NEJM CARDIOVASCULAR DISEASE ARTICLES - Part 2 pdf

This article 10.1056/NEJMoa067484 was published at www.nejm.org on February Results The overall risk of death hazard ratio, 1.03; 95% confidence interval [CI], 0.80 to 1.30 and the com

clinical therapeutics

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.

Amiodarone for Atrial Fibrillation

Peter Zimetbaum, M.D

From the Division of Cardiology, Beth rael Deaconess Medical Center, Boston Address reprint requests to Dr Zimet- baum at Beth Israel Deaconess Medical Center, 185 Pilgrim Rd., Boston, MA 02215,

Is-or at pzimetba@bidmc.harvard.edu.

N Engl J Med 2007;356:935-41.

Copyright © 2007 Massachusetts Medical Society

A 73-year-old man with stable coronary artery disease, hypertension, and chronic

re-nal insufficiency presents with recurrent atrial fibrillation at 80 to 90 beats per

min-ute His symptoms include shortness of breath and fatigue He has had atrial

fibrilla-tion twice in the past year; with each episode, electrical cardioversion resulted in

marked improvement in his symptoms His echocardiogram shows symmetric left

ventricular hypertrophy with evidence of diastolic dysfunction His medications

in-clude warfarin and metoprolol (25 mg twice daily) He is referred to a cardiologist,

who recommends rhythm control with oral amiodarone.

The Clinical ProblemAtrial fibrillation is the most common cardiac arrhythmia seen in clinical practice

It currently affects more than 2 million Americans, with a projected increase to

10 million by the year 2050.1 Atrial fibrillation may occur in a paroxysmal,

self-remit-ting pattern or may persist unless cardioversion is performed It is rarely, if ever, a

one-time event but can be expected to recur unpredictably Symptoms, including

palpitations, dyspnea, fatigue, and chest pain, are present in 85% of patients at the

onset of the arrhythmia but often dissipate with rate- or rhythm-control therapy.2

The morbidity and mortality associated with this disorder relate to these symptoms

as well as to hemodynamic and thromboembolic complications Strategies to

main-tain sinus rhythm have not been shown to reduce total mortality or the risk of stroke

but have been shown to improve functional capacity and quality of life.3-5 The

fail-ure to reduce the mortality associated with rhythm-control strategies is in part due

to the toxicity of the therapies used to maintain sinus rhythm.6

Pathophysiology and Effect of Ther apy

The actual mechanism of atrial fibrillation is probably a focal source of automatic

firing, a series of small reentrant circuits, or a combination of the two.7 Atrial

fibrilla-tion is triggered by atrial premature depolarizafibrilla-tions, which frequently arise from

muscular tissue in the pulmonary veins or other structures in the left or, less

com-monly, right atrium.8 Clinical factors such as hypertension, aging, and congestive

heart failure, as well as recurrent atrial fibrillation itself, result in structural changes

in the atria, including dilatation and fibrosis.9 This type of mechanical remodeling

promotes the development and perpetuation of atrial fibrillation Continued rapid

electrical firing in the atria also results in loss of the normal adaptive shortening of

atrial and pulmonary-vein myocyte refractory periods in response to the rapid heart

rate, a process called electrical remodeling.10

The hemodynamic consequences of atrial brillation result primarily from the loss of atrio-ventricular synchrony but also from the rapid rate and irregularity of the ventricular response.9 Pa-tients with clinical syndromes that impair dia-stolic compliance (e.g., left ventricular hypertro-phy) are most likely to have functional deterioration and symptoms, with loss of the atrial contribution

fi-to ventricular filling; such patients are also fore most likely to benefit from restoration of si-nus rhythm

there-The precise mechanism through which arrhythmic drugs such as amiodarone suppress atrial fibrillation remains unknown.11 Amioda-rone (with its active metabolite, desethylamio-darone) blocks sodium, potassium, and calcium channels It is also a relatively potent noncom-petitive alpha-blocker and beta-blocker but has no clinically significant negative inotropic effect.9,11

anti-At rapid heart rates, sodium channel blockade is increased.12

The consequences of these channel-blocking effects can be demonstrated electrophysiologi-cally Most important, potassium-channel block-ade slows repolarization, causing an increase in the duration of the action potential and in the re-fractoriness of cardiac tissue; this has the effect

of prolonging the QT interval (Fig 1) Amiodarone

is also uniquely effective in preventing tally induced atrial electrical remodeling.13

experimen-Clinical Ev idenceAmiodarone has consistently been demonstrated

to be superior to other antiarrhythmic tions for the maintenance of sinus rhythm.14-16The Canadian Trial of Atrial Fibrillation random-

medica-ly assigned 403 patients with paroxysmal or sistent atrial fibrillation to treatment with amio-darone or with propafenone or sotalol.14 During

per-a meper-an follow-up period of 468±150 dper-ays, rence of atrial fibrillation was documented in 63%

recur-of patients taking propafenone or sotalol, as pared with 35% of those taking amiodarone The Sotalol Amiodarone Atrial Fibrillation Efficacy Trial compared the efficacy of sotalol, amioda-rone, and placebo in 665 patients with persistent atrial fibrillation.15 Recurrence of atrial fibrilla-tion after 1 year was documented in 35% of pa-tients taking amiodarone, 60% of those taking sotalol, and 82% of those taking placebo

com-Clinical UseAmiodarone is approved by the Food and Drug Administration for the treatment of lethal ven-tricular arrhythmias but not for the management

of atrial fibrillation Nonetheless, it is widely scribed for this indication.17,18

pThe safe and effective use of amiodarone quires a firm understanding of its unusual phar-macokinetics as well as the potential for drug interactions and adverse events Amiodarone is a highly lipophilic compound with a large volume

re-of distribution (66 liters per kilogram re-of body weight) This property results in a delayed onset

of action (an interval of 2 to 3 days) and a long elimination half-life (up to 6 months).19 As a result, there is a substantial lag between the initiation, modification, or discontinuation of treatment with amiodarone and a change in drug activity Amiodarone is metabolized to desethylamioda-rone in the liver, and its use should be avoided

in patients with advanced hepatic disease There

is no clinically significant renal metabolism of amiodarone, and the dose is not affected by re-nal dysfunction or dialysis Amiodarone crosses the placenta in pregnant women and is excreted

in varying amounts in breast milk.20 Its use should therefore be avoided in women who are pregnant

or breast-feeding

Amiodarone is an excellent choice for use in patients with structural heart disease or conges-tive heart failure.9,21 It is generally reserved as an alternative to other agents for patients without underlying heart disease, given its multitude of side effects.9 Many physicians hesitate to use amio-darone in young patients because of the concern about side effects related to long-term use.Contraindications to the use of amiodarone include severe sinus-node dysfunction and ad-vanced conduction disease (except in patients with

a functioning artificial pacemaker) The drug should also be used cautiously in patients with severe lung disease (which may interfere with the detection of adverse effects)

Before choosing amiodarone for the treatment

of atrial fibrillation, clinicians should consider other options Rate control alone (i.e., the use of agents to maintain a slow ventricular response rate in atrial fibrillation) is often as effective as rhythm control in managing the symptoms of this arrhythmia, and it has been shown to be at

least as effective as rhythm control with respect

to the long-term outcome.3 Therefore, a trial of

rate control should always be considered Other

antiarrhythmic drugs, such as sotalol and

propafe-none, should also be considered, with the

rec-ognition that the balance of risks and benefits

for these agents as compared with amiodarone

depends on the clinical setting.9 Finally, sive procedures, such as pulmonary-vein isolation, have an increasing role in the management of this disorder,22 although in most cases, these approach-

inva-es have been used only after the failure of other therapies

Before initiating treatment with amiodarone,

Author Fig # Title ME DE Artist

Figure 1 Electrophysiological Action of Amiodarone.

During normal sinus rhythm (Panel A), myocardial activation is initiated in the sinus node, with a resulting coordinated wavefront of polarization that spreads across both atria (arrows) to the atrioventricular node and specialized conduction system (green) Atrial fibril- lation (Panel B) is triggered by atrial premature depolarizations arising in the region of the pulmonary veins (red asterisk) and propa- gates in an irregular and unsynchronized pattern (arrows) The resulting pattern of ventricular activation is irregular (as shown on the electrocardiographic recording) Amiodarone (Panel C) has several electrophysiological effects Chief among these in the control of atri-

de-al fibrillation is the effect on the potassium channel blockade, which slows repolarization, thus prolonging the action potentide-al and the refractoriness of the myocardium Waves of depolarization are more likely to encounter areas of myocardium that are unresponsive; thus, propagation is prevented Although the prolongation of the action potential is most apparent on the electrocardiogram as an ef- fect on the ventricular myocardium (prolonged QT interval), a similar effect occurs in the atria

it is critical to establish therapeutic tion, because the potential exists for conversion

anticoagula-to sinus rhythm (with a consequent risk of boembolism) at any point during the drug-load-ing phase The recommended criterion for anti-coagulation is an international normalized ratio (INR) of 2.0 to 3.0 for 3 consecutive weeks or a transesophageal echocardiogram demonstrat-ing the absence of left atrial thrombus

throm-Amiodarone therapy is initiated with a ing dose of approximately 10 g in the first 1 to

load-2 weeks This loading dose can be given in divided doses — for example, 400 mg given orally twice

a day for 2 weeks followed by 400 mg given orally each day for the next 2 weeks Reducing the in-dividual dose and administering it three times daily may reduce the gastrointestinal intolerance sometimes associated with amiodarone loading

A more protracted loading period with a lower daily dose may be used when sinus- or atrioven-tricular-node dysfunction is a concern

It is relatively safe to initiate treatment with amiodarone in the ambulatory setting.23 Electro-cardiographic monitoring (with 12-lead electro-cardiography or an event recorder) should be per-formed at least once during the loading period to evaluate the patient for excessive prolongation of the QT interval (>550 msec) or bradycardia Pro-longation of the QT interval is common and gen-erally responds to dose reduction.15

Given the delay in the onset of antiarrhythmic action with amiodarone, it is common for atrial fibrillation to persist or recur during the loading phase of drug administration; however, this does not predict rates of sinus rhythm at 1 month.24Approximately 30% of patients have a reversion

to sinus rhythm during this loading phase, and the remainder can undergo electrical cardiover-sion, which has a high rate of success.15,23Once the loading phase is completed, the main-tenance dose of amiodarone for atrial fibrillation

is 200 mg a day Monitoring of levels of rone or desethylamiodarone is not recommended, given the lack of correlation between drug levels and efficacy or adverse events.12 However, moni-toring with the use of various laboratory tests for evidence of adverse effects is recommended

amioda-Amiodarone interferes with the hepatic tabolism of many medications, the most common

me-of which are digoxin and warfarin Generally, goxin should be discontinued if possible, or the

di-dose at least reduced by 50% The INR must be monitored closely during amiodarone loading and maintenance therapy It is usually necessary to reduce the warfarin dose by 25 to 50% when the drug is coadministered with amiodarone.The cost of amiodarone is typically about $1.25 per tablet in the United States In addition, the initial screening tests performed before treatment begins (chest radiography and tests of pulmonary, thyroid, and liver function) cost approximately

$250, with a similar expense annually to screen for adverse effects

Adver se EffectsAmiodarone is associated with both cardiovas-cular and noncardiovascular adverse events (Ta-ble 1) Side effects resulting in discontinuation

of therapy occur in 13 to 18% of patients after

1 year.12,15 The most frequent cardiovascular side effect is bradycardia, which is often dose-related, occurs more frequently in elderly patients than in younger patients, and can often be mitigated by dose reduction.24,25 Prolongation of the QT inter-val is seen in most patients but is associated with

a very low incidence of torsades de pointes (<0.5%)

as compared with other drugs that prolong the

QT interval (e.g., sotalol and dofetilide).17Clinical evidence of hypothyroidism occurs in

up to 20% of patients taking amiodarone It ops most often in patients with preexisting auto-immune thyroid disease and those living in areas replete with iodine (that is, they are not iodine-deficient).26 Hypothyroidism is easily managed with levothyroxine and generally is not cause for discontinuing amiodarone.12,26 Hyperthyroidism occurs in 3% of patients in areas where dietary iodine is sufficient but in 20% of patients in iodine-deficient areas It can be difficult to rec-ognize clinically because many of the typical ad-renergically mediated signs are blocked by amio-darone The recurrence of atrial fibrillation during maintenance amiodarone therapy should prompt

devel-an evaluation for amiodarone-induced roidism Management requires the assistance of an experienced endocrinologist and may require dis-continuation of amiodarone therapy Thyrotropin levels should be checked in all patients before amiodarone therapy is initiated and at least every

hyperthy-6 months thereafter.12Pulmonary toxicity is one of the most serious

complications of amiodarone use It occurs in less

than 3% of patients and is thought to be related

to the total cumulative dosage.12 In the Atrial

Fi-brillation Follow-up Investigation of Rhythm

Man-agement study, there was a slightly increased

inci-dence of pulmonary toxicity in patients with

preexisting pulmonary disease, but mortality from

pulmonary causes and overall mortality were not

higher among these patients than among those

without preexisting pulmonary disease.27 The

man-agement of acute pulmonary toxicity involves

dis-continuation of therapy, supportive management,

and, in extreme cases, corticosteroid

administra-tion.12 Screening pulmonary-function tests and

chest radiography should be performed at

base-line, and chest radiography should be performed

yearly thereafter.9,12 Pulmonary-function tests

should be repeated if symptoms develop

Hepatic toxicity is a rare complication of

amio-darone therapy when the drug is used in low doses

Amiodarone can cause nonalcoholic

steatohepa-titis, which is manifested as an asymptomatic

in-crease in hepatic aminotransferase levels (more

than two times the upper limit of the normal

range) This condition can generally be reversed by

discontinuing the drug but can result in cirrhosis if unheeded Liver-function tests should be measured

at baseline and every 6 months thereafter.9,12,28Corneal microdeposits are seen in virtually all patients receiving long-term amiodarone thera-

py and are rarely of clinical significance.12 Optic neuropathy has been reported in less than 1% of patients, but it may be a result of associated medi-cal conditions rather than an effect of amioda-rone Nonetheless, the potential severity of optic neuropathy warrants discontinuation of amioda-rone therapy if the condition is suspected Oph-thalmologic examinations are recommended at baseline only for patients with preexisting ab-normalities

Dermatologic side effects of amiodarone use include photosensitivity, with susceptibility to sun-burn, particularly in patients with a fair complex-ion Avoidance of direct exposure to the sun and use of sunscreen can diminish this reaction

A gray-bluish skin discoloration may be seen in patients who take large doses of amiodarone for long periods.29 Alopecia is also an infrequent side effect of amiodarone

Neurologic side effects, which occur in up to

Table 1 Adverse Effects of Oral Amiodarone.

<1%

Baseline electrocardiogram at least once during loading period, es- pecially if conduction disease is present; yearly thereafter

Consider reduction of loading dose in elderly patients and those with un- derlying sinoatrial or atrioventricu- lar conduction disease; reduce dose or discontinue if QT interval exceeds 550 msec

Hepatic 15% Aspartate and alanine

aminotrans-ferase measurements at line and every 6 months there- after

base-Avoid in patients with severe liver disease

Avoid in presence of preexisting, functioning thyroid nodule; higher incidence of thyroid effects in pa- tients with autoimmune thyroid disease

non-Pulmonary <3% Pulmonary-function tests at

base-line and if symptoms develop;

chest radiograph at baseline and yearly thereafter

Discontinue amiodarone immediately

if pulmonary effects suspected

Dermatologic 25–75% Routine Recommend use of sunscreen with a

high sun protection factor

Avoid in presence of preexisting optic neuritis

30% of patients, include ataxia, tremor, peripheral polyneuropathy, insomnia, and impaired memo-

ry These effects are often dose-related and occur more often in elderly patients than in younger pa-tients

Ar e as of Uncertaint yThe side effects of low-dose amiodarone therapy (200 mg daily) in patients taking the drug for more than 5 years — the duration of clinical stud-ies that have been conducted — are unknown

Some patients, particularly those who are elderly and those with relatively little body fat, can be treated with a very low dose (100 mg per day)

There are no available data from clinical trials that support this reduced-dose strategy, but it is common practice

Amiodarone is frequently used for the vention and treatment of atrial fibrillation as-sociated with cardiac surgery, including the maze procedure for cure of atrial fibrillation.9 Atrial fibrillation associated with cardiac surgery oc-curs most frequently in the first few days after surgery but can also occur weeks after surgery

pre-For patients undergoing cardiac surgery, darone is given at a dose of 600 mg a day for 1 to

amio-2 weeks before surgery and is continued for 4 to

6 weeks after surgery Although this approach is supported by data from clinical trials, beta-block-ers have also been reported to reduce rates of postoperative atrial fibrillation,30 and none of the major studies of amiodarone compared it with the use of a beta-blocker alone

The use of amiodarone in combination with other antiarrhythmic drugs has not been thor-oughly studied One intriguing combination is that of angiotensin-receptor blockers with amio-darone Emerging data suggest that the combi-nation of these two agents is more effective than either is alone.31

GuidelinesRecently published guidelines of the American Heart Association, the American College of Car-diology, and the European Society of Cardiology

recommend reserving amiodarone as an tive agent for most patients with atrial fibrilla-tion, the exceptions being those who have clini-cal heart failure or hypertension with substantial left ventricular hypertrophy.9 For patients at very high risk for recurrence of atrial fibrillation (e.g., those with severe mitral regurgitation), amioda-rone may be the best choice of a first-line agent, given the low likelihood that treatment with oth-

alterna-er antiarrhythmic agents will be successful

R ecommendationsFor the patient described in the vignette, it is rea-sonable to attempt to maintain sinus rhythm be-cause of the presence of symptoms in spite of a well-controlled ventricular response His symp-toms are probably due to diastolic dysfunction The presence of coronary artery disease limits the choice of antiarrhythmic drug to amiodarone, sotalol, and dofetilide The patient’s renal insuf-ficiency makes sotalol and dofetilide unattractive options The preferred agent to maintain sinus rhythm in this patient is therefore amiodarone Baseline screening studies should include tests

of liver, thyroid, and pulmonary function as well

as chest radiography The warfarin dose should

be decreased by at least 25% when the loading dose of amiodarone is administered It is reason-able to initiate amiodarone therapy in the outpa-tient setting A slightly reduced loading dose (e.g.,

600 mg per day in one dose or divided doses for

3 to 4 weeks) is reasonable, given that the patient’s baseline heart rate is already well controlled on

a low dose of a beta-blocker (which may suggest underlying atrioventricular-node conduction dis-ease) The patient should undergo electrocardi-ography weekly or should be discharged with a loop recorder to monitor heart rhythm, heart rate, and duration of the QT interval If conversion has not occurred by the end of the loading period, electrical cardioversion should be performed, fol-lowed by a reduction in the dose of amiodarone

to 200 mg daily The warfarin dose may need to

be increased as the amiodarone dose is reduced

No potential conflict of interest relevant to this article was reported

References

Miyasaka Y, Barnes M, Gersh B, et al

Secular trends in incidence of atrial lation in Olmsted County, Minnesota, 1980

fibril-to 2000, and implications on the

2006;114:119-25 [Erratum, Circulation 2006;114:e498.]

Reynolds MR, Lavelle T, Essebag V,

2.

Cohen DJ, Zimetbaum P Influence of age, sex, and atrial fibrillation recurrence on quality of life outcomes in a population of patients with new-onset atrial fibrillation:

the Fibrillation Registry Assessing Costs,

Therapies, Adverse events and Lifestyle

(FRACTAL) study Am Heart J 2006;152:

1097-103.

Wyse DG, Waldo AL, DiMarco JP, et

al A comparison of rate control and rhythm

control in patients with atrial fibrillation

N Engl J Med 2002;347:1825-33.

Van Gelder IC, Hagens VE, Bosker HA,

et al A comparison of rate control and

rhythm control in patients with recurrent

persistent atrial fibrillation N Engl J Med

2002;347:1834-40.

Chung MK, Shemanski L, Sherman

DG, et al Functional status in rate- versus

rhythm-control strategies for atrial

fi-brillation: results of the Atrial

Fibrilla-tion Follow-up InvestigaFibrilla-tion of Rhythm

Management (AFFIRM) Functional

Sta-tus Substudy J Am Coll Cardiol 2005;46:

1891-9.

Steinberg JS, Sadaniantz A, Kron J, et

al Analysis of cause-specific mortality in

the Atrial Fibrillation Follow-up

Investi-gation of Rhythm Management (AFFIRM)

study Circulation 2004;109:1973-80.

Allessie M, Ausma J, Schotten U

Elec-trical, contractile and structural

remodel-ing durremodel-ing atrial fibrillation Cardiovasc

Res 2002;54:230-46.

Haissaguerre M, Jais P, Shah DC, et al

Spontaneous initiation of atrial fibrillation

by ectopic beats originating in pulmonary

veins N Engl J Med 1998;339:659-66.

Fuster V, Ryden LE, Cannom DS, et al

ACC/AHA/ESC 2006 Guidelines for the

Management of Patients with Atrial

Fibril-lation: a report of the American College of

Cardiology/American Heart Association

Task Force on Practice Guidelines and the

European Society of Cardiology

Commit-tee for Practice Guidelines (Writing

Com-mittee to Revise the 2001 Guidelines for

the Management of Patients with Atrial

Fibrillation): developed in collaboration

with the European Heart Rhythm

Associ-ation and the Heart Rhythm Society

Circu-lation 2006;114:e257-e354.

Nattel S New ideas about atrial

fibril-lation 50 years on Nature 2002;415:219-26.

Roden DM Antiarrhythmic drugs:

Nacca-160:1741-8.

Shinagawa K, Shiroshita-Takeshita A, Schram G, Nattel S Effects of antiarrhyth- mic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone Circu- lation 2003;107:1440-6.

Roy D, Talajic M, Dorian P, et al odarone to prevent recurrence of atrial fibrillation N Engl J Med 2000;342:913- 20.

Ami-Singh BN, Ami-Singh SN, Reda DJ, et al

Amiodarone versus sotalol for atrial brillation N Engl J Med 2005;352:1861- 72.

fi-AFFIRM First Antiarrhythmic Drug Substudy Investigators Maintenance of sinus rhythm in patients with atrial fibril- lation: an AFFIRM substudy of the first antiarrhythmic drug J Am Coll Cardiol 2003;42:20-9.

Kaufman ES, Zimmerman PA, Wang T,

et al Risk of proarrhythmic events in the Atrial Fibrillation Follow-up Investigation

of Rhythm Management (AFFIRM) study:

a multivariate analysis J Am Coll Cardiol 2004;44:1276-82.

Zimetbaum P, Ho KK, Olshansky B, et

al Variation in the utilization of rhythmic drugs in patients with new-onset atrial fibrillation Am J Cardiol 2003;91:81- 3.

antiar-Mitchell LB, Wyse DG, Gillis AM, Duff

HJ Electropharmacology of amiodarone therapy initiation: time courses of onset

of electrophysiologic and antiarrhythmic effects Circulation 1989;80:34-42.

Ito S Drug therapy for breast-feeding women N Engl J Med 2000;343:118-26.

Singh SN, Fletcher RD, Fisher SG, et

al Amiodarone in patients with tive heart failure and asymptomatic ven- tricular arrhythmia: Survival Trial of An- tiarrhythmic Therapy in Congestive Heart Failure N Engl J Med 1995;333:77-82.

Wazni OM, Marrouche NF, Martin

DO, et al Radiofrequency ablation versus antiarrhythmic drugs as first-line treat- ment of symptomatic atrial fibrillation:

a randomized trial JAMA 40.

2005;293:2634-Kochiadakis GE, Igoumenidis NE, lomou MC, Kaleboubas MD, Chlouverakis

So-GI, Vardas PE Efficacy of amiodarone for the termination of persistent atrial fibril- lation Am J Cardiol 1999;83:58-61.

Hauser TH, Pinto DS, Josephson ME, Zimetbaum P Early recurrence of arrhyth- mia in patients taking amiodarone or class 1C agents for treatment of atrial fibrilla- tion or atrial flutter Am J Cardiol 2004;

93:1173-6.

Idem Safety and feasibility of a

clini-cal pathway for the outpatient initiation

of antiarrhythmic medications in patients with atrial fibrillation or atrial flutter

Am J Cardiol 2003;91:1437-41.

Pearce EN, Farwell AP, Braverman LE

Thyroiditis N Engl J Med

2003;348:2646-55 [Erratum, N Engl J Med 2003;349:

620.]

Olshansky B, Sami M, Rubin A, et al

Use of amiodarone for atrial fibrillation

in patients with preexisting pulmonary disease in the AFFIRM study Am J Car- diol 2005;95:404-5.

Sanyal AJ, American logical Association AGA technical review

Gastroentero-on nGastroentero-onalcoholic fatty liver disease troenterology 2002;123:1705-25.

Gas-Ahmad S Amiodarone and reversible alopecia Arch Intern Med 1995;155:1106.

Mitchell LB, Exner DV, Wyse DG, et al

Prophylactic Oral Amiodarone for the vention of Arrhythmias that Begin Early After Revascularization, Valve Replace- ment, or Repair: PAPABEAR: a random- ized controlled trial JAMA 2005;294:3093- 100.

Pre-Madrid AH, Bueno MG, Rebollo JM, et

al Use of irbesartan to maintain sinus rhythm in patients with long-lasting atri-

al fibrillation: a prospective and ized study Circulation 2002;106:331-6.

random-Copyright © 2007 Massachusetts Medical Society

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original article

Analysis of 14 Trials Comparing Eluting Stents with Bare-Metal StentsAdnan Kastrati, M.D., Julinda Mehilli, M.D., Jürgen Pache, M.D., Christoph Kaiser, M.D., Marco Valgimigli, M.D., Ph.D., Henning Kelbæk, M.D., Maurizio Menichelli, M.D., Manel Sabaté, M.D., Maarten J Suttorp, M.D., Ph.D., Dietrich Baumgart, M.D., Melchior Seyfarth, M.D., Matthias E Pfisterer, M.D.,

Sirolimus-and Albert Schömig, M.D

From Deutsches Herzzentrum, Technische

Universität, Munich, Germany (A.K., J.M.,

J.P., M Seyfarth, A.S.); University of Basel,

Basel, Switzerland (C.K., M.E.P.); Univer­

sity of Ferrara, Ferrara, Italy (M.V.); Rigs­

hospitalet, Copenhagen (H.K.); San

Camillo Hospital, Rome (M.M.); Cardio­

vascular Institute, Hospital de la Santa

Creu i Sant Pau, Barcelona (M Sabaté);

St Antonius Hospital, Nieuwegein, the

Netherlands (M.J.S.); and Preventicum–

Klinik für Diagnostik, Essen, Germany

(D.B.) Address reprint requests to Dr

Kastrati at Deutsches Herzzentrum, Laza­

rettstr 36, 80636 Munich, Germany, or at

kastrati@dhm.mhn.de.

This article (10.1056/NEJMoa067484) was

published at www.nejm.org on February

Results

The overall risk of death (hazard ratio, 1.03; 95% confidence interval [CI], 0.80 to 1.30) and the combined risk of death or myocardial infarction (hazard ratio, 0.97; 95% CI, 0.81 to 1.16) were not significantly different for patients receiving siroli-mus-eluting stents versus bare-metal stents There was a significant reduction in the combined risk of death, myocardial infarction, or reintervention (hazard ratio, 0.43; 95% CI, 0.34 to 0.54) associated with the use of sirolimus-eluting stents There was no significant difference in the overall risk of stent thrombosis with sirolimus-eluting stents versus bare-metal stents (hazard ratio, 1.09; 95% CI, 0.64 to 1.86) However, there was evidence of a slight increase in the risk of stent thrombosis associated with sirolimus-eluting stents after the first year

Conclusions

The use of sirolimus-eluting stents does not have a significant effect on overall long-term survival and survival free of myocardial infarction, as compared with bare-metal stents There is a sustained reduction in the need for reintervention after the use of sirolimus-eluting stents The risk of stent thrombosis is at least as great

as that seen with bare-metal stents

Restenosis after percutaneous

cor-onary intervention (PCI) reduces the

qual-ity of life and increases the morbidqual-ity of

patients with this complication1; it may even

in-crease the risk of death.2 Drug-eluting stents are

highly effective in preventing restenosis after PCI.3

It has been anticipated that by reducing the rate

of restenosis, drug-eluting stents may have the

potential to improve the long-term prognosis of

patients treated with these devices However,

ini-tial randomized studies focused on restenosis

it-self and had insufficient power and duration to

assess the incidence of less frequent adverse

events, such as death

Recent reports have identified pathologic

re-sponses of the vessel wall to drug-eluting stents

that may serve as precursors to adverse clinical

events.4 Such studies have raised concern that

drug-eluting stents might actually worsen, rather

than improve, long-term prognosis However,

ef-forts to examine this issue by combining data

from previous randomized trials have been

limit-ed to publishlimit-ed trial-level data and have not

in-cluded all the relevant studies.5-7 The aim of this

study was to assess the long-term outcome after

implantation of sirolimus-eluting stents on the

basis of data from individual patients from

ran-domized clinical trials comparing this device with

bare-metal stents

Methods

Inclusion Criteria

We included in our analysis the results of

ran-domized clinical trials that compared

sirolimus-eluting stents (Cypher or Cypher Select, Cordis)

with bare-metal stents for management of

coro-nary artery disease if results for a mean follow-up

period of at least 1 year were reported or made

available by the trials’ investigators or sponsors

Data Sources

We searched the National Library of Medicine

(PubMed, at www.pubmed.gov), the National

In-stitutes of Health clinical trials registry (www

clinicaltrials.gov), and the Cochrane Central

Reg-ister of Controlled Trials (www.mrw.interscience

wiley.com/cochrane/cochrane_clcentral_articles_

fs.html) for randomized trials comparing

siro-limus-eluting stents with bare-metal stents in

patients with coronary artery disease We also

searched Internet-based sources of information on

the results of clinical trials in cardiology (www

cardiosource.com/clinicaltrials, www.theheart

org, www.clinicaltrialresults.com, and www.tctmd

com), as well as conference proceedings from ings of the American College of Cardiology, the American Heart Association, and the European Society of Cardiology Relevant reviews and edi-torials published within the past year in major medical journals were identified and assessed for possible information on trials of interest Searches were restricted to the period from January 2002 through September 2006

meet-We found and screened 16 randomized als,8-23 the main characteristics of which are shown in Table 1 Two randomized trials, Reduc-tion of Restenosis in Saphenous Vein Grafts with Cypher Sirolimus-Eluting Stent (RRISC)16 and Sirolimus-Eluting Stent in the Prevention of Re-stenosis in Small Coronary Arteries (SES-SMART),19were not included in this analysis because each had a mean follow-up of less than 1 year; the findings of these trials are displayed in Table 1 of the Supplementary Appendix (available with the full text of this article at www.nejm.org)

tri-Data Collection and Quality Assessment

An electronic form containing the data fields to be completed for individual patients was sent to all principal investigators or sponsors of the trials

Data from nine randomized trials8,11,13,14,17,18,20,22,23were provided by the principal investigators; data from the remaining five trials9,10,12,15,21 were pro-vided by the sponsor, who had no role in the study design or analysis or in the writing of or decision

to publish the manuscript

The data requested for each patient included the date of randomization, treatment allocation, diabetes status, event status (including death, myo-cardial infarction, coronary reintervention [per-cutaneous or surgical], and stent thrombosis and the respective dates of occurrence), and the date of the last follow-up visit All data were thoroughly checked for consistency (logical checking and checking against the original publications) Any queries were resolved and the final database en-tries verified by the responsible trial investigator

We also evaluated each trial for the adequacy

of allocation concealment, performance of the analysis according to the intention-to-treat prin-ciple, and blind assessment of the outcomes of interest We used the criteria recommended by Altman and Schulz24 and by Jüni et al.25 to de-

cide whether the treatment allocation was

ade-quately concealed Some trials used a modified

intention-to-treat principle (i.e., excluding patients

who did not receive the study stent) (see Table 2

of the Supplementary Appendix)

Study Outcomes

The primary end point of this analysis was death

from any cause Secondary end points were the

composite of death or myocardial infarction and

the composite of death, myocardial infarction, or

reintervention (major adverse cardiac events) We

also assessed the occurrence of stent thrombosis

(see Table 2 of the Supplementary Appendix for

the end-point definitions used in individual trials)

It is important to note that in eight trials, data

for patients who underwent target-lesion

revascu-larization were censored with respect to the

sub-sequent assessment of stent thrombosis The

ad-judication of events in each trial was performed by

the same event committee over the entire

follow-up period

Statistical Analysis

We performed survival analyses with the use of

the Mantel–Cox test stratified according to trial

Survival was defined as the interval from

random-ization until the event of interest Data for

pa-tients who did not have the event of interest were

censored at the date of the last follow-up visit

The log-rank test was used to calculate hazard

ratios and their 95% confidence intervals (CIs)

Trials in which the event of interest was not

observed in either study group were omitted from

the analysis of that event For trials in which

only one of the groups had no event of interest,

the estimate of treatment effect and its standard

error were calculated after adding 0.5 to each cell

of the 2×2 table for the trial.26

We assessed the heterogeneity across trials by

the Cochran test and by calculating the I2

statis-tic (describing the percentage of total variation

across trials that was due to heterogeneity rather

than chance), as proposed by Higgins et al.27 We

pooled hazard ratios from individual trials

ac-cording to the method of DerSimonian and Laird

for random effects.28

Sensitivity analyses were performed by

com-paring the treatment effects obtained with each

trial removed consecutively from the analysis with

the overall treatment effects In addition, we used

a random-effects meta-regression analysis to

esti-mate the extent to which including four ates — the nature of the study with respect to blinding (double blinding or no double blinding), the length of follow-up, the protocol-mandated duration of dual antiplatelet therapy, and the presence of acute myocardial infarction — as

covari-22p3

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Hazard Ratio Trial

Sirolimus Stent Bare-Metal Stent

70 60 50 0

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PRISON II RAVEL SCANDSTENT SCORPIUS SESAMI SIRIUS STRATEGY TYPHOON Overall

10/264 2/50 0/54 7/80 10/175 29/250 2/100 14/120 1/163 5/95 3/160 45/533 10/87 8/355 146/2486

13/281 3/50 2/29 5/80 11/177 24/250 3/100 8/118 1/159 4/98 7/160 46/525 12/88 8/357

Figure 1 Hazard Ratios for Individual Trials and for the Pooled Population and Kaplan–Meier Estimates for 5-Year Survival

In Panel A, hazard ratios are shown on a logarithmic scale The size of each square is proportional to the weight of the individual study, measured as the inverse of the estimated variance of the log hazard ratio In Panel B, Kaplan– Meier curves are shown for survival for the pooled population during a 5­year period in each of the stent groups.

inclusion criteria for the trial might have enced the treatment effect Using the Mantel–Cox model, we checked for statistically significant interaction between the treatment effect (siroli-mus-eluting stent vs bare-metal stent) and the

influ-presence of diabetes mellitus (the only fied subgroup that was analyzed)

prespeci-All P values are two-sided Results were sidered to be statistically significant at a P value

con-of less than 0.05 Statistical analysis was formed with the use of Stata software, version 9.2 (Stata) Survival curves are presented as simple, nonstratified Kaplan–Meier curves across all trials and constructed with the use of S-Plus software, version 4.5 (Insightful)

per-R esultsOur analysis included 14 trials and 4958 patients,

1411 of whom had diabetes mellitus.8-15,17,18,20-23Table 1 displays the main characteristics of these trials The age of the patients in the trials ranged from 59.3 to 66.6 years, and the length of follow-

up ranged from 12.1 to 58.9 months

Figure 1A shows the absolute numbers of deaths in each trial according to treatment group, with the hazard ratio for each trial There was

no statistical evidence of heterogeneity across the

14 trials In total, there were 146 deaths (83 from cardiac causes) in patients with sirolimus-eluting stents and 147 deaths (79 from cardiac causes)

in patients with bare-metal stents Overall, the use of sirolimus-eluting stents was associated with a hazard ratio for death of 1.03 (95% CI, 0.80 to 1.30; P = 0.80), as compared with that of bare-metal stents

Sequential exclusion of each individual trial from the analysis of death yielded hazard ratios that ranged from 0.96 (95% CI, 0.74 to 1.25) to 1.06 (95% CI, 0.84 to 1.34) and were not sig-nificantly different from the overall hazard ratio (P≥0.71) No significant influence of prespecified covariates on the treatment effect was observed, including the length of follow-up (P = 0.44), the protocol-mandated duration of dual antiplatelet therapy (P = 0.69), the presence of patients with acute myocardial infarction in the trial (P = 0.56),

or the presence of double blinding in the trial sign (P = 0.70) Figure 1B shows the overall 5-year survival curves for the two treatment groups.Figure 2A shows the absolute numbers of pa-tients who died or had a myocardial infarction in each trial according to treatment group, with the hazard ratio for each trial There was no statisti-cal evidence of heterogeneity across the 14 trials

de-In total, 241 patients with sirolimus-eluting stents 22p3

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728 798

1168 1148

1985 1983

2486 2472

Figure 2 Hazard Ratios for Death or Myocardial Infarction and Kaplan–Meier

Estimates for Survival Free of Myocardial Infarction.

In Panel A, hazard ratios are shown on a logarithmic scale The size of each

square is proportional to the weight of the individual study, measured as the

inverse of the estimated variance of the log hazard ratio In Panel B, Kaplan–

Meier curves are shown for survival free of myocardial infarction for the

pooled population during a 5­year period in each of the stent groups.

either died or had a myocardial infarction, as

com-pared with 252 patients with bare-metal stents

Overall, use of sirolimus-eluting stents was

as-sociated with a hazard ratio for death or

myo-cardial infarction of 0.97 (95% CI, 0.81 to 1.16;

P = 0.76), as compared with use of bare-metal

stents Figure 2B shows the overall 5-year curves

for survival free of myocardial infarction in the

two study groups

Figure 3A shows the absolute numbers of

pa-tients who died, had a myocardial infarction, or

required reintervention in each trial according to

treatment group, with the hazard ratio for each

trial In total, 331 patients with sirolimus-eluting

stents died, had a myocardial infarction, or

re-quired reintervention, as compared with 649

pa-tients with bare-metal stents Overall, the use of

sirolimus-eluting stents was associated with a

hazard ratio for death, myocardial infarction, or

reintervention of 0.43 (95% CI, 0.34 to 0.54;

P<0.001), as compared with the use of bare-metal

stents Although the point estimates for

individ-ual trials all favored sirolimus-eluting stents,

there was a significant heterogeneity across trials

with a high I2 value Figure 3B shows the overall

5-year curves for survival free of myocardial

infarction and reintervention in the two study

groups

No significant interaction between treatment

groups and the diagnosis of diabetes was

ob-served for any of the three end points of the

study, including death (P = 0.19), death or

myocar-dial infarction (P = 0.39), and death, myocarmyocar-dial

infarction, or reintervention (P = 0.49) We

none-theless performed a separate analysis of the rate

of death in the subgroup of patients with diabetes

Figure 4A shows the absolute numbers of deaths

in each trial by treatment group, with the hazard

ratio for the subgroup of patients with diabetes in

each trial There was no significant heterogeneity

across trials In total, 59 patients with diabetes

and sirolimus-eluting stents died, as compared

with 56 patients with diabetes and bare-metal

stents The overall hazard ratio associated with

sirolimus-eluting stents was 1.27 (95% CI, 0.83 to

1.95; P = 0.26) Figure 4B shows the overall 5-year

survival curves in the subgroup of patients with

Hazard Ratio Trial

Sirolimus Stent Bare-Metal Stent

P(heterogeneity)=0.001

I 2 =62%

P(overall effect)<0.001

80 90

70 60

50 0

Years after Randomization

Sirolimus stent

Bare-metal stent 100

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32/264 5/50 8/54 10/80 26/175 59/250 6/100 20/120 7/163 15/95 11/160 91/533 17/87 24/355 331/2486

41/281 14/50 11/29 33/80 58/177 73/250 25/100 28/118 51/159 32/98 26/160 164/525 31/88 62/357

Figure 3 Hazard Ratios for Death, Myocardial Infarction, or Reintervention and Kaplan–Meier Curves for Survival Free of Myocardial Infarction and Reintervention.

Panel A shows significant heterogeneity in the effect of treatment result­ ing from the differing magnitude of risk reduction observed in patients with sirolimus­eluting stents among the 14 trials Hazard ratios are shown on a logarithmic scale The size of each square is proportional to the weight of the individual study, measured as the inverse of the esti­ mated variance of the log hazard ratio In Panel B, Kaplan–Meier curves are shown for survival free of myocardial infarction and reintervention for the pooled population during a 5­year period in each of the stent groups.

trials) was observed in 65 patients (34 with limus-eluting stents and 31 with bare-metal stents) The hazard ratio for stent thrombosis was 1.09 (95% CI, 0.64 to 1.86; P = 0.75) After the first year, stent thrombosis occurred in nine pa-tients, eight of whom had sirolimus-eluting stents

siro-(Fig 5A) Over the 4-year period after the first year following the procedure, the overall risk of stent thrombosis was 0.6% (95% CI, 0.3 to 1.2)

in the sirolimus-stent group and 0.05% (95% CI, 0.01 to 0.4) in the bare-metal–stent group (P = 0.02) Figure 5B shows the curves of probability of stent thrombosis in the two study groups after the trial-defined minimum duration of recom-mended use of dual antiplatelet therapy (Table 1) The overall risk of stent thrombosis during 4 years after this time was 0.8% (95% CI, 0.5 to 1.5) in the sirolimus-stent group and 0.3% (95% CI, 0.1

to 0.6) in the bare-metal–stent group (P = 0.16)

In 8 of the 14 trials, data for patients going target-lesion revascularization were cen-sored with respect to the subsequent assessment

under-of stent thrombosis This censoring resulted in the exclusion of five additional cases of stent thrombosis, all in the bare-metal–stent group

In contrast, in the other six trials, such censoring did not occur, which resulted in the inclusion of one case of stent thrombosis that occurred after target-lesion revascularization in the sirolimus-stent group

Discussion

In our study, we analyzed individual data for tients with coronary heart disease from 14 ran-domized trials comparing sirolimus-eluting stents with bare-metal stents We found that the use of sirolimus-eluting stents was associated with rates

pa-of death alone or combined with myocardial farction that were similar to those observed with the use of bare-metal stents Sirolimus-eluting stents were also associated with a sustained re-duction in the need for reintervention but with

in-an overall risk of stent thrombosis that was at least as high as that seen with bare-metal stents.Several previous analyses of trials comparing drug-eluting stents and bare-metal stents in pa-tients with coronary artery disease have been re-ported.5-7,29-34 In these previous studies, aggre-gate data from published reports, rather than data from individual patients, were examined The superiority of analysis of data from individual patients over meta-analysis of lumped study out-comes has been emphasized.35-38 In particular for survival data, the lack of adjustment for censor-ing leads to an imprecise estimate of the overall treatment effect and interstudy heterogeneity.39Access to data for individual patients also makes 22p3

1.27 (0.83 to 1.95)

Sirolimus Stent Better Stent Better Bare-Metal

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Figure 4 Hazard Ratios for Death in a Subgroup of Patients with Diabetes

and Kaplan–Meier Curves for Overall Survival.

In Panel A, hazard ratios are shown on a logarithmic scale The size of each

square is proportional to the weight of the individual study, measured as

the inverse of the estimated variance of the log hazard ratio In Panel B,

Kaplan–Meier curves are shown for survival for the pooled subgroup of

patients with diabetes during a 5­year period in each of the stent groups.

it possible to analyze the timing of events We

made an extensive effort to identify and

incorpo-rate all trials comparing sirolimus-eluting stents

with bare-metal stents As a result, we believe that

we have reduced the likelihood of study-selection

bias, the major risk of any meta-analysis, which

may have been present in previous reports

The effect of the use of sirolimus-eluting stents

on long-term mortality has not previously been

established Contrary to the expectation that

pre-vention of restenosis by sirolimus-eluting stents

might lead to improved survival, recent reports

suggested that sirolimus-eluting stents were

as-sociated with an increased rate of death as early

as 2 years after the procedure.5,6 Although this

finding was not statistically significant, it

gener-ated much concern among the medical

commu-nity.40 Our study shows no difference in mortality

between patients with sirolimus-eluting stents and

those with bare-metal stents during a 5-year

pe-riod The same finding was true for the combined

end point of death or myocardial infarction

No significant increase in the overall rate of

stent thrombosis was seen with sirolimus-eluting

stents However, this complication was

signifi-cantly more frequent in patients with

sirolimus-eluting stents after the first year following the

procedure, a finding that was consistent with

another recent report.41 This difference is

chrono-logically associated with the end of the

protocol-specified interval of dual antiplatelet therapy with

thienopyridines and aspirin Although an

accu-rate assessment of this issue cannot be made

without knowledge of the actual timing of

dis-continuation of thienopyridine therapy in

individ-ual patients, our findings, as well as other

recent-ly published observations,42 may suggest the need

for a longer duration of dual antiplatelet therapy

in patients receiving sirolimus-eluting stents

As noted, there were another five cases of

stent thrombosis that were censored from the

analysis of the original trials because they

oc-curred after target-lesion revascularization One

case of stent thrombosis that was included in our

count would have been excluded if such censoring

had been applied to all the trials Whether such

cases of stent thrombosis should be included in

comparisons of this kind is open to question

Proponents of inclusion would argue that

post-revascularization episodes of stent thrombosis

are an inseparable part of the experience of

re-ceiving a stent and that such episodes are more

common with bare-metal stents because lesion revascularization is required more often in patients with such stents The argument for ex-cluding such episodes is that they may have oc-curred not as a result of the original stent choice, but as a result of the subsequent revasculariza-tion procedure, and thus that they do not reflect the biologic effects of the specific stent type

target-Our observation that there is no late difference

in hard end points (death or myocardial tion) despite an increase in late stent thrombosis

infarc-22p3

1 2

0

Years after Minimum Duration of Recommended

Dual Antiplatelet Therapy

Sirolimus stent Bare-metal stent 3

1 2

0

Years after Randomization

Sirolimus stent Bare-metal stent 3

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No at Risk

Sirolimus stent

1021 1039

761 838

1208 1201

2042 2046

2486 2472

Figure 5 Kaplan–Meier Curves for Stent Thrombosis in the Pooled Population According to Stent Type and the Duration of Dual Antiplatelet Therapy.

Panel A shows that after the first year following the index procedure, stent thrombosis occurred in eight patients in the sirolimus­stent group and in only one patient in the bare­metal–stent group Panel B shows the proba­ bility of stent thrombosis after the use of a trial­defined minimum duration

of recommended dual antiplatelet therapy, according to stent type.

associated with sirolimus-eluting stents may be explained by the small proportion of patients with this complication in the trials Also, the negative effect of late stent thrombosis on clinical out-come might have been offset by the reduction in the need for reintervention with the sirolimus-eluting stent and, consequently, by the exposure

of a lower number of patients to postprocedural complications, as suggested by recent analyses.43

We paid special attention to patients with betes through a prespecified subgroup analysis

dia-Patients with diabetes are at increased risk for adverse events after PCI,44,45 and aortocoronary bypass surgery is often considered to be a better treatment option for them The effect of drug-eluting stents on the long-term outcome of pa-tients with diabetes is not known In the Siroli-mus-Coated Bx Velocity Balloon-Expandable Stent

in the Treatment of De Novo Native Coronary Artery Lesions (SIRIUS) trial, the largest trial in our analysis, patients with diabetes continued to have a relatively high rate of restenosis even after receiving drug-eluting stents.21 In our study, there was no statistical interaction between the presence

of diabetes and the effect of sirolimus-eluting stents on the outcome of patients, including the rate of death However, when we analyzed mor-tality in the subgroup of patients with diabetes, there was a trend toward a higher hazard ratio

in patients with sirolimus-eluting stents This servation suggests that patients with diabetes should be observed and followed especially care-fully after treatment with sirolimus-eluting stents

ob-It also justifies further collection of data on the long-term outcome of patients with diabetes who are treated with such stents In addition, it will

be important to evaluate whether other available

or new drug-eluting stents may offer better sults to patients with diabetes

re-In conclusion, the use of sirolimus-eluting stents did not have a significant effect on overall long-term survival or on survival free of myocar-dial infarction, as compared with bare-metal stents There was a sustained reduction in the need for reintervention after the placement of sirolimus-eluting stents The risk of stent throm-bosis was at least as great as that seen with bare-metal stents

Supported by Deutsches Herzzentrum, Munich, Germany.

Dr Kastrati reports receiving lecture fees from Bristol-Myers Squibb, Cordis, GlaxoSmithKline, Lilly, Medtronic, Novartis, and Sanofi-Aventis; Dr Valgimigli, lecture fees from Guilford and Merck and grant support from Merck; Dr Kelbæk, unrestricted grant support from Cordis to fund part of the salary of a re- search nurse; Dr Pfisterer, lecture fees from Medtronic; and Dr Schömig, unrestricted grant support for the Department of Car- diology he chairs from Amersham/General Electric, Bayerische Forschungsstiftung, Bristol-Myers Squibb, Cordis, Cryocath, Guidant, Medtronic, Nycomed, and Schering No other potential conflict of interest relevant to this article was reported.

References

Assali AR, Moustapha A, Sdringola S,

et al Acute coronary syndrome may occur with in-stent restenosis and is associated with adverse outcomes (the PRESTO trial)

Am J Cardiol 2006;98:729-33.

Schühlen H, Kastrati A, Mehilli J, et al

Restenosis detected by routine graphic follow-up and late mortality after coronary stent placement Am Heart J 2004;147:317-22.

angio-Iijima R, Mehilli J, Schomig A, trati A Clinical evidence on polymer-based sirolimus and paclitaxel eluting stents

Nordmann AJ, Briel M, Bucher HC

Mortality in randomized controlled trials comparing drug-eluting vs bare metal stents in coronary artery disease: a meta- analysis Eur Heart J 2006;27:2784-814.

Camenzind E Safety of drug-eluting stents: insights from meta analysis (Ac- cessed February 9, 2007, at http://www.

Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL Late throm- bosis of drug-eluting stents: a meta-analy- sis of randomized clinical trials Am J Med 2006;119:1056-61.

Kaiser C, Brunner-La Rocca HP, Buser

PT, et al Incremental cost-effectiveness of drug-eluting stents compared with a third- generation bare-metal stent in a real-world setting: randomised Basel Stent Kosten Effektivitats Trial (BASKET) Lancet 2005;

366:921-9 [Erratum, Lancet 2005;366:

2086.]

Schampaert E, Cohen EA, Schluter M,

et al The Canadian study of the eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS) J Am Coll Cardiol 2004;43:1110-5.

sirolimus-Chan C, Zambahari R, Kaul U, Cohen

SA, Buchbinder M Outcomes in diabetic patients with multivessel disease and long lesions: results from the DECODE STUDY

Sabate M, Jimenez-Quevedo P, lillo DJ, et al Randomized comparison of sirolimus-eluting stent versus standard stent for percutaneous coronary revascu- larization in diabetic patients: the diabe- tes and sirolimus-eluting stent (DIABETES) trial Circulation 2005;112:2175-83 Schofer J, Schlüter M, Gershlick AH,

Angio-et al Sirolimus-eluting stents for ment of patients with long atheroscle- rotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS) Lancet 2003;362:1093-9 Pache J, Dibra A, Mehilli J, Dirsch- inger J, Schömig A, Kastrati A Drug-elut- ing stents compared with thin-strut bare stents for the reduction of restenosis:

treat-a prospective, rtreat-andomized tritreat-al Eur Hetreat-art

J 2005;26:1262-8.

Suttorp MJ, Laarman GJ, Rahel BM, et

al Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II):

a randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of

11.

12.

13.

14.

total coronary occlusions Circulation

2006;114:921-8.

Morice M-C, Serruys PW, Sousa JE, et

al A randomized comparison of a

siroli-mus-eluting stent with a standard stent

for coronary revascularization N Engl J

Med 2002;346:1773-80.

Vermeersch P, Agostoni P, Verheye S,

et al Randomized double-blind

compar-ison of sirolimus-eluting stent versus

bare-metal stent implantation in diseased

saphenous vein grafts: six-month

angi-ographic, intravascular ultrasound, and

clinical follow-up of the RRISC Trial J Am

Coll Cardiol 2006;48:2423-31.

Kelbaek H, Thuesen L, Helqvist S, et

al The Stenting Coronary Arteries in

Non-stress/Benestent Disease (SCANDSTENT)

trial J Am Coll Cardiol 2006;47:449-55.

Baumgart D A German multicenter

randomized controlled open-label study

of the cypher sirolimus eluting stent in

the treatment of diabetic patients with de

novo native coronary artery lesions

(Ac-cessed February 9, 2007, at http://www.

attendeeinteractive.com.)

Ardissino D, Cavallini C, Bramucci E,

et al Sirolimus-eluting vs uncoated stents

for prevention of restenosis in small

coro-nary arteries: a randomized trial JAMA

2004;292:2727-34.

Menichelli M Randomised trial of

sirolimus stent vs bare metal stent in

acute myocardial infarction (SESAMI)

(Ac-cessed February 9, 2007, at http://www.

europcronline.com/fo/planning/event/

europcr/consult_event.php?id=491.)

Moses JW, Leon MB, Popma JJ, et al

Sirolimus-eluting stents versus standard

stents in patients with stenosis in a native

coronary artery N Engl J Med 2003;349:

1315-23.

Valgimigli M, Percoco G, Malagutti P,

et al Tirofiban and sirolimus-eluting stent

vs abciximab and bare-metal stent for

acute myocardial infarction: a

random-ized trial JAMA 2005;293:2109-17.

Spaulding C, Henry P, Teiger E, et al

Sirolimus-eluting versus uncoated stents

in acute myocardial infarction N Engl J

System-Egger M, Smith GD, Altman D, eds

Systematic reviews in health care: analysis in context London: BMJ Publish- ing, 2001:357.

meta-Higgins JP, Thompson SG, Deeks JJ, Altman DG Measuring inconsistency in meta-analyses BMJ 2003;327:557-60.

DerSimonian R, Laird N sis in clinical trials Control Clin Trials 1986;7:177-88.

Meta-analy-Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents Lan- cet 2004;364:583-91.

Holmes DR Jr, Moses JW, Schofer J, Morice MC, Schampaert E, Leon MB Cause

of death with bare metal and eluting stents Eur Heart J 2006;27:2815- 22.

sirolimus-Moreno R, Fernandez C, Hernandez

R, et al Drug-eluting stent thrombosis:

results from a pooled analysis including

10 randomized studies J Am Coll Cardiol 2005;45:954-9.

Indolfi C, Pavia M, Angelillo IF eluting stents versus bare metal stents

Drug-in percutaneous coronary Drug-interventions (a meta-analysis) Am J Cardiol 2005;95:

1146-52.

Biondi-Zoccai GG, Agostoni P, Abbate

A, et al Adjusted indirect comparison of intracoronary drug-eluting stents: evidence from a metaanalysis of randomized bare- metal-stent-controlled trials Int J Cardiol 2005;100:119-23.

Katritsis DG, Karvouni E, Ioannidis

JP Meta-analysis comparing drug-eluting stents with bare metal stents Am J Car- diol 2005;95:640-3.

Simmonds MC, Higgins JP, Stewart

LA, Tierney JF, Clarke MJ, Thompson SG

Meta-analysis of individual patient data from randomized trials: a review of meth- ods used in practice Clin Trials 2005;2:

Stewart LA, Tierney JF To IPD or not

to IPD? Advantages and disadvantages of systematic reviews using individual pa- tient data Eval Health Prof 2002;25:76- 97.

Clarke MJ, Stewart LA Meta-analyses using individual patient data J Eval Clin Pract 1997;3:207-12.

Stewart LA, Parmar MK sis of the literature or of individual patient data: is there a difference? Lancet 1993;

Meta-analy-341:418-22.

Vale CL, Tierney JF, Stewart LA fects of adjusting for censoring on meta- analyses of time-to-event outcomes Int J Epidemiol 2002;31:107-11.

Ef-Shuchman M Trading restenosis for thrombosis? New questions about drug- eluting stents N Engl J Med 2006;355:

1949-52.

Pfisterer M, Brunner-La Rocca HP, Buser PT, et al Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observa- tional study of drug-eluting versus bare- metal stents J Am Coll Cardiol 2006;48:

2584-91.

Eisenstein EL, Anstrom KJ, Kong DF,

et al Clopidogrel use and long-term cal outcomes after drug-eluting stent im- plantation JAMA 2007;297:159-68.

clini-Stone GW Perspectives on ing stent safety and efficacy with regula- tory recommendations Presented at the FDA Circulatory System Devices Panel of the Medical Devices Advisory Committee, Washington, DC, December 7–8, 2006

drug-elut-(Accessed February 9, 2007, at http://

www.fda.gov/ohrms/dockets/ac/06/slides/

2006-4253oph1_04_Stone.pdf.) Carrozza JP Jr, Kuntz RE, Levine MJ,

et al Angiographic and clinical outcome

of intracoronary stenting: immediate and long-term results from a large single-cen- ter experience J Am Coll Cardiol 1992;20:

328-37.

Elezi S, Kastrati A, Pache J, et al betes mellitus and the clinical and angi- ographic outcome after coronary stent placement J Am Coll Cardiol 1998;32:

o r i g i n a l a r t i c l e

The n e w e n g l a n d j o u r n a l of m e d i c i n e

Angiotensin-Converting–Enzyme Inhibition

in Stable Coronary Artery Disease

The PEACE Trial Investigators*

The writing committee for the Prevention

of Events with Angiotensin Converting

En-zyme Inhibition (PEACE) Trial (Eugene

Braunwald, M.D., Harvard Medical School

and Brigham and Women’s Hospital,

Bos-ton; Michael J Domanski, M.D., National

Heart, Lung, and Blood Institute, Bethesda,

Md.; Sarah E Fowler, Ph.D., George

Wash-ington University, Rockville, Md.; Nancy L.

Geller, Ph.D., National Heart, Lung, and

Blood Institute; Bernard J Gersh, M.D.,

Mayo Clinic Foundation, Rochester, Minn.;

Judith Hsia, M.D., George Washington

University, Washington, D.C.; Marc A

Pfef-fer, M.D., Ph.D., Harvard Medical School

and Brigham and Women’s Hospital;

Made-line M Rice, Ph.D., George Washington

University, Rockville, Md.; Yves D

Rosen-berg, M.D., National Heart, Lung, and Blood

Institute; and Jean L Rouleau, M.D.,

Univer-sity of Montreal, Montreal) takes

respon-sibility for the content of this article

Ad-dress reprint requests to Dr Braunwald at

the TIMI Study Group, Brigham and

Wom-en’s Hospital, 350 Longwood Ave., Boston,

MA 02115.

*The investigators and research

coordina-tors who participated in the PEACE Trial

are listed in the Appendix.

m e t h o d s

In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE)Trial, we tested the hypothesis that patients with stable coronary artery disease andnormal or slightly reduced left ventricular function derive therapeutic benefit from theaddition of ACE inhibitors to modern conventional therapy The trial was a double-blind, placebo-controlled study in which 8290 patients were randomly assigned toreceive either trandolapril at a target dose of 4 mg per day (4158 patients) or matchingplacebo (4132 patients)

r e s u l t s

The mean (±SD) age of the patients was 64±8 years, the mean blood pressure133±17/78±10 mm Hg, and the mean left ventricular ejection fraction 58±9 percent.The patients received intensive treatment, with 72 percent having previously undergonecoronary revascularization and 70 percent receiving lipid-lowering drugs The incidence

of the primary end point — death from cardiovascular causes, myocardial infarction,

or coronary revascularization — was 21.9 percent in the trandolapril group, as pared with 22.5 percent in the placebo group (hazard ratio in the trandolapril group,0.96; 95 percent confidence interval, 0.88 to 1.06; P=0.43) over a median follow-upperiod of 4.8 years

com-c o n com-c l u s i o n s

In patients with stable coronary heart disease and preserved left ventricular functionwho are receiving “current standard” therapy and in whom the rate of cardiovascularevents is lower than in previous trials of ACE inhibitors in patients with vascular dis-ease, there is no evidence that the addition of an ACE inhibitor provides further benefit

in terms of death from cardiovascular causes, myocardial infarction, or coronary cularization

revas-a b s t r revas-a c t

a c e i n h i b i t i o n i n c o r o n a r y d i s e a s e

lockade of the

renin–angioten-sin system has been shown to prolong

survival and reduce adverse outcomes in

or left

Indeed, converting–enzyme (ACE) inhibitors have become

In addition, post hoc analyses of patients from the

and the Survival and Ventricular Enlargement

both randomized studies that volved patients with moderate-to-severe left ven-

in-tricular dysfunction, showed a reduction in the rate

of acute myocardial infarction in patients who were

treated with an ACE inhibitor These observations

raised the possibility that patients with coronary

artery disease might benefit from ACE-inhibitor

treatment, independently of their left ventricular

function

More recent studies have suggested that patients

at high risk for coronary events indeed benefit from

ACE-inhibitor therapy In the Heart Outcomes

and the European Trial

on Reduction of Cardiac Events with Perindopril in

tients with coronary or other vascular disease or

pa-with diabetes and another cardiovascular risk

fac-tor had reduced rates of death from cardiovascular

causes or acute myocardial infarction when

as-signed to an ACE inhibitor as compared with

place-bo Although both of these trials enrolled patients

without a history of heart failure, many of the

en-rollees, especially those in the HOPE study, had an

increased risk of adverse cardiovascular events

The goal of the Prevention of Events with

Angio-tensin Converting Enzyme Inhibition (PEACE) Trial

was to test whether ACE-inhibitor therapy, when

added to modern conventional therapy, would

re-duce the rate of nonfatal myocardial infarction,

death from cardiovascular causes, or

revasculariza-tion in low-risk patients with stable coronary artery

disease and normal or slightly reduced left

was designed by Drs Pfeffer, Braunwald,

Doman-ski, Geller, and Verter The data were held and

ana-lyzed by the clinical and statistical coordinating

center under the supervision of Dr Fowler Themanuscript was written by Dr Braunwald, Dr Pfef-fer, and the other members of the writing commit-tee Drs Fowler, Pfeffer, and Braunwald take re-sponsibility for the data presented

c o n d u c t o f t h e t r i a l

Patients underwent randomization from November

1996 to June 2000 and were followed up for as long

as 7 years (median, 4.8 years), until December 31,

2003 The study was conducted after approval fromthe institutional review boards at 187 sites (listed inthe Appendix) in the United States (including PuertoRico), Canada, and Italy Patients gave their writteninformed consent to participate An independentdata and safety monitoring board reviewed patientsafety data and interim results A morbidity andmortality review committee reviewed and classifiedall outcomes

In February 2002, given the increasing evidence

of the benefit of ACE inhibitors or receptor blockers in patients with diabetes mellitus

the steering committee, out knowledge of the outcome data and with ap-proval from the data and safety monitoring board,advised the investigators to substitute open-labelACE inhibitors for the masked study treatment inpatients with diabetes and either overt proteinuria

with-or hypertension and microalbuminuria

e n d p o i n t s

Fourteen thousand one hundred patients were quired to test the hypothesis that an ACE inhibitorwould reduce the rate of the original primary endpoint, which consisted of death from cardiovascu-lar causes or nonfatal myocardial infarction Thesecondary end point was a composite of death fromcardiovascular causes, nonfatal myocardial infarc-tion, or coronary revascularization In October 1997,after 1584 patients had undergone randomization,the steering committee (without any knowledge ofoutcome data from the trial) concluded that re-cruiting 14,100 patients was not feasible and ex-panded the primary end point to include coronaryrevascularization The sample size was reduced to

re-8100 patients, and the original primary end pointbecame a secondary end point

The study prespecified five other end pointsbased on combinations of death from cardiovas-cular causes, nonfatal myocardial infarction, revas-cularization, unstable angina, new congestive heartfailure, stroke, peripheral vascular disease, and car-

b

m e t h o d s

The n e w e n g l a n d j o u r n a l of m e d i c i n e

diac arrhythmia In post hoc analyses, the primary

studies,

as well as new-onset congestive heart failure quiring hospitalization or causing death and new-onset diabetes, were also examined

re-r e c re-r u i t m e n t a n d re-r a n d o m i z a t i o n

Potentially eligible subjects participated in a week run-in phase during which they were request-

two-ed to take trandolapril (Mavik, Abbott Laboratories)

at a dose of 2 mg per day They were then excluded

if their compliance was poor or if they had side fects or an abnormal rise in the serum concentra-tion of creatinine or potassium Consenting patientswho successfully completed the run-in phase wererandomly assigned to receive either trandolapril or

ef-a mef-atching plef-acebo; ref-andomizef-ation wef-as performedwith the use of permuted blocks, stratified accord-ing to clinical site

At a visit six months after randomization, tients who had tolerated the dose of 2 mg per dayreceived a new six-month supply of study medica-tion (trandolapril at a dose of 4 mg per day or match-ing placebo) Patients continued to be evaluated

pa-at six-month intervals for primary and secondaryend points and for compliance with their assigneddrug regimen The patients, investigators, and staffmembers remained blinded to the treatment as-signments

s t a t i s t i c a l a n a l y s i s

With the revised sample size, the trial had 90 cent power to detect an 18 percent relative reduc-tion in the incidence of the primary end point, as-suming a 19 percent cumulative incidence of therevised primary end point in the placebo group,when the log-rank test was used at a 0.05 level ofsignificance The sample-size calculation, based on

assumed a 15 percent rate ofdiscontinuation of active treatment and a 15 per-cent rate of crossover to active treatment

The data and safety monitoring board revieweddata related to safety and the primary end point

and anO’Brien–Fleming spending function to control the

and recommended continuation ofthe trial until its scheduled conclusion Statisticalanalyses of the primary and secondary end pointsfollowed the intention-to-treat principle Relativerisks, heterogeneity among strata, and interactionsbetween treatment assignment and covariates were

Allreported P values are two-sided

r e s u l t s

* ACE denotes angiotensin-converting enzyme.

† A subgroup of echocardiograms was reviewed by a core laboratory to confirm

eligibility.

Table 1 Eligibility Criteria.*

Inclusion criteria

Age 50 yr or older

Coronary artery disease documented by at least one of the following:

Myocardial infarction at least 3 mo before enrollment

Coronary-artery bypass grafting or percutaneous transluminal coronary

angioplasty at least 3 mo before enrollment

Obstruction of ≥50% of the luminal diameter of at least one native vessel

on coronary angiography

Left ventricular ejection fraction >40% on contrast or radionuclide

ventricu-lography or echocardiography, a qualitatively normal left ventriculogram,

or the absence of left ventricular wall-motion abnormalities on

echocardi-ography†

Toleration of the medication and successful completion of the run-in phase,

with ≥80% compliance with the medication

Exclusion criteria

Current use of or a current condition requiring use of an ACE inhibitor

or a contraindication to ACE inhibitors

Current use of an angiotensin II–receptor antagonist

Hospitalization for unstable angina within the preceding 2 mo

Valvular heart disease deemed to require surgical intervention

Coronary-artery bypass grafting or percutaneous transluminal angioplasty

within the preceding 3 mo

Planned elective coronary revascularization

Serum creatinine >2.0 mg/dl (177 µmol/liter)

Serum potassium >5.5 mmol/liter

Limited chance of 5-yr survival

Psychosocial condition precluding long-term adherence

Unable or unwilling to give consent

Female sex and of childbearing potential and not using contraception

Current use in a research trial of medication not approved by the U.S Food

and Drug Administration or the Health Protection Branch of the

Cana-dian Department of National Health and Welfare

a c e i n h i b i t i o n i n c o r o n a r y d i s e a s e

* Plus–minus values are means ±SD To convert the values for creatinine to micromoles per liter, multiply by 88.4 To

con-vert the values for cholesterol to millimoles per liter, multiply by 0.02586.

† P<0.05 for the comparison with placebo.

‡ Race was self-declared.

§ Data on ejection fraction were available for 3952 patients in the trandolapril group and 3926 patients in the placebo group.

¶ Four patients had ejection fractions between 30 percent and 50 percent.

Table 2 Baseline Characteristics of the Patients.*

Country (% of patients)

Medical history (% of patients)

Percutaneous coronary intervention or coronary-artery bypass grafting 72 72

Diabetes with a history of hypertension or diastolic blood pressure

≥90 mm Hg or systolic blood pressure ≥140 mm Hg

Blood pressure before run-in phase (mm Hg)