We would continue injections at these intervals until the retina was dry. We would then gradually extend the interval between follow-up visits, depending on the examination findings. In our experience, most treatment failures are due to missed follow-up visits. Patients should be reminded repeatedly to call if their vision worsens. Physicians should have a system in place for calling patients who have been lost to follow-up because such patients have a high risk of recurrent neovascularization with permanent scarring and vision loss. Finally, ophthalmologists should be aware of the patient’s overall medical condition and should communicate clearly with the patient’s other physicians when warranted. Supported by the Robert C. Watzke Research Fund, Research to Prevent Blindness, the Foundation Fighting Blindness, a grant (EY016822) from the National Eye Institute, and the Howard Hughes Medical Institute. No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Robert F. Mullins, Ph.D., for his critical review and advice; Alton Szeto Illustration for the drawings that served as the design for Figure 2; and Patricia Duffel for her reference help.

References 1. Friedman DS, O’Colmain BJ, Muñoz B,

et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564-72. 2. Brown GC, Brown MM, Sharma S, et al.

The burden of age-related macular degeneration: a value-based medicine analysis. Trans Am Ophthalmol Soc 2005;103:17386. 3. Edwards AO, Ritter R III, Abel KJ,

n engl j med 363;17 BACK to TOC

nejm.org

Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421-4. 4. Hageman GS, Anderson DH, Johnson

october 21, 2010

1653

77

The

n e w e ng l a n d j o u r na l

LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/ CFH) predisposes individuals to agerelated macular degeneration. Proc Natl Acad Sci U S A 2005;102:7227-32. 5. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419-21. 6. Hammond CJ, Webster AR, Snieder H, Bird AC, Gilbert CE, Spector TD. Genetic influence on early age-related maculopathy: a twin study. Ophthalmology 2002; 109:730-6. 7. Heiba IM, Elston RC, Klein BE, Klein R. Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study. Genet Epidemiol 1994;11: 51-67. [Erratum, Genet Epidemiol 1994; 11:571.] 8. Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT. Genetic risk of age-related maculopathy: population-based familial aggregation study. Arch Ophthalmol 1998;116:1646-51. 9. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-9. 10. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 2005;14:3227-36. 11. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC. The US twin study of agerelated macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005;123:321-7. 12. Zareparsi S, Buraczynska M, Branham KE, et al. Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet 2005;14:1449-55. 13. Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP. Smoking and age-related macular degeneration: a review of association. Eye (Lond) 2005;19:935-44. 14. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPEBruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705-32. 15. Penfold PL, Madigan MC, Gillies MC, Provis JM. Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 2001;20:385-414. 16. Bok D. The retinal pigment epithelium: a versatile partner in vision. J Cell Sci Suppl 1993;17:189-95. 17. Hayreh SS, Baines JA. Occlusion of the posterior ciliary artery. II. Chorio-retinal lesions. Br J Ophthalmol 1972;56:73653.

1654 BACK to TOC

of

m e dic i n e

18. Zarbin MA. Current concepts in the

pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004;122:598614. 19. Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36:182-91. 20. Green WR. Histopathology of age-related macular degeneration. Mol Vis 1999;5: 27. 21. Green WR, Enger C. Age-related macular degeneration histopathologic studies: the 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993;100:1519-35. 22. Frank RN, Amin RH, Eliott D, Puklin JE, Abrams GW. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol 1996;122:393-403. 23. Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 1996; 37:1929-34. 24. Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised agerelated macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 1996;37:855-68. 25. Miller JW, Adamis AP, Shima DT, et al. Vascular endothelial growth factor/ vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 1994;145:574-84. 26. Otani A, Takagi H, Oh H, et al. Vascular endothelial growth factor family and receptor expression in human choroidal neovascular membranes. Microvasc Res 2002;64:162-9. 27. Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006;26:859-70. 28. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:5862. 29. Subfoveal neovascular lesions in agerelated macular degeneration: guidelines for evaluation and treatment in the macular photocoagulation study. Arch Ophthalmol 1991;109:1242-57. 30. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31. 31. Boyer DS, Antoszyk AN, Awh CC, Bhisitkul RB, Shapiro H, Acharya NR.

n engl j med 363;17

nejm.org

Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007;114:246-52. 32. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-44. 33. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials — TAP report. Arch Ophthalmol 1999;117:1329-45. [Erratum, Arch Ophthalmol 2000;118:488.] 34. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 1991;109: 1220-31. 35. Spaide R. Ranibizumab according to need: a treatment for age-related macular degeneration. Am J Ophthalmol 2007;143: 679-80. 36. Brown MM, Brown GC, Brown HC, Peet J. A value-based medicine analysis of ranibizumab for the treatment of subfoveal neovascular macular degeneration. Ophthalmology 2008;115:1039-45. 37. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009;116:57-65. 38. Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol 2010;49:287-97. 39. Bashshur ZF, Haddad ZA, Schakal AR, Jaafar RF, Saad A, Noureddin BN. Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: the second year of a prospective study. Am J Ophthalmol 2009;148(1):59-65. 40. Fong DS, Custis P, Howes J, Hsu JW. Intravitreal bevacizumab and ranibizumab for age-related macular degeneration: a multicenter, retrospective study. Ophthalmology 2010;117:298-302. 41. Ehlers JP, Spirn MJ, Shah CP, et al. Ranibizumab for exudative age-related macular degeneration in eyes previously treated with alternative vascular endothelial growth factor inhibitors. Ophthalmic Surg Lasers Imaging 2010;41:182-9. 42. Tufail A, Patel PJ, Egan C, et al. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study. BMJ 2010;340:c2459. 43. Martin DF, Maguire MG, Fine SL. Identifying and eliminating the roadblocks to comparative-effectiveness research. N Engl J Med 2010;363:105-7. 44. Lalwani GA, Rosenfeld PJ, Fung AE, et

october 21, 2010

78

clinical ther apeutics al. A variable-dosing regimen with intravitreal ranibizumab for neovascular agerelated macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43-58. 45. Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of bevacizumab after a single intravitreal injec-

tion in humans. Am J Ophthalmol 2008; 146:508-12. 46. American Academy of Ophthalmology Retina Panel. Preferred practice pattern guidelines. age-related macular degeneration. San Francisco: American Academy of Ophthalmology, 2008. (http://one.aao .org/CE/PracticeGuidelines/PPP_Content

.aspx?cid=f413917a-8623-4746-b441f817265eaf b4.) 47. Schmidt-Erfurth UM, Richard G, Augustin A, et al. Guidance for the treatment of neovascular age-related macular degeneration. Acta Ophthalmol Scand 2007;85:486-94. Copyright © 2010 Massachusetts Medical Society.

Palmyra, Syria

Christian Müller, M.D.

n engl j med 363;17 BACK to TOC

nejm.org

october 21, 2010

1655

79

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical therapeutics

Dietary Therapy in Hypertension Frank M. Sacks, M.D., and Hannia Campos, Ph.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors’ clinical recommendations. From the Department of Nutrition, Harvard School of Public Health (F.M.S., H.C.); and Channing Laboratory and Cardiology Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (F.M.S.) ― all in Boston. Address reprint requests to Dr. Sacks at the Department of Nutrition, Harvard School of Public Health, Bldg. 1, 2nd Fl., Boston, MA 02115, or at fsacks@hsph .harvard.edu. N Engl J Med 2010:362:2102-12. Copyright © 2010 Massachusetts Medical Society.

A 57-year-old woman presents to an outpatient clinic for evaluation of hypertension. She has no history or symptoms of cardiovascular disease and reports having gained 15 kg over the past 30 years. Her blood pressure is 155/95 mm Hg, her weight 86 kg, her height 165 cm, her body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) 31, and her waist circumference 98 cm. Her serum triglyceride level is 175 mg per deciliter (2.0 mmol per liter), high-density lipoprotein cholesterol 42 mg per deciliter (1.1 mmol per liter), low-density lipoprotein cholesterol 110 mg per deciliter (2.8 mmol per liter), and glucose 85 mg per deciliter (4.7 mmol per liter). Her clinical profile is thus consistent with the metabolic syndrome.1 She is a nonsmoker, is sedentary, and eats a diet that is high in white bread, processed meats, and snacks and drinks containing sugars and sodium and is low in fruits and vegetables. She is interested in adopting a healthier lifestyle.

The Cl inic a l Probl em Hypertension is defined as a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher.2 However, morbidity increases among persons whose blood pressure is above 115/75 mm Hg. High blood pressure is associated with an increased risk of stroke, myocardial infarction, heart failure, renal failure, and cognitive impairment.2-4 Systolic blood pressure above 115 mm Hg is the most important determinant of the risk of death worldwide,2 being responsible for 7.6 million cardiovascular deaths annually.3 From 1960 through 1991, blood pressure decreased in the United States, and after the first 10 years of this interval, the rate of cardiovascular deaths decreased.2 Effective hypertension screening and treatment were probably the reason for these beneficial trends. However, from 1990 through 2002, blood pressure increased.5,6 Intake of fruits and vegetables and adherence to healthful dietary patterns declined during this period7,8 and the prevalence of abdominal obesity increased9; both trends have contributed to hypertension. Among most populations in industrialized countries, the prevalence of hypertension increases dramatically with age; in the United States it rises from about 10% in persons 30 years of age to 50% in those 60 years of age.6 However, some persons, including strict vegetarians,10-12 populations whose diet consists mostly of vegetable products,11,13 and those whose sodium intake is low,13-15 have virtually no increase in hypertension with age.

S t r ategie s a nd E v idence Pathophysiology and Effect of Therapy

Essential hypertension is the name for hypertension that cannot be attributed to a specific renal or adrenal disease, such as chronic renal failure or an adrenal tumor; 2102 BACK to TOC

n engl j med 362;22

nejm.org

june 3, 2010

80

clinical ther apeutics

the vast majority of patients with hypertension have essential hypertension. The pathophysiology of essential hypertension is complex, with much remaining to be discovered (Fig. 1, and Section 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The three cornerstones of dietary treatment of hypertension — a healthful dietary pattern, reduced sodium intake, and reduced body fat — influence the pathophysiology of hypertension at many of its points of control. High sodium intake is strongly correlated with the development of hypertension.16-18 Sodium intake initiates an autoregulatory sequence that leads to increased intravascular fluid volume and cardiac output, peripheral resistance, and blood pressure. The elevation in blood pressure results in a phenomenon called pressure natriuresis, in which increased renal perfusion pressure leads to increased excretion of fluid and sodium. In essential hypertension, however, sodium excretion is impaired. It is hypothesized that in most cases essential hypertension is a genetic disorder involving many individual genes, each of which influences the body’s handling of sodium to varying degrees18 and becomes expressed in the context of an unhealthful dietary environment, particularly one characterized by excessive intake of salt. Numerous other factors contribute to the pathophysiology of hypertension. Especially in the elderly, large conduit arteries such as the aorta and carotid arteries become stiff and less compliant, increasing systolic blood pressure.19 Proliferation of smooth-muscle cells and endothelial dysfunction occur in resistance vessels, including small arteries and arterioles, causing vasoconstriction and increasing peripheral vascular resistance.20-22 Although the systemic renin– angiotensin–aldosterone axis is often suppressed in the presence of elevated blood pressure, angiotensin II activity is increased locally in various tissues, including the kidneys, vascular endothelium, and adrenal glands.23,24 Increased activity in the sympathetic nervous system may also be a factor.25-30 Both aging19,31-33 and obesity25-30 contribute to the pathogenesis of hypertension through several mechanisms (Fig. 1, and Section 1 in the Supplementary Appendix). Two effective interventions for lowering blood pressure in patients with hypertension are reducing sodium intake and reducing weight. Reductions in dietary salt lessen the amount of sodium n engl j med 362;22 BACK to TOC

the kidney has to excrete to restore normal blood volume. Compliance in the aorta and carotid artery in older patients with hypertension is improved when sodium intake is reduced.34 Reduction in sodium intake also improves arterial vasodilatation.21,22 Weight loss moderates activation of the renin–angiotensin–aldosterone axis35,36 and the sympathetic nervous system37,38 and diminishes sodium retention.39 Decreases in abdominal visceral fat also improve the functioning of both conduit and resistance vessels.40 In addition to sodium restriction and weight loss, several other dietary modifications that are collectively termed “a healthful dietary pattern” have been shown to reduce blood pressure. Although the mechanisms of these diets have not been fully clarified, adherence to these diets has been found to reset the pressure–natriuresis curve so that a lower pressure suffices to excrete sodium and reduce blood volume,41 reduce aortic stiffness,42 and improve vasodilatation in small resistance vessels.43,44 As compared with the typical U.S. diet, the kinds of dietary patterns that have been proved to lower blood pressure emphasize fruits, vegetables, and low-fat dairy products; include whole grains, poultry, fish, and nuts; make use of unsaturated vegetable oils; and contain smaller amounts of red meat, sweets, and sugar-containing beverages.45,46 Clinical trials of such diets have not usually emphasized the identification of specific nutrients or single foods that lower blood pressure but rather have used epidemiologic data to define dietary patterns, such as Mediterranean-style diets47,48 and vegetarian diets.11,12 (see Section 2 in the Supplementary Appendix for a discussion of the effects of specific foods and nutrients on blood pressure). Clinical Evidence

The most carefully studied and established healthful dietary patterns are the Dietary Approaches to Stop Hypertension (DASH) diet,45,49 variants of that diet,46,50 and variations of the Mediterranean diet.51,52 In the original DASH trial,49 459 adults whose systolic blood pressure was less than 160 mm Hg and whose diastolic blood pressure was 80 to 95 mm Hg, 133 of whom had hypertension, were randomly assigned to a control diet typical of the average U.S. diet, a diet rich in fruits and vegetables, or a combination diet rich in fruits, vegetables, and low-fat dairy products and relatively low in saturated and total fat. Sodium intake and body weight were maintained at nejm.org

june 3, 2010

2103

81

The

A

High-sodium, high-calorie diet

n e w e ng l a n d j o u r na l

of

m e dic i n e

Increased sympathetic nervous system activity Intrinsic renal factors (genetic and prenatal) regulate sodium excretion Large conduit arteries become less compliant High sodium level activates local angiotensin II in heart and arteries Increased cardiac output

Increased blood pressure

Abnormal pressure natriuresis and sodium retention Increased tissue angiotensin II in kidneys and adrenal glands

Smooth-muscle cell proliferation and rearrangement Endothelial-cell dysfunction in small resistance vessels Increased peripheral resistance

Abdominal fat further increases conduit artery stiffness, sympathetic nervous system activity, and angiotensin II levels

B

Low-sodium, low-calorie diet Weight loss reduces sympathetic nervous system activity

Weight loss, low sodium intake, and healthy diet reduce stiffness of large conduit arteries

Decreased blood pressure

Healthy diet improves renal sodium excretion

Weight loss, low sodium intake, and healthy diet improve function of small resistance vessels and decrease peripheral resistance

Decreased abdominal fat

Figure 1. Mechanisms Linked to Increases in Blood Pressure and the Therapeutic Effects of Healthful Dietary Patterns, Sodium Reduction, and Weight Loss.

2104 BACK to TOC

n engl j med 362;22

nejm.org

june 3, 2010

82

clinical ther apeutics

n engl j med 362;22 BACK to TOC

145

Mean Systolic Blood Pressure (mm Hg)

constant levels. After 8 weeks, among the participants with hypertension, the diet rich in fruits and vegetables reduced systolic and diastolic blood pressure by 7.2 and 2.8 mm Hg more, respectively, than the control diet (P<0.001 and P = 0.01, respectively). The combination diet resulted in greater reductions (11.4 and 5.5 mm Hg, respectively, as compared with the control diet; P<0.001 for each). The effects were less pronounced among participants who did not have hypertension at baseline. In a subsequent trial, the effect of various levels of sodium intake was studied in the context of the DASH diet in 412 participants with blood pressure levels at enrollment similar to those of participants in the original DASH trial.53 Patients were randomly assigned to either the DASH “combination” diet (now commonly termed the DASH diet) or a control diet. Participants in each group were then given a diet with high, intermediate, and low levels of sodium (3.5, 2.3, and 1.2 g per day, respectively) for 30 days each in random order. Body weight was held constant by adjusting total caloric intake. Reducing sodium intake resulted in a significant incremental reduction in both systolic and diastolic blood pressure in both groups (Fig. 2). In a secondary analysis from the sodium trial, the blood-pressure–lowering effects of the DASH diet and low sodium were each accentuated as age increased54 (Fig. 3). Systolic blood pressure was 12 mm Hg higher among participants between 55 and 76 years of age than among those between 21 and 41 years of age when they were given a typical U.S. diet that was high in sodium. This difference in systolic blood pressure is similar to that in the U.S. population when the same age groups are compared.55 In marked contrast, systolic blood pressure was the same among older and younger participants when they were given the DASH diet with low sodium content. This finding suggests that the typical rise in blood pressure that occurs with age during adult life may be prevented or reversed if the lowsodium DASH diet is followed. Women, blacks, and those with the metabolic syndrome have a mildly enhanced reduction in blood pressure in response to a low-sodium diet.53,54,56,57 It is not possible to identify individual patients for whom sodium reduction is especially effective58 (see Section 3 in the Supplementary Appendix). Two reduced-carbohydrate versions of the

Control diet 140

135

Higher to lower sodium Control: −8 DASH: −7

−2.1 (−0.1 to −4.0)

−8.0 (−4.9 to −11.1)

−6.0 (−4.0 to −7.9) −7.5 (−4.2 to −10.8)

DASH diet −1.6 (0.6 to −3.8)

130

−5.1 (−3.0 to −7.3) Lower-sodium DASH vs. higher-sodium control: −15

125 0

−6.7 (−3.5 to −9.8)

High (3.5 g)

Intermediate (2.3 g)

Low (1.2 g)

Dietary Sodium

Figure 2. Sodium Reduction, the DASH Diet, and Changes in Systolic Blood Pressure. The figure shows the additive beneficial effects of the DASH diet and reduced intake of sodium on systolic blood pressure in patients with mild hypertension who were older than 45 years of age. The participants were a subgroup of those in the study of the effects of the DASH diet and reductions in dietary sodium,53 who were randomly assigned to follow a DASH diet (33 participants) or a typical U.S. diet (37 participants) for 90 days. During that period, each group consumed three versions of the diet adjusted for daily sodium content. The participants in each group consumed each of the sodiumadjusted diets for 30 days in a crossover design; body weight was held constant. The two downward-sloping arrows on the left depict the effect of intermediate sodium intake as compared with higher sodium intake, and the two downward-sloping arrows on the right depict the effect of lower sodium intake as compared with intermediate sodium intake. The dotted lines show the effect of the DASH diet as compared with the typical U.S. diet at each level of dietary sodium. Numbers shown represent the mean changes with 95% confidence intervals. Adapted from Bray et al.54

DASH diet were studied in 164 adults enrolled in the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart).46,50 One diet higher in unsaturated fat and another higher in protein were compared with a diet similar to the standard DASH diet but slightly higher in carbohydrates. As compared with the high-carbohydrate diet, the high-protein diet reduced mean systolic blood pressure in participants with hypertension by 3.5 mm Hg and mean diastolic blood pressure by 2.4 mm Hg (P = 0.006 and P = 0.008, respectively).50 The comparable effects of the diet high in unsaturated fat were 2.9 and 1.9 mm Hg, respectively (P = 0.02 for both). As with the DASH diet itself, these effects were less pronounced in participants who did not have hypertension at baseline. The traditional Mediterranean diet47,48 has many similarities to DASH-type diets, especially nejm.org

june 3, 2010

2105

83

Mean Systolic Blood Pressure (mm Hg)

The

n e w e ng l a n d j o u r na l

145 Typical diet, high sodium

140 135 130 125 120

DASH diet, low sodium

115 0

23–41

42–47

48–54

55–76

Age (yr)

Figure 3. Effects of a Low-Sodium DASH Diet on Systolic Blood Pressure with Increasing Age. A total of 412 participants were randomly assigned to follow a DASH diet (208 participants) or a typical U.S. diet (control group, 204 participants) for 90 days. During that period, each group consumed three versions of the diet adjusted for daily sodium content: high (3.5 g), intermediate (2.3 g), and low (1.2 g). The participants in each group consumed each of the sodium-adjusted diets for 30 days in a crossover design; body weight was held constant. Mean (±SD) systolic blood pressure is depicted for the DASH group during the period of low sodium intake and for the control group during the period of high sodium intake, according to age, at the end of the 30-day period; there were 45 to 58 participants per group in each of the four age ranges shown. The slope for the control group during the period of high sodium intake was 0.3 mm Hg per year, spanning 30 years. The slope for the DASH-diet group during the period of low sodium intake was 0 mm Hg per year. I bars denote 95% confidence intervals. Data are from Sacks et al.53

to the diet from the OmniHeart study that was higher in unsaturated fat. In controlled trials involving patients with the metabolic syndrome51 or type 2 diabetes,52 a reduced-carbohydrate Mediterranean diet lowered blood pressure and improved serum lipid levels more than a low-fat diet. In these trials, unlike the DASH trials, weight was not held constant through caloric adjustment; in both cases, patients assigned to the Mediterranean diet lost more weight than those assigned to the low-fat diet. Epidemiologic studies generally support evidence from clinical trials on the effects of dietary management, as do community-based and clinic-based intervention programs (see Sections 4 and 5 in the Supplementary Appendix). The effect of adding weight loss to the DASH diet was evaluated in 144 adults in the Exercise 2106 BACK to TOC

n engl j med 362;22

of

m e dic i n e

and Nutrition Interventions for Cardiovascular Health (ENCORE) study.59 Participants were randomly assigned to a control diet, to the DASH diet alone, or to a reduced-calorie modification of the DASH diet. At 4 months, blood pressure was reduced by 3.4/3.8 mm Hg in the control group, by 11.2/7.5 mm Hg in the group given the DASH diet alone (P<0.001 for both systolic and diastolic pressures as compared with the control diet), and 16.1/9.9 mm Hg with the DASH diet plus weight management (P = 0.02 for systolic blood pressure and P = 0.05 for diastolic blood pressure as compared with the DASH diet alone). Clinical Use

Dietary management is appropriate for all patients with hypertension. In addition, patients with prehypertension (systolic blood pressure between 120 and 139 mm Hg or diastolic blood pressure between 80 and 89 mm Hg) should adopt the same dietary changes, given the benefit of dietary therapy at these blood-pressure levels. Drug therapy plays an essential role in treating hypertension. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure emphasizes that in patients for whom lifestyle modification (including dietary therapy, physical activity, and moderation of alcohol consumption) does not reduce blood pressure below 140/90 mm Hg (or 130/80 mm Hg for patients with diabetes or chronic renal disease), drug therapy should be implemented and modified over time given a patient’s response.2 However, medication should not supplant dietary management; rather, the two forms of treatment should be considered complementary. The DASH diet is effective in combination with angiotensin-receptor blockers.60 Sodium reduction is highly effective in older patients with hypertension who are taking antihypertensive medicines61 and in those with resistant hypertension taking several antihypertensive agents.62 We guide patients in adopting a healthful diet with the use of a chart or table such as that shown in Table 1. In simple terms, we encourage patients to eat poultry, fish, nuts, and legumes instead of red meat; low-fat and nonfat dairy products instead of full-fat dairy products; vegetables and fruit instead of snacks and desserts high in sugars; breads and pastas made from whole grain instead of white flour; fruit itself nejm.org

june 3, 2010

84

clinical ther apeutics

rather than fruit juice; and polyunsaturated and monounsaturated cooking oils such as olive, canola, soybean, peanut, corn, sunflower, or safflower rather than butter, coconut oil, or palm-kernel oil. Table 1 provides information about the number of servings and portion sizes for each type of food that should be consumed in 1 week. Adopting a healthful dietary approach means making the correct choices at the market so that the most healthful foods will be available at home. The recommendations in Table 1 include a food-shopping guide. In the United States, it is common to place healthful foods at the periphery of the market; most weekly shopping should be concentrated there. Use of canned and processed foods should be limited, unless their salt content has been reduced or virtually eliminated. For convenience, low-sodium, frozen, or canned vegetables can be substituted for fresh ones. Sections of the market that contain sweetened beverages, candies, and cookies should be avoided entirely. Sodium restriction is central to the dietary management of hypertension. Patients should become familiar with reading the food labels that specify the sodium content of packaged and processed foods.63 Processed foods are often high in sodium. A low sodium diet is sometimes less palatable for patients who are accustomed to a high-sodium diet; however, tastes adapt quickly, and studies have shown that low-sodium diets can be as acceptable to patients as higher-sodium diets.64 Herbs, spices, and citrus fruit (juice or peel) and other acidic ingredients such as vinegar can be added to dishes to compensate for low sodium content and may even be preferred over foods with higher amounts of sodium. Patients should not skip meals, should consume one third of their daily food intake at breakfast, and should limit eating in restaurants to no more than once weekly. Eating in many restaurants subverts the goal of a low-sodium diet, since one serving of some soups, sandwiches, fried chicken, or pizza can far exceed the total recommended daily amount of sodium.65 The health care reform law includes a requirement that all chain restaurants with more than 20 locations provide information for consumers regarding the amount of sodium and other dietary components in menu items.66 Compliance with dietary therapy is better, and success rates in achieving blood-pressure control are higher, when accompanied by active guidance n engl j med 362;22 BACK to TOC

or counseling of the patient by clinicians or ancillary medical personnel with expertise in dietary management.67-72 We always recommend that patients record their dietary intake for 1 or 2 weeks and discuss this record with a dietitian, who will provide specific meal plans. This is especially important when weight loss is needed. Followup with a dietitian is essential, whether arranged in individual or group appointments. In addition, numerous Web sites73-76 and books77-80 can provide patients with further information and guidance on healthful diets. The costs associated with dietary treatment of hypertension are relatively modest. In one study in the Boston area conducted in 2006, the cost of the DASH meal plan was $31 per week in areas with low socioeconomic status and $40 per week in areas with high socioeconomic status; perceived affordability was similar for patients interviewed in clinics in both areas.81 An initial consultation with a dietitian costs approximately $150, and follow-up consultations about $100. Coverage of this service by health insurance or employer programs varies. Adverse Effects

Adverse events generally occurred less frequently in persons following the DASH diet and its variants or Mediterranean diets49,52,53 (see Section 6 in the Supplementary Appendix).

A r e a s of Uncer ta in t y One crucial frontier of dietary research is that of devising and evaluating effective behavioral and community-based interventions. In the DASH trials, dietary modifications were studied over a short time span, and participants were carefully monitored for compliance. Compliance is an essential element in the long-term dietary treatment therapy of hypertension, and we need to learn what components of behavioral interventions lead to adherence.82 In addition, no large, longterm, clinical-outcomes trial of these diets has been performed, although one long-term observational study of an earlier randomized trial and one relatively short-term randomized trial reported a decrease in the incidence of cardiovascular events with sodium reduction (see Section 7 in the Supplementary Appendix).83,84 However, we believe that it is not necessary to conduct a largescale, randomized trial to address this question in nejm.org

june 3, 2010

2107

85

2108

BACK to TOC

n engl j med 362;22

nejm.org

2 1

Poultry

Red meats 10 3 4

Milk

Yogurt

Cheese

Dairy products

2

Use freely

Fish and shellfish

Meat, poultry, and fish

Herbs, alliums, and other seasonings

4

8

1 slice

1 cup

1 glass (8 oz)

2–4 oz

6–8 oz

6–8 oz

1 glass (8 oz)

1/4 cup

1 medium or 1/2 cup chopped

1/4 lb

1 container

1/2 gallon

1/4 lb

1 lb

1 lb

1 qt

1 bag

15–20 individual items

1/2 lb

8–12 individual items

1–2 heads

1–2 bunches

1–2 bags or heads

Total Amount Purchased per Wk

Soft or hard

Choose low-fat or nonfat products (about 32 oz)

Choose low-fat or nonfat products

Beef, pork, lamb, low-sodium cold cuts

Turkey, chicken, low-sodium cold cuts

Cod, sea bass, halibut; fresh or canned salmon, tuna, or sardines; mollusks, shrimp, crabmeat

Thyme, ginger, garlic, onion, bay leaf, lemon juice

Orange, grapefruit, unsweetened carrot

Raisins, apricots, prunes, cherries (about 1/2 lb)

Apples, pears, grapes, bananas, peaches, plums, oranges, tangerines, berries, cantaloupe, pineapple

Celery, green beans, peas, lima beans, sprouts

Tomatoes, carrots, squash, peppers, sweet potatoes, corn, eggplant, avocados (about 3 lb)

Broccoli, cabbage, cauliflower (about 1 lb)

Kale, collard greens, mustard greens (about 1 lb)

Lettuce, mixed spring greens, spinach bunch (about 1 lb)

Do most weekly shopping in this section

Recommendations

of

Juice

20

1/2 cup

1/2 cup

1/2 cup

1/2 cup

1 cup

Serving Size

n e w e ng l a n d j o u r na l

Dried

Fresh

Fruits

3

15

Colorful‡

Other

3

Cruciferous

4 4

Salad greens

Servings per Wk

Other greens

Leafy greens

Vegetables†

Market periphery

Weekly purchases

Type of Food

Table 1. Recommended Weekly and Occasional Food Purchases for One Person Following a Healthful Diet Containing 2100 kcal and 1500 mg of Sodium per Day.*

The

m e dic i n e

june 3, 2010

86

BACK to TOC

4 3 1

Tomato products

Chips and other snacks

Chocolate or sweets

n engl j med 362;22

nejm.org

june 3, 2010

7

Salt

1/3 tsp

1

1/2 cup

1 tsp

1 tsp

1 tsp

1 tbs

1 cup (cooked)

1/2 cup

1 oz

1/2 cup

2/3 cup

1 slice

1/2 cup

1 cup

1 oz

2 1/3 tsp

3

1/2 cup

1/2 cup

1/2 cup

1/3 cup

3/4 cup

1/2 cup

1 1/2 cups

1 bar or similar amount

3 bags

2 jars or cans

1 bag

1 jar

1 can or bag

1 bag or jar

Choose only low-sodium products¶

Salt for cooking or added at the table

Large eggs

Ice cream, sorbet, frozen yogurt, other (4 oz)

Table sugar, jelly, honey, maple syrup

Choose low-sodium items

Soft, oil-based spreads free of trans fat

Canola, corn, sunflower, olive, soybean

Pasta, brown rice, bulgur, quinoa, wheat berries

Oats, bran, whole wheat flakes, other whole grains

Skip these aisles

Granola bars, chocolate bars (about 1 oz)

Tortilla chips, popcorn, pretzels (about 1 1/2 oz per bag)

Sauce, juice, whole or diced (about 12 oz per jar or can)

Bread, rolls, pancakes, waffles (about 1 1/2 lb); choose wholegrain products

Black pepper, cayenne, cinnamon, paprika

Black, green, stuffed (about 1/4 lb)

Chickpeas, lentils, black beans (about 1 lb)

Walnuts, almonds, peanuts (about 1/2 lb)

* Patients should observe the following general recommendations: don’t skip meals, and consume one third of daily calorie intake at breakfast; limit eating out to once weekly and choose meals with a low salt content — just one slice of pizza, a turkey sandwich, or a pasta dish can easily contain 2000 mg of sodium. Examples of conversion from standard to metric measures: 1 oz equals 28 g; 1 teaspoon, 5 g; 1 cup leafy greens, about 75 g. † Unsalted frozen or canned vegetables can be substituted for fresh vegetables. ‡ Choose at least four different types of vegetables from this category. § Also visit the processed-food aisle as needed for other food items in the less frequent purchases category. ¶ Look for lower-sodium, unsalted, or reduced-salt items. Compare brands and choose those with lower sodium content. The total amount of sodium consumed in a week from processed foods or eating out should not exceed 2000 mg. ∥ Weekly allowances are provided for items that are generally purchased less than once a week. The amounts for weekly intake should be set aside in individual containers to make it easier to keep track of how much is consumed.

3

Eggs

24

Sugars 1

21

Desserts

16

12

Cooking oils

Salad dressings and mayonnaise

3

Pasta, rice, and grains

Table fats

2

Breakfast cereals

Less frequent purchases∥

Other food aisles (sweetened beverages, candy, cookies)

20

Use freely

Spices

Baked goods

3 2

Legumes

Olives

10

Nuts (whole or butter)

Processed-food aisles§

clinical ther apeutics

2109

87

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

view of the known benefits of healthful diets with mended for the management of hypertension, regard to blood pressure and other risk factors. and it is therefore reasonable to assume that dietary change could normalize her blood pressure. The patient should be given written instrucGuidel ine s tions on how to adopt a healthful diet such as the We recommend the American Heart Association DASH diet, a reduced-carbohydrate version of the guidelines for cardiovascular health and the di- DASH diet, or a Mediterranean-style diet. The inetary management of hypertension.85,86 These structions should include ways to substantially guidelines endorse foods and approaches to diet reduce sodium intake. We also recommend a similar to those included in the DASH diet and small consistent daily reduction in caloric intake cite intake of 65 mmol, or 1.5 g, of sodium per of 200 to 300 kcal per day, coupled with an inday as optimal. In addition, a target BMI of less crease in physical activity. Her physician should than 25 is recommended. Finally, the guidelines schedule a consultation with a dietitian, including recommend no more than two alcoholic drinks a regular schedule of follow-up visits. The paper day for men and one for women and people tient should monitor her blood pressure at home, of lighter weight. (One drink is equivalent to 12 oz with an automated machine, at least once a of beer, 5 oz of wine, or 1.5 oz of 80-proof liquor, month, preferably more frequently. A trial of inteneach of which represents approximately 14 g of sive dietary treatment is warranted for 6 months to try to achieve the targeted goal for blood presethyl alcohol.) sure (systolic blood pressure <140 mm Hg, diastolic blood pressure <90 mm Hg) before mediC onclusions a nd cation is introduced. R ec om mendat ions The diet of the patient described in our vignette is very different from the healthful diets recom-

No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

References 1. Alberti KG, Eckel RH, Grundy SM, et al.

Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120: 1640-5. 2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52. 3. Lawes CM, Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001. Lancet 2008;371:1513-8. 4. Rao MV, Qiu Y, Wang C, Bakris G. Hypertension and CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES), 1999-2004. Am J Kidney Dis 2008;51:Suppl 2:S30-S37. 5. Hajjar I, Kotchen JM, Kotchen TA. Hypertension: trends in prevalence, incidence and control. Annu Rev Public Health 2006;27:465-90. 6. Ezzati M, Oza S, Danaei G, Murray CJ. Trends and cardiovascular mortality effects of state-level blood pressure and uncontrolled hypertension in the United States. Circulation 2008;117:905-14.

2110 BACK to TOC

Mellen PB, Gao SK, Vitolins MZ, Goff DC Jr. Deteriorating dietary habits among adults with hypertension: DASH dietary accordance, NHANES 1988-1994 and 19992004. Arch Intern Med 2008;168:308-14. 8. Blanck HM, Gillespie C, Kimmons JE, Seymour JD, Serdula MK. Trends in fruit and vegetable consumption among U.S. men and women, 1994-2005. Prev Chronic Dis 2008;5:A35. 9. Okosun IS, Prewitt TE, Cooper RS. Abdominal obesity in the United States: prevalence and attributable risk of hypertension. J Hum Hypertens 1999;13:425-30. 10. Saile F. Uber den einflus der vegetarischen ernahrung auf den blutdruck. Med Klin 1930;25:929-31. 11. Sacks FM, Rosner B, Kass EH. Blood pressure in vegetarians. Am J Epidemiol 1974;100:390-8. 12. Sacks FM, Kass EH. Low blood pressure in vegetarians: the effects of specific foods and nutrients. Am J Clin Nutr 1988; 48:Suppl:795-800. 13. Epstein FH, Eckoff RD. The epidemiology of high blood pressure — geographic distributions and etiological factors. In: Stamler J, Stamler R, Pullman TN, eds. The epidemiology of hypertension. New York: Grune & Stratton, 1967:155-66. 14. Rodriguez BL, Labarthe DR, Huang B, Lopez-Gomez J. Rise in blood pressure with age: new evidence of population differences. Hypertension 1994;24:779-85. 7.

n engl j med 362;22

nejm.org

15. Elliott P, Stamler J, Nichols R, et al.

Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure within and across populations. BMJ 1996; 312:1249-53. [Erratum, BMJ 1997;315:458.] 16. Adrogué HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356:1966-78. 17. Primary hypertension: pathogenesis. In: Kaplan NM. Kaplan’s clinical hypertension. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2006:50-121. 18. O’Shaughnessy KM, Karet FE. Salt handling and hypertension. Annu Rev Nutr 2006;26:343-65. 19. Blacher J, Safar ME. Large-artery stiffness, hypertension and cardiovascular risk in older patients. Nat Clin Pract Cardiovasc Med 2005;2:450-5. 20. Berk BC. Biology of the vascular wall in hypertension. In: Brenner BM, ed. Brenner & Rector’s the kidney. 7th ed. Vol. 2. Philadelphia: Saunders Elsevier, 2004:19992022. 21. Gates PE, Strain WD, Shore AC. Human endothelial function and microvascular ageing. Exp Physiol 2009;94:311-6. 22. de Jongh RT, Serné EH, Ijzerman RG, Stehouwer CD. Microvascular function: a potential link between salt sensitivity, insulin resistance and hypertension. J Hypertens 2007;25:1887-93. 23. Lee MA, Böhm M, Paul M, Ganten D. Tissue renin-angiotensin systems: their

june 3, 2010

88

clinical ther apeutics role in cardiovascular disease. Circulation 1993;87:Suppl:IV-7–IV-13. 24. Re RN. Mechanisms of disease: local renin-angiotensin-aldosterone systems and the pathogenesis and treatment of cardiovascular disease. Nat Clin Pract Cardiovasc Med 2004;1:42-7. 25. Landsberg L, Young JB. Diet and the sympathetic nervous system: relationship to hypertension. Int J Obes 1981;5:Suppl 1:79-91. 26. Esler M, Straznicky N, Eikelis N, Masuo K, Lambert G, Lambert E. Mechanisms of sympathetic activation in obesityrelated hypertension. Hypertension 2006; 48:787-96. 27. Victor RG, Shafiq MM. Sympathetic neural mechanisms in human hypertension. Curr Hypertens Rep 2008;10:241-7. 28. Feldstein C, Julius S. The complex interaction between overweight, hypertension, and sympathetic overactivity. J Am Soc Hypertens 2009;3:353-65. 29. Hall JE, Hildebrandt DA, Kuo J. Obesity hypertension: role of leptin and sympathetic nervous system. Am J Hypertens 2001;14:103S-115S. 30. Hall JE. The kidney, hypertension, and obesity. Hypertension 2003;41:625-33. 31. Seals DR, Moreau KL, Gates PE, Eskurza I. Modulatory influences on ageing of the vasculature of healthy humans. Exp Gerontol 2006;41:501-7. 32. Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney disease: the role of fetal programming. Hypertension 2006;47:502-8. 33. Sealey JE, Blumenfeld JD, Bell GM, Pecker MS, Sommers SC, Laragh JH. On the renal basis for essential hypertension: nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasocontrictionvolume relationship. J Hypertens 1988;6: 763-77. 34. Safar ME, Temmar M, Kakou A, Lacolley P, Thornton SN. Sodium intake and vascular stiffness in hypertension. Hypertension 2009;54:203-9. 35. Engeli S, Böhnke J, Gorzelniak K, et al. Weight loss and the renin-angiotensinaldosterone system. Hypertension 2005;45: 356-62. 36. Ho JT, Keogh JB, Bornstein SR, et al. Moderate weight loss reduces renin and aldosterone but does not influence basal or stimulated pituitary-adrenal axis function. Horm Metab Res 2007;39:694-9. 37. Straznicky NE, Lambert EA, Lambert GW, Masuo K, Esler MD, Nestel PJ. Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome. J Clin Endocrinol Metab 2005;90:5998-6005. 38. Straznicky NE, Lambert EA, Nestel PJ, et al. Sympathetic neural adaptation to hypocaloric diet with or without exercise training in obese metabolic syndrome subjects. Diabetes 2010;59:71-9.

39. Rocchini AP, Key J, Bondie D, et al.

The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989;321:580-5. 40. Pierce GL, Beske SD, Lawson BR, et al. Weight loss alone improves conduit and resistance artery endothelial function in young and older overweight/obese adults. Hypertension 2008;52:72-9. 41. Akita S, Sacks FM, Svetkey LP, Conlin PR, Kimura G. Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on pressure-natriuresis relationship. Hypertension 2003;42:8-13. 42. Al-Solaiman Y, Jesri A, Zhao Y, Morrow JD, Egan BM. Low-sodium DASH reduces oxidative stress and improves vascular function in salt-sensitive humans. J Hum Hypertens 2009;23:826-35. 43. Rallidis LS, Lekakis J, Kolomvotsou A, et al. Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity. Am J Clin Nutr 2009;90:263-8. 44. McCall DO, McGartland CP, McKinley MC, et al. Dietary intake of fruits and vegetables improves microvascular function in hypertensive subjects in a dose-dependent manner. Circulation 2009;119:2153-60. 45. Sacks FM, Obarzanek E, Windhauser MM, et al. Rationale and design of the Dietary Approaches to Stop Hypertension trial (DASH): a multicenter controlledfeeding study of dietary patterns to lower blood pressure. Ann Epidemiol 1995;5: 108-18. 46. Swain JF, McCarron PB, Hamilton EF, Sacks FM, Appel LJ. Characteristics of the dietary patterns tested in the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart): options for a hearthealthy diet. J Am Diet Assoc 2008;108: 257-65. 47. Trichopoulou A. Mediterranean diet: the past and the present. Nutr Metab Cardiovasc Dis 2001;11:Suppl:1-4. 48. Kokkinos P, Panagiotakos DB, Polychronopoulos E. Dietary influences on blood pressure: the effect of the Mediterranean diet on the prevalence of hypertension. J Clin Hypertens (Greenwich) 2005; 7:165-70. 49. Appel LJ, Moore TJ, Obarzanek E, et al. The effect of dietary patterns on blood pressure: results from the Dietary Approaches to Stop Hypertension trial. N Engl J Med 1997;336:1117-24. 50. Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA 2005;294: 2455-64. 51. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292:1440-6.

n engl j med 362;22 BACK to TOC

nejm.org

52. Esposito K, Maiorino MI, Ciotola M,

et al. Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med 2009;151:306-14. [Erratum, Ann Intern Med 2009;151:591.] 53. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001;344:3-10. 54. Bray GA, Vollmer WM, Sacks FM, Obarzanek E, Svetkey LP, Appel LJ. A further subgroup analysis of the effects of the DASH diet and three dietary sodium levels on blood pressure: results of the DASH-Sodium Trial. Am J Cardiol 2004; 94:222-7. [Erratum, Am J Cardiol 2010;105: 579.] 55. Goff DC, Howard G, Russell GB, Labarthe DR. Birth cohort evidence of population influences on blood pressure in the United States, 1887-1994. Ann Epidemiol 2001;11:271-9. 56. Uzu T, Kimura G, Yamauchi A, et al. Enhanced sodium sensitivity and disturbed circadian rhythm of blood pressure in essential hypertension. J Hypertens 2006;24: 1627-32. 57. Chen J, Gu D, Huang J, et al. Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study. Lancet 2009;373:829-35. 58. Obarzanek E, Proschan MA, Vollmer WM, et al. Individual blood pressure responses to changes in salt intake: results from the DASH-Sodium trial. Hypertension 2003;42:459-67. 59. Blumenthal JA, Babyak MA, Hinderliter A, et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med 2010;170:126-35. 60. Conlin PR, Erlinger TP, Bohannon A, et al. The DASH diet enhances the blood pressure response to losartan in hypertensive patients. Am J Hypertens 2003;16: 337-42. 61. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA 1998;279:839-46. 62. Pimenta E, Gaddam KK, Oparil S, et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension. Hypertension 2009;54:47581. 63. Grimes CA, Riddell LJ, Nowson CA. Consumer knowledge and attitudes to salt intake and labelled salt information. Appetite 2009;53:189-94. 64. Karanja N, Lancaster KJ, Vollmer WM, et al. Acceptability of sodium-reduced re-

june 3, 2010

2111

89

clinical ther apeutics search diets, including the Dietary Approaches to Stop Hypertension diet, among adults with prehypertension and stage 1 hypertension. J Am Diet Assoc 2007;107: 1530-8. 65. Salt-assault: brand-name comparisons of processed foods. 2nd ed. Washington, DC: Center for Science and the Public Interest, 2008:1-31. (Accessed May 7, 2010, at http://www.cspinet.org/new/pdf/ saltupdatedec08.pdf.) 66. Pear R. New health initiatives put spotlight on prevention. New York Times. April 5, 2010:A10. (Accessed May 7, 2010, at http://www.nytimes.com/2010/04/05/ health/policy/05health.html.) 67. Rankins J, Sampson W, Brown B, Jenkins-Salley T. Dietary Approaches to Stop Hypertension (DASH) intervention reduces blood pressure among hypertensive African American patients in a neighborhood health care center. J Nutr Educ Behav 2005;37:259-64. 68. Svetkey LP, Stevens VJ, Brantley PJ, et al. Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial. JAMA 2008; 299:1139-48. 69. Hsieh YC, Hung CT, Lien LM, et al. A significant decrease in blood pressure through a family-based nutrition health education programme among community residents in Taiwan. Public Health Nutr 2008;12:570-7. 70. Wood DA, Kotseva K, Connolly S, et al. Nurse-coordinated multidisciplinary, family-based cardiovascular disease prevention programme (EUROACTION) for

patients with coronary heart disease and asymptomatic individuals at high risk of cardiovascular disease: a paired, clusterrandomised controlled trial. Lancet 2008; 371:1999-2012. 71. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009;360: 859-73. 72. Eriksson MK, Franks PW, Eliasson M. A 3-year randomized trial of lifestyle intervention for cardiovascular risk reduction in the primary care setting: the Swedish Björknäs study. PLoS One 2009;4(4):e5195. 73. Oldways Web site. (Accessed May 7, 2010, at http://www.oldwayspt.org.) 74. Mediterranean Foods Alliance Web site. (Accessed May 7, 2010, at http:// mediterraneanmark.org/index.html.) 75. MayoClinic.com. DASH diet recipes. (Accessed May 7, 2010, at http://www .mayoclinic.com/health/dash-diet-recipes/ RE00089.) 76. DASH for Health Web site. (Accessed May 7, 2010, at http://www.dashforhealth .com.) 77. Katzen M, Willett W. Eat, drink, and weigh less: a flexible and delicious way to shrink your waist without going hungry. New York: Hyperion, 2006. 78. Your guide to lowering your blood pressure with DASH. Bethesda, MD: National Heart, Lung, and Blood Institute, 2006. 79. Moore T, Svetkey L, Lin PH, Karanja N. The DASH diet for hypertension. New York: Free Press, 2001:1-264.

80. American Heart Association. No-fad

diet: a personal plan for healthy weight loss. New York: Clarkson Potter, 2005. 81. Young CM, Batch BC, Svetkey LP. Effect of socioeconomic status on food availability and cost of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern. J Clin Hypertens (Greenwich) 2008;10:603-11. 82. Williamson DA, Anton SD, Han H, et al. Adherence is a multi-dimensional construct in the POUNDS LOST trial. J Behav Med 2010;33:35-46. 83. Cook NR, Cutler JA, Obarzanek E, et al. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the Trials of Hypertension Prevention (TOHP). BMJ 2007;334:885-8. 84. Chang HY, Hu YW, Yue CS, et al. Effect of potassium-enriched salt on cardiovascular mortality and medical expenses of elderly men. Am J Clin Nutr 2006;83: 1289-96. 85. Appel LJ, Brands DW, Daniels SR, Karanja N, Elmer PJ, Sacks FM. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension 2006;47:296-308. 86. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 2006;114:82-96. [Errata, Circulation 2006;114(1):e27, 114(23): e629.] Copyright © 2010 Massachusetts Medical Society.

COLLECTIONS OF ARTICLES ON THE JOURNAL’S WEB SITE

The Journal’s Web site (NEJM.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.

2112 BACK to TOC

n engl j med 362;22

nejm.org

june 3, 2010

90

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical therapeutics

Mitral-Valve Repair for Mitral-Valve Prolapse Subodh Verma, M.D., Ph.D., and Thierry G. Mesana, M.D., Ph.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors’ clinical recommendations.

A 55-year-old man with a holosystolic murmur of increasing intensity has been seen regularly by his family physician for the past 3 years. He is referred to a cardiologist. The patient reports no shortness of breath, chest pain, or palpitations. An electrocardiogram shows normal sinus rhythm. A transthoracic echocardiogram reveals severe, anteriorly directed mitral regurgitation with isolated prolapse of the middle scallop of the posterior leaflet. Flow reversal is detected in the pulmonary veins. The calculated regurgitant volume is 75 ml, the regurgitant fraction 63%, and the effective regurgitant orifice 53 mm2, features consistent with severe mitral regurgitation. The transthoracic echocardiogram also shows mildly depressed left ventricular function (ejection fraction, 58%), slightly elevated left ventricular dimensions (end-systolic dimension, 42 mm), and normal right ventricular systolic pressure. The patient is referred to a cardiac surgeon for consideration of mitral-valve repair.

The Cl inic a l Probl em Mitral-valve prolapse is defined as the displacement of some portion of one or both leaflets of the mitral valve into the left atrium during systole. In developed countries, it is the most common cause of chronic mitral regurgitation; in a study of the Framingham Offspring Study cohort, the prevalence of mitral-valve prolapse was 2.5%.1 More than 150 million people worldwide may be affected.2-4 The disorder has both genetic and acquired forms, and several chromosomal loci for autosomal dominant mitral-valve prolapse have been identified.5-9 Although mitral-valve prolapse is more common in women, more men are referred for surgery4; whether this reflects a difference between the sexes in the morphologic features or natural history of the disorder or referral bias is unclear. The natural history of mitral-valve prolapse is heterogeneous and is largely determined by the severity of mitral regurgitation. Although a majority of patients remain asymptomatic and may have a near-normal life expectancy, approximately 5 to 10% have progression to severe mitral regurgitation.10,11 Left untreated, mitralvalve prolapse with severe mitral regurgitation results in limiting symptoms, left ventricular dysfunction, heart failure, pulmonary hypertension, and atrial fibrillation. Spontaneous rupture of mitral chordae may occur, and endocarditis and stroke are serious complications. The mortality rate of persons who have mitral-valve prolapse with severe mitral regurgitation is approximately 6 to 7% per year.12,13

From the Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Toronto (S.V.); and the Division of Cardiac Surgery, Ottawa Heart Institute, University of Ottawa, Ottawa (T.G.M.). Address reprint requests to Dr. Verma at St. Michael’s Hospital, University of Toronto, 30 Bond St., Toronto, ON M5B 1W8, Canada, or at [email protected]. N Engl J Med 2009;361:2261-9. Copyright © 2009 Massachusetts Medical Society.

Pathoph ysiol o gy a nd the Effec t of Ther a py The mitral valve and subvalvular apparatus include the annulus, valve leaflets, chordae tendineae, papillary muscles, and left ventricular wall. The valve has anterior and posterior leaflets, and each leaflet typically consists of three discrete segments or scallops. These are designated P1, P2, and P3 in the posterior mitral-valve leaflet, n engl j med 361;23 BACK to TOC

nejm.org

december 3, 2009

2261

91

The

n e w e ng l a n d j o u r na l

A

of

m e dic i n e

Aortic valve

Left coronary artery

Right fibrous trigone Bundle of His

Left fibrous trigone

Anterior leaflet

AC

Circumflex artery

PC

Posterior leaflet Coronary sinus

Annulus

B

C

Annulus Leaflet

AC

A3

A1 P1

A2

Secondary cord

PC Primary cord

P3

P2 Papillary muscle

Figure 1. The Mitral Valve. The mitral valve has anterior and posterior leaflets, which are separated by the anterior commissure (AC) and the posterior commissure (PC) (Panel A). The leaflets are inserted on the circumference of the mitral annulus, which is in continuity with the aortic annulus and the left and right fibrous trigones. The circumflex coronary artery, coronary sinus, aortic valve, and bundle of His are all close to the mitral valve. Panel B shows the mitral-valve leaflets, each of which usually consists of three discrete segments or scallops. These are designated A1, A2, and A3 for the anterior leaflet and P1, P2, and P3 for the posterior leaflet. The valve leaflets each receive chordae tendineae from the anterolateral and posteromedial papillary muscles (Panel C). Primary chordae are attached to the free edge of the valve leaflet, and secondary chordae are attached to the ventricular surface of the leaflet.

and A1, A2, and A3 in the anterior leaflet (Fig. 1). muscles. Competence of the mitral valve relies on The valve leaflets receive chordae tendineae from coordinated interaction of the valve and subvalvuthe anterolateral and posteromedial papillary lar apparatus. During systole, the papillary mus2262 BACK to TOC

n engl j med 361;23

nejm.org

december 3, 2009

92

clinical ther apeutics

cles contract, increasing tension on the chordae tendineae and preventing the valve leaflets from everting into the left atrium. Mitral-valve prolapse is characterized predominantly by myxomatous degeneration. In younger patients, the disease is often manifested by excess leaflet tissue and is known as Barlow’s syndrome, the most extreme form of myxomatous degeneration. On the other hand, in older patients, the prolapsing mitral valve tends not to have excess leaflet tissue, an entity known as fibroelastic deficiency. Both conditions can lead to leaflet prolapse and chordal elongation or rupture, representing the spectrum of degenerative mitral-valve disease.14 These anatomic abnormalities result in the mitral orifice not closing completely during systole, causing regurgitation. Annular dilatation may also develop over time, leading to further progression of mitral regurgitation. Patients with mild-to-moderate mitral regurgitation from mitral-valve prolapse may remain asymptomatic and without clinical deterioration for many years. However, increasing severity of mitral regurgitation, even among asymptomatic patients, imposes a volume load on the left ventricle, which, if sustained over time, results in ventricular dilatation, hypertrophy, neurohumoral activation, and heart failure. In addition, elevation in the mean left atrial pressure leads to left atrial enlargement, atrial fibrillation, pulmonary congestion, and pulmonary hypertension. The goal of surgical correction for mitral-valve prolapse is to restore a competent mitral valve. There are two options for surgical correction of severe mitral regurgitation due to mitral-valve prolapse: valve replacement or valve repair. Mitral-valve replacement can be performed with the use of either a mechanical or a biologic prosthesis. However, there are several drawbacks to mitral-valve replacement. These include the need for lifelong anticoagulation therapy and the risk of thromboembolism with the use of mechanical valves; the risk of prosthetic-valve deterioration and failure with the use of bioprosthetic valves; and the risk of prosthetic-valve endocarditis. In addition, if the chordae tendineae are severed during surgery, the ventricular wall is no longer anchored to the valve apparatus, and the tethering effect of the chordae is lost. As a result, left ventricular wall stress increases and left ventricular function deteriorates.15-19 The goals of mitral-valve repair are to obtain a proper line of coaptation on both leaflets, to correct annular n engl j med 361;23 BACK to TOC

dilatation, and to preserve (or repair, if necessary) the subvalvular apparatus.

Cl inic a l E v idence We are unaware of any randomized trials that have compared medical management to surgery for severe mitral regurgitation due to mitral-valve prolapse. However, evidence from observational series strongly suggests that surgical intervention is beneficial.12,20-22 One study evaluated the effect of early surgery on long-term outcomes in 221 patients who had mitral regurgitation with flail leaflets.20 The 63 patients undergoing surgery within 1 month after diagnosis had a significantly better 10-year survival rate than those whose mitral regurgitation was managed conservatively (79% vs. 65%; adjusted risk ratio, 0.30; 95% confidence interval [CI], 0.12 to 0.71; P = 0.008). In another report, 394 patients with mitral regurgitation and flail leaflets were studied.21 During a median follow-up period of 3.9 years, the linearized mortality rate associated with nonsurgical management was 2.6% per year. Mitral-valve surgery was performed in 315 patients (repair in 250, replacement in 65). Surgical intervention was independently associated with a reduced risk of death (adjusted hazard ratio for death, 0.42; 95% CI, 0.21 to 0.84; P = 0.01). To our knowledge, there are also no randomized trials comparing mitral-valve repair with replacement. Again, however, data from observational studies suggest a benefit of mitral repair.23-26 A meta-analysis of 29 studies compared mitral-valve repair with replacement for various conditions, including myxomatous degeneration.23 Mitral-valve replacement was associated with lower survival than was repair (hazard ratio for death, 1.58; 95% CI, 1.41 to 1.78). In a study from Finland, mitral-valve repair was compared with replacement in 184 consecutive patients who were followed for a mean of 7.3 years.24 There was a significant survival benefit for the patients who underwent mitral-valve repair as compared with those who underwent replacement (5-year survival, 81.2% vs. 73.5%), which persisted after adjustment for baseline propensity score (P = 0.02). In contrast, in a report from the Cleveland Clinic, 3286 patients who underwent an isolated primary operation for degenerative mitral-valve disease (mitral repair, 93%; mitral replacement, 7%) between 1985 and 2005 were studied.25 Propensity scoring was

nejm.org

december 3, 2009

2263

93

The

n e w e ng l a n d j o u r na l

used to select 195 matched pairs for analysis. Among the propensity-matched patients, there was no significant difference in survival at 5, 10, or 15 years.

Cl inic a l Use Patients with mitral-valve prolapse should have a careful assessment of symptoms and should undergo electrocardiography (primarily to evaluate cardiac rhythm) and transthoracic echocardiography to assess the mechanism and severity of mitral regurgitation, as well as left ventricular size and function. A semiquantitative scale is often used to grade mitral regurgitation: 1+ (trace), 2+ (mild), 3+ (moderate), and 4+ (severe). However, quantitative Doppler assessments are recommended to define severe mitral regurgitation more precisely; these variables include a regurgitant volume of at least 60 ml, a regurgitant fraction of at least 50%, and an effective regurgitant orifice of at least 40 mm2.27 Patients who have severe mitral regurgitation with symptoms or with left ventricular dysfunction (ejection fraction, <60%), dilatation (left ventricular end-systolic dimension, >40 mm), or both should be offered surgery.28,29 Likewise, asymptomatic patients without left ventricular dysfunction or dilatation but with atrial fibrillation or pulmonary hypertension should be considered for surgery. Asymptomatic persons with mild-to-moderate mitral regurgitation and no evidence of left ventricular dysfunction or dilatation should be observed until the development of either symptoms or severe mitral regurgitation. Before the advent of mitral-valve repair, valve replacement was the preferred procedure for severe mitral regurgitation. Valve replacement may still be preferred in certain situations, such as in patients with advanced age, infective endocarditis, a requirement for a combined or complex surgical procedure, or extensive calcifications of the leaflets or annulus. In such cases, chordalsparing valve replacement for mitral regurgitation may be a suitable alternative to repair. Individual and institutional experience is crucial in determining the likelihood of success of a repair procedure. High-volume centers have the lowest mortality rates and the highest proportion of patients undergoing mitral-valve repair rather than replacement.30 In counseling the patient, the surgeon should precisely evaluate the likelihood of successful repair in light of his or 2264 BACK to TOC

n engl j med 361;23

of

m e dic i n e

her own experience and may recommend a second opinion. If there is a possibility that intraoperative conversion to mitral replacement may be necessary, the decision between a mechanical valve and a bioprosthesis should be discussed with the patient before the operation. Mitral-valve surgery is not recommended in patients with clinically significant coexisting conditions, such as advanced respiratory, hepatic, or renal dysfunction, or those with marked extracardiac arteriopathy or recent cerebrovascular events. Depressed left ventricular function is an independent predictor of poor outcomes but is not a contraindication to mitral-valve repair.31 In patients with coexisting coronary artery disease, mitral-valve repair combined with coronaryartery bypass surgery should be the procedure of choice.32 Two validated scoring systems for determining risk during cardiac surgery are commonly used to determine perioperative risk.33,34 We routinely perform intraoperative transesophageal echocardiography during all mitralvalve repair procedures.28,29 Transesophageal echocardiography provides precise anatomic and functional information that is helpful in planning the operation, including the extent of leaflet deformity, the mechanism and severity of mitral regurgitation, the condition of the subvalvular apparatus, the diameter of the mitral annulus, left atrial dimensions, and ventricular function.35 Successful mitral-valve repair encompasses four general principles.36 First, repair must restore an adequate surface of coaptation of both leaflets in systole.14,37 Second, full leaflet motion should be restored or preserved. Third, to prevent progressive dilatation, an annuloplasty ring or band should be used to reinforce the repair by stabilizing the annulus. Mitral-valve repair without annuloplasty reinforcement is not recommended. Last, the surgeon should ensure that no more than trace-to-mild mitral regurgitation is present at the completion of the repair. In patients with isolated prolapse of the posterior middle scallop (P2), which is encountered in the majority of patients with degenerative mitral regurgitation, repair usually involves limited resection of this scallop, including the removal of the minimum number possible of adjacent chordae and supporting apparatus. The remaining segments of the posterior leaflet, namely P1 and P3, are then brought together (Fig. 2). If excessive posterior-leaflet tissue is present, the

nejm.org

december 3, 2009

94

clinical ther apeutics

A

Isolated prolapse of the posterior middle scallop

B

A1

B1

P1

P2

Excessive tissue

P3

Incision line Incision lines

A2

Resected area

B2

Resected area

Plication sutures

A3

B3

Reapproximation of remaining tissue

Completed sliding plasty

A4

B4

Annuloplasty ring

Annuloplasty ring

Figure 2. Mitral-Valve Prolapse. The most common leaflet abnormality seen in mitral-valve prolapse is isolated prolapse of the posterior middle scallop (P2) (Panel A1). In patients with isolated prolapse of P2, repair usually involves limited resection of this scallop by means of a quadrangular or triangular incision (Panel A2). The remaining parts of the posterior leaflet, namely P1 and P3, are then brought together (Panel A3). After the leaflet repair is complete, an annuloplasty ring or band is used to reinforce and stabilize the annulus, thus preventing progressive dilatation (Panel A4). If excessive posterior leaflet tissue is present (Panel B1), the height of the posterior leaflet is reduced by incising P1 and P3 from the annulus (Panel B2), followed by reapproximation of the free edges (“sliding plasty”) (Panel B3). After the leaflet repair is complete, an annuloplasty ring or band is inserted (Panel B4).

n engl j med 361;23 BACK to TOC

nejm.org

december 3, 2009

2265

95

The

n e w e ng l a n d j o u r na l

height of the posterior leaflet is reduced by incisions in P1 and P3, followed by reapproximation of the free edges (“sliding plasty”) (Fig. 2). Finally, the annulus, which is distorted or dilated or both, is stabilized with an annuloplasty ring or band (Fig. 2). Limited resection, artificial chordal replacement (with Gore-Tex expanded polytetrafluoroethylene sutures), or both may be appropriate, followed by annuloplasty reinforcement, in cases of mitral-valve prolapse without redundant leaflet tissue. Repairs of the anterior leaflet, either in isolation or with concomitant posterior leaflet repair, are more complex procedures that are best handled by surgeons who are experienced in mitral repair. Various techniques may be used, including limited triangular resection of the anterior leaflet, chordal transposition, chordal shortening, artificial (Gore-Tex) chordal replacement, and edge-to-edge repair10,21,28,38-41 (Fig. 3). The repair is assessed initially by visual inspection and by injecting saline through the mitral valve to look for regurgitation (the “saline test”), and then by intraoperative transesophageal echocardiography after the patient is weaned from cardiopulmonary bypass. Patients should not leave the operating theater with more than 1+ mitral regurgitation on transesophageal echocardiography.36,42 Since anesthesia may result in substantial changes in preload and afterload, it is important to perform the intraoperative transesophageal echocardiography under conditions that approximate postoperative conditions in a patient who is awake. This can be achieved by adjusting inotropes and vasopressors to raise the afterload and blood pressure. After mitral-valve repair, the left ventricle must be able to eject the entire stroke volume into the aorta. This constitutes a substantial increase in afterload as compared with ejection into the left atrium. Therefore, afterload reduction is important to maintain optimal cardiac output. In addition, because myocardial dysfunction may be present (even in patients with an apparently normal preoperative ejection fraction),43 inotropic support may be necessary to improve contractility. Patients with a low preoperative ejection fraction and heart failure may require more intensive treatment to allow the left ventricle to recover, including temporary pacing, intraaortic balloon counterpulsation, or in rare cases, support with a ventricular assist device. 2266 BACK to TOC

n engl j med 361;23

of

m e dic i n e

In the absence of preoperative atrial fibrillation, and if normal sinus rhythm is maintained throughout hospital admission, aspirin alone may be sufficient for patients who had mitral-valve repair with ring annuloplasty. Otherwise, patients typically undergo anticoagulation with warfarin for 3 months, with a target international normalized ratio of 2.0 to 2.5. Antibiotic prophylaxis for dental procedures is recommended in all patients receiving an annuloplasty ring or other prosthetic material.44 There are currently no standard recommendations regarding postoperative echocardiographic follow-up after mitral-valve repair. It is customary at our center to perform transthoracic echocardiography once before discharge and again at 6 to 8 weeks after discharge. Usually patients are then transferred to the care of their cardiologist and family physician, and we recommend that echocardiography be performed annually thereafter. We estimate that the overall costs for mitralvalve repair, including hospital admission, professional fees, operating time, and prosthetic material (annuloplasty ring or band), are currently approximately $40,000 at our institution. Data from the Nationwide Inpatient Sample indicate that the mean estimated institutional cost for mitral repair in the United States increased from $28,405 in 2001 to $38,642 in 2005.45

A dv er se Effec t s Mitral-valve repair is associated with an operative mortality of 3% or less.22,38,46-50 This figure is nearer 1% in high-volume centers.30 The most common cause of death is heart failure. Predictors of death include advanced age, poorer New York Heart Association class, atrial fibrillation, lower preoperative ejection fraction, greater preoperative left ventricular end-systolic dimension, and coexisting conditions including diabetes, renal disease, chronic lung disease, and obesity.22,38,51,52 In an analysis from the Society of Thoracic Surgeons National Adult Cardiac Surgery Database,52 major postoperative complications before discharge included prolonged (>24 hours) ventilatory support (7.3% of patients), renal failure (2.6%), and stroke (1.4%). Reoperation during initial hospitalization was required in 6.3% of patients. Thromboembolism after mitral-valve repair occurs in approximately 5% of patients within the first 5 years after surgery.38,39

nejm.org

december 3, 2009

96

clinical ther apeutics

Figure 3. Special Repair Techniques. Ruptured chordae tendineae can be replaced with an artificial substitute (Gore-Tex expanded polytetrafluoroethylene sutures) (Panel A). Ruptured or surgically severed primary chordae can be replaced with secondary chordae, a process called chordal transfer (Panel B). Edge-to-edge repair (Panel C) is performed by sewing the anterior and posterior leaflets together at the central points of their middle scallops, which corrects the prolapse while leaving two functional valve orifices on each side.

Intraoperative conversion to mitral-valve replacement occurs in 2 to 10% of cases. Systolic anterior motion of the mitral valve may occur postoperatively if leaflet coaptation is not optimal, and mitral stenosis can occur if the annuloplasty ring is too small. Other rare adverse effects of mitral-valve repair include damage to important structures around the mitral apparatus, such as the circumflex coronary artery, the aortic valve, and the bundle of His. The most important late complication of mitral-valve repair is recurrent mitral regurgitation, which may occur in as many as 30% of patients.36 Reoperation to treat recurrent mitral regurgitation after primary repair is required in approximately 0.5 to 1.5% of patients per year.49,51

Chordal replacement

A

Ruptured chorda tendinea

Gore-Tex sutures

Chordal transfer

B

Missing primary chorda tendinea Secondary chorda tendinea

A r e a s of Uncer ta in t y We are unaware of any randomized trials that have compared mitral-valve repair with mitralvalve replacement for mitral-valve prolapse, and it is unlikely that such a trial will be conducted. Therefore, the current recommendation for mitralvalve repair in the treatment of severe degenerative mitral regurgitation is based on observational data. It is unclear whether asymptomatic patients who have severe mitral regurgitation without left ventricular dysfunction or dilatation, atrial fibrillation, or pulmonary hypertension should undergo early surgery. Some investigators have found evidence of reduced morbidity and mortality with surgery and recommend early intervention,22,50 whereas others have found that watchful waiting does not seem to result in worse outcomes.46 The guidelines of the American Heart Association (AHA) and the American College of Cardiology (ACC) recommend mitral-valve repair for such patients if the operative success rate is expected to exceed 90%.28,29 Conversely, the European Son engl j med 361;23 BACK to TOC

Transfer

Edge-to-edge repair

C

nejm.org

Annuloplasty ring Anterior leaflet

Posterior leaflet

december 3, 2009

2267

97

The

n e w e ng l a n d j o u r na l

ciety of Cardiology (ESC) recommends watchful waiting.53 There is growing experience with minimally invasive mitral-valve repair performed through a right minithoracotomy. In a single-center series involving 1339 patients, the 30-day mortality rate was 2.4%, the 5-year survival rate was estimated to be 82.6%, and the reoperation rate was 3.7%.54 These results are similar to those obtained with traditional mitral-valve repair. This approach requires further evaluation with respect to widespread generalizability and cost-effectiveness; it is currently performed at only a few specialized centers.

Guidel ine s The ACC and the AHA established guidelines for the management of valvular disease in 2006, with an update in 2008.28,29 These guidelines gave a class I recommendation to mitral-valve surgery for chronic severe mitral regurgitation in the presence of symptoms, a left ventricular ejection fraction of less than 60%, or an end-systolic dimension of more than 40 mm. Mitral-valve repair was recommended over replacement for most patients (class I recommendation). The guidelines advise that such persons be referred to surgical centers at which the surgeons are experienced in mitral-valve repair. The ESC guidelines of 2007 made similar recommendations.53 As noted above, References 1. Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of mitralvalve prolapse. N Engl J Med 1999;341:1-7. 2. The changing spectrum of valvular heart disease pathology. In: Braunwald E, ed. Harrison’s advances in cardiology. New York: McGraw-Hill, 2002:317-23. 3. Hayek E, Gring CN, Griffin BP. Mitral valve prolapse. Lancet 2005;365:507-18. 4. Avierinos JF, Inamo J, Grigioni F, Gersh B, Shub C, Enriquez-Sarano M. Sex differences in morphology and outcomes of mitral valve prolapse. Ann Intern Med 2008;149:787-95. 5. Shell WE, Walton JA, Clifford ME, Willis PW III. The familial occurrence of the syndrome of mid-late systolic click and late systolic murmur. Circulation 1969;39:327-37. 6. Devereux RB, Brown WT, Kramer-Fox R, Sachs I. Inheritance of mitral valve prolapse: effect of age and sex on gene expression. Ann Intern Med 1982;97:826-32. 7. Disse S, Abergel E, Berrebi A, et al. Mapping of a first locus for autosomal dominant myxomatous mitral-valve pro-

2268 BACK to TOC

of

m e dic i n e

the societies differ somewhat in terms of their recommendations for patients who have asymptomatic mitral-valve prolapse with severe mitral regurgitation but normal left ventricular volumes and function; the ACC–AHA guidelines give a class IIA recommendation in this regard.

R ec om mendat ions The patient in the vignette is asymptomatic but has signs of ventricular dysfunction and elevated left ventricular dimensions. He should therefore be offered mitral-valve surgery and should be referred to a center with demonstrated expertise in mitral-valve repair. His operative risk should be formally assessed with the use of one of the validated risk-scoring algorithms. Intraoperative transesophageal echocardiography should be performed to provide a detailed anatomical and functional assessment at the time of surgery that would permit a final decision to be made about the specifics of the operative procedure. Unless severe deformity of the valve leaflets or subvalvular apparatus is present, we would recommend mitral-valve repair rather than replacement. Since mitral-valve prolapse is often genetically transmitted, it may be worth considering echocardiographic screening of first-degree relatives.

Dr. Mesana reports receiving honoraria from Medtronic. No other potential conflict of interest relevant to this article was reported. We thank Dr. Gilbert Tang for assistance in preparation of the manuscript.

lapse to chromosome 16p11.2-p12.1. Am J Hum Genet 1999;65:1242-51. 8. Freed LA, Acierno JS Jr, Dai D, et al. A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4. Am J Hum Genet 2003;72:1551-9. 9. Nesta F, Leyne M, Yosefy C, et al. New locus for autosomal dominant mitral valve prolapse on chromosome 13: clinical insights from genetic studies. Circulation 2005;112:2022-30. 10. Barlow JB, Pocock WA. Mitral valve prolapse, the specific billowing mitral leaflet syndrome, or an insignificant nonejection systolic click. Am Heart J 1979; 97:277-85. 11. Abrams J. Mitral valve prolapse: a plea for unanimity. Am Heart J 1976;92:413-5. 12. Ling LH, Enriquez-Sarano M, Seward JB, et al. Clinical outcome of mitral regurgitation due to flail leaflet. N Engl J Med 1996;335:1417-23. 13. Rosen SE, Borer JS, Hochreiter C, et al. Natural history of the asymptomatic/ minimally symptomatic patient with severe mitral regurgitation secondary to

n engl j med 361;23

nejm.org

mitral valve prolapse and normal right and left ventricular performance. Am J Cardiol 1994;74:374-80. 14. Filsoufi F, Salzberg SP, Aklog L, Adams DH. Acquired disease of the mitral valve. In: Selke F, Swanson S, del Nido P, eds. Sabiston and Spencer surgery of the chest. 7th ed. Philadelphia: Elsevier Saunders, 2005:1299-333. 15. Pitarys CJ II, Forman MB, Panayiotou H, Hansen DE. Long-term effects of excision of the mitral apparatus on global and regional ventricular function in humans. J Am Coll Cardiol 1990;15:557-63. 16. Goldman ME, Mora F, Guarino T, Fuster V, Mindich BP. Mitral valvuloplasty is superior to valve replacement for preservation of left ventricular function: an intraoperative two-dimensional echocardiographic study. J Am Coll Cardiol 1987; 10:568-75. 17. Yacoub M, Halim M, Radley-Smith R, McKay R, Nijveld A, Towers M. Surgical treatment of mitral regurgitation caused by floppy valves: repair versus replacement. Circulation 1981;64:II-210–II-216.

december 3, 2009

98

clinical ther apeutics 18. David TE, Uden DE, Strauss HD. The

importance of the mitral apparatus in left ventricular function after correction of mitral regurgitation. Circulation 1983;68: II-76–II-82. 19. Okita Y, Miki S, Ueda Y, Tahata T, Sakai T, Matsuyama K. Comparative evaluation of left ventricular performance after mitral valve repair or valve replacement with or without chordal preservation. J Heart Valve Dis 1993;2:159-66. 20. Ling LH, Enriquez-Sarano M, Seward JB, et al. Early surgery in patients with mitral regurgitation due to flail leaflets: a long-term outcome study. Circulation 1997;96:1819-25. 21. Grigioni F, Tribouilloy C, Avierinos JF, et al. Outcomes in mitral regurgitation due to flail leaflets: a multicenter European study. JACC Cardiovasc Imaging 2008;1:133-41. 22. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352:875-83. 23. Shuhaiber J, Anderson RJ. Meta-analysis of clinical outcomes following surgical mitral valve repair or replacement. Eur J Cardiothorac Surg 2007;31:267-75. 24. Jokinen JJ, Hippeläinen MJ, Pitkänen OA, Hartikainen JE. Mitral valve replacement versus repair: propensity-adjusted survival and quality-of-life analysis. Ann Thorac Surg 2007;84:451-8. 25. Gillinov AM, Blackstone EH, Nowicki ER, et al. Valve repair versus valve replacement for degenerative mitral valve disease. J Thorac Cardiovasc Surg 2008;135: 885-93. 26. Zhao L, Kolm P, Borger MA, et al. Comparison of recovery after mitral valve repair and replacement. J Thorac Cardiovasc Surg 2007;133:1257-63. 27. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777-802. 28. American College of Cardiology, American Heart Association Task Force on Practice Guidelines. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48(3):e1-e148. 29. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular

heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease): endorsed by the Society of Cardiovascular Anesthesiologists, Soceity for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52(13):e1-e142. 30. Gammie JS, O’Brien SM, Griffith BP, Ferguson TB, Peterson ED. Influence of hospital procedural volume on care process and mortality for patients undergoing elective surgery for mitral regurgitation. Circulation 2007;115:881-7. 31. Talwalkar NG, Earle NR, Earle EA, Lawrie GM. Mitral valve repair in patients with low left ventricular ejection fractions: early and late results. Chest 2004;126:70915. 32. Gillinov AM, Faber C, Houghtaling PL, et al. Repair versus replacement for degenerative mitral valve disease with coexisting ischemic heart disease. J Thorac Cardiovasc Surg 2003;125:1350-62. 33. Society of Thoracic Surgeons (STS) online risk calculator. (Accessed November 6, 2009, at http://209.220.160.181/ STSWebRiskCalc261/.) 34. European System for Cardiac Operative Risk Evaluation (EUROSCORE). (Accessed November 6, 2009, at http://www. euroscore.org/calc.html.) 35. Shernan SK. Perioperative transesophageal echocardiographic evaluation of the native mitral valve. Crit Care Med 2007; 35:Suppl:S372-S383. 36. Filsoufi F, Carpentier A. Principles of reconstructive surgery in degenerative mitral valve disease. Semin Thorac Cardiovasc Surg 2007;19:103-10. 37. Adams DH, Filsoufi F. Another chapter in an enlarging book: repair degenerative mitral valves. J Thorac Cardiovasc Surg 2003;125:1197-9. 38. Gillinov AM, Cosgrove DM III, Blackstone EH, et al. Durability of mitral valve repair for degenerative disease. J Thorac Cardiovasc Surg 1998;116:734-43. 39. Duran CG, Pomar JL, Revuelta JM, et al. Conservative operation for mitral insufficiency: critical analysis supported by postoperative hemodynamic studies of 72 patients. J Thorac Cardiovasc Surg 1980; 79:326-37. 40. Mesana TG, Ibrahim M, Kulik A, et al. The “hybrid flip-over” technique for anterior leaflet prolapse repair. Ann Thorac Surg 2007;83:322-3. 41. Mesana T, Ibrahim M, Hynes M. A technique for annular placation to facilitate sliding plasty after extensive mitral valve posterior leaflet resection. Ann Thorac Surg 2005;79:720-2. 42. David TE. Outcomes of mitral valve repair for mitral regurgitation due to degenerative disease. Semin Thorac Cardiovasc Surg 2007;19:116-20.

n engl j med 361;23 BACK to TOC

nejm.org

43. Starling MR, Kirsh MM, Montgomery

DG, Gross MD. Impaired left ventricular contractile function in patients with longterm mitral regurgitation and normal ejection fraction. J Am Coll Cardiol 1993;22: 239-50. 44. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007;116:1736-54. 45. Barnett SD, Ad N. Surgery for aortic and mitral valve disease in the United States: a trend of change in surgical practice between 1998 and 2005. J Thorac Cardiovasc Surg 2009;137:1422-9. 46. Rosenhek R, Rader F, Klaar U, et al. Outcome of watchful waiting in asymptomatic severe mitral regurgitation. Circulation 2006;113:2238-44. 47. Mohty D, Orszulak TA, Schaff HV, Avierinos JF, Tajik JA, Enriquez-Sarano M. Very long-term survival and durability of mitral valve repair for mitral valve prolapse. Circulation 2001;104:Suppl 1:I-1–I-7. 48. Akins CW, Hilgenberg AD, Buckley MJ, et al. Mitral valve reconstruction versus replacement for degenerative or ischemic mitral regurgitation. Ann Thorac Surg 1994;58:668-75. 49. Lee EM, Shapiro LM, Wells FC. Superiority of mitral valve repair in surgery for degenerative mitral regurgitation. Eur Heart J 1997;18:655-63. 50. Kang D-H, Kim JH, Rim JH, et al. Comparison of early surgery versus conventional treatment in asymptomatic severe mitral regurgitation. Circulation 2009;119:797-804. 51. Suri RM, Schaff HV, Dearani JA, et al. Survival advantage and improved durability of mitral repair for leaflet prolapse subsets in the current era. Ann Thorac Surg 2006;82:819-26. 52. O’Brien SM, Shahian DM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2 — isolated valve surgery. Ann Thorac Surg 2009;88:Suppl:S23-S42. 53. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28:230-68. 54. Seeburger J, Borger MA, Falk V, et al. Minimal invasive mitral valve repair for mitral regurgitation: results of 1339 consecutive patients. Eur J Cardiothorac Surg 2008;34:760-5. Copyright © 2009 Massachusetts Medical Society.

december 3, 2009

2269

99

Current Concepts Current Concepts articles present current approaches to a wide variety of clinical problems. These concise reviews are intended for the practicing physician.

BACK to TOC

100

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article Current Concepts

Point-of-Care Ultrasonography Christopher L. Moore, M.D., and Joshua A. Copel, M.D.

U

ltrasonography is a safe and effective form of imaging that has been used by physicians for more than half a century to aid in diagnosis and guide procedures. Over the past two decades, ultrasound equipment has become more compact, higher quality, and less expensive, which has facilitated the growth of point-of-care ultrasonography — that is, ultrasonography performed and interpreted by the clinician at the bedside. In 2004, a conference on compact ultrasonography hosted by the American Institute of Ultrasound in Medicine (AIUM) concluded that “the concept of an ‘ultrasound stethoscope’ is rapidly moving from the theoretical to reality.” This conference included representatives from 19 medical organizations; in November 2010, the AIUM hosted a similar forum attended by 45 organizations.1-3 Some medical schools are now beginning to provide their students with hand-carried ultrasound equipment for use during clinical rotations.4 Although ionizing radiation from computed tomographic (CT) scanning is increasingly recognized as a potentially major cause of cancer, ultrasonography has been used in obstetrics for decades, with no epidemiologic evidence of harmful effects at normal diagnostic levels.5,6 However, ultrasonography is a user-dependent technology, and as usage spreads, there is a need to ensure competence, define the benefits of appropriate use, and limit unnecessary imaging and its consequences.7-10 This article provides an overview of the history and current status of compact, point-of-care ultrasonography, with examples and discussion of its use.

From the Departments of Emergency Medicine (C.L.M.) and Obstetrics, Gynecology, and Reproductive Sciences (J.A.C.), Yale University School of Medicine, New Haven, CT. Address reprint requests to Dr. Moore at the Department of Emergency Medicine, Yale University School of Medicine, 464 Congress Ave., Suite 260, New Haven, CT 06519, or at chris.moore@ yale.edu. N Engl J Med 2011;364:749-57. Copyright © 2011 Massachusetts Medical Society.

His t or y of Ultr a sonogr a ph y a nd the Ba sic Technol ogy Medical ultrasonography was developed from principles of sonar pioneered in World War I,11 and the first sonographic images of a human skull were published in 1947.12 The first ultrasound images of abdominal disease were published in 1958,13 and ultrasonography was widely adopted in radiology, cardiology, and obstetrics over the next several decades. Although clinicians from other specialties occasionally reported using ultrasonography, point-of-care ultrasonography did not really begin to progress until the 1990s, when more compact and affordable machines were developed. The early portable machines were hampered by poor image quality, but in 2010, many point-of-care units can nearly match the imaging quality of the larger machines. Ultrasound is defined as a frequency above that which humans can hear, or more than 20,000 Hz (20 kHz). Therapeutic ultrasound, designed to create heat using mechanical sound waves, is typically lower in frequency than diagnostic ultrasound and is not discussed in this article. The frequency of diagnostic ultrasound is in the millions of Hertz (MHz). Lower-frequency ultrasound has better penetration, but at lower resolution. Higher-frequency ultrasound provides better images, but it does not visualize deep structures well. A typical transabdominal or

n engl j med 364;8 BACK to TOC

nejm.org

february 24, 2011

749

101

The

n e w e ng l a n d j o u r na l

cardiac probe has a frequency in the range of 2 to 5 MHz, whereas some dermatologic ultrasound probes have frequencies as high as 100 MHz. Ultrasonography uses a “crystal” — a quartz or composite piezoelectric material — that generates a sound wave when an electric current is applied. When the sound wave returns, the material in turn generates a current. The crystal thus both transmits and receives the sound. Early ultrasonography used a single crystal to create a onedimensional image known as A-mode. The standard screen image that machines now generate is known as B-mode (also called two-dimensional or gray-scale ultrasonography), and is created by an array of crystals (often 128 or more) across the face of the transducer. Each crystal produces a scan line that is used to create an image or frame, which is refreshed many times per second to produce a moving image on the screen (Fig. 1). Additional modes, including three-dimensional, four-dimensional, Doppler, and tissue Doppler modes, are now commonly available but are not addressed in this article. Ultrasound penetrates well through fluid and solid organs (e.g., liver, spleen, and uterus); it does not penetrate well through bone or air, limiting its usefulness in the skull, chest, and areas of the abdomen where bowel gas obscures the image. Fluid (e.g, blood, urine, bile, and ascites), which is completely anechoic, appears black on ultrasound images, making ultrasonography particularly useful for detecting fluid and differentiating cystic or vascular areas from solid structures. Two-dimensional ultrasound is used to visualize a plane that is then shown on the screen. This plane may be directed by the user in any anatomical plane on the patient: sagittal (or longitudinal), transverse (or axial), coronal (or frontal), or some combination (oblique). An indicator on the probe is used to orient the user to the orientation of the plane on the screen. By convention, in general and obstetrical imaging, the indicator corresponds to the left side of the screen as it is viewed. Cardiology uses the opposite convention for echocardiography, with the indicator corresponding to the right of the screen. Users should be aware of these conventions when conducting integrated examinations that include both general and cardiac imaging.14

750 BACK to TOC

n engl j med 364;8

of

m e dic i n e

P oin t- of- C a r e A ppl ic at ions Point-of-care ultrasonography is defined as ultrasonography brought to the patient and performed by the provider in real time. Point-of-care ultrasound images can be obtained nearly immediately, and the clinician can use real-time dynamic images (rather than images recorded by a sonographer and interpreted later), allowing findings to be directly correlated with the patient’s presenting signs and symptoms.15 Point-of-care ultrasonography is easily repeatable if the patient’s condition changes. It is used by various specialties in diverse situations (Table 1) and may be broadly divided into procedural, diagnostic, and screening applications. Procedural Guidance

Ultrasound guidance may improve success and decrease complications in procedures performed by multiple specialties, including central and peripheral vascular access, thoracentesis, paracentesis, arthrocentesis, regional anesthesia, incision and drainage of abscesses, localization and removal of foreign bodies, lumbar puncture, biopsies, and other procedures.16 Procedural guidance may be static or dynamic. With static guidance, the structure of interest is identified, and the angle required by the needle is noted, with the point of entry marked on the skin. In dynamic procedures, ultrasonography visualizes the needle in real time. Static guidance may initially be easier to perform, but properly performed dynamic guidance provides more accurate guidance and is generally preferred by experienced users. In response to the 1999 Institute of Medicine report To Err Is Human, the Agency for Healthcare Research and Quality listed “use of real-time ultrasound guidance during central line insertion to prevent complications” as 1 of the 12 most highly rated patient safety practices designed to decrease medical errors.17 The use of ultrasound to guide central venous access has been shown to reduce the failure rate, the risk of complications, and the number of attempts, as compared with the landmark technique, particularly in the case of less experienced users or patients with more complex conditions.18,19 The evidence for these benefits of ultrasound guidance is greatest

nejm.org

february 24, 2011

102

Current Concepts

A

B

Indicator to patient’s right

Inferior vena cava

Indicator

Splenic vein

Spine

Aorta

Sagittal plane Indicator

Coronal plane

Transverse plane

Figure 1. Basic (B-Mode) Two-Dimensional Ultrasound Image. A typical ultrasound transducer, shown in Panel A, has 128 or more crystals arranged across the face of the probe. Each crystal transmits and receives bursts of sound (typically in the megahertz range), creating a scan line. The scan lines together make up a frame, which is refreshed many times per second and displayed on a two-dimensional screen to create a moving image. As shown in Panel B, the plane of the ultrasound can be directed in any anatomical plane or between planes. By convention, in abdominal imaging, the probe indicator (a bump or groove on the probe) is to the left of the screen and is generally directed toward the patient’s right side in a transverse plane. The ultrasound image shown is a transverse image of the abdominal aorta. The indicator is directed to the patient’s right side, corresponding to the left side of the screen. The aorta is black (fluid-filled) and located just anterior to the vertebral bodies. (See also Video 4, available with the full text of this article at NEJM.org.)

n engl j med 364;8 BACK to TOC

nejm.org

february 24, 2011

751

103

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 1. Selected Applications of Point-of-Care Ultrasonography, According to Medical Specialty.* Specialty

Ultrasound Applications

Anesthesia

Guidance for vascular access, regional anesthesia, intraoperative monitoring of fluid status and cardiac function

Cardiology

Echocardiography, intracardiac assessment

Critical care medicine

Procedural guidance, pulmonary assessment, focused echocardiography

Dermatology

Assessment of skin lesions and tumors

Emergency medicine

FAST, focused emergency assessment, procedural guidance

Endocrinology and endocrine surgery

Assessment of thyroid and parathyroid, procedural guidance

General surgery

Ultrasonography of the breast, procedural guidance, intraoperative assessment

Gynecology

Assessment of cervix, uterus, and adnexa; procedural guidance

Obstetrics and maternal–fetal medicine

Assessment of pregnancy, detection of fetal abnormalities, procedural guidance

Neonatology

Cranial and pulmonary assessments

Nephrology

Vascular access for dialysis

Neurology

Transcranial Doppler, peripheral-nerve evaluation

Ophthalmology

Corneal and retinal assessment

Orthopedic surgery

Musculoskeletal applications

Otolaryngology

Assessment of thyroid, parathyroid, and neck masses; procedural guidance

Pediatrics

Assessment of bladder, procedural guidance

Pulmonary medicine

Transthoracic pulmonary assessment, endobronchial assessment, procedural guidance

Radiology and interventional radiology

Ultrasonography taken to the patient with interpretation at the bedside, procedural guidance

Rheumatology

Monitoring of synovitis, procedural guidance

Trauma surgery

FAST, procedural guidance

Urology

Renal, bladder, and prostate assessment; procedural guidance

Vascular surgery

Carotid, arterial, and venous assessment; procedural assessment

* FAST denotes focused assessment with sonography for trauma.

Videos showing point-of-care ultrasonography are available at NEJM.org

Click here to access videos.

752 BACK to TOC

for the internal jugular site, with less evidence for the femoral and subclavian sites and in pediatric patients.20 A needle may be imaged dynamically with the use of either an “in-plane” or “out-of-plane” ultrasound approach (Fig. 2, and Video 1, available at NEJM.org). For vascular access, an in-plane approach corresponds to the long axis of the vessel. An in-plane, or long-axis, approach is generally preferred for dynamic vascular access, particularly for central venous access, because the entire length of the needle, including the tip, can be visualized throughout the procedure. However, it may be more difficult to keep the needle in view with the use of an in-plane approach, and for smaller vessels, it may be challenging to image the entire vessel in the long axis. An out-of-plane approach is perpendicular to n engl j med 364;8

the needle and corresponds to the short axis of the vessel. The advantage of this approach is that the needle can be centered over the middle of the vessel. It is also easier to keep the vessel and the needle in view in the short axis. However, an out-of-plane approach may underestimate the depth of the needle tip if the ultrasound plane cuts across the shaft of the needle, proximal to the tip. A detailed description of ultrasoundguided central venous access of the internal jugular vein is provided by Ortega et al. as part of the Journal’s Videos in Clinical Medicine series.21 Diagnostic Assessment

The concept of a focused (“limited,” or “goaldirected”) examination is important in point-ofcare ultrasonography. Clinicians from diverse specialties can become very adept at using ultra-

nejm.org

february 24, 2011

104

Current Concepts

A

In-plane view of the needle (long axis of the vessel)

Needle shaft

B

Needle tip

Out-of-plane view of the needle (short axis of the vessel)

Needle in cross-section Reverberation artifact

Figure 2. Ultrasound Guidance for Vascular Access and Other Procedures Involving Needles. Panel A shows a long-axis, “in-plane” view of the needle. Although it may be more difficult to keep the needle and structure of interest in view, the long-axis view is advantageous because it shows the entire needle, including the tip (ultrasound image at right). Panel B shows a short-axis approach, with the characteristic “target sign” of the needle in the vessel lumen. The ultrasound image also shows a reverberation artifact, which occurred in this case when the ultrasound beam struck a metallic object. The artifact appears as closely spaced, tapering lines below the needle. Although the visualized portion of the needle is centered in the lumen, the disadvantage of the short axis is that the plane of the ultrasound may cut through the needle shaft proximally, underestimating the depth of the tip. (See also Video 1.)

sonography to examine a particular organ, disease, or procedure that is directly relevant to their area of expertise, whereas imaging specialists typically perform more comprehensive examinations (Table 1). n engl j med 364;8 BACK to TOC

Point-of-care ultrasonography may involve the use of a series of focused ultrasonographic examinations to efficiently diagnose or rule out certain conditions in patients presenting with particular symptoms or signs, such as hypoten-

nejm.org

february 24, 2011

753

105

The

n e w e ng l a n d j o u r na l

A

FAST Examination

Pleural line

Rib shadow

A line (normal reverberation artifact)

B

Rib

Rib

Pleural line Rib shadow

Rib shadow

m e dic i n e

the use of point-of-care ultrasonography for pulmonary assessment.

Skin and subcutaneous tissue

Rib

of

B lines (lung rockets)

Figure 3. Ultrasound Images of the Pleural Line in a Healthy Patient and in a Patient with Alveolar Interstitial Syndrome. In Panel A, a high-frequency linear probe is placed with the indicator toward the patient’s head (screen left), in the midclavicular line at approximately the third intercostal space. At the posterior edge of the rib, a hyperechoic (bright) pleural line is seen, which is the interface between the visceral and parietal pleura. In a moving image of a normal lung, shimmering or “sliding” would be seen at the pleural line, indicating that the visceral pleura is closely associated with the parietal pleura. An “A line” (a normal reverberation artifact) is also seen. In Panel B, a phased-array sector probe is placed at the same anatomical location on a different patient. This sector image is much deeper, but it shows the same structures, as well as pathological “B lines,” artifacts that extend to the bottom of the screen (“lung rockets”). This patient had alveolar interstitial syndrome from congestive heart failure. (See also Video 3.)

FAST was a term coined at an international consensus conference in 1996 to describe an integrated, goal-directed, bedside examination to detect fluid, which is likely to be hemorrhage in cases of trauma.22 The extended FAST (e-FAST) also includes examination of the chest for pneumothorax.23 The e-FAST examination combines five focused examinations for the detection of: free intraperitoneal fluid, free fluid in the pelvis, pericardial fluid, pleural effusion, and pneumothorax. Peritoneal fluid is detected using views of the hepatorenal space (Morison’s pouch), splenorenal space, and retrovesicular spaces. The thorax is evaluated for fluid at the flanks and for pneumothorax anteriorly. The pericardium may be evaluated for effusion, particularly in cases of penetrating trauma (see Video 2). A FAST examination may be completed in less than 5 minutes and has been shown to have a sensitivity of 73 to 99%, a specificity of 94 to 98%, and an overall accuracy of 90 to 98% for clinically significant intraabdominal injury in trauma.24 The use of the FAST examination has been shown to reduce the need for CT or diagnostic peritoneal lavage and to reduce the time to appropriate intervention, resulting in a shorter hospital stay, lower costs, and lower overall mortality, although more rigorous study of patientcentered outcomes is recommended.25,26 A complete or partial FAST examination may also be helpful in evaluating patients who do not have trauma for ascites, intraperitoneal hemorrhage, pleural effusion, pneumothorax, or pericardial effusion. Pulmonary Ultrasonography

sion, chest pain, or dyspnea. In patients with trauma, this approach is known as FAST (focused assessment with sonography for trauma). Pointof-care ultrasonography allows immediate, dynamic, and repeated assessments in these situations and has the potential for detecting conditions such as pneumothorax in which ultrasonography was traditionally thought to be unhelpful. Here we focus on an integrated point-ofcare examination for trauma (FAST), as well as 754 BACK to TOC

n engl j med 364;8

The use of ultrasound to detect pneumothorax was first described in a horse in 1986, and then in humans shortly afterward.27 In a normal lung, the visceral and parietal pleura are closely associated, and ultrasound shows shimmering or sliding at the pleural interface during respiration (Fig. 3, and Video 3). The absence of sliding indicates a pneumothorax. A small pneumothorax may be missed with the use of ultrasonography, and patients with blebs or scarring may have false positive findings.28 However, for assessing pa-

nejm.org

february 24, 2011

106

Current Concepts

tients with trauma for pneumothorax, ultrasonography has been shown to be more than twice as sensitive as conventional supine chest radiography for detecting occult pneumothorax (pneumothorax seen only on CT), with similarly high specificity (>98%).23 The presence of a “lung point” sign, where the visceral pleura intermittently comes in contact with the parietal pleura, is nearly 100% specific for the detection of pneumothorax. Comet tails are an ultrasound artifact that arises when ultrasound encounters a small air– fluid interface. In 1997, Lichtenstein et al. described the sonographic identification of alveolar interstitial syndrome, diagnosed on the basis of comet tails that extend from the pleural line to the bottom of the screen, also known as “B lines” (Fig. 3B). Alveolar interstitial syndrome is an ultrasonographic finding in several different conditions.29 In an acute condition, alveolar interstitial syndrome usually represents pulmonary edema, but it may also be seen in the acute respiratory distress syndrome and more chronic interstitial diseases and may be a focal finding in infectious or ischemic processes. Characteristics of the artifacts may be helpful in distinguishing these conditions. Ultrasonography has been shown to be more accurate than auscultation or chest radiography for the detection of pleural effusion, consolidation, and alveolar interstitial syndrome in the critical care setting.30 In the emergency care setting, the presence of B lines on pleural ultrasonography predicts fluid overload, adding diagnostic accuracy to the physical examination and measurement of brain natriuretic peptide.31 The presence of B lines has been shown to be dynamic, disappearing in patients undergoing hemodialysis.31,32

routine screening for carotid stenosis, peripheral vascular disease, or ovarian cancer in the general population (class D recommendation — “ineffective or harms outweigh benefits”), although research is ongoing to determine whether more narrowly defined populations may benefit from such screening.34 In 2005, the USPSTF gave a class B recommendation for one-time ultrasound screening for abdominal aortic aneurysm in men between the ages of 65 and 75 years who had ever smoked, leading to the incorporation of screening for abdominal aortic aneurysm into Medicare reimbursement.35,36 The USPSTF reports that ultrasonography has a sensitivity of 95% and a specificity of nearly 100% when performed in “a setting with adequate quality assurance.” Imaging of the abdominal aorta is performed with a curvilinear probe of 2 to 5 MHz. With the patient in a supine position, gentle pressure is applied to move bowel gas out of the way. The aorta should be imaged as completely as possible from the proximal (celiac trunk) to the distal bifurcation and should include assessment of the iliac arteries when possible. It should be measured at its maximum diameter from outside wall to outside wall in two planes, transverse and longitudinal. Challenges include ensuring that the aorta is imaged, not the inferior vena cava or another fluid-filled structure, and ensuring that the entire diameter is measured (Fig. 1, and Video 4). Ultrasonography of the abdominal aorta has been shown to be fairly straightforward to learn as a focused examination, and screening by primary care providers using point-of-care ultrasonography may provide an economical method for wider screening, although more study is needed in this area.

Screening

Screening with ultrasonography is attractive because it is noninvasive and lacks ionizing radiation. Ultrasonography has been described as a screening test for cardiovascular and gynecologic disease, and compact ultrasonography has been incorporated into “mobile screening labs.”33 However, the benefits of screening must be weighed against the harms, particularly false positive findings that lead to unnecessary testing, intervention, or both. The U.S. Preventive Services Task Force (USPSTF) has specifically recommended that ultrasonography not be used for n engl j med 364;8 BACK to TOC

Point- of- C a r e Ultr a sonogr a ph y in O ther Se t t ings Point-of-care ultrasonography is increasingly being used in resource-limited settings. The World Health Organization states that plain radiography and ultrasonography, singly or in combination, will meet two thirds of all imaging needs in developing countries.37 Ultrasonography has been used at the Mount Everest base camp to diagnose high-altitude pulmonary edema, and ultrasonography is the only diagnostic imaging technique

nejm.org

february 24, 2011

755

107

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

used on the International Space Station, where astronauts obtain images that are interpreted on earth.38,39 The use of hand-carried ultrasonographic devices has been described in prehospital settings, including ambulance and disaster settings, as well as in battlefield medicine (the scenario for which hand-carried ultrasonography was initially developed).40-42 The e-FAST examination for internal bleeding and pneumothorax has been the most extensively described application in the prehospital setting (Video 2).

in some cases obviating the need for more resource-intensive imaging performed by a consulting radiologist.47 However, indiscriminate use of ultrasonography could lead to further unnecessary testing, unnecessary interventions in the case of false positive findings, or inadequate investigation of false negative findings. More imaging could simply lead to increased expense without added benefit, or might even be harmful. As a user-dependent technology, point-of-care ultrasonography requires consideration of appropriate training and quality assurance. In addition, methodologically rigorous studies are needed to P ol ic y C onsider at ions assess patient-centered outcomes for point-ofFrom 2000 to 2006, physician fees billed for care ultrasonography.25,48-50 medical imaging in the United States more than doubled, with the proportion of billing for “inC onclusions office” imaging rising from 58 to 64%.43 Although the rate of imaging increased among both The use of point-of-care ultrasonography will radiologists and nonradiologists, the rate of in- continue to diffuse across medical specialties crease was faster among nonradiologists.44,45 and care situations. Future challenges include Most of this increase was related to “advanced” gaining a better understanding of when and how imaging (CT, magnetic resonance imaging, and point-of-care ultrasonography can be used effecnuclear medicine), but certain applications of tively, determining the training and assessment ultrasonography by nonradiologists (particularly that will be required to ensure competent use of breast and cardiac applications) increased at a the technology, and structuring policy and revery rapid rate.46 imbursement to encourage appropriate and effecWith appropriate use, point-of-care ultrasonog- tive use. raphy can decrease medical errors, provide more Dr. Moore reports receiving consulting fees from SonoSite efficient real-time diagnosis, and supplement or and Philips; and Dr. Copel, speaking fees from Siemens, World replace more advanced imaging in appropriate Class CME, the Institute for Advanced Medical Education, and Educational Symposia, grant support from Philips, and reimsituations. In addition, point-of-care ultrasonog- bursement for travel expenses from Philips and Esaote and serving raphy may allow more widespread, less-expen- as a paid member of the editorial board of Contemporary OB/GYN at sive screening for defined indications. It may be modernmedicine.com. No other potential conflict of interest relevant to this article was reported. particularly cost-effective in a reimbursement Disclosure forms provided by the authors are available with scheme based on episodes of care (“bundling”), the full text of this article at NEJM.org. References 1. Greenbaum LD, Benson CB, Nelson

LH III, Bahner DP, Spitz JL, Platt LD. Proceedings of the Compact Ultrasound Conference sponsored by the American Institute of Ultrasound in Medicine. J Ultrasound Med 2004;23:1249-54. 2. Alpert JS, Mladenovic J, Hellmann DB. Should a hand-carried ultrasound machine become standard equipment for every internist? Am J Med 2009;122:1-3. 3. AIUM Ultrasound Practice Forum, 2010: point-of-care use of ultrasound. (http://www.aium.org/advertising/ 2010Forum.pdf.) 4. Rao S, van Holsbeeck L, Musial JL, et al. A pilot study of comprehensive ultrasound education at the Wayne State Uni-

756 BACK to TOC

versity School of Medicine: a pioneer year review. J Ultrasound Med 2008;27:745-9. 5. Brenner DJ, Hall EJ. Computed tomography — an increasing source of radiation exposure. N Engl J Med 2007;357:227784. 6. Barnett SB. Routine ultrasound scanning in first trimester: what are the risks? Semin Ultrasound CT MR 2002;23:38791. 7. Filly RA. Is it time for the sonoscope? If so, then let’s do it right! J Ultrasound Med 2003;22:323-5. 8. Adler RS. The use of compact ultrasound in anesthesia: friend or foe. Anesth Analg 2007;105:1530-2. 9. Bree RL, Benson CB, Bowie JD, et al.

n engl j med 364;8

nejm.org

The role of radiology in the era of compact ultrasound systems: SRU Conference, October 14 and 15, 2003. Ultrasound Q 2004;20:19-21. 10. Greenbaum LD. It is time for the sonoscope. J Ultrasound Med 2003;22:321-2. 11. Dussik KT. On the possibility of using ultrasound waves as a diagnostic aid. Z Neurol Psychiat 1942;174:153-68. (In German.) 12. Edler I, Lindström K. The history of echocardiography. Ultrasound Med Biol 2004;30:1565-644. 13. Donald I, Macvicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet 1958;1:1188-95. 14. Moore C. Current issues with emer-

february 24, 2011

108

Current Concepts gency cardiac ultrasound probe and image conventions. Acad Emerg Med 2008; 15:278-84. 15. Gluckman JL, Mann W, Portugal LG, Welkoborsky H-J. Real-time ultrasonography in the otolaryngology office setting. Am J Otolaryngol 1993;14:307-13. 16. Nicolaou S, Talsky A, Khashoggi K, Venu V. Ultrasound-guided interventional radiology in critical care. Crit Care Med 2007;35:Suppl:S186-S197. 17. Making health care safer: a critical analysis of patient safety practices. Rockville, MD: Agency for Healthcare Research and Quality. (AHRQ publication no. 01-E058.) 18. Randolph AG, Cook DJ, Gonzales CA, Pribble CG. Ultrasound guidance for placement of central venous catheters: a meta-analysis of the literature. Crit Care Med 1996;24:2053-8. 19. Hind D, Calvert N, McWilliams R, et al. Ultrasonic locating devices for central venous cannulation: meta-analysis. BMJ 2003;327:361-8. 20. Kumar A, Chuan A. Ultrasound guided vascular access: efficacy and safety. Best Pract Res Clin Anaesthesiol 2009;23:299311. 21. Ortega R, Song M, Hansen CJ, Barash P. Ultrasound-guided internal jugular vein cannulation. N Engl J Med 2010;362(16): e57. (Video available at NEJM.org.) 22. Scalea TM, Rodriguez A, Chiu WC, et al. Focused Assessment with Sonography for Trauma (FAST): results from an international consensus conference. J Trauma 1999;46:466-72. 23. Kirkpatrick AW, Sirois M, Laupland KB, et al. Hand-held thoracic sonography for detecting post-traumatic pneumothoraces: the Extended Focused Assessment with Sonography for Trauma (EFAST). J Trauma 2004;57:288-95. 24. Melanson SW. The FAST Exam: a review of the literature. In: Jehle D, Heller MB, eds. Ultrasonography in trauma: the FAST Exam. Dallas: American College of Emergency Physicians, 2003:127-45. 25. Melniker LA, Leibner E, McKenney MG, Lopez P, Briggs WM, Mancuso CA. Randomized controlled clinical trial of point-of-care, limited ultrasonography for trauma in the emergency department: the first Sonography Outcomes Assessment Program trial. Ann Emerg Med 2006;48: 227-35.

26. Hosek WT, McCarthy ML. Trauma ul-

trasound and the 2005 Cochrane Review. Ann Emerg Med 2007;50:619-20. 27. Rantanen NW. Diseases of the thorax. Vet Clin North Am Equine Pract 1986;2: 49-66. 28. Dulchavsky SA, Schwarz KL, Kirkpatrick AW, et al. Prospective evaluation of thoracic ultrasound in the detection of pneumothorax. J Trauma 2001;50:201-5. 29. Lichtenstein D, Mézière G, Biderman P, Gepner A, Barré O. The comet-tail artifact: an ultrasound sign of alveolar-interstitial syndrome. Am J Respir Crit Care Med 1997;156:1640-6. 30. Lichtenstein D, Goldstein I, Mourgeon E, Cluzel P, Grenier P, Rouby JJ. Comparative diagnostic performances of auscultation, chest radiography, and lung ultrasonography in acute respiratory distress syndrome. Anesthesiology 2004;100: 9-15. 31. Liteplo AS, Marill KA, Villen T, et al. Emergency Thoracic Ultrasound in the Differentiation of the Etiology of Shortness of Breath (ETUDES): sonographic B-lines and N-terminal pro-brain-type natriuretic peptide in diagnosing congestive heart failure. Acad Emerg Med 2009;16: 201-10. 32. Noble VE, Murray AF, Capp R, SylviaReardon MH, Steele DJR, Liteplo A. Ultrasound assessment for extravascular lung water in patients undergoing hemodialysis. Chest 2009;135:1433-9. 33. Payne JW. Screening with holes in it? Washington Post. July 19, 2005. (http:// www.washingtonpost.com/wp-dyn/ content/article/2005/07/18/ AR2005071801175.html.) 34. Screening for carotid artery stenosis. Rockville, MD: U.S. Preventive Services Task Force, December 2007. (http://www .uspreventiveservicestaskforce.org/uspstf/ uspsacas.htm.) 35. U.S. Preventive Services Task Force. Screening for abdominal aortic aneurysm: recommendation statement. Ann Intern Med 2005;142:198-202. 36. Thompson SG, Ashton HA, Gao L, Scott RA. Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomised Multicentre Aneurysm Screening Study. BMJ 2009;338:2307-18. 37. Aide-memoire for diagnostic imaging services. Geneva: World Health Organi-

zation, 2009. (http://whqlibdoc.who.int/ aide-memoire/a71903.pdf.) 38. Otto C, Hamilton DR, Levine BD, et al. Into thin air: extreme ultrasound on Mt Everest. Wilderness Environ Med 2009; 20(3):283-9. 39. Sargsyan AE, Hamilton DR, Jones JA, et al. FAST at MACH 20: clinical ultrasound aboard the International Space Station. J Trauma 2005;58:35-9. 40. Nelson BP, Chason K. Use of ultrasound by emergency medical services: a review. Int J Emerg Med 2008;1:253-9. 41. Brooks AJ, Price V, Simms M. FAST on operational military deployment. Emerg Med J 2005;22:263-5. 42. Beck-Razi N, Fischer D, Michaelson M, Engel A, Gaitini D. The utility of focused assessment with sonography for trauma as a triage tool in multiple-casualty incidents during the second Lebanon war. J Ultrasound Med 2007;26:1149-56. 43. Medicare imaging payments. Washington, DC: Government Accountability Office, 2008. (GAO-08-452.) 44. Hillman BJ, Olson GT, Griffith PE, et al. Physicians’ utilization and charges for outpatient diagnostic imaging in a Medicare population. JAMA 1992;268:2050-4. 45. Maitino AJ, Levin DC, Parker L, Rao VM, Sunshine JH. Practice patterns of radiologists and nonradiologists in utilization of noninvasive diagnostic imaging among the Medicare population. Radiology 2003;228:795-801. 46. Miller ME. MedPAC recommendations on imaging services. Washington, DC: Subcommittee on Health Committee on Ways and Means, 2005. 47. Schoen C, Guterman S, Shih A, et al. Bending the curve: options for achieving savings and improving value in U.S. health spending. Washington, DC: The Commonwealth Fund, 2007. 48. Rose JS. Ultrasonography and outcomes research: one small step for mankind or another drop in the bucket? Ann Emerg Med 2006;48:237-9. 49. Liu SS, Ngeow JE, Yadeau JT. Ultrasound-guided regional anesthesia and analgesia: a qualitative systematic review. Reg Anesth Pain Med 2009;34:47-59. 50. Vance S. The FAST scan: are we improving care of the trauma patient? Ann Emerg Med 2007;49:364-6. Copyright © 2011 Massachusetts Medical Society.

RECEIVE IMMEDIATE NOTIFICATION WHEN AN ARTICLE IS PUBLISHED ONLINE FIRST

To be notified by e-mail when Journal articles are published Online First, sign up at NEJM.org.

n engl j med 364;8 BACK to TOC

nejm.org

february 24, 2011

757

109

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article Current Concepts

Myocardial Infarction Due to Percutaneous Coronary Intervention Abhiram Prasad, M.D., and Joerg Herrmann, M.D.

A

pproximately 1.5 million patients undergo percutaneous coronary intervention (PCI) in the United States every year.1 Depending on local practices and the diagnostic criteria used, 5 to 30% of these patients (75,000 to 450,000) have evidence of a periprocedural myocardial infarction.2,3 At the higher estimate, the incidence of these events is similar to the annual rate of major spontaneous myocardial infarction.1 Thus, many cardiologists and internists are likely to encounter patients with coronary artery disease who have sustained a periprocedural myocardial infarction. However, the clinical significance of these events and their management remain a matter of considerable controversy and uncertainty (Table 1).4-6 Questions that often arise include the following: Do we need to routinely screen patients for periprocedural myocardial infarction? Which patients should be observed in the hospital for a prolonged period after periprocedural myocardial infarction? What are the therapeutic implications, and what should we tell patients who sustained a periprocedural myocardial infarction despite an otherwise successful procedure? Is a periprocedural myocardial infarction prognostically equivalent to a spontaneous myocardial infarction? Is periprocedural myocardial infarction a valid end point in clinical trials? The aim of this review is to address these questions and to provide a current perspective on this issue.

From the Department of Internal Medicine and the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN. Address reprint requests to Dr. Prasad at the Mayo Clinic, 200 First St. SW, Rochester, MN 55905, or at prasad.abhiram@ mayo.edu. N Engl J Med 2011;364:453-64. Copyright © 2011 Massachusetts Medical Society.

Defini t ions a nd Pr edic t or s of P CI-R el ated M yonecrosis Current PCI guidelines give a class I recommendation for the measurement of cardiac biomarkers (the MB fraction of creatine kinase [CK-MB], cardiac troponin, or both) in patients who have signs or symptoms suggestive of myocardial infarction during or after PCI and for those who have undergone complicated procedures.7 In addition, a class IIa recommendation is given for routine measurements of cardiac biomarkers 8 to 12 hours after the procedure. In either case, “a new CK-MB or troponin I or T rise greater than 5 times the upper limit of normal would constitute a clinically significant periprocedural MI [myocardial infarction].”7 The more recent consensus document on the universal definition of myocardial infarction specifically classifies cardiac-biomarker levels that are more than 3 times the upper reference limit as indicative of a periprocedural myocardial infarction and recommends measurement of cardiac troponin as the preferred biomarker.8 Given the availability of high-sensitivity cardiac troponin assays, this guideline establishes the threshold for a diagnosis of periprocedural myocardial infarction at very low levels of myonecrosis. The predictors of periprocedural myocardial infarction can be broadly categorized as patient-, lesion-, and procedure-related risk factors.2 The major risk factors, in terms of both frequency and potency, are complex lesions (e.g., the presence of thrombus, stenosis of a saphenous-vein graft, or a type C lesion), complex procedures n engl j med 364;5 BACK to TOC

nejm.org

february 3, 2011

453

110

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 1. Evidence for and against the Clinical Significance of Periprocedural Myocardial Infarction.* Evidence for Clinical Significance

Evidence against Clinical Significance

Patients with elevated cardiac biomarkers after PCI have evidence of focal infarction on cardiac imaging

Virtually all data correlating PMI to adverse clinical outcomes are derived from retrospective studies that have shown associations but not causal relationships

A large number of studies have shown a correlation between PMI and adverse clinical outcomes (see the Supplementary Appendix, available with the full text of this article at NEJM.org), and these studies greatly outnumber those that do not

Retrospective studies are generally limited because they cannot adequately adjust for all possible confounding variables with respect to baseline clinical, angiographic, and procedural characteristics that may determine the likelihood of both PMI and adverse outcomes

There is a positive correlation between the magnitude of postprocedural biomarker elevation and the likelihood of adverse outcomes

Most studies did not use high-sensitivity cardiac troponin assays; when these assays were used, the studies did not apply the currently recommended 99th percentile cutoff value for the upper limit of the normal range

Studies have shown that pre-PCI interventions such as statin therapy reduce the frequency of PMI and improve long-term outcomes

In most cases, PMI results in minimal myonecrosis and therefore does not substantially impair cardiac function — one of the most important determinants of outcome in coronary artery disease

* PCI denotes percutaneous coronary intervention, and PMI periprocedural myocardial infarction.

(e.g., treatment of multiple lesions or use of rotational atherectomy), and associated complications (e.g., abrupt vessel closure, side-branch occlusion, distal embolization, or no reflow).2,9-12 In contrast, patient-related factors, such as advanced age, diabetes mellitus, renal failure, multivessel disease, and left ventricular dysfunction, are the important determinants of clinical outcomes after PCI.2,9-11 The occurrence of periprocedural ischemic symptoms, particularly chest pain at the end of the procedure, or electrocardiographic evidence of ischemia defines the subgroup of patients most likely to have periprocedural myocardial infarction.11,13

Mech a nisms of P CI-R el ated M yonecrosis

proximately 5% of the left ventricular mass.3 The size of distal infarcts correlates directly with the extent to which the plaque volume is reduced (embolized) by PCI, since more debris is sent downstream, but this is not so for the proximal type of injury. Moreover, the composition of the plaque influences the extent of periprocedural myonecrosis. PCI for plaques with large necrotic cores leads to greater degrees of myonecrosis, whereas fibrous plaques are relatively inert in this regard.17,18 Embolization of plaque material has been detected on intracoronary Doppler ultrasonography during PCI. Although it occurs at each phase of the intervention, embolization is most pronounced during stent implantation.19 Even though the number of microemboli correlates positively with the severity of myocardial microvascular dysfunction and myonecrosis, there is considerable overlap with regard to the magnitude of plaque microembolization between patients with and those without periprocedural myocardial infarction.19,20 This finding suggests that factors other than the burden of plaque microembolization influence the likelihood of periprocedural myocardial infarction, such as the release of vasoactive factors from the atherosclerotic plaque, platelet activation, and preexisting vulnerability of the myocardium.2

Large periprocedural myocardial infarcts are usually due to angiographically visible complications; however, this is generally not the case in the vast majority of patients with elevated biomarker levels after PCI.6,14,15 Cardiac magnetic resonance imaging (MRI) has confirmed two distinct locations for procedural myonecrosis: adjacent to the site of the intervention, where the injury is most likely due to epicardial side-branch occlusion, and downstream from the intervention site, where it is most likely due to compromise of the microT r a di t iona l F o cus on vascular circulation (Fig. 1).2,16 Acute myocardial P os tpro cedur a l M yonecrosis injury occurs with equal frequency at the two locations and is detected on MRI in 25% of pa- In the CK-MB and early cardiac troponin era, nutients after PCI, with a mean infarct size of ap- merous studies evaluated the clinical significance 454 BACK to TOC

n engl j med 364;5

nejm.org

february 3, 2011

111

current concepts

Figure 1. Mechanisms Underlying Periprocedural Myocardial Infarction. Cardiac-biomarker elevation before percutaneous coronary intervention (PCI) is primarily due to spontaneous rupture of vulnerable plaques, epicardial thrombosis, and subsequent myocardial injury. In the absence of abrupt, PCI-related epicardial-artery closure, periprocedural myocardial infarction is related to either side-branch occlusion or iatrogenic plaque rupture by balloons and stents, which promotes microvascular injury owing to distal embolization, the release of vasoactive peptides, or both.

of cardiac-biomarker elevations after PCI, and these studies have been systematically reviewed in a previous publication.2 The general conclusion from the retrospective analyses was that a CK-MB elevation higher than 5 times the upper limit of normal was independently associated with n engl j med 364;5 BACK to TOC

an increased risk of in-hospital adverse cardiac events, whereas lower levels did not appear to influence in-hospital outcomes significantly (Table 2).21,26,40-43 Data indicating a relationship between the CK-MB level and long-term survival were less consistent. The results of several studies sug-

nejm.org

february 3, 2011

455

112

456

BACK to TOC

Q-wave MI

n engl j med 364;5

Stent placement

nejm.org

2.4

CK-MB, >88 ng/ml (CK-MB, >10× ULN)

13.6 3.6

CK-MB, 8.8–40 ng/ml

CK-MB, >40 ng/ml

PCI

2.9

CK-MB, >44–88 ng/ml (CK-MB, >5–10× ULN)

63.0

4.5

CK-MB, >26.4–44 ng/ml (CK-MB, >3–5× ULN)

Ellis et al.26

14.5

CK-MB, >8.8–26.4 ng/ml (CK-MB, >1–3× ULN)

Increased length of stay for CK-MB >1× ULN

NA

48

4

15±15

13±3

12

12

24

mo

Length of Follow-up

Increased risk of death (15.1, 16.9, and 19.4% for CK-MB <1, 1–5, and >5× ULN, respectively)

Increased risk of death (1.2, 1.9, and 8.9% for CK-MB <1, 1–5, and >5× ULN, respectively)

Increased risk of death (odds ratio, 1.89 for CK-MB >3× ULN; 6.36 for CK-MB >10× ULN)

No association

Increased risk of death or MI (odds ratio, 1.57 for CK-MB >3× ULN)

Increased risk of death or MI (odds ratio, 1.5 for CK-MB >5× ULN)

Increased risk of death (hazard ratio, 2.2 for CK-MB >8× ULN; 9.9 for Q-wave MI)

Multivariate Adjusted Long-Term Outcomes

of

8409

2.4 64.0

CK-MB, >5× ULN 3478

3.7

CK-MB, >3–5× ULN

Increased risks of chest pain (58% vs. 9–12%), heart failure (35% vs. 6–7%), and increased length of stay for CK-MB >5× ULN vs. other elevations and normal levels

NA

NA

Increased risk of death (odds ratio, 8 for CK-MB >8× ULN; 67 for Q-wave MI)

In-Hospital Outcomes†

n e w e ng l a n d j o u r na l

Brener et al.25

12.6

CK-MB, 1–3× ULN

Kini et al.24‡

20 PCI

PCI

CK-MB, >12 ng/ml NA

85.4 25

1675

1326

CK-MB, 4–12 ng/ml

Ajani et

al.23

12.8

0.6

24.1

PCI

CK-MB, >20 ng/ml

67.3

CK-MB, 4–20 ng/ml

Dangas et al.22 4085

%

Incidence

7.7

PCI

Type of Intervention

29.6

68.9

%

Incidence of ACS

CK-MB, >32 ng/ml

7147

No. of Patients

CK-MB, >4–32 ng/ml

Stone et al.21

Study

Table 2. Large Cohort Studies of Cardiac-Biomarker Elevation after Percutaneous Coronary Intervention (PCI), and Outcomes.*

The

m e dic i n e

february 3, 2011

113

BACK to TOC

n engl j med 364;5

nejm.org

february 3, 2011

2.0 6.5 0.3

cTnI, 10–15.9 ng/ml

cTnI, ≥16.0 ng/ml

Q-wave MI

9.1

7.6

4.6

PCI

PCI

16.0

36.5

61.0

cTnI, 6–9.9 ng/m

1157

1128

cTnI, 2–5.9 ng/ml

Nallamothu et al.32

cTnI, ≥5× ULN

cTnI, 1–4× ULN

Natarajan et

6.4

CK-MB, >25 ng/ml

al.31

14.6

CK-MB, 5–25 ng/ml

Drug-eluting stenting PCI

5.1 40.9

CK-MB, >20 ng/ml 1807

4.4

Jang et al.30

19.9

CK-MB, >12–20 ng/ml

PCI

CK-MB, 4–12 ng/ml

30.4

15.2 3864

CK-MB, >20 ng/ml

Andron et al.29

32.1

Saphenous-vein graft PCI

CK-MB, 4–20 ng/ml

79.0

5

CK-MB, >88 ng/ml (CK-MB, >10× ULN) 1693

6

CK-MB, >44–88 ng/ml (CK-MB, >5–10× ULN)

Hong et al.28

6

PCI

CK-MB, >26.4–44 ng/ml (CK-MB, >3–5× ULN)

NA 21

3573

CK-MB, >8.8–26.4 ng/ml (CK-MB, >1–3× ULN)

Brener et al.27

NA

Increased risk of major cardiac events (3.8 for cTnI ≥5× ULN)

No association

NA

Increased need for balloon pump (7.8% vs. 1.1%) and repeat PCI (4.2% vs. 1.2%) for CK-MB elevation vs. no elevation

NA

11±7

12

13±7

6–42

12

36

Increased risk of death (hazard ratio, 2.4 for cTnI ≥8× ULN, 8.9 for Q-wave MI)

No association

Increased risk of death (0.5, 1.1, and 2.6% for CK-MB <1, 1–5, and >5× ULN, respectively)

Increased risk of death (hazard ratio, 1.3, 1.76, and 2.26 for CK-MB 1–3, >3–5 and >5× ULN, respectively)

Increased risk of death (hazard ratio, 3.3 for CK-MB >5× ULN)

Increased risk of death (hazard ratio, 1.1 for CK-MB >10× ULN)

current concepts

457

114

458

BACK to TOC

33

n engl j med 364;5

nejm.org

16.0

CK-MB, >5 ng/ml

24

8

24

12

25±8

24

26

mo

Length of Follow-up

Increased risk of death (odds ratio, 1.04 per peak CK-MB ratio unit)§

No association

No association

No association

Increased risk of death (hazard ratio, 1.6)

No association

Increased risk of death (hazard ratio, 1.2 per log2 increase in cTnT)

Multivariate Adjusted Long-Term Outcomes

* Plus–minus values are means ±SD. Only data from studies that included at least 1000 patients, long-term outcome data, and concentration-based biomarker analysis are shown. Hazard ratios were determined by means of a multivariate Cox proportional-hazards regression model, if available; otherwise, odds ratios were determined by multivariate analysis. Acute coronary syndromes (ACS) included angina at rest and urgent priority interventions. CK-MB denotes the MB fraction of creatine kinase, cTnI cardiac troponin I, cTnT cardiac troponin T, MI myocardial infarction, NA not available, and ULN upper limit of the normal range. † Outcomes other than evolving myocardial infarction are shown. P<0.05 for all comparisons. ‡ In this study, the final analysis was based on mass immunoassay. § This ratio was calculated by dividing the maximum post-PCI level by the ULN or baseline level of CK-MB.

44.2

cTnI, >0.15 ng/ml

NA

Increased risk of major adverse cardiovascular events (odds ratio, 2.1 for cTnI >3× ULN)

NA

NA

No association

NA

Increased length of stay

In-Hospital Outcomes†

of

Cavallini et al.39

15.4 40.8

19.8

19.7

23.4

51.9

20

19.6

%

Incidence

CK-MB, >4 ng/ml PCI

PCI

PCI

PCI

PCI

PCI

PCI

Type of Intervention

cTnI, >0.45 ng/ml 50.8

70.9

45.1

0.0

43.3

31.0

47.9

%

Incidence of ACS

15.2

3494

1129

2362

3200

1601

1208

1949

No. of Patients

n e w e ng l a n d j o u r na l

cTnI, 0.15–0.45 ng/ml

Fuchs et al.38

cTnI, >0.45 ng/ml

cTnI, 0.15–0.45 ng/ml

Cavallini et al.37

cTnI, >0.30 ng/ml

De Labriolle et al.36

cTnI, ≥0.15 ng/ml

Feldman et al.35

Increase in cTnT >0.1 ng/ml

Hubacek et al.34

cTnT, ≥0.03 ng/ml

Prasad et al.

Study

Table 2. (Continued.)

The

m e dic i n e

february 3, 2011

115

current concepts

gested that any elevation in CK-MB was associated with reduced long-term survival and that there was a direct correlation between the magnitude of myonecrosis and mortality.26,39,41,42 In contrast, other studies have shown that only large myocardial infarctions, variably defined as a CK-MB level exceeding 5 or 8 times the upper limit of normal or the presence of new Q waves, were predictive of a poor long-term outcome, especially if they were related to an unsuccessful revascularization procedure (Table 2).21,40,43,44 Studies evaluating the relationship between the postprocedural cardiac troponin level and longterm mortality, in general, have not excluded patients with acute coronary syndromes, many of whom would have had abnormal cardiac-biomarker levels at baseline.31,32,35,39,45-47 Thus, the reported frequency of postprocedural elevations in cardiac troponin has been highly variable, and although some studies showed that the serum concentration of cardiac troponin was an independent predictor of survival, others did not (Table 2). The inconsistent findings were most likely due to heterogeneity of the inclusion criteria, variations in the sensitivity and specificity of the biomarker assays, different sample sizes, and differences in the duration of follow-up. Two recent meta-analyses concluded that an elevated cardiac troponin level after PCI does provide prognostic information.48,49 Both analyses were influenced by studies from our catheterization laboratories on postprocedural cardiac troponin T elevations in which we had reached a similar conclusion.33,50 However, the studies included in the meta-analyses (including our own) had used cardiac troponin cutoff values for normal that were higher than the currently recommended 99th percentile, thereby limiting the accuracy of their conclusions.8

Focus on Pr epro cedur a l R isk To date, virtually all studies of periprocedural myocardial infarction have been limited by the lack of precision with which they determined preprocedural risk. Contemporary cardiac troponin assays have greatly enhanced our ability to detect myonecrosis before and after PCI.46,51 In a recent analysis, using the currently recommended 99th percentile value as the cutoff for a normal cardiac troponin T level, we found that approximately one third of patients who underwent nonemergency PCI had evidence of preprocedural n engl j med 364;5 BACK to TOC

myonecrosis.6 These patients had a greater atherosclerotic burden and more unstable disease than patients without evidence of preprocedural myonecrosis, a finding that is consistent with previous reports.52 Applying the universal definition of myocardial infarction to patients with normal preprocedural cardiac troponin T levels, another one third of patients sustained a periprocedural myocardial infarction after the procedure when cardiac troponin T was used to detect myonecrosis, as compared with only 1 in 15 patients when CK-MB was used.6 The preprocedural rather than postprocedural cardiac-biomarker level was a powerful independent predictor of shortterm and long-term mortality.6 Similar findings have been reported in two additional recent studies that used cardiac troponin I within the framework of the universal definition of myocardial infarction36,37 and in an analysis from the Evaluation of Drug Eluting Stents and Ischemic Events (EVENT) registry.53 These observations may seem surprising, since one might argue that the clinical effect of myocardial infarction should be the same regardless of its cause. However, most periprocedural myocardial infarcts are very small in relation to the magnitude of myonecrosis, especially in patients with stable coronary artery disease. Among patients with normal preprocedural cardiac troponin values, less than 5% have CK-MB values that are higher than 5 times the upper reference limit after PCI, and Q-wave infarctions are rare (<0.1%). Instead, CK-MB levels that are higher than 5 times the upper reference limit are generally observed in patients with elevated preprocedural cardiac troponin T.6 Thus, it is likely that in the older studies that explored the effect of periprocedural myocardial infarction on outcomes, a large proportion of the patients who had been classified as biomarker-negative on the basis of CK or CK-MB levels at the time of PCI actually had non–ST-segment elevation myocardial infarction according to contemporary definitions. This conclusion is supported by the high proportion of patients (about 50% on average) who had acute coronary syndromes in the previous studies (Table 2, and the Supplementary Appendix, available with the full text of this article at NEJM.org). In summary, recent studies reveal that the preprocedural cardiac troponin level is a powerful independent predictor of prognosis after PCI.

nejm.org

february 3, 2011

459

116

The

n e w e ng l a n d j o u r na l

Moreover, these studies suggest that the association between postprocedural myonecrosis and outcomes after an otherwise successful PCI is, in general, a reflection of the preprocedural risk, which can be estimated by measuring baseline cardiac troponin levels with the use of contemporary high-sensitivity assays in conjunction with the clinical and angiographic characteristics of the patient.

Pro gnos t ic Signific a nce of Per ipro cedur a l v er sus Sp on ta neous E v en t s On the basis of the traditional concept of periprocedural myocardial infarction described above, this complication has often been equated with spontaneous myocardial infarction in clinical trials.54 The validity of this assumption has not been examined in detail, and it has been confounded by the variable definitions of periprocedural myocardial infarction used in the past. The current universal definition of myocardial infarction attempts to address this issue by introducing a specific category (type 4a) for periprocedural myocardial infarction to distinguish it from spontaneous myocardial infarction (types 1 and 2).8 Akkerhuis and colleagues compared the effect of periprocedural myocardial infarction as detected by CK-MB elevation with that of spontaneous myocardial infarction on 6-month mortality in a heterogeneous group of patients who had acute coronary syndromes without ST-segment elevation; the data were derived from five different clinical-trial databases.55 The authors reported a positive correlation between CK-MB levels and mortality in both groups, although the absolute mortality was significantly higher among patients who had spontaneous myocardial infarction than among those who had periprocedural myocardial infarction. The authors concluded that the clinical significance of periprocedural myocardial infarction should be considered similar to the adverse consequences of spontaneous myocardial infarction. However, the study was conducted in the era of balloon angioplasty, before the widespread use of stents, and the analysis was not adjusted for confounding clinical variables. To address these limitations, an analysis was conducted of data from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial (Clinical.Trials.gov number, NCT00093158) 460 BACK to TOC

n engl j med 364;5

of

m e dic i n e

involving 7773 patients with moderate-to-highrisk, non–ST-segment elevation acute coronary syndromes who underwent PCI.15 Periprocedural myocardial infarction and spontaneous myocardial infarction during follow-up developed in 6.0% and 2.6% of the cohort, respectively. Among patients with either type of myocardial infarction, as compared with those without myocardial infarction, unadjusted mortality at 1 year was significantly higher. After adjustment for differences in baseline and procedural characteristics between the two groups, spontaneous myocardial infarction was a powerful independent predictor of an increased risk of death, whereas periprocedural myocardial infarction was not significantly associated with an increased risk of death. Similar observations have been made among patients with diabetes and stable coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial (NCT00006305), in which a first spontaneous, symptomatic myocardial infarction was associated with higher mortality, as compared with myocardial infarction induced by percutaneous or surgical revascularization.56 Taken together, contemporary studies indicate that spontaneous myocardial infarction is a powerful predictor of mortality. Periprocedural myocardial infarction, although frequent, is a marker of atherosclerotic burden and procedural complexity, but in most cases, it does not have important independent prognostic significance in stable coronary artery disease or in non–ST-elevation acute coronary syndromes. Although large periprocedural myocardial infarcts may affect prognosis, they rarely occur in the absence of procedural complications or in patients with normal baseline cardiac troponin levels.

A r e a s of Uncer ta in t y There is a pressing need for the interventional community and the associated professional organizations to examine the new data and provide more practical guidelines for defining periprocedural myocardial infarction. This process should include an assessment of the appropriateness of relying on biomarkers alone and of the low threshold used for the universal definition, as compared with a definition that includes clinical criteria such as symptoms or evidence of ischemia or infarction on electrocardiography or cardiac imaging.

nejm.org

february 3, 2011

117

current concepts

Figure 2. Recommendations for the Prevention and Management of Periprocedural Myocardial Infarction. ACS denotes acute coronary syndromes, CK-MB MB fraction of creatine kinase, and GP glycoprotein.

Pre-PCI Troponin Level Normal

Since most of the data on periprocedural myocardial infarction are derived from patients with normal levels of cardiac biomarkers before the procedure (predominantly those with stable or unstable angina), clearer guidelines are needed with regard to whether periprocedural myocardial infarction can be diagnosed in patients with non– ST-elevation myocardial infarction in whom biomarkers are rising before PCI and, if so, what diagnostic criteria should be used. This is probably not feasible in contemporary practice, since PCI is often performed within 24 hours after hospital admission. Another practical issue that needs to be addressed is whether the class IIa recommendation to routinely measure biomarkers after PCI is still appropriate and, if so, what the therapeutic implications of an elevated post-PCI level would be. A recent report from the National Cardiovascular Data Registry indicates that the majority of hospitals in the United States do not routinely measure cardiac biomarkers at the time of PCI.14 The improved understanding of the clinical significance of periprocedural myocardial infarction has important implications for the design of future randomized trials (i.e., periprocedural myocardial infarction and spontaneous myocardial infarction should not be considered equivalent clinical end points). This issue has most recently been relevant with respect to the interpretation of data from the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PLATFORM trial (NCT00385138).54 In that study, the majority of patients had acute coronary syndromes without ST-segment elevation and underwent PCI within 24 hours after presentation. This did not allow a reliable distinction between spontaneous myocardial infarction and periprocedural myocardial infarction, and led the investigators to conclude that the result of the trial “calls into question the definition of periprocedural MI used.” Differentiating spontaneous myocardial infarction from periprocedural myocardial infarction will be increasingly difficult in clinical practice, since most invasively managed cases involve cardiac catheterization during a period when pren engl j med 364;5 BACK to TOC

Elevated

Recognize increased risk and inform patient Consider initiation of antiplatelet therapy (e.g., GP IIb/IIIa inhibitors, clopidogrel) and high-dose statin therapy Manage ACS according to standard guidelines Treat decompensated heart failure, if present Provide optimal care for coexisting conditions such as renal dysfunction, anemia, and diabetes

Proceed with PCI

PCI

If appropriate, use distal protection for vein-graft interventions No procedural complications

Procedural complications or symptoms of ischemia, or both

Observe in hospital according to standard local practice Consider measuring post-PCI troponin or CK-MB at 8–16 hr (e.g., for those with complex PCI)

nejm.org

PCI

If appropriate, use distal protection for vein-graft interventions

Allow longer in-hospital observation Measure post-PCI CK-MB or troponin at 8–16 hr or as clinically indicated

Post-PCI Troponin Level

If troponin elevated, consider measuring CK-MB

Normal

Elevated

Provide standard post-PCI care and secondary prevention for coronary artery disease

CK-MB >5× upper reference limit or equivalent magnitude of troponin elevation or new Q waves Prolong in-hospital observation (by at least 1 day) Assess for left ventricular dysfunction If indicated, repeat angiography to identify procedural complications and need for intervention Troponin greater than upper reference limit and CK-MB <5× upper reference limit Prolong duration of observation only if clinically indicated (e.g., procedural complication) Intensify secondary prevention for coronary artery disease to ensure optimal management

february 3, 2011

461

118

The

n e w e ng l a n d j o u r na l

procedural biomarker levels would generally be rising. Thus, we would caution against including myocardial infarction as a component of the primary composite end point in future clinical trials of PCI in acute coronary syndromes or using it as a surrogate for long-term outcomes, although one might reasonably consider it as a secondary efficacy end point or a safety end point.

Impl ic at ions for Pr ac t ice Our recommendation is that cardiac troponin levels be routinely measured before PCI is performed (Fig. 2). A normal preprocedural level of cardiac troponin will assist in risk stratification by identifying patients in whom PCI can be performed with very low risk and who may be considered for early discharge from the hospital. In addition, a pre-PCI elevation in cardiac troponin identifies high-risk patients with complex or thrombotic lesions who may benefit from the preprocedural initiation of potent antiplatelet therapies and statins to improve outcomes.2,57,58 Post-PCI levels should be routinely measured in patients who have undergone complex procedures, who have suboptimal angiographic results, or who have procedural complications, as well as in those who have signs or symptoms of myocardial ischemia, in order to quantify the extent of myocardial injury. However, a reasonable case can be made for not routinely measuring postprocedural cardiac troponin levels in uncomplicated, successful PCI, since it is not likely that in such cases relevant additional information can be gained that will be independent of the preprocedural risk and procedural outcomes. The role of postprocedural monitoring of biomarkers for risk stratification in the secondary prevention of coronary artery disease or as a metric of quality remains to be established. There are no established cutoff values for cardiac troponin that define a “large” periprocedural myocardial infarct, and until such values can be clearly identified, a CK-MB level that is more than 5 times the upper reference limit, the presence of new Q waves, or both would appear to be reasonable criteria for defining a periproce-

of

m e dic i n e

dural myocardial infarction as extensive. We believe that, in general, this definition can reliably be applied only to patients with normal cardiac troponin levels before PCI. In the absence of data that can be used to help direct practice, we recommend that patients with large periprocedural myocardial infarction be monitored in the hospital for an additional day because of the reported risks of arrhythmias, hemodynamic instability, heart failure, and death (Table 2, and the Supplementary Appendix). For the purpose of preprocedural consent, one should discuss the frequency of a large periprocedural myocardial infarction (<5%) with the patient and inform the patient if it occurs after the intervention. The care of patients with acutely elevated preprocedural cardiac troponin who sustain major periprocedural myonecrosis should, in general, be based on the guidelines for managing acute coronary syndromes. Patients whose condition unexpectedly deteriorates soon after PCI (e.g., those with recurrent and unrelenting chest pain, particularly in combination with ST-segment shifts or echocardiographic evidence of ischemia or pericardial effusion) should undergo repeat coronary angiography. The goal is to identify procedural complications that are amenable to further intervention, such as acute stent thrombosis, coronary dissection, or perforation, to limit myonecrosis and relieve symptoms. In most cases, this involves repeat PCI; it is rare in current practice for patients to require cardiac surgery. Perhaps the most important implication for the long-term care of the vast majority of patients with periprocedural myocardial infarction is the realization that they represent a higher-risk cohort owing to a greater disease burden and more unstable disease. These patients should therefore be targeted for optimal secondary prevention based on the current guidelines. Occasionally, patients with stable coronary artery disease have extensive periprocedural myocardial infarction. The long-term care of such patients should be similar to that for patients with spontaneous myocardial infarction. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

References 1. Lloyd-Jones D, Adams RJ, Brown TM,

et al. Heart disease and stroke statistics — 2010 update: a report from the American Heart Association. Circulation 2010; 121(7):e46-e215. 2. Herrmann J. Peri-procedural myocar-

462 BACK to TOC

dial injury: 2005 update. Eur Heart J 2005;26:2493-519. 3. Porto I, Selvanayagam JB, Van Gaal WJ, et al. Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary

n engl j med 364;5

nejm.org

intervention: insights from delayedenhancement magnetic resonance imaging, Thrombolysis in Myocardial Infarction myocardial perfusion grade analysis, and intravascular ultrasound. Circulation 2006;114:662-9.

february 3, 2011

119

current concepts 4. Bhatt DL, Topol EJ. Does creatinine

kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Periprocedural cardiac enzyme elevation predicts adverse outcomes. Circulation 2005;112:906-15. 5. Cutlip DE, Kuntz RE. Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Cardiac enzyme elevation after successful percutaneous coronary intervention is not an independent predictor of adverse outcomes. Circulation 2005;112: 916-22. 6. Prasad A, Rihal CS, Lennon RJ, Singh M, Jaffe AS, Holmes DR Jr. Significance of periprocedural myonecrosis on outcomes after percutaneous coronary intervention: an analysis of preintervention and postintervention troponin T levels in 5487 patients. Circ Cardiovasc Interv 2008;1:10-9. 7. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006;113(7):e166-e286. 8. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur Heart J 2007;28:2525-38. 9. Mandadi VR, DeVoe MC, Ambrose JA, et al. Predictors of troponin elevation after percutaneous coronary intervention. Am J Cardiol 2004;93:747-50. 10. Blankenship JC, Haldis T, Feit F, et al. Angiographic adverse events, creatine kinase-MB elevation, and ischemic end points complicating percutaneous coronary intervention (a REPLACE-2 substudy). Am J Cardiol 2006;97:1591-6. 11. Cai Q, Skelding KA, Armstrong AT Jr, Desai D, Wood GC, Blankenship JC. Predictors of periprocedural creatine kinasemyocardial band elevation complicating elective percutaneous coronary intervention. Am J Cardiol 2007;99:616-20. 12. van Gaal WJ, Ponnuthurai FA, Selvanayagam J, et al. The Syntax score predicts peri-procedural myocardial necrosis during percutaneous coronary intervention. Int J Cardiol 2009;135:60-5. 13. Alcock RF, Roy P, Adorini K, et al. Incidence and determinants of myocardial infarction following percutaneous coronary interventions according to the revised Joint Task Force definition of troponin T elevation. Int J Cardiol 2010;140: 66-72. 14. Wang TY, Peterson ED, Dai D, et al. Patterns of cardiac marker surveillance after elective percutaneous coronary intervention and implications for the use of periprocedural myocardial infarction as a quality metric: a report from the National Cardiovascular Data Registry (NCDR). J Am Coll Cardiol 2008;51:2068-74.

15. Prasad A, Gersh BJ, Bertrand ME, et

al. Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009;54:477-86. 16. Srinivasan M, Rihal C, Holmes DR, Prasad A. Adjunctive thrombectomy and distal protection in primary percutaneous coronary intervention: impact on microvascular perfusion and outcomes. Circulation 2009;119:1311-9. 17. Uetani T, Amano T, Ando H, et al. The correlation between lipid volume in the target lesion, measured by integrated backscatter intravascular ultrasound, and post-procedural myocardial infarction in patients with elective stent implantation. Eur Heart J 2008;29:1714-20. 18. Hong YJ, Mintz GS, Kim SW, et al. Impact of plaque composition on cardiac troponin elevation after percutaneous coronary intervention: an ultrasound analysis. JACC Cardiovasc Imaging 2009;2:45868. 19. Bahrmann P, Werner GS, Heusch G, et al. Detection of coronary microembolization by Doppler ultrasound in patients with stable angina pectoris undergoing elective percutaneous coronary interventions. Circulation 2007;115:600-8. 20. Herrmann J, Haude M, Lerman A, et al. Abnormal coronary flow velocity reserve after coronary intervention is associated with cardiac marker elevation. Circulation 2001;103:2339-45. 21. Stone GW, Mehran R, Dangas G, Lansky AJ, Kornowski R, Leon MB. Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: a device-specific analysis of 7147 patients. Circulation 2001;104:642-7. 22. Dangas G, Mehran R, Feldman D, et al. Postprocedure creatine kinase-MB elevation and baseline left ventricular dysfunction predict one-year mortality after percutaneous coronary intervention. Am J Cardiol 2002;89:586-9. 23. Ajani AE, Waksman R, Sharma AK, et al. Usefulness of periprocedural creatinine phosphokinase-MB release to predict adverse outcomes after intracoronary radiation therapy for in-stent restenosis. Am J Cardiol 2004;93:313-7. 24. Kini A, Marmur JD, Kini S, et al. Creatine kinase-MB elevation after coronary intervention correlates with diffuse atherosclerosis, and low-to-medium level elevation has a benign clinical course: implications for early discharge after coronary intervention. J Am Coll Cardiol 1999; 34:663-71. 25. Brener SJ, Ellis SG, Schneider J, Topol EJ. Frequency and long-term impact of myonecrosis after coronary stenting. Eur Heart J 2002;23:869-76.

n engl j med 364;5 BACK to TOC

nejm.org

26. Ellis SG, Chew D, Chan A, Whitlow

PL, Schneider JP, Topol EJ. Death following creatine kinase-MB elevation after coronary intervention: identification of an early risk period: importance of creatine kinase-MB level, completeness of revascularization, ventricular function, and probable benefit of statin therapy. Circulation 2002;106:1205-10. 27. Brener SJ, Lytle BW, Schneider JP, Ellis SG, Topol EJ. Association between CK-MB elevation after percutaneous or surgical revascularization and three-year mortality. J Am Coll Cardiol 2002;40:1961-7. 28. Hong MK, Mehran R, Dangas G, et al. Creatine kinase-MB enzyme elevation following successful saphenous vein graft intervention is associated with late mortality. Circulation 1999;100:2400-5. 29. Andron M, Stables RH, Egred M, et al. Impact of periprocedural creatine kinaseMB isoenzyme release on long-term mortality in contemporary percutaneous coronary intervention. J Invasive Cardiol 2008; 20:108-12. 30. Jang JS, Hong MK, Park DW, et al. Impact of periprocedural myonecrosis on clinical events after implantation of drugeluting stents. Int J Cardiol 2008;129:36872. 31. Natarajan MK, Kreatsoulas C, Velianou JL, Mehta SR, Pericak D, Goodhart DM. Incidence, predictors, and clinical significance of troponin-I elevation without creatine kinase elevation following percutaneous coronary interventions. Am J Cardiol 2004;93:750-3. 32. Nallamothu BK, Chetcuti S, Mukherjee D, et al. Prognostic implication of troponin I elevation after percutaneous coronary intervention. Am J Cardiol 2003;91: 1272-4. 33. Prasad A, Singh M, Lerman A, Lennon RJ, Holmes DR Jr, Rihal CS. Isolated elevation in troponin T after percutaneous coronary intervention is associated with higher long-term mortality. J Am Coll Cardiol 2006;48:1765-70. 34. Hubacek J, Basran RS, Shrive FM, Shewchuk L, Goodhart DM, Anderson TJ. Prognostic implications of C-reactive protein and troponin following percutaneous coronary intervention. Can J Cardiol 2009;25(2):e42-e47. 35. Feldman DN, Minutello RM, Bergman G, Moussa I, Wong SC. Relation of troponin I levels following nonemergent percutaneous coronary intervention to short- and long-term outcomes. Am J Cardiol 2009;104:1210-5. 36. De Labriolle A, Lemesle G, Bonello L, et al. Prognostic significance of small troponin I rise after a successful elective percutaneous coronary intervention of a native artery. Am J Cardiol 2009;103:639-45. 37. Cavallini C, Verdecchia P, Savonitto S, et al. Prognostic value of isolated troponin I elevation after percutaneous coronary intervention. Circ Cardiovasc Interv 2010;3:431-5.

february 3, 2011

463

120

current concepts 38. Fuchs S, Kornowski R, Mehran R, et

al. Prognostic value of cardiac troponin-I levels following catheter-based coronary interventions. Am J Cardiol 2000;85:107782. 39. Cavallini C, Savonitto S, Violini R, et al. Impact of the elevation of biochemical markers of myocardial damage on longterm mortality after percutaneous coronary intervention: results of the CK-MB and PCI study. Eur Heart J 2005;26:1494-8. 40. Kugelmass AD, Cohen DJ, Moscucci M, et al. Elevation of the creatine kinase myocardial isoform following otherwise successful directional coronary atherectomy and stenting. Am J Cardiol 1994;74: 748-54. 41. Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinaseMB fraction after percutaneous coronary interventions. Circulation 1996;94:1528-36. 42. Kong TQ, Davidson CJ, Meyers SN, Tauke JT, Parker MA, Bonow RO. Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA 1997;277:461-6. 43. Saucedo JF, Mehran R, Dangas G, et al. Long-term clinical events following creatine kinase–myocardial band isoenzyme elevation after successful coronary stenting. J Am Coll Cardiol 2000;35:113441. 44. Jeremias A, Baim DS, Ho KK, et al. Differential mortality risk of postprocedural creatine kinase-MB elevation following successful versus unsuccessful stent procedures. J Am Coll Cardiol 2004;44: 1210-4. 45. Cantor WJ, Newby LK, Christenson RH, et al. Prognostic significance of ele-

vated troponin I after percutaneous coronary intervention. J Am Coll Cardiol 2002;39:1738-44. 46. Kizer JR, Muttrej MR, Matthai WH, et al. Role of cardiac troponin T in the longterm risk stratification of patients undergoing percutaneous coronary intervention. Eur Heart J 2003;24:1314-22. 47. Kini AS, Lee P, Marmur JD, et al. Correlation of postpercutaneous coronary intervention creatine kinase-MB and troponin I elevation in predicting mid-term mortality. Am J Cardiol 2004;93:18-23. 48. Nienhuis MB, Ottervanger JP, Bilo HJ, Dikkeschei BD, Zijlstra F. Prognostic value of troponin after elective percutaneous coronary intervention: a meta-analysis. Catheter Cardiovasc Interv 2008;71:31824. 49. Testa L, Van Gaal WJ, Biondi Zoccai GG, et al. Myocardial infarction after percutaneous coronary intervention: a metaanalysis of troponin elevation applying the new universal definition. QJM 2009; 102:369-78. 50. Herrmann J, Von Birgelen C, Haude M, et al. Prognostic implication of cardiac troponin T increase following stent implantation. Heart 2002;87:549-53. 51. Miller WL, Garratt KN, Burritt MF, Lennon RJ, Reeder GS, Jaffe AS. Baseline troponin level: key to understanding the importance of post-PCI troponin elevations. Eur Heart J 2006;27:1061-9. 52. Heeschen C, van Den Brand MJ, Hamm CW, Simoons ML. Angiographic findings in patients with refractory unstable angina according to troponin T status. Circulation 1999;100:1509-14. 53. Jeremias A, Kleiman NS, Nassif D, et al. Prevalence and prognostic signifi-

cance of preprocedural cardiac troponin elevation among patients with stable coronary artery disease undergoing percutaneous coronary intervention: results from the Evaluation of Drug Eluting Stents and Ischemic Events registry. Circulation 2008;118:632-8. 54. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361:2330-41. 55. Akkerhuis KM, Alexander JH, Tardiff BE, et al. Minor myocardial damage and prognosis: are spontaneous and percutaneous coronary intervention-related events different? Circulation 2002;105:554-6. 56. Chaitman BR, Hardison RM, Adler D, et al. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation 2009; 120:2529-40. 57. Herrmann J, Lerman A, Baumgart D, et al. Preprocedural statin medication reduces the extent of periprocedural nonQ-wave myocardial infarction. Circulation 2002;106:2180-3. 58. Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) randomized trial. J Am Coll Cardiol 2009;54:558-65. Copyright © 2011 Massachusetts Medical Society.

NEW NEJM APPLICATION FOR iPHONE

The NEJM Image Challenge app brings a popular online feature to the smartphone. Optimized for viewing on the iPhone and iPod Touch, the Image Challenge app lets you test your diagnostic skills anytime, anywhere. The Image Challenge app randomly selects from 300 challenging clinical photos published in NEJM, with a new image added each week. View an image, choose your answer, get immediate feedback, and see how others answered. The Image Challenge app is available at the iTunes App Store.

464 BACK to TOC

n engl j med 364;5

nejm.org

february 3, 2011

121

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article current concepts

MDR Tuberculosis — Critical Steps for Prevention and Control Eva Nathanson, M.Sc., Paul Nunn, F.R.C.P., Mukund Uplekar, M.D., Katherine Floyd, Ph.D., Ernesto Jaramillo, M.D., Ph.D., Knut Lönnroth, M.D., Ph.D., Diana Weil, M.Sc., and Mario Raviglione, M.D. From the Stop TB Department, World Health Organization, Geneva. Address reprint requests to Dr. Jaramillo at the Stop TB Dept., World Health Organization, CH-1211 Geneva, Switzerland, or at [email protected]. N Engl J Med 2010;363:1050-8. Copyright © 2010 Massachusetts Medical Society.

1050 BACK to TOC

M

ultidrug-resistant (MDR) tuberculosis is defined as disease caused by strains of Mycobacterium tuberculosis that are at least resistant to treatment with isoniazid and rifampicin; extensively drug-resistant (XDR) tuberculosis refers to disease caused by multidrug-resistant strains that are also resistant to treatment with any fluoroquinolone and any of the injectable drugs used in treatment with second-line anti-tuberculosis drugs (amikacin, capreomycin, and kanamycin). MDR tuberculosis and XDR tuberculosis are serious threats to the progress that has been made in the control of tuberculosis worldwide over the past decade.1,2 In 2008, an estimated 440,000 cases of MDR tuberculosis emerged globally.1 India and China carry the greatest estimated burden of MDR tuberculosis, together accounting for almost 50% of the world’s total cases. More than three quarters of the estimated cases of MDR tuberculosis occur in previously untreated patients. The proportion of MDR cases among new cases and previously treated cases of tuberculosis reported globally from 1994 through 2009 ranged from 0 to 28.3% and from 0 to 61.6%, respectively (Fig. 1). The highest proportions of MDR cases, and the most severe drug-resistance patterns, appear in the countries of the former Soviet Union. By 2009, a total of 58 countries had reported at least one case of XDR tuberculosis. In eight countries, reported cases of XDR tuberculosis account for more than 10% of all cases of MDR tuberculosis, and six of these countries were part of the former Soviet Union. By far the largest number of cases of XDR tuberculosis has been reported from South Africa (10.5% of all cases of MDR tuberculosis in that country), owing to rapid spread among people infected with the human immunodeficiency virus (HIV). National programs are failing to diagnose and treat MDR tuberculosis. Globally, just under 30,000 cases of MDR tuberculosis were reported to the World Health Organization (WHO) in 2008 (7% of the estimated total), of which less than one fifth were managed according to international guidelines. The vast majority of the remaining cases probably are not diagnosed or, if diagnosed, are mismanaged. This problem remains despite the evidence that management of MDR tuberculosis is cost-effective3 and that treatment of MDR tuberculosis, and even treatment of XDR tuberculosis, is feasible in persons who are not infected with HIV.4,5 In some countries, the incidence of tuberculosis is rising, and the incidence of MDR tuberculosis appears to be rising even faster (e.g., in Botswana and South Korea).6 However, in Estonia, Hong Kong, the United States, and Orel and Tomsk Oblasts (in the Russian Federation), the incidence of tuberculosis is falling, and the incidence of MDR tuberculosis appears to be falling even faster.1,6 This trend is

n engl j med 363;11

nejm.org

september 9, 2010

122

current concepts

0 to <3% 3 to <6% 6 to <12% 12 to <18% ≥18% No data available Figure 1. Distribution of the Proportion of Cases of MDR Tuberculosis among New Cases of Tuberculosis, 1994–2009. The following 27 countries are responsible for 85% of the world’s estimated cases of MDR tuberculosis and are classified as countries with a high burden of MDR tuberculosis: China, India, Russia, Pakistan, Bangladesh, South Africa, Ukraine, Indonesia, Philippines, Nigeria, Uzbekistan, Democratic Republic of Congo, Kazakhstan, Vietnam, Ethiopia, Myanmar, Tajikistan, Azerbaijan, Moldova, Kyrgyzstan, Belarus, Georgia, Bulgaria, Lithuania, Armenia, Latvia, and Estonia. Adapted from the 2010 report on MDR and XDR tuberculosis from the WHO.1

the result of high-quality care and control practices that result in high rates of case detection and cure, drug-susceptibility testing for all patients, and the provision of appropriate treatment for all patients carrying drug-resistant strains. In short, preventing initial infection with MDR tuberculosis and managing the treatment of existing cases appropriately are the keys to containing the spread of this disease. The WHO-recommended Stop TB Strategy7 provides the framework for treating and caring for those who are sick and controlling the epidemic of drug-susceptible and drug-resistant disease. The DOTS approach, which underpins the Stop TB Strategy, calls for political commitment to national programs designed to control disease by means of early diagnosis with the use of bacteriologic testing, standardized treatment with supervision and patient support, and provision and management of the drugs used in treatment; the approach also includes the monitoring of treatment and evaluation of its effectiveness. Between 1995 and 2008, a total of 36 million people were treated successfully with the use of the

n engl j med 363;11 BACK to TOC

DOTS approach, and 6 million lives were saved.8 Specific guidelines for controlling drug-susceptible and drug-resistant disease already exist,9,10 and the Global Plan to Stop TB, 2006 through 2015, developed by the Stop TB Partnership, specifies the scale at which these interventions need to be funded and implemented to achieve global targets.11 However, to date, planning, funding, and implementation are falling far behind the milestones that have been set. Prompted by concern that political support for the management of MDR tuberculosis is insufficient, WHO, the Bill and Melinda Gates Foundation, and the Chinese Ministry of Health organized a ministerial conference in Beijing in April 2009.12 The report from the conference in Beijing and the subsequent resolution (number 62.15) approved by the World Health Assembly in May 2009 state that significant changes in several components of the health care system must be made if MDR tuberculosis is to be eliminated.13,14 This review assesses the critical factors impeding control and discusses the solutions required to address them.

nejm.org

september 9, 2010

1051

123

The

n e w e ng l a n d j o u r na l

Prevention is better than cure. Thus, the top priority for the control and, ultimately, elimination of MDR tuberculosis is prevention of its emergence.15 Once MDR tuberculosis has emerged, however, urgent measures are required to curb its effects on efforts to control the disease. The major obstacles and approaches to controlling MDR tuberculosis are described below and summarized in Table 1. Three topics of great importance — the global shortage of health care workers,16 the need for improvements in surveillance systems,1 and the urgent need for intensified research on new diagnostic tests, drugs, and vaccines17 — have been well described elsewhere and are beyond the scope of this article. Financing Control and Care

To achieve the goal of universal access to diagnosis and treatment described in the Global Plan to Stop TB, 1.3 million cases of MDR tuberculosis in the 27 countries with the highest burden of MDR disease will need to be treated between 2010 and 2015.1 The total estimated cost of such treatment is several billion U.S. dollars, an amount far in excess of the existing level of funding. The national strategic plans in these countries must incorporate the preparation of ambitious budgets for the prevention and control of MDR tuberculosis. These plans must be consistent with policies on health care financing, including socialprotection schemes (the delivery of commodities to reduce the social vulnerability of poor populations), and with broader planning and financing frameworks. These countries — especially the middle-income countries among them — must mobilize their domestic resources. In 2001, the WHO Commission on Macroeconomics and Health indicated that these middle-income countries could finance all, or almost all, of their health care needs.18 While maximizing the use of domestic resources, they should also target resources available from international financing organizations, such as the Global Fund to Fight AIDS (Acquired Immunodeficiency Syndrome), Tuberculosis, and Malaria and UNITAID, an organization that provides grants allowing countries to purchase diagnostic tests and drugs used in the treatment of HIV–AIDS, malaria, and tuberculosis. The failure to adequately fund a re-

BACK to TOC

n engl j med 363;11

m e dic i n e

sponse to MDR tuberculosis would have catastrophic consequences in terms of both human lives and tuberculosis control in general.

Cr i t ic a l W e a k ne sse s a nd How t o A ddr ess Them

1052

of

Abolishing Financial Barriers

Health expenditures that account for more than 40% of household income (after deducting the cost of basic subsistence) have been defined as catastrophic.19 In virtually all countries with a high burden of MDR tuberculosis, treatment costs (per course of treatment) for one person are more than 100% of the gross national income per capita (the cost of second-line anti-tuberculosis drugs alone is typically $2,000 to $4,000 per patient).1 Collective financing mechanisms are therefore required to guarantee universal access to health care. The main source of funding should be domestic resources, such as contributions from taxes, payroll deductions, or mandatory insurance premiums.20,21 Most countries in Africa, Asia, and the Middle East have not attained universal health coverage,22 although there are exceptions. Lessons need to be drawn from universal healthfinancing schemes applied in such diverse settings as Mexico, Rwanda, and Thailand, where access to care may facilitate early detection and treatment of all tuberculosis cases. Even before universal health coverage is achieved, immediate steps can be taken to reduce catastrophic health expenditures for patients with tuberculosis and their households.23 These steps include decentralization of services to reduce the indirect costs that patients seeking care incur, provision of patient incentives and social support to promote adherence to treatment, and subsidization of care provided in the private sector that is in line with guidelines from national tuberculosis programs. Engaging All Care Providers

A substantial proportion of patients with tuberculosis or MDR tuberculosis seek care with providers who are not linked to national tuberculosis programs.24,25 In five countries with a high burden of MDR tuberculosis, more than half of all sales of first-line anti-tuberculosis drugs occur in the private sector, and the proportion is even higher for sales of second-line drugs.26 Many physicians in the private sector and some in the public sector do not follow internationally recommended treatment regimens for tuberculosis, use medicines of questionable quality, and ne-

nejm.org

september 9, 2010

124

BACK to TOC

n engl j med 363;11

nejm.org

september 9, 2010

Persons with infectious MDR-TB and XDR-TB remain in the community for long periods of time because of delayed diagnosis and initiation of treatment with second-line anti-TB drugs; hospitalization of patients with MDR-TB or XDR-TB poses problem of nosocomial transmission and is costly and inconvenient for patients In 2008, in 27 countries with the highest burden of MDR-TB, only 1% of patients with newly diagnosed TB and 3% of patients with previously treated TB underwent drug-susceptibility testing Use of counterfeit and poor-quality anti-TB drugs, which can lead to development and amplification of drug resistance, is well documented, but there is no accurate estimate of the scale of the problem Wide availability of anti-TB drugs over the counter in retail pharmacies encourages self-treatment and the purchase of inadequate quantities and combinations of medicines Ongoing transmission of MDR-TB and XDR-TB occurs in health care facilities and congregate settings because of inadequate infection control Shortage of trained staff to effectively manage the 1.6 million MDRTB cases expected by 2015 is exacerbated in many low-income countries by active recruitment of staff by industrialized countries Estimates of the burden of drug-resistant TB globally and by country remain incomplete and less than accurate Tools for prevention, diagnosis, and treatment of TB and drug-resistant TB are obsolete

Optimize MDR-TB and XDR-TB management and care

Address laboratory crisis

Ensure access to quality-assured anti-TB drugs

Restrict availability of anti-TB drugs

Prioritize TB infection control

Address global health workforce crisis

Improve surveillance systems

Invest in research and development of new diagnostic tests, drugs, and vaccines

Ensure collaboration between development and technical agencies to facilitate development and field testing of new tools for prevention, diagnosis, and treatment of TB

Establish or strengthen continuous surveillance systems for drug-resistant TB

Revise or update strategic plans for increasing the TB health care workforce (including private health care providers) to improve basic TB control and to scale up MDR-TB control

Engage wide range of stakeholders across the health system (e.g., hospital administrators, architects, engineers, and health care workers), including those concerned with control of other infections with airborne potential, such as influenza, to implement infection-control policies

Restrict drug availability to accredited providers by combining government policy, agreement with providers and industry on improved marketing practices, and optimization of the protocol for drug management and supply specified by the national TB program

Secure affordable, quality-assured anti-TB drugs using national procurement mechanisms while building up a reliable second-line anti-TB drug market, with manufacturers investing in increased volumes and improved quality

Strengthen laboratory services by using new molecular technologies

Ensure timely diagnosis and treatment initiation for patients with MDR-TB or XDR-TB; implement appropriate models of care, preferably outpatient, to ensure patient-centered care, avoid disease transmission in health care facilities, and make rational use of financial resources

Engage diverse providers (public, voluntary, private, and corporate) to align TB-management practices with WHO International Standards for TB Care

Improve health care financing schemes to strive for universal access to prevention and control; decentralize services to reduce indirect costs; promote patient adherence to treatment; and subsidize care provided in the private sector

Maximize use of domestic resources while targeting resources from the Global Fund to Fight AIDS, Tuberculosis, and Malaria, UNITAID, and other external funding mechanisms

Proposed Solution

* The international group known as UNITAID purchases and distributes diagnostic tests and drugs used in the treatment of HIV–AIDS, malaria, and tuberculosis. AIDS denotes acquired immunodeficiency syndrome, MDR-TB multidrug-resistant tuberculosis, TB tuberculosis, WHO World Health Organization, and XDR-TB extensively drug-resistant tuberculosis.

A substantial proportion of patients seek care from providers who do not follow internationally recommended standards of treatment

In countries with a high burden of MDR-TB, treatment costs for a single patient constitute more than 100% of the gross national income per capita

Abolish financial barriers

Engage all care providers in appropriate MDR-TB prevention and control

Estimated cost for 2010–2015 is $16.2 billion (in U.S $), increasing annually from <$1.3 billion in 2010 to $4.4 billion in 2015; funding needed is already in excess of the planned national MDR-TB budgets for 2010

Problem

Finance control and treatment for MDR-TB and XDR-TB

Goal

Table 1. Critical Challenges in the Control of MDR Tuberculosis and XDR Tuberculosis and Potential Solutions Supported by the WHO.*

current concepts

1053

125

The

n e w e ng l a n d j o u r na l

glect essential principles of case management.27,28 Such practices lead to the development, amplification, and spread of drug resistance. In addition, collaboration with public and private hospitals warrants special attention.29 Guidance on implementing a mix of public and private approaches to tuberculosis care is available,30 and many national tuberculosis programs have begun to incorporate diverse sources of care, including public, voluntary, private, and corporate providers. Nonetheless, only a fraction of the tuberculosis cases diagnosed by practitioners outside the public sector are registered with or referred to national tuberculosis programs.31,32 These approaches should therefore be scaled up and applied to the prevention and management of MDR tuberculosis as well. National tuberculosis programs need to play a stewardship role and provide guidelines, training, technical and financial support, and the supervision needed to align the practices of private providers with the International Standards for TB Care.33 Effective engagement of diverse care providers will require national tuberculosis programs to both augment their own capacities and strengthen private provider networks to enable them to shoulder their responsibility for managing tuberculosis and MDR tuberculosis. Professional associations need to act as intermediaries between national tuberculosis programs and private providers. Nongovernmental organizations have introduced successful programs for the management of MDR tuberculosis in a number of countries and are key players in scaling up diagnosis and treatment.34,35 But collaborative approaches and appropriate incentives alone may not enlist the support of all relevant care providers — some regulation may be necessary. In some countries with a high burden of tuberculosis, providers are not required to notify the government when a new case of tuberculosis has been diagnosed. And even in countries where notification is required, systems have not been established to ensure that the requirement is met. Case notification for both tuberculosis and MDR tuberculosis must be made mandatory; providers who follow best practices should be certified and accredited and should be offered access to free supplies of quality-assured antituberculosis drugs for their patients.30 Sustainable engagement of all care providers will require national tuberculosis programs to work in close

1054 BACK to TOC

n engl j med 363;11

of

m e dic i n e

partnership with health professionals, representatives of the pharmaceutical industry, pharmacists, and drug regulatory authorities, in addition to consumer and patient associations. Optimizing Disease Management and Care

Transmission of drug-resistant tuberculosis occurs in the community,36 as indicated by the high frequencies of MDR tuberculosis among previously untreated patients in some countries. In most countries with limited resources, patients with MDR or XDR tuberculosis must complete two unsuccessful courses of treatment with firstline anti-tuberculosis drugs before being eligible for treatment with second-line drugs.37 Moreover, in many countries, treatment of MDR tuberculosis is started only after the diagnosis has been confirmed, a process that takes months when conventional methods are used. As a result, persons with infectious MDR or XDR tuberculosis remain in the community for long periods of time. Prompt diagnosis and treatment of tuberculosis and MDR tuberculosis can keep the case reproduction number of MDR strains below their replacement rate — and perhaps even below that of non-MDR strains.6 Outbreaks of MDR tuberculosis have occurred in hospitals, and patients with tuberculosis who are hospitalized have a higher risk of acquiring MDR tuberculosis than do those who are treated as outpatients.38,39 Treating MDR tuberculosis in a hospital is more expensive than doing so on an ambulatory basis. Hospital treatment is also more socially and economically disruptive for most patients.40 In addition, the number of hospital beds may become insufficient as countries expand treatment for MDR tuberculosis. Despite the complexities involved in caring for patients with MDR tuberculosis, including lengthy therapy with poorly tolerated drugs, clinic-based or community-based care has proved to be feasible and effective in several countries, including Nepal41 and Peru.42 However, the effectiveness of outpatient care depends on the availability of primary care facilities, qualified health care workers, and social support networks to promote adherence to treatment. Countries need to select the model of care that is right for them, taking into account the personal rights and needs of patients and communities,43 the numbers of patients who have both MDR tuberculosis and

nejm.org

september 9, 2010

126

current concepts

HIV–AIDS, the social circumstances of patients,44 risk of the development of drug resistance.51 The the health care infrastructure, and the ability of use of counterfeit and poor-quality anti-tubercuthe country to mobilize resources. losis drugs, which can lead to the development and amplification of drug resistance, is well docResponding to the Laboratory Crisis umented, but there is no accurate estimate of the Weak laboratory capacity remains a serious im- scale of the problem.52,53 International quality pediment to prompt diagnosis and better control standards have been developed but are often igof MDR tuberculosis.1 The goal of universal ac- nored, and an insufficient number of manufaccess to drug-susceptibility testing has not yet been turers have been approved under the WHO Preachieved. In 2008, drug-susceptibility testing was qualification Programme.54 performed in only 1% of new tuberculosis cases To effectively prevent and manage MDR tuand 3% of previously treated cases in the 27 berculosis, countries need to secure affordable, countries with the highest burden of MDR tuber- quality-assured, anti-tuberculosis drugs through culosis. national procurement mechanisms. Affordable Today, rapid molecular tests for MDR tubercu- and quality-assured, second-line anti-tuberculolosis are available.45 For instance, one new auto- sis drugs can also be accessed through the WHO mated rapid test for rifampicin resistance holds Green Light Committee, which ensures managepromise for easier detection of MDR tuberculosis ment of MDR tuberculosis that is in line with even in community settings.46 The implementa- international quality standards in 70 countries.1 tion of this and other rapid tests, especially in However, of particular concern for efforts to incountries with a high prevalence of concurrent crease the scale of MDR tuberculosis manageHIV infection and MDR tuberculosis, can prevent ment is the insufficient supply of quality-assured, fatal delays in detection.47 The establishment of second-line anti-tuberculosis drugs.13 As of April quality-assured diagnostic capacity, including rapid 2010, only two manufacturers that produce three diagnostic technologies to identify MDR tubercu- of the seven second-line anti-tuberculosis drugs losis, is feasible in resource-limited settings.48 Use on the WHO Model List of Essential Medicines of the new molecular technologies offers one of had been approved by the WHO Prequalification the best avenues for improving overall diagnostic Programme.54 Building up a reliable market of capacity in the laboratory.49 At present, however, second-line anti-tuberculosis drugs, with manuthe adoption of the new rapid tests will not elimi- facturers investing in increased volumes and imnate the need for conventional drug-susceptibility proved quality, requires more accurate forecasttesting with the use of solid or liquid culture. Con- ing of demand. In addition, national authorities ventional susceptibility testing is required to de- need to expedite the enrollment of many more termine susceptibility to drugs other than rifam- patients under proper management conditions. picin and isoniazid.9 While countries expand laboratory capacity and introduce the new rapid Restricting Drug Availability tests, targeted drug-susceptibility testing should be Anti-tuberculosis drugs are widely available over performed in specific groups of patients at risk for the counter in retail pharmacies in many coundrug resistance. Expansion of diagnostic capacity tries.55 This encourages self-treatment and the for MDR tuberculosis must be coupled with ac- purchase of inadequate quantities and combinacess to second-line anti-tuberculosis drugs. Efforts tions of medicines. Even when the drugs are preto shorten the time required for diagnosis must scribed, those prescribing the drugs outside naoccur in tandem with measures that minimize or- tional tuberculosis programs may not abide by ganizational delay to ensure prompt initiation of recommended regimens, and some patients may purchase only part of the prescription because of treatment. financial constraints.56 Prescription and dispensEnsuring Access to Quality-Assured Drugs ing of medicines in general, and of antibiotics in In 2007, only 15% of reported new cases of tuber- particular, are poorly monitored and regulated culosis were treated with fixed-dose combina- in most countries.57 Even when regulations exist, tions of anti-tuberculosis drugs,50 despite their their enforcement is often insufficient. logistic advantages and potential to reduce the An essential step toward improved prevention

n engl j med 363;11 BACK to TOC

nejm.org

september 9, 2010

1055

127

The

n e w e ng l a n d j o u r na l

of MDR tuberculosis is to encourage the engagement of private and public providers with national tuberculosis programs on a voluntary basis.30 A more forceful approach would be to restrict the right to prescribe and dispense the drugs to the national tuberculosis program itself or to providers that have been accredited by the program. Either approach would require a combination of new government policy and dialogue with care providers, including pharmacists, and the pharmaceutical industry. Such measures undertaken by national tuberculosis programs to optimize drug management and supply have been successful in some countries, including Brazil, Ghana, Syria, and Tanzania. Consumers also need to be aware of the risks of poor prescribing practices and, as discussed above, the clinical and public health threats posed by substandard medicines.52,57 Demand-driven efforts to push for more accountability and enforcement of regulations by national authorities may be highly effective. Further advances in social responsibility and improved marketing practices on the part of drug manufacturers are also essential, along with supportive government measures. Prioritizing Control of Tuberculosis Infection

As a result of inadequate measures of infection control, there is ongoing transmission of MDR tuberculosis and XDR tuberculosis in health care facilities and congregate settings (e.g., prisons).38 To date, virtually no country with a high burden of tuberculosis has implemented systematic measures to reduce the risk of tuberculosis transmission in health facilities.1 Health care workers, especially those working in tuberculosis hospitals and in resource-limited settings, are at substantially higher risk of contracting tuberculosis and MDR tuberculosis than the general population.58,59 All health care facilities that admit patients with tuberculosis or patients suspected of having tuberculosis should implement tuberculosis-control measures that complement general measures of infection control, especially those which target other airborne infections.60 Home-based and community treatment of MDR tuberculosis should be promoted. To curb the increased risk of nosocomial tuberculosis and MDR tuberculosis among health care workers, some countries have added

1056 BACK to TOC

n engl j med 363;11

of

m e dic i n e

tuberculosis to the list of recognized occupational hazards.59 Infection control requires engagement with a wide range of stakeholders across the health care system, including hospital administrators, architects, engineers, doctors, nurses, and laboratory staff. On the policy level, infection control requires collaborative action among those concerned with infections with airborne potential, such as influenza.

The Urgen t Need for Ac tion Critical weaknesses in current approaches to the treatment and control of MDR tuberculosis and XDR tuberculosis have been identified and are being addressed at the global level. In 2009, the Beijing Call for Action13 and the passage of World Health Assembly Resolution 62.1514 signaled a major step forward in coordinated planning for the treatment and control of MDR tuberculosis and in the commitment to achieve universal access to diagnosis and treatment by 2015 for patients who have the disease. Resolutions, however, are useful only insofar as they stimulate the appropriate policymakers in governments to act on them. By October 2009, 20 of the 27 countries with the highest burden of MDR tuberculosis were updating their national tuberculosis-control plans to include a component addressing MDR tuberculosis, in compliance with the World Health Assembly resolution. Furthermore, for the countries that have received grants from the Global Fund in its ninth round of grants, funding requested for the management of MDR tuberculosis was by far the largest requested for all aspects of tuberculosis control: more than $500 million (in U.S. dollars) was requested for the management of MDR tuberculosis in 28 countries over a period of 5 years. Every one of the recommendations in this article for improving the treatment and control of MDR tuberculosis requires action beyond national tuberculosis control programs, sometimes in the political environment outside the health care system. This is a highly ambitious but necessary agenda for health authorities in the affected countries and for the global health community. The steps involved in controlling MDR tuberculosis are also important steps toward strengthening health care systems, including progress in achieving universal health care coverage. If this

nejm.org

september 9, 2010

128

current concepts

policy agenda is not pursued with urgency, the human and financial costs to societies will be profound. Supported by a grant from the Bill and Melinda Gates Foundation. No potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Karin Bergström, Léopold Blanc, Robert Matiru, Andrea Pantoja, Fabio Scano, Karin Weyer, and Matteo Zignol for their support in developing the background documents for the ministerial meeting in Beijing in April 2009 and for reviewing earlier versions of the manuscript.

References 1. World Health Organization. Multi-

drug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. 2010. (Accessed August 16, 2010, at http://whqlibdoc.who .int/publications/2010/9789241599191_eng .pdf.) 2. Raviglione MC, Smith IM. XDR tuberculosis — implications for global public health. N Engl J Med 2007;356:656-9. 3. Tupasi TE, Gupta R, Quelapio MI, et al. Feasibility and cost-effectiveness of treating multidrug-resistant tuberculosis: a cohort study in the Philippines. PLoS Med 2006;3(9):e352. 4. Orenstein EW, Basu S, Shah NS, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis 2009;9:153-61. 5. Sotgiu G, Ferrara G, Matteelli A, et al. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J 2009;33:871-81. 6. Dye C. Doomsday postponed? Preventing and reversing epidemics of drug resistant tuberculosis. Nat Rev Microbiol 2009; 7:81-7. 7. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367: 952-5. 8. Lönnroth K, Castro KG, Chakaya JM, et al. Tuberculosis control and elimination 2010-50: cure, care, and social development. Lancet 2010;375:1814-29. 9. World Health Organization. Treatment of tuberculosis: guidelines. 4th ed. 2009 (WHO/HTM/TB/2009.420). Geneva, 2010. 10. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis: emergency update 2008. (Accessed August 16, 2010, at http://whqlibdoc.who.int/publications/ 2008/9789241547581_eng.pdf.) 11. Stop TB. Partnership: global plan to stop TB, 2006-2015. (Accessed August 16, 2010, at http://www.stoptb.org/global/ plan/default.asp.) 12. Cheng MH. Ministerial meeting agrees plan for tuberculosis control. Lancet 2009; 373:1328. 13. World Health Organization. Global tuberculosis control and patient care: a ministerial meeting of high M/XDR-TB burden countries. (Accessed August 16, 2010, at

http://www.who.int/tb_beijingmeeting/en/ index.html.) 14. Idem. Prevention and control of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. World Health Assembly resolution 62.15. May 2009. (Accessed August 16, 2010, at http://apps.who.int/gb/ebwha/pdf_files/ A62/A62_R15-en.pdf.) 15. Reichman LB. Unsexy tuberculosis. Lancet 2009;373:28. 16. The world health report 2006: working together for health. Geneva: World Health Organization, 2006. (Accessed August 16, 2010, at http://www.who.int/whr/ 2006/whr06_en.pdf.) 17. Fauci AS. Opinion: fighting TB should be priority. New York: Msnbc.com, 2009. (Accessed August 16, 2010, at http://www .msnbc.msn.com/id/33890464/ns/ health-infectious_diseases/.) 18. Macroeconomics and health: investing in health for economic development. Report of the Commission on Macroeconomics and Health. Geneva: World Health Organization, 2001. (Accessed August 16, 2010, at http://whqlibdoc.who.int/ publications/2001/924154550X.pdf.) 19. Xu K, Evans DB, Kawabata K, Zeramdini R, Klavus J, Murray CJL. Household catastrophic health expenditure: a multicountry analysis. Lancet 2003;362:111-7. 20. Social health protection: an ILO strategy towards universal access to health care. Social security policy briefings. Paper 1. Geneva: International Labour Organization, 2008. (Accessed August 16, 2010, at http://www.ilo.org/public/english/ protection/secsoc/downloads/policy/ policy1e.pdf.) 21. World Health Organization. Social health insurance: sustainable health financing, universal coverage and social health insurance. April 2005. (Accessed August 16, 2010, at http://apps.who.int/gb/ ebwha/pdf_files/WHA58/A58_20-en.pdf.) 22. Garrett L, Chowdhury AM, PablosMéndez A. All for universal health coverage. Lancet 2009;374:1294-9. 23. Hanson C, Floyd K, Weil D. Tuberculosis in the poverty alleviation agenda. In: Raviglione M, ed. TB: a comprehensive international approach. New York: Informa Healthcare, 2006:1097-114. 24. Pantoja A, Floyd K, Unnikrishnan KP, et al. Economic evaluation of public-pri-

n engl j med 363;11 BACK to TOC

nejm.org

vate mix for tuberculosis care and control, India. I. Socio-economic profile and costs among tuberculosis patients. Int J Tuberc Lung Dis 2009;13:698-704. 25. Lönnroth K, Aung T, Maung W, Kluge H, Uplekar M. Social franchising of TB care through private GPs in Myanmar: an assessment of treatment results, access, equity and financial protection. Health Policy Plan 2007;22:156-66. 26. Pathway to patients: charting the dynamics of the global TB drug market. New York: TB Alliance, 2007. (Accessed August 16, 2010, at http://www.tballiance .org/downloads/publications/Pathway_to_ Patients_Compendium_FINAL.pdf.) 27. Loveday M, Thomson L, Chopra M, Ndlela Z. A health systems assessment of the KwaZulu-Natal tuberculosis programme in the context of increasing drug resistance. Int J Tuberc Lung Dis 2008; 12:1042-7. 28. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912-6. 29. Uplekar M. Stopping tuberculosis: time to turn urgent attention to hospitals. Int J Tuberc Lung Dis 2008;12:986. 30. World Health Organization. Engaging all health care providers in TB control: guidance on implementing public-private mix approaches. 2006. (Accessed August 16, 2010, at http://whqlibdoc.who.int/hq/ 2006/WHO_HTM_TB_2006.360_eng.pdf.) 31. Lönnroth K, Uplekar M, Blanc L. Hard gains through soft contracts: productive engagement of private providers in tuberculosis control. Bull World Health Organ 2006;84:876-83. 32. Irawati SR, Basri C, Arias MS, et al. Hospital DOTS linkage in Indonesia: a model for DOTS expansion into government and private hospitals. Int J Tuberc Lung Dis 2007;11:33-9. 33. Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tuberculosis care. Lancet Infect Dis 2006;6:710-25. 34. Van Deun A, Maug AK, Salim MA, et al. Short, highly effective and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010 May 4 (Epub ahead of print). 35. Cox HS, Kalon S, Allamuratova S, et al. Multidrug-resistant tuberculosis treatment

september 9, 2010

1057

129

current concepts outcomes in Karakalpakstan, Uzbekistan: treatment complexity and XDR-TB among treatment failures. PLoS ONE 2007;2(11): e1126. 36. Marais BJ, Victor TC, Hesseling AC, et al. Beijing and Haarlem genotypes are overrepresented among children with drugresistant tuberculosis in the Western Cape Province of South Africa. J Clin Microbiol 2006;44:3539-43. 37. Basu S, Friedland GH, Medlock J, et al. Averting epidemics of extensively drugresistant tuberculosis. Proc Natl Acad Sci U S A 2009;106:7672-7. 38. Nodieva A, Jansone I, Broka L, Pole I, Skenders G, Baumanis V. Recent nosocomial transmission and genotypes of multidrug-resistant Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2010;14:427-33. 39. Gelmanova IY, Keshavjee S, Golubchikova VT, et al. Barriers to successful tuberculosis treatment in Tomsk, Russian Federation: non-adherence, default and the acquisition of multidrug resistance. Bull World Health Organ 2007;85:70311. 40. Heller T, Lessells RJ, Wallrauch CG, et al. Community-based treatment for multidrug-resistant tuberculosis in rural KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 2010;14:420-6. 41. Malla P, Kanitz EE, Akhtar M, et al. Ambulatory-based standardized therapy for multi-drug resistant tuberculosis: experience from Nepal, 2005-2006. PLoS ONE 2009;4:e8313. 42. Shin S, Furin J, Bayona J, Mate K, Kim JY, Farmer P. Community-based treatment of multidrug-resistant tuberculosis in Lima, Peru: 7 years of experience. Soc Sci Med 2004;59:1529-39. 43. Singh JA, Upshur R, Padayatchi N. XDR-TB in South Africa: no time for de-

nial or complacency. PLoS Med 2007;4(1): e50. 44. Floyd K, Hutubessy R, Samyshkin Y, et al. Health-systems efficiency in the Russian Federation: tuberculosis control. Bull World Health Organ 2006;84:43-51. 45. World Health Organization. Molecular line probe assays for rapid screening of patients at risk of multidrug-resistant tuberculosis (MDR-TB). Policy statement. June 27, 2008. (Accessed August 16, 2010, at http://www.who.int/tb/dots/laboratory/ lpa_policy.pdf.) 46. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010;363:1005-15. 47. Gandhi NR, Shah NS, Andrews JR, et al. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med 2009;181:80-6. 48. Paramasivan CN, Lee E, Kao K, et al. Experience establishing tuberculosis laboratory capacity in a developing country setting. Int J Tuberc Lung Dis 2010;14:5964. 49. Birx D, de Souza M, Nkengasong JN. Laboratory challenges in the scaling up of HIV, TB, and malaria programs: the interaction of health and laboratory systems, clinical research, and service delivery. Am J Clin Pathol 2009;131:849-51. 50. Global tuberculosis control: epidemiology, strategy, financing. WHO report 2009. Geneva: World Health Organization, 2009. (WHO/HTM/TB/2009.411.) (Accessed August 16, 2010, at http://www.who.int/tb/ publications/global_report/en/index.html.) 51. Blomberg B, Fourie B. Fixed-dose combination drugs for tuberculosis: application in standardised treatment regimens. Drugs 2003;63:535-53.

52. Caudron JM, Ford N, Henkens M,

Macé C, Kiddle-Monroe R, Pinel J. Substandard medicines in resource-poor settings: a problem that can no longer be ignored. Trop Med Int Health 2008;13: 1062-72. 53. Newton PN, Green MD, Fernández FM, Day NP, White NJ. Counterfeit antiinfective drugs. Lancet Infect Dis 2006;6: 602-13. 54. World Health Organization. Prequalification programme. (Accessed August 16, 2010, at http://apps.who.int/prequal/.) 55. Kobaidze K, Salakaia A, Blumberg HM. Over the counter availability of antituberculosis drugs in Tbilisi, Georgia, in the setting of a high prevalence of MDRTB. Interdiscip Perspect Infect Dis 2009; 2009:513-609. 56. Uplekar M, Juvekar S, Morankar S, Rangan S, Nunn P. Tuberculosis patients and practitioners in private clinics in India. Int J Tuberc Lung Dis 1998;2:324-9. 57. Cars O, Högberg LD, Murray M, et al. Meeting the challenge of antibiotic resistance. BMJ 2008;337:a1438. 58. Skodric-Trifunovic V, Markovic-Denic L, Nagorni-Obradovic L, Vlajinac H, Woeltje KF. The risk of occupational tuberculosis in Serbian health care workers. Int J Tuberc Lung Dis 2009;13:640-4. 59. Naidoo S, Jinabhai CC. TB in health care workers in KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 2006;10:67682. 60. WHO policy on TB infection control in health-care facilities, congregate settings and households. Geneva: World Health Organization, 2009. (Accessed August 16, 2010, at http://whqlibdoc.who .int/publications/2009/9789241598323_eng .pdf.) Copyright © 2010 Massachusetts Medical Society.

IMAGES IN CLINICAL MEDICINE

The Journal welcomes consideration of new submissions for Images in Clinical Medicine. Instructions for authors and procedures for submissions can be found on the Journal’s Web site at NEJM.org. At the discretion of the editor, images that are accepted for publication may appear in the print version of the Journal, the electronic version, or both.

1058 BACK to TOC

n engl j med 363;11

nejm.org

september 9, 2010

130

Other Clinical Resources Videos in Clinical Medicine allow you to watch common clinical procedures on your computer or handheld device. Peer-reviewed for accuracy and chaptered for easy reference, these brief videos provide a concise review of a procedure, including preparation, equipment, and more. Interactive Medical Cases allow readers to follow along with experts managing an actual case, from presentation through outcome. You are presented with patient information, then asked multiplechoice questions. Videos, lab results and brief commentary explain important concepts.

BACK to TOC

131

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

videos in clinical medicine

Clinical Evaluation of the Knee Teresa L. Schraeder, M.D., Richard M. Terek, M.D., and C. Christopher Smith, M.D. The knee is one of the most complex joints in the body. Not surprisingly, knee problems are one of the most common musculoskeletal symptoms evaluated by the primary care physician.1 Anatomy

The knee joint consists of three bones — the femur, tibia, and patella — with three areas of articulation. The important soft-tissue structures of the knee include the four major ligaments — the anterior cruciate, posterior cruciate, and medial and lateral collateral ligaments — the joint capsule, the medial and lateral menisci, the quadriceps tendon, and the patellar tendon. The menisci are fibrocartilaginous structures located between the tibiofemoral articulations; they increase stability and distribute contact forces on the articular cartilage (Fig. 1 and 2).

From Mt. Auburn Hospital, Cambridge, MA (T.L.S.); Warren Alpert Medical School (T.L.S.) and the Department of Orthopaedics (R.M.T.), Brown University, Providence, RI; and the Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, and Harvard Medical School (C.C.S.) — both in Boston. Address reprint requests to Dr. Terek at the Department of Orthopaedic Surgery, Brown University, 2 Dudley St., Suite 200, Providence, RI 02905, or at [email protected]. N Engl J Med 2010;363(4):e5. Copyright © 2010 Massachusetts Medical Society.

Common Knee Injuries

All the bones and soft tissues of the knee are subject to injury. The most common problems that are reported in a physician’s office are related to soft-tissue inflammation, injury, or arthritis. Injuries to soft tissue and injuries resulting from overuse are often caused by reproducible mechanisms of physical trauma or forces. Fractures are less common and include fractures of the tibial plateau, the femoral condyles, or the patella. Knowledge of the mechanisms of knee injury can be essential to making an accurate diagnosis. An injury caused by valgus stress to the knee can result in medial collateral ligament strain or rupture, and an injury caused by varus stress can result in lateral collateral ligament strain or rupture. Abrupt noncontact deceleration or twisting and pivoting with simultaneous valgus stress to the knee can cause rupture of the anterior cruciate ligament, whereas abrupt posterior translation of the tibia can result in rupture of the posterior cruciate ligament. Twisting and pivoting of the knee while it is bearing weight can cause a meniscal tear. Overuse injuries are often manifested as pain in the structure subject to repetitive stress. For example, repetitive jumping can lead to patellar tendonitis, also called jumper’s knee, whereas repeated application of direct pressure to the patella through kneeling can cause prepatellar bursitis, sometimes referred to as housemaid’s knee.

Click here to access the video.

History

Obtaining a complete history is the first step in determining the cause of knee pain. The key elements include location and characterization of pain, mechanism of injury, sound of a “pop” at the time of injury (which can indicate a ligamentous tear or fracture), immediate or delayed swelling, recent infections, ability to bear weight, locking sensation or instability (or incidents of subluxation), and prior injuries to the joint.

n engl j med 363;4 BACK to TOC

nejm.org

july 22, 2010

e5

132

The new england journal of medicine

To assess nontraumatic causes of subacute or chronic knee pain (in addition to questions about location and characterization of pain), the clinician should inquire about fever, morning stiffness, pain after exercise, tick bites (to assess risk of Lyme disease), infections (including sexually transmitted diseases, such as gonorrhea), history of gout or psoriasis, and activities contributing to long-term overuse. General Examination of the Knee

Figure 1. Anatomy of the Right Knee, Anterior View.

Gait is an important element of the physical examination of the knee. The clinician should always evaluate the patient’s gait and weight-bearing abilities, since the findings can help distinguish knee pathology from pain referred from the hip, lower back, or foot. When clinically appropriate, a useful part of the clinical evaluation of knee pain is observing the patient execute a duckwalk, which requires the patient to squat and attempt to walk in that position. The duckwalk requires an intact ligamentous system and a knee free of significant meniscal pathology, effusions, and bony abnormalities, such as arthritis. Thus, if a patient can perform a duckwalk, he or she probably has no ligamentous instability, large effusions, or meniscal tears. The alignment of the knees should also be evaluated, with the patient standing with feet together. Look for a varus (bow-legged) or valgus (knock-kneed) deformity. Such deformities can predispose the patient to osteoarthritis or indicate the presence of significant osteoarthritis.2 Quadriceps atrophy can indicate disuse after an injury. If there is any suspicion of quadriceps atrophy the circumference of each thigh should be measured to confirm or rule out any changes to the underlying musculature. It is also important to carefully assess the skin around the knee. Abnormalities such as hematoma, rash (e.g., psoriasis), abrasions or lacerations, and cellulitis provide important diagnostic clues. Palpation of the Knee

Figure 2. Anatomy of the Right Knee, Posterior View.

Always examine both knees, beginning with the unaffected knee. This approach will reassure the patient and limit any apprehension about the examination, and it will also establish a baseline against which the affected knee can be compared. Using the back of the hand, assess for warmth as an indicator of inflammation. Next, with the knee at a 90-degree angle, palpate the knee, beginning with the anterior structures. Start by placing your thumbs on the tibial tuberosity and move superiorly. As you move superiorly, palpate the patellar tendon and its insertion at the inferior pole of the patella; pain in this area, especially in an athlete, might indicate patellar tendonitis. In a patient with a direct trauma to the knee, carefully palpate for areas of tenderness that might indicate a fracture. In such patients, five specific findings or factors should prompt consideration of radiographic imaging to rule out a traumatic fracture: an age of 55 years or older, tenderness at the head of the fibula, isolated patellar tenderness, inability to flex the knee to 90 degrees, or inability to bear weight and complete at least four steps. These five factors constitute the Ottawa knee rules, a validated decision-making tool with a sensitivity of 100%.3,4 Radiography should also be considered if an injury to the anterior cruciate ligament is suspected; such an injury can be associated with avulsion fractures of the lateral tibial plateau. In a patient with focal tenderness, erythema, and warmth and swelling anterior to the patella, acute prepatellar bursitis should be considered. Patients with this condition, which can be septic and may require aspiration or drainage, typically have a history of recurrent kneeling or of direct trauma. n engl j med 363;4

BACK to TOC

nejm.org

july 22, 2010

133

Clinical Evaluation of the Knee

Pain, swelling, and a palpable defect at the insertion of the quadriceps tendon into the superior aspect of the patella suggests rupture of a quadriceps tendon. This injury may be accompanied by a “pop” when it occurs, followed by diminished or complete absence of extensor strength. The clinician should identify the inferior pole of the patella and move medially to examine the medial joint line. Pain along the medial joint line might represent medial compartment osteoarthritis, injury to the medial collateral ligament, or a medial meniscal tear. Tenderness at the midpoint between the anterior aspect of the medial joint line and the tibial tuberosity may indicate pes anserine bursitis (located at the insertion of the hamstring tendons into the tibia). Pes anserine bursitis is often found in runners with tight hamstrings and in patients with valgus deformity; in the latter case, it is often associated with osteoarthritis of the knee. The clinician should also examine the lateral joint line for tenderness, which can be caused by lateral compartment osteoarthritis, injury to the lateral collateral ligament, or a lateral meniscal tear. Focal pain at the lateral femoral condyle is suggestive of iliotibial band syndrome. Palpation of the popliteal fossa can reveal a tender, fluid-filled mass called a Baker’s cyst. This results from a posterior extension of knee-joint effusions and often accompanies osteoarthritis. Assessment of Effusion

The absence of the normal indentations on the peripatellar grooves on either side of the patella may indicate the presence of a large intraarticular effusion. Two maneuvers can help confirm the presence of an intraarticular effusion. In the first maneuver, with the knee extended, use the nondominant hand to squeeze the intraarticular fluid from the suprapatellar region into the space between the patella and femur. With the dominant hand, exert pressure superiorly from the tibia while using your index finger to push the patella against the patellofemoral groove. When an effusion is present, you can easily ballot the patella. The second maneuver used to assess for an effusion should also be performed with the knee in extension. Gently milk the fluid into the suprapatellar pouch by moving your hand proximally along the medial aspect of the patella. Next milk or compress the fluid from the suprapatellar pouch to the medial knee by moving your hand from the superior lateral region to the inferior lateral region; if there is an effusion, compressing the lateral regions will cause a bulge to appear medial to the patella in the areas that are naturally concave. Comparison with the unaffected knee is essential. If an effusion is present, arthrocentesis may be necessary for diagnostic or therapeutic reasons.5 Range of Motion

Both active and passive range of motion of the knee should be tested. The normal range of extension is 0 to −10 degrees, and the normal range of flexion is 130 to 150 degrees. The location and movement of the patella should be noted: watch for any signs of abnormal tracking, crepitus, or pain. If retropatellar pain and crepitus occur while the patella is being compressed against the trochlea during active extension, patellofemoral syndrome or patellofemoral arthritis (chondromalacia) should be considered. Pain with active range of motion but painfree passive range of motion suggest a soft-tissue disorder such as tendonitis. Pain that is equal on both passive and active range of motion is more likely to suggest an intraarticular process.

n engl j med 363;4 BACK to TOC

nejm.org

july 22, 2010

134

The new england journal of medicine

Assessment of the Medial Collateral and Lateral Collateral Ligaments

Injury to the medial or lateral collateral ligaments typically involves direct trauma to the contralateral side of the knee — for example, a direct blow to the lateral side results in valgus stress and injury to the medial collateral ligament. To assess the medial collateral ligament, apply valgus stress to the knee. With the knee flexed to 25 degrees, place one hand on the outer aspect of the knee to apply medial pressure, and the other hand on the inner aspect of the distal tibia to apply lateral pressure; you are testing for tenderness or laxity along the medial collateral ligament.6,7 Similarly, the lateral collateral ligament can be tested by applying lateral pressure to the inner knee and medial pressure to the outer ankle or lower leg, which causes varus stress to the knee. When assessing the medial or lateral collateral ligaments, tenderness along the ligament, but less than 5 mm of laxity and a solid end point, indicates a firstdegree sprain. In a second-degree sprain, a solid end point is maintained but there is increased laxity when the knee is tested at 25 degrees of flexion and no laxity in full extension. In a third-degree sprain or a complete tear of the ligament, there will be a soft end point and more than 10 mm of laxity when the knee is at 25 degrees of flexion; if there is also laxity with full extension, there may be additional damage to the cruciate ligament.6 Assessment of the Anterial Cruciate Ligament

The anterior drawer test and the Lachman test provide information about the integrity of the anterior cruciate ligament. In the anterior drawer test, the patient should be supine, with the knee flexed to 90 degrees and the foot placed flat on the table. Stabilize the foot (you can sit on the end of the patient’s foot) and place your thumbs on the tibial plateau and your fingers around the calf, relaxing the hamstrings; pull forward to test the anterior cruciate ligament. If the ligament is intact, it should abruptly stop the anterior motion of the tibia with a solid end point. The affected and unaffected legs should have similar degrees of anterior translation. The Lachman test is a more sensitive and specific test for assessment of the anterior cruciate ligament.7,8 In this maneuver, the patient is supine and asked to relax the hamstrings. Use one hand to stabilize the femur while placing the knee at 20 degrees of flexion. With the other hand, grasp the proximal tibia and briskly pull the tibia forward. If there is more than 6 to 8 mm of laxity, more laxity than in the unaffected knee, or a soft end point, the ligament may be torn.9 If you are unable to firmly grasp and stabilize the femur, you can modify the Lachman maneuver by placing your knee under the patient’s knee, firmly pressing down on the distal femur with one hand, and pulling the tibia anteriorly with your other hand. A large hemorrhagic effusion of rapid onset frequently accompanies anterior cruciate ligament tears and bony fractures and contributes to the patient’s discomfort. Arthrocentesis can be of both diagnostic and therapeutic benefit and can also facilitate a more accurate examination. Assessment of the Posterior Cruciate Ligament

To test the integrity of the posterior cruciate ligament, perform the posterior drawer test and assess for evidence of a tibial sag. As in the anterior drawer test, the patient should be supine and the knee flexed to 90 degrees. The foot should be flat on the table. Stabilize the foot (you can sit on the end of the patient’s foot) and place your thumbs on the tibial tubercle and your fingers around the calf, then briskly push the tibia posteriorly to test the posterior cruciate ligament. If the ligament is intact, there should be a solid end point and little posterior translation of the tibia. n engl j med 363;4 BACK to TOC

nejm.org

july 22, 2010

135

Clinical Evaluation of the Knee

The tibial sag test is another test of the integrity of this ligament.6 Have the patient flex both knees at 90 degrees and place both feet flat on the table; then observe the alignment of the tibial plateau. Normally, the tibial plateau extends 1 cm beyond the femoral condyle. If the affected tibia is displaced posteriorly on the femur, or sags, as compared with the unaffected tibial plateau, the posterior cruciate ligament may be ruptured. Assessment of the Meniscus

Patients with meniscal injuries may report clicking, catching, or locking of the knee. In addition, they frequently have an effusion of delayed onset, appearing hours or even days after the injury. In addition to assessment of the knee for joint-line tenderness, there are two common maneuvers that can be used to assess for possible meniscal tears. In the McMurray test, the patient is supine. To test the medial meniscus, place one hand over the anterior aspect of the knee, with fingers and thumb on the medial and lateral joint lines. Grasp the patient’s heel with the other hand and externally rotate the tibia, using the first hand to apply valgus force at the knee during passive flexion and extension. The maneuver is repeated when applying internal rotation and varus stress to test the lateral meniscus. Clicking, catching, or popping at the joint line during early extension or midextension may indicate a meniscal tear.10 In the Apley compression test, or grind test, the patient lies prone and the knee is flexed to 90 degrees. Stabilize the thigh by placing your knee or hand firmly on top of the patient’s posterior thigh. Grasp the foot and apply a downward compressive force while rotating the tibia internally and externally. Pain on compression is considered positive for a meniscal tear.7,11 Suspicion of a meniscal tear should prompt a careful assessment of the anterior cruciate ligament; likewise, suspicion of a torn anterior cruciate ligament should prompt a careful assessment of the meniscus. Injuries to these two structures often occur together. Summary

In summary, a thorough history and physical examination are the first steps in evaluating knee pain and making an accurate diagnosis, after which decisions about imaging studies (radiography, magnetic resonance imaging, and ultrasonography), treatment, and referral to specialists can be made. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

n engl j med 363;4 BACK to TOC

nejm.org

References 1. Cherry DK, Woodwell DA, Rechstein-

er EA. National Ambulatory Medical Care Survey: 2005 summary. Advance data from Vital and Health Statistics. No. 387. (Accessed June 28, 2010, at http://www .cdc.gov/nchs/data/ad/ad387.pdf.) 2. Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA 2001;286:188-95. [Erratum, JAMA 2001;286:792.] 3. Stiell IG, Greenberg GH, Wells GA, et al. Derivation of a decision rule for the use of radiography in acute knee injuries. Ann Emerg Med 1995;26:405-13. 4. Stiell IG, Greenberg GH, Wells GA, et al. Prospective validation of a decision rule for the use of radiography in acute knee injuries. JAMA 1996;275:611-5. 5. Thomsen TW, Shen S, Shaffer RW, Setnik GS. Arthrocentesis of the knee. N Engl J Med 2006;354(19):e19. (Available at NEJM.org.) 6. Malanga GA, Andrus S, Nadler SF, McLean J. Physical examination of the knee: a review of the original test description and scientific validity of common orthopedic tests. Arch Phys Med Rehabil 2003;84:592-603. 7. Solomon DH, Simel DL, Bates DW, Katz JN, Schaffer JL. Does this patient have a torn meniscus or ligament of the knee? JAMA 2001;286:1610-20. 8. Jackson JL, O’Malley PG, Kroenke K. Evaluation of acute knee pain in primary care. Ann Intern Med 2003;139:575-88. 9. Torg JS, Conrad W, Kalen V. Clinical diagnosis of anterior cruciate ligament instability in the athlete. Am J Sports Med 1976;4:84-93. 10. McMurray TP. The semilunar cartilages. Br J Surg 1942;29:407-14. 11. Apley AG. The diagnosis of meniscus injuries: some new clinical methods. J Bone Joint Surg Am 1947;29:78-84. Copyright © 2010 Massachusetts Medical Society.

july 22, 2010

136

HOME

ARTICLES

INTERACTIVE MEDICAL CASE

ISSUES The

SPECIALTIES & TOPICS

n e w e ng l a n d j o u r na l

FOR AUTHORS of

Keyword, Title, Author, or Citation

m e dic i n e TOOLS

Graham T. McMahon, M.D., M.M.Sc., Editor, Joel T. Katz, M.D., Associate Editor, Bruce D. Levy, M.D., Associate Editor, Joseph Loscalzo, M.D., Ph.D., Associate Editor

Lying Low

interactive medical case

Downlo CME

John J. Ross, M.D., Anand Vaidya, M.D., and Ursula B. Kaiser, M.D. N Engl J Med 2011; 364:e10 February 10, 2011

Lying Low

Case

John J. Ross, M.D., Anand Vaidya, M.D., and Ursula B. Kaiser, M.D. TOPICS

Hematolo Oncology Medical E Training, a Primary C Gastroent General Endocrino General Neurology Neurosurg General Geriatrics General Surgery G Psychiatr Emergenc General

An 88-year-old woman presented to the emergency room with confusion. She began having transient episodes of confusion, dizziness, tremors, and anxiety a year earlier. These episodes were unpredictable, lasting for minutes and then abating spontaneously, and had been increasing in frequency since they began. The patient felt well between episodes and reported no abnormal sensation . . . Learn more about Interactive Medical Cases

Click here to access the Interactive Medical Case. To save your progress and resume later, Sign-in or Create a FREE account. Your work is saved automatically upon sign-in.

Play as a guest. Please note that your work will not be saved. Play now. TRENDS:

Hand H About Interactive Medical Cases

Feedback | Take Our Survey

March 31,

Giant S

Each interactive case presents an evolving patient history and a series of questions and exercises designed to test your diagnostic and therapeutic skills. You will receive immediate feedback on your answers and treatment choices, along with the opportunity to compare your final score with those of your peers. Video, animation, and interactive content allow you to learn more about mechanisms, diagnostic tests, and treatments.

March 31,

Bocepre Genotyp March 31,

Signing in at the beginning of the case allows you to save your progress and resume later. Work by users who are not signed in will not be saved. A link at the end of the case leads to a CME examination; you can claim up to 2 AMA PRA Category 1 Credits™ for participating. Please share your opinions about the case by taking our survey. Pilot Phase: For a limited time, the Interactive Medical Cases will be in a pilot phase, during which this content and service will be available free. Your feedback is welcome and will be used to improve the interface and functionality of future Interactive Medical Cases. See All Interactive Medical Cases

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

BACK to TOC

137 CONTENT: Home Current Issue Articles Issue Index Specialties & Topics Multimedia & Images Archive 1812-1989 INFORMATION FOR: Authors Reviewers Subscribers Institutions Media Advertisers