LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

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VENTRICULAR ARRHYTHMIAS

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LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS Applying Group Results to Individual Cases John S. Strobel, MD, and Andrew E. Epstein, MD

The evolution of management of ventricular arrhythmia has occurred largely as a result of randomized, controlled clinical trials.'" l7 The Cardiac Arrhythmia Suppression Trial was pivotal in changing the approach to arrhythmia investigation. First, the study of treatments for ventricular arrhythmias should include a placebo arm whenever feasible and ethical. In comparing two therapies, one of which is subsequently proven to be superior to the other, it is incorrect to assume that the inferior therapy provides outcomes similar to no therapy. The superior therapy may be similar to no therapy, whereas the inferior therapy may be detrimental. Similarly, the superior therapy may provide outcomes only slightly better than no therapy, whereas the inferior therapy may provide slightly worse outcomes (Fig. l).39 Second, total mortality rate is the most important endpoint, because many patients at risk of developing ventricular arrhythmias have competing risks for death, and the classification of death in clinical trials is fraught with ina~curacies.3~ Applying the results of clinical trials to everyday practice in an appropriate manner can be as difficult as conducting clinical trials themselves. One must remember that a cer-

tain treatment that has proven benefit in a specific patient population may not necessarily be beneficial if applied to a more general population. The applicability of many otherwise well-conducted studies has been diminished by the narrowly focused populations of patients studied. This is particularly relevant in the treatment of ventricular arrhythmias. Studying patients at high risk of recurrent ventricular arrhythmias is important, but the overall impact on arrhythmia prevention is low (Fig. 2).38Arrhythmia trials have studied progressively broader patient populations. This article summarizes the results of large clinical trials in the management of ventricular arrhythmias and attempts to provide guidelines for applying their results to everyday clinical practice. SECONDARY PREVENTION TRIALS CASCADE

Prior to the Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation (CASCADE) studyIs*9, l2 patients who were resuscitated from ventricular fibrillation

From the Department of Medicine, Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, Alabama

CARDIOLOGY CLINICS VOLUME 18 NUMBER 2 * MAY 2000

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Years Figure 1. The difficulty in the interpretation of trials comparing two active therapies. A, The natural history of survival for a specific disease. This would reflect the placebo arm in a placebo-controlledtrial. B, Two therapies (T-1 and T-2) are compared. T-2 is inferior to T-1 and comparable to placebo in prolonging survival in this population. C,T-2 is inferior to T-1 and is detrimental when compared to the natural history curve. In addition, although T-1 is superior to T-2 it offers no overall benefit when compared to the natural history. D, T-1 is beneficial and t - 2 is detrimental when compared to the natural history of this disease. (From Myerburg RJ, Mitrani R, lnterian A, et al: Interpretation of outcomes of antiarrhythmic clinical trials: Design features and population impact. Circulation 97:151&1521, 1998; with permission.)

(xl000) Figure 2. The incidence and absolute number of sudden cardiac deaths is shown in six different populations. Although the incidence in the high-risk subgroups is high, the absolute number of events that occur in these populations as a percentage of the total number of sudden cardiac deaths is low. (From Myerburg RJ, Kessler KM, Castellanos A Sudden cardiac death: Structure, function, and time-dependence of risk. Circulation 85:12-10, 1992; with permission.)

LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

(VF) often underwent serial electrophysiologic testing or Holter monitoring to assess the efficacy of antiarrhythmic drugs in suppressing the inducibility of ventricular arrhythmias or spontaneous ectopy and nonsustained arrhythmias, respectively. Although not known with certainty at the time of the study, suppressibility by antiarrhythmic drugs of induced arrhythmias was thought to predict long-term prevention of recurrent VF?I Amiodarone was known to be effective in preventing recurrence of ventricular arrhythmias but was associated with many potentially serious adverse effects.27In addition, implantable cardioverter-defibrillators (ICDs) were not generally available when CASCADE was designed and initiated. CASCADE evaluated two different approaches to the management of patients who had survived out-ofhospital cardiac arrest and who were at high risk for recurrent cardiac arrest. The empiric use of amiodarone without extensive electrophysiologic or Holter testing was compared with standard (predominantly class Ia) antiarrhythmic drug therapy guided by electrophysiologic testing or Holter monitoring. CASCADE enrolled 228 patients between 1984 and 1991 who had been resuscitated from an episode of out-of-hospital VF who did not have a Q-wave myocardial infarction or an identifiable primary reversible cause of VF. Survivors of VF who were considered to have a high (more than 20%) risk of recurrent VF who had either inducible ventricular tachycardia (VT) or VF at electrophysiologic study or complex arrhythmias on Holter monitoring, or both, were eligible for enrollment. Patients randomized to empiric amiodarone therapy received 1200 mg per day for up to 10 days, followed by 200 to 800 mg daily for 1 to 2 months, depending on drug tolerance. The maintenance dose then was tapered to 100 to 400 mg daily. Patients randomized to conventional therapy guided by electrophysiologic testing or Holter monitoring received procainamide, quinidine, disopyramide, tocainide, mexiletine, encainide, flecainide, propafenone, or combination therapy, in that order, until adequate suppression of ventricular arrhythmias was achieved. Acceptable endpoints included suppression of inducible VTIVF or slowing of the induced VT cycle length by at least 100 ms if complete suppression of inducible VT could not be accomplished with any drug. If no suppression or slowing of VT could be accomplished, the patient then was crossed over to amiodarone

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treatment. Patients who had no inducible ventricular arrhythmias at the baseline electrophysiologic study, but who had frequent or complex ventricular arrhythmias (couplets or VT), were administered drugs based on suppression of arrhythmias assessed by Holter monitoring. Successful suppression was considered if at least 70% of premature ventricular contractions (PVCs) or 90% of runs of VT were absent during drug therapy. The primary endpoint of CASCADE was the total cardiac mortality rate, including sudden arrhythmic cardiac death, documented resuscitated out-of-hospital VF, and nonarrhythmic cardiac death. In addition, in patients with an ICD, syncope followed by a shock was designated as the equivalent of a cardiac arrest. As mentioned previously, because ICDs were not used widely before 1988, they were implanted in that period at the discretion of the patient’s physician. After 1988, ICDs were implanted in all patients in whom the surgery was feasible. ICD therapy was not randomized, and the authors appropriately made no attempt to compare outcomes between patients who did and did not receive them. Of the 228 patients randomized, 113 were treated with amiodarone and 115 with conventional antiarrhythmic therapy. Coronary artery disease was present in 82% of patients. Although only 42% of patients had a history of congestive heart failure (CHF), the average ejection fraction was 0.35. The mean dose of amiodarone was 183 mglday, 158 mglday, and 185 mglday at 12, 24, and 36 months, respectively, in the amiodarone group. In the conventional drug-therapy group, 57 patients had inducible ventricular arrhythmias. Complete suppression was achieved in 35 and slowing of VT was achieved in 10 patients. Twelve patients who continued to have inducible VT that was not slowed by more than 100 ms compared with baseline were given the drug that best slowed the VT and were also were treated with an ICD if feasible. Of the patients treated using Holter-guided therapy, 25 (56%)of 45 had at least 90% suppression of VT and 70% suppression of ventricular ectopy. In nine patients, VT was not completely suppressed; in one patient, suppression of ectopy did not achieve 70%; and in 10 patients, neither VT nor ectopy were suppressed. Thus, in the conventionally treated group 22 (19%)of 15 patients did not achieve a therapeutic endpoint of antiarrhythmic therapy. Most patients were treated with

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quinidine, procainamide, or a combination of antiarrhythmic drugs. An ICD was implanted in 105 patients, 53 in the amiodarone group and 52 in the conventional therapy group. The primary endpoints of total cardiac mortality rate, resuscitated cardiac arrest, and syncopal ICD shock were reduced significantly by amiodarone from 23% to 9% at 1 year and from 44% to 24% at 3 years (Fig. 3). If the endpoints of sustained VT requiring cardioversion and near-syncopal ICD shocks were added to the primary endpoints, a significant reduction in events through amiodarone again was noted. In the amiodarone group, 15% and 34% at 1 and 3 years, respectively, developed one of these endpoints, versus 34% and 55% at 1 and 3 years, respectively, in the conventional drug group. Finally, ”true cardiac death,” which excluded those patients resuscitated from VF or those receiving an ICD shock after syncope, was reduced by amiodarone from 22% to 15% at 2 years. Although the numbers of patients in specific subgroups were small, the authors noted that there was no difference in total cardiac and arrhythmia-free survival rates in patients who had inducible arrhythmias versus those

who did not have inducible arrhythmias at baseline. Similarly, there were no differences in outcome between conventionally treated patients whose inducible arrhythmias were suppressed and those in whom arrhythmias were not suppressed. These observations differ from those of others, that survival without cardiac arrest was greater in patients whose arrhythmias were either noninducible or inducible but suppressed with antiarrhythmic 54 dr~gs.2~. Despite efforts by the investigators to reduce the amiodarone dosage to lower, more tolerable levels, the rate of discontinuation of amiodarone was 29% compared with only 17% in the conventional treated group. Amiodarone pulmonary toxicity, defined as the constellation of dyspnea, rales, interstitial or alveolar infiltrates, and a decrease in pulmonary diffusion capacity in the absence of pulmonary infection or CHF, occurred in nine patients, an actuarial incidence of 10% at 3 years. No patient died from pulmonary toxicity. CASCADE demonstrated several important points. First, the empiric use of amiodarone was more effective for preventing recurrent cardiac arrest than conventional antiarrhyth-

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Figure 3. Cumulative “cardiac survival” including total cardiac mortality, resuscitated cardiac arrest and syncopal defibrillator shocks in the CASCADE study. (Modified from The CASCADE Investigators: Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE study). Am J Cardiol 72:28&287, 1993;with permission.)

LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

mic drugs guided by electrophysiologic testing. It should be noted that a placebo group was not included in this study, so it is not known whether conventional antiarrhythmic drug therapy (or empiric amiodarone, for that matter) resulted in a similar or worse mortality rate as placebo, especially in view of the fact that several patients in the conventionally treated group received drugs that were later shown to worsen the mortality rate in the Cardiac Arrhythmia Suppression Trial.14,l7 Second, the “superior” therapy in this trial still resulted in a high rate of recurrent cardiac arrest. Finally, although a large number of adverse drug reactions were attributed to amiodarone, some of the alleged toxicity was based on changes in pulmonary diffusion capacity without clinical symptoms or signs that today would be required for the diagnosis.

AVID

The unsatisfactory prevention of death by antiarrhythmic drugs and the growing availability of ICDs led to clinical trials designed to test the usefulness of these devices to prevent arrhythmic death and prolong life. It was tempting to quickly assume that ICDs could accomplish these tasks. ICD implantation itself, however, was associated with significant risks in these patients with coronary disease, CHF, and ventricular arrhythmias, especially in early-generation systems that required thoracotomy for implantation. More important, it was not clear that prevention of cardiac arrest resulting from ventricular tachyarrhythmias would translate necessarily into prolonged life if a patient subsequently died of refractory CHF, recurrent myocardial infarction (MI), or another cause. Thus, the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial was implemented? Patients were eligible for AVID if they were resuscitated from VF, sustained VT with syncope, or sustained VT with an ejection fraction no more than 0.40 and hemodynamic compromise including near-syncope, CHF, or angina. Patients were randomized to therapy with an antiarrhythmic drug or an ICD. Patients randomized to drug therapy received empiric amiodarone or sotalol guided by electrophysiologic study or Holter monitoring. Almost all patients randomized to ICD therapy received a transvenous system, and al-

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most all randomized to drug therapy ultimately received amiodarone. A registry was maintained of all patients who qualified for the study but did not undergo randomization in order to compare randomized and nonrandomized patients. The registry also followed patients with VF or VT who were not eligible for randomization. Screening was performed on 6035 patients, of whom 4621 entered the registry; 1885 were eligible for randomization and 1016 were randomized. Baseline characteristics of the patients randomized to drug or device therapy were similar except for a greater incidence of atrial fibrillation or atrial flutter and class I11 CHF in the group treated with antiarrhythmic drugs. VF was the index arrhythmia in 455 patients (&YO), syncopal VT in 216 patients (21%), and hemodynamically unstable VT in 345 patients (34%). The mean left-ventricular ejection fraction was 0.32 in the ICD group and 0.31 in the antiarrhythmic-drug group. A nonthoracotomy lead system was used in 93% of the 507 ICD patients; 2% received no device. Empiric amiodarone was given immediately to 70% of the antiarrhythmic drug group. The remaining patients’ (n = 153) antiarrhythmic drug therapy was randomized. Of the 74 patients assigned to sotalol, 53 had sufficient spontaneous or inducible arrhythmia to guide therapy, but only 13 had adequate arrhythmia suppression. The patients assigned to sotalol who did not have sufficient spontaneous or inducible arrhythmia to guide therapy or who did not have adequate arrhythmia suppression were given amiodarone (58 patients), another antiarrhythmic drug (one patient), or an ICD (two patients). The mean daily amiodarone dose was 331 mg, 294 mg, and 256 mg at 1, 2, and 3 years, respectively. More patients in the ICD group were treated with p-blockers and digitalis. The AVID trial was terminated prematurely in April 1997, when ICD therapy was shown to result in a significant survival advantage compared with antiarrhythmic drug therapy. In the ICD group, 80 deaths occurred, compared with 122 deaths in the antiarrhythmic drug group. Over a mean follow-up of 18 months, the crude death rates were 16% in the ICD group compared with 24% in the drug group. The relative reduction in mortality rate afforded by an ICD was 39%, 27%, and 31% at 1, 2, and 3 years, respectively (Fig. 4). The average unadjusted length of additional life associated with defibrillator therapy was 3 months at 3 years.

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Figure 4. Overall survival in the AVID trial. Survival was significantly better in the defibrillator group compared to the antiarrhythmic drug group. (From The AVID investigators: A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. New Engl J Med 337:15761583, 1997; with permission.)

Of the patients with an ICD and VT, 68%, 81%, and 85% received ICD therapy (either pacing or a shock) at 1,2, and 3 years, respectively. Of the patients with an ICD and VF, 15%, 39%, and 69%, respectively, received an ICD therapy at the same time intervals. Crossover to alternate therapy occurred in 20% of patients by 24 months and was higher in those initially assigned to the ICD arm, because of frequent ICD therapies. Pulmonary toxicity occurred in 5% of patients at 2 years, and one patient died of pulmonary toxicity. Complications of ICD implantation were rare and included bleeding or hematoma in 19 patients, infection in 10 patients, pneumothorax in eight patients, cardiac perforation in one patient, and lead dislodgement or migration in three patients. Five patients had an unsuccessful first attempt at ICD implantation. The AVID trial was the subject of numerous editorials and evoked numerous, often emotional, responses from physicians and scientists (often associated with the ICD industry) regarding its need and ethicality.* As already noted, treatment with an ICD demonstrated an improvement in overall survival compared *References 10, 15, 20, 21, 26, 31, 37, 41, 48, 49.

with antiarrhythmic drug therapy. Neither the absolute survival nor the magnitude of difference in survival, however, was as impressive as predicted by observational studies.2z, 55 Indeed, the reZative risk reduction of 39% at 1 year and 31% at 3 years appears more modest if one notes that the absolute risk reduction was 7% at 1year and 11%at 3 years in these patients with serious ventricular arrhythmias. Finally, contrary to criticisms that AVID patients were not representative of all patients resuscitated from near-fatal ventricular arrhythmias, the registry demonstrated that the clinical characteristics of patients who underwent randomization were similar to those of nonrandomized patients.34 Thus, with these caveats in mind, for the individual patient who has survived an episode of VF or unstable VT, the ICD should be used as first-line therapy. CIDS

The Canadian Implantable Defibrillator Study (CIDS) was similar in design to AVID. It compared amiodarone to ICD therapy in patients at high risk for recurrent ventricular tachyarrhythmias. Inclusion criteria included

LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

documented VF, out-of-hospital cardiac arrest requiring defibrillation or cardioversion, documented sustained VT causing syncope, documented VT at a rate of at least 150 beats per minute causing near syncope or angina in a patient with a left-ventricular ejection fraction no more than 0.35, or profound unmonitored syncope with subsequent documentation of either spontaneous VT or at least 10 seconds or sustained (at least 30 seconds) monomorphic VT induced by programmed ventricular stimulation. This latter group was not included in the AVID trial. When the study began, the primary endpoint was arrhythmic death or death occurring within 30 days of randomization. The primary endpoint was changed in 1995 to death from any cause, requiring the enrollment of an additional 260 patients. There were 720 patients enrolled. The mean ejection fraction was 0.33, and 64% had an ejection fraction of no more than 0.35. Most patients (50%) were enrolled for cardiac arrest, and only 15%had unmonitored syncope with subsequent documentation of VT. The study, as yet unpublished but presented at the 1998 Annual Session of the American College of Cardiology, revealed a 20% reduction in mortality rate in the ICD-treated patients (P = .07)." CASH

The Cardiac Arrest Study Hamburg (CASH) evaluated the use of a class I (propafenone), class I1 (metoprolol),or class I11 (amiodarone) antiarrhythmic drug or an ICD in survivors of cardiac arrest. Patients were randomized in a 3:l ratio to drug or ICD therapy after being resuscitated from cardiac arrest secondary to documented VT or VF unrelated to MI. After undergoing electrophysiologic testing, patients received propafenone (450 to 900 mg/d), metoprolol (12.5 to 200 mg/d), amiodarone (1000 mg/d for 7 days, followed by 400 to 600 mg/d), or an ICD with no concomitant antiarrhythmic therapy. Electrophysiologic testing then was repeated in all patients, but subsequent treatment was not altered in response to the test results. The primary endpoint of the study was total mortality rate, with secondary endpoints of recurrent cardiac arrest, recurrent hemodynamically unstable VT, drug withdrawal, or heart tran~plantation.4~ There were 346 patients randomized pri-

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marily to an ICD (n = 99), amiodarone (n = 92), or metoprolol (n = 97). Only 58 patients received propafenone, because this arm of the study was discontinued as a result of excessive deaths in March 1992. Enrollment continued from 1987 until 1996, and all patients concluded a minimum follow-up of 2 years in 1998. The long duration of enrollment has been criticized because of the rapid evolution of therapies over this time. Furthermore, the statistical management of the trial has been the subject of debate.52Although the final report has yet to be published, the investigators have reported a 2-year 39% reduction in total mortality rate in the ICD arm compared with the drug arm (amiodarone/metoprolol), and no difference in mortality rate between amiodarone and m e t o p r ~ l o l . ~ ~ After an average follow-up of 11 months, the mortality rate in the propafenone group was 29.3%, compared with 11.5% in the ICD group. Prior to therapy, programmed stimulation resulted in inducible VT or VF in 18 (33%) of 55 patients treated with propafenone. Ten patients remained inducible, two patients had spontaneous recurrence of VT, and one patient refused a second test following propafenone administration. Thus, the drug apparently protected only five patients. Of these five patients, one had recurrent cardiac arrest and one had recurrent VT. Of the 10 patients who remained inducible, two (20%) died suddenly. Of the 37 patients who were initially noninducible prior to drug administration, five (14%) developed inducible sustained VT after propafenone, but none of these patients had recurrent arrhythmias or died. Sudden death occurred in six patients in the propafenone group. The drug was discontinued for recurrent sustained or frequent nonsustained VT in 12 patients. This again highlights the limited effectiveness and potential harm of class I drugs for the treatment of ventricular arrhythmias. PRIMARY PREVENTION TRIALS GESICA

The Group for the Study of Survival in Heart Failure in Argentina (Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina, or GESICA)I3studied the use of low-dose amiodarone as primary prevention against sudden death in patients with severe CHF. As the authors noted, sudden death in

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this population accounts for more than 40% of all deaths?, **, 43 GESICA included patients with New York Heart Association class 11,111, or IV CHF and two of the three following measures of systolic myocardial dysfunction: chest radiograph cardiothoracic ratio of more than 0.55, left-ventricular ejection fraction measured by radioisotopes of no more than 0.35, and end-diastolic diameter measured by echocardiography of at least 3.2 cm/m2. Patients with asymptomatic nonsustained VT of more than 10 beats were excluded. All patients received usual heart-failure therapy including diuretics, digitalis, and angiotensin-converting enzyme (ACE) inhibitors, but not P-blockers. Patients were randomized to amiodarone or no therapy (open label). Patients assigned to amiodarone received 600 mg daily for 14 days followed by 300 mg daily for 2 years. The primary endpoint of the study was total mortality rate, with secondary endpoints of sudden death, death caused by progressive heart failure, and hospitalization for heart failure. The patients were recruited from 26 hospitals in Argentina. The average patient was male (80%)) had class I11 (48%) or class IV

(31%)heart failure and a left-ventricular ejection fraction of 19%, and was on an appropriate medical regimen for heart failure (90% were taking an ACE inhibitor). Unlike most patients in the United States with heart failure, however, only 39% had coronary artery disease with a prior MI. There were 106 deaths in the control group and 87 deaths in the amiodarone group, a relative risk reduction of 28% (Fig. 5). The relative risk reductions for progressive heart failure and sudden death were 23% and 27%, respectively, but these differences were not significant. The reduction by amiodarone in total mortality rate appeared to be the result of an early (30-day) reduction in sudden death followed by a later decrease in the rate of deaths from progressive heart failure. Hospital admissions or deaths caused by progressive heart failure was reduced significantly. There was no difference in treatment effect for patients with or without nonsustained VT. Side effects were infrequent, occurred in 6.1% of patients, and required discontinuation of therapy in 4.6% of patients. One interesting aspect of the GESICA trial is that amiodarone reduced the total mortality

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Days from Randomization Figure 5. Total mortality in the GESICA trial. Survival was significantly improved by treatment with low-dose amiodarone. (Modified from Doval HC, Nu1 DR, Grancelli HO, et al: Randomised trial of low-dose amiodarone in severe congestive heart failure: Grupo de Estudio de la Sobrevida en la lnsuficiencia Cardiaca en Argentina (GESICA). Lancet 344:493-498,1994;with permission.)

LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

rate without significantly reducing deaths from arrhythmias. Several reasons for the benefit of amiodarone in these patients have been postulated, including the coronary vasodilator effects, noncompetitive a- and p-adrenergic blockade, and ability to improve leftventricular systolic and diastolic function. If these benefits were related to the antiadrenergic properties of amiodarone, then p-blocker therapy would be more appropriate**and less likely to have the serious side effects associated with amiodarone. Another interesting point is that the annual sudden death rate was 15% in the control group. Based on this, some have suggested that these patients would be better treated with an ICD, especially if they were candidates for heart transp l a n t a t i ~ n The . ~ ~ study is limited by the absence of blinding, because both patients and investigators were aware of treatment status. STAT-CHF

The Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure (STATCHF),50like GESICA, studied the potential benefit of amiodarone in patients with CHF. STAT-CHF included patients with CHF, at least 10 PVCs per hour, an ejection fraction of no more than 0.40, and either an echocardiographic left-ventricular internal diameter of more than 55 mm or a cardiothoracic ratio of more than 0.50. All patients received vasodilator therapy and digoxin, and diuretics were given as deemed appropriate. Patients were randomized to amiodarone (800 mg daily for 14 days, 400 mg daily for 50 weeks, then 300 mg daily) or placebo. The primary endpoint was total mortality rate. From 24 Veterans Affairs medical centers, 1303 patients were screened and 674 (52%) were randomized. A total of 336 patients were assigned to receive amiodarone and 338 placebo. No differences in baseline characteristics existed. The majority of patients was male (99%, as this was a Department of Veterans Affairs-sponsored trial) with ischemic heart disease (72%), an ejection fraction less than 0.30 (67%),and New York Heart Association class I1 CHF (56%);More than 250 PVCs per hour and more than 77 asymptomatic episodes of nonsustained VT per day were observed in these patients. Amiodarone had no significant effect on survival, with 131 (39%)and 143 (42%)deaths

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occurring in the amiodarone and placebo groups, respectively, during the study. The actuarial survival at 2 years was approximately 70% in both groups. Approximately half of the deaths in each group were classified as sudden; at 2 years the rate of sudden death was 15% in the amiodarone group and 19% in the placebo group. Pump failure was the cause of death in 27%. A trend in favor of amiodarone was noted in the patients with nonischemic heart disease (P = .07) (Fig. 6), a group similar to the patients in the GESICA trial. Survival was not improved in the subgroups of amiodarone patients who had nonsustained VT at baseline or in whom either PVCs or nonsustained VT were suppressed. Drug discontinuation was noted in 27% in the amiodarone group compared with 23% in the placebo group, a much higher rate than was observed in the GESICA study, perhaps because the blinded status of STAT-CHF. Amiodarone did not decrease the rate of sudden death. This raises the possibility that many sudden deaths in this population may be bradycardic or even nonarrhythmic. The difference in benefit between this study and the GESICA study has been attributed to differences in the patients studied, namely the greater number of patients with ischemic heart disease in STAT-CHF. This may be the case, because the competing risks for death in a patient with underlying coronary artery disease may be greater than those of a patient with nonischemic cardiomyopathy. Other important differences included a longer duration of follow-up (45 versus 13 months), a higher dropout rate (25% versus 2.9%), and a lower placebo mortality rate (55% versus 30%) in STAT-CHF compared with GESICA. EMIAT

Similar to the trials that studied the use of amiodarone in patients with CHF, the European Myocardial Infarct Amiodarone Trial (EMIAT)32and Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT)’ studied the use of amiodarone as primary prophylaxis in a different high-risk population, that is, patients at high risk for death following MI. EMIAT did not require the presence of asymptomatic arrhythmias by enrolling patients with a documented MI and an ejection fraction of no more than 0.40. Patients were assigned randomly to placebo or

STROBEL & EPSTEIN Nonischemic

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Figure 6. Overall survival in the CHF-STAT trial according to the presence or absence of ischemic cardiomyopathy. There is a trend toward significant improvement in survival in the patients with nonischemic cardiomyopathy, a subgroup of patients similar to those studied in the GESICA trial. (Modified from Singh SN, Fletcher RD, Fisher SG, et al: Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia: Survival trial of antiarrhythmic therapy in congestive heart failure. New Engl J Med 333:77-82,1995; with permission.)

amiodarone, 800 mg daily for 14 days, 400 mg daily for 14 weeks, then 200 mg daily. The primary endpoint was death from any cause, and the secondary endpoints were cardiac death, arrhythmic death, and arrhythmic death plus resuscitated cardiac arrest. Of the 23,493 patients recruited, 7565 underwent radionuclide ventriculography, of whom 3255 (43%) had an ejection fraction of no more than 0.40. The investigators excluded 1769 patients for contraindications including lack of consent, imminent cardiac surgery, or other serious illness. Thus 1486 patients were enrolled in the trial a mean of 15 days after the index MI. There were 743 patients in the placebo group and 743 patients in the amiodarone group (Fig. 7). Although baseline characteristics were similar, a history of prior MI and New York Heart Association class I1 or class I11 symptoms were more frequently present in the amiodarone group. The mean left-ventricular ejection fraction was 0.30 in both groups. Frequent ventricular ectopy (at least 10 PVCs per hour or more than three beats of nonsustained VT on Holter monitoring) was present in 40% of the patients. There was no difference in the all-cause mortality rate (14% in both groups) or total cardiac mortality rate between the treatment groups. The investigators described a trend toward reduction in arrhythmic deaths by amiodarone and a significant reduction in the

combined endpoint of arrhythmic death and resuscitated cardiac death in the amiodarone group. A statistical analysis of the EMIAT data by others19suggested that this difference approached, but did not achieve, significance. Regardless, the 37% reduction in arrhythmic death in the amiodarone group was offset by increases in nonarrhythmic and noncardiac mortality rates. A tendency towards a favorable interaction between the use of p-blockers and amiodarone was noted and subsequently supported by pooling data from EMIAT with CAMIAT.5 Once again, amiodarone failed to improve survival in a population of patients at high risk of sudden death. As the authors noted, the prevention of arrhythmic death did not preclude death from other nonarrhythmic mechanisms. This emphasizes the importance of total mortality rate as an outcome measure in cardiac arrhythmia trials.33The study, initiated in 1990, was criticized for the low rate of use of p-blockers (45%)and ACE inhibitors (59%) in both groups. Although the use of these drugs was not different between groups, they can affect total, arrhythmic, and nonarrhythmic mortality rates. CAMIAT

The inclusion criteria for CAMIAT were somewhat more restrictive than the inclusion

LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

criteria for EMIAT because of the requirement for spontaneous ventricular ectopy. Eligible patients had had a MI within the previous 6 to 45 days and at least 10 PVCs or at least one run of VT. Patients were screened at 36 hospitals in Canada. Eligible patients were randomized to placebo or amiodarone 10 mg/kg for 2 weeks, then 400 mg daily. The dosage subsequently was reduced to 200 mg to 300 mg depending on whether arrhythmia suppression occurred. Unlike EMIAT, the primary endpoint of the study was the composite of resuscitated VF or arrhythmic death. Secondary outcomes included arrhythmic death, cardiac death, and death from any cause. The study used a one-sided test of significance to determine differences in outcome between the study groups.

I L

Approximately 24,000 patients were screened, of whom only 4800 met the ECG monitoring criteria. Of these, 2400 patients met other inclusion criteria and 1202 of these consented and were enrolled. There were 606 patients in the amiodarone group and 596 in the placebo group. Patients were followed for a minimum of 1 year and a maximum of 2 years. The authors stated that only 56% of the patients met the eligibility criteria for MI, which were typical chest pain lasting at least 20 minutes, cardiac enzyme elevation, or new Q waves on the electrocardiogram. Most patients (97%) had characteristic chest pain as their criterion for enrollment. Baseline characteristics of the patients were comparable, with about one third of the patients having a history of MI before their qualifying MI. CHF

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STROBEL & EPSTEIN

was present in 21% and 26% of the amiodarone and placebo groups, respectively. A high percentage (60%) of the patients was taking P-blockers at the time of enrollment. The authors comment that there was increasing use of P-blockers in the latter phase of the trial, but the percentage is not stated specifically. By an intention-to-treat analysis, the primary endpoint of resuscitated VF or arrhythmic death was reduced by amiodarone (onesided P=.O29), but the event rate in both groups was low (Fig. 8). There were 31 events in the placebo group (average annual rate 3.71%) versus 15 events in the drug group (average annual rate 2.29%). Recalculation of the data using a two-tailed P value in an intent-to-treat analysis by other authors showed that the P value was .061.19 The allcause mortality rate was also low and not significantly different between the two groups (5.23% in the amiodarone group versus 6.41% in the placebo group) (Fig. 9). Not surprisingly, the rates of resuscitated VF and arrhythmic death were substantially greater in patients with CHF or MI before the qualifying event or pulmonary edema at the time of the qualifying event. The rates of discontinuation of amiodarone (36%) or placebo (25%) were high, which may reflect trepidation on the part of the investigators to risk organ toxicity from amiodarone in a primary pre-

vention context. The risk of toxicity may be better accepted in secondary prevention trials, in which the risk of death is perceived to be higher. CAMIAT has several weaknesses. First, slightly more than half of the patients who were enrolled in the study had a documented MI, and of these, most were enrolled on the basis of typical chest pain for greater than 20 minutes. This is not firm evidence for myocardial necrosis. Although these patients may have had coronary artery disease, many may not have had a verified infarction. This may account for the low event rate during the study. Furthermore, the study did not use total mortality rate as a primary endpoint.= The classification of death in arrhythmia trials is difficult.16,46 Finally, the use of a one-sided test of sigruficance in the statistical analysis assumes that amiodarone can only be beneficial or neutral if used in this group of patients. SWORD

The Survival With Oral D-sotalol (SWORD) study53attempted to prevent death using an antiarrhythmic drug in patients at high risk for sudden cardiac death. At the time the study was conceived, the detrimental effects of class I antiarrhythmic drugs in these pa-

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LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

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tients were well known. Amiodarone, a class I11 drug, was known to be relatively safe and thought to have a neutral or positive effect in preventing sudden death. It was hoped that other class I11 drugs, without the potentially serious side effects of amiodarone, would be effective in preventing sudden death, d-Sotalo1 is a pure class I11 antiarrhythmic drug and lacks the p-blocker effects of d,l-sotalol, an effect that may increase its tolerability in patients with left-ventricular dysfunction. SWORD was a placebo-controlled, randomized study assessing the effect of d-sotalol on the total mortality rate in patients with a previous MI and left-ventricular dysfunction. Eligible patients had a previous MI and an ejection fraction of no more than 0.40. Patients assigned d-sotalol were monitored closely for QTc prolongation, and the study drug was reduced or discontinued if the QTc exceeded prespecified limits. The primary endpoint was death from any cause, with a secondary endpoint of cardiac death. The investigators had planned on enrolling 6300 patients, but the trial was stopped after only 3121 patients were randomized. There were 1549 patients assigned to d-sotalol and 1572 to placebo. Baseline characteristics of the two groups were similar. It was assumed that

twice as many patients with recent as with remote MI would be enrolled, but the ratio was reversed, with 915 (29%) patients with recent and 2206 (71%) patients with remote MI. The mean left-ventricular ejection fraction was 0.31, and almost all patients (93%) had class I1 or class I11 CHF. Most patients (70%) were taking ACE inhibitors, and 33% were taking p-blockers. The trial was discontinued prematurely because excess deaths became evident among the d-sotalol patients (Fig. 10). There were 30 excess deaths in the d-sotalol group (78/1549 or 5%) compared with the placebo group (48/ 1572 or 3.1%).The authors reported no excess serious arrhythmic events in the d-sotalol group, and the reported incidence of torsades de pointes was very low (0.2%). Interestingly, the adverse effect of the drug was more pronounced in female patients and in the patients with left-ventricular ejection fractions of at least 0.30. Subsequently, the authors reported that the d-sotalol-associated mortality rate was greater in those with a remote MI. There were very few objective data to support torsades de pointes or proarrhythmia as the explanation of the increased mortality rate.45 Despite the lack of data, many still suspect

350

STROBEL & EPSTEIN

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that the increased risk of death was related to proarrhythmia. The characteristics of the patients in this trial may have influenced the results. For cardiac-arrest survivors with coronary artery disease there is a "time-dependence" of risk for cardiac arrest rec~rrence.2~ If this holds true for patients following MI, then patients would be at highest risk of ventricular tachyarrhythmias sooner rather than later after MI. In addition, patients with lower left-ventricular ejection fractions are also at higher risk of sudden death following MI. As the authors note, in the patients at high risk, that is, those with a recent infarction and a low ejection fraction, the detrimental effects of d-sotalol (proarrhythmia) may have neutralized the beneficial effects (prevention of arrhythmia). On the other hand, the low-risk patients who had remote MIS and higher ejection fractions would have encountered only the detrimental effects of the drug without receiving its benefits, resulting in an excess mortality rate. As with the other trials, the lack of a difference in arrhythmic death rates has little meaning given the difficulty in assigning the cause of death in clinical trials. MADIT

The Multicenter Automatic Defibrillator Implantation Trial (MADIT)36was the first

trial to study the prophylactic use of ICDs to prevent death from ventricular tachyarrhythmias. The patients were a high-risk group with prior MI, a low ejection fraction, and inducible but nonsuppressible ventricular arrhythmias. There was no placebo arm, but a "conventional" therapy arm was used. MADIT was conducted at 32 hospital centers between 1990 and 1996. Patients were eligible if they had a Q-wave or enzymepositive MI more than 3 weeks before entry, asymptomatic nonsustained VT, and a leftventricular ejection fraction less than 0.35. Patients were randomized to an ICD or socalled conventional medical therapy. The choice of conventional medical therapy was left to the choice of the patient's attending physician. The primary endpoint was death from any cause. A total of 253 patients were eligible for the study, and 196 patients gave consent to be enrolled. One third of the patients was enrolled from 2 of the 32 centers. There were 101 patients in the conventional therapy arm and 95 patients in the ICD arm. A registry of patients who were screened was not kept. It is not known how many patients underwent electrophysiologic study, why they were chosen for electrophysiologic study, or how many patients were noninducible or inducible but nonsuppressible. The baseline characteristics of the randomized

LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

patients were similar. The average left-ventricular ejection fraction was 0.26. The average length of nonsustained VT was 9 to 10 beats. After over 5 years of enrollment, the study was terminated prematurely because superiority of the ICD had been demonstrated (Fig. 11). There were 39 deaths in the conventional therapy arm and 15 in the defibrillator arm. Sixteen crossovers occurred. Eleven of the conventional-therapy patients received an ICD for an adverse drug reaction (2), syncope (2), ventricular arrhythmia (6), or aborted cardiac arrest (1). In the defibrillator group, five patients never received an ICD and two patients had the ICD deactivated during the course of the study. There was no evidence that the use of any of the antiarrhythmic medications or any of the baseline variables had a significant influence on the risk of death, but, as the authors note, the power to detect these interactions was limited by the small number of patients in the study. The mortality rate was higher in the conventional-therapy patients who were receiving amiodarone at 1 month than those not receiving the drug (36% versus 26%). Shock discharge occurred in 60% of the defibrillator patients within 2 years after implantation, but most of the defibrillators did not have stored electrogram capabilities, so appropriateness of the shocks could not be assessed.

351

The MADIT study has been criticized for the ”unconventional” therapy that the conventional therapy group received.24Barely half of the patients in this arm were receiving ACE inhibitors (Table 1).Studies demonstrating improved survival with ACE inhibitors were published before or during the trial, and it is not clear why these patients did not receive this very conventional therapy proven to benefit the population being studied. Although the number of patients receiving ACE inhibitors did not differ significantly from the ICD group, the addition of this therapy could have reduced the overall number of deaths, thus reducing the overall difference observed in the two arms. There was a significant difference in the use of p-blockers and amiodarone. In the conventional therapy group, 74% and 45% were receiving amiodarone but only 8% and 5% were receiving a p-blocker at 1 month and at last contact with the patient in the study, respectively. Stated another way, 50% were receiving neither amiodarone nor a pblocker. In the ICD group, whom 27% received a p-blocker and 7% received amiodarone. Thus, in the conventional arm, a drug that had not been proven to prolong life in this group of patients (amiodarone) often was substituted for a drug that had been proven to prolong life and prevent sudden death (p-blockers).This point alone could ex-

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STROBEL & EPSTEIN

Table 1. CARDIAC MEDICATIONS 1 MONTH AFTER ENROLLMENT AND AT THE LAST CONTACT, ACCORDING TO TREATMENT GROUP 1 Month

Last Contact

Conventional Therapy (n = 93)

ICD (n = 93)

74 8 10 7 15 8

2 26 12 1 27 56

45 5 9 14 23

7 27 11 4 31 44

55 38 52

60 58 53

51 30 47

57 57 52

Antiarrhythmic medication Amiodarone P-blockers Class I antiarrhythmic agents Sotalol P-blockers or sotalol No antiarrhythmic medication Other cardiac medication Angiotensin-converting enzyme inhibitors Digitalis Diuretics

Conventional Therapy (n = 82)

ICD (n = 86)

percentage 11

ICD-implantable cardioverter-defibrillator. Adapted from Moss AJ, Hall WJ, Cannom DS, et al: Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 335193S1940, 1996; with permission.

plain much of the difference in survival, both arrhythmic and nonarrhythmic, that was observed in this study. Even if the results of MADIT are taken at face value and accepted, it is uncertain that they would significantly alter clinical practice. After 63 months, 32 hospital centers had enrolled just 196 patients. Because no registry was maintained, the denominator of this number is unknown. To apply this to clinical practice, all patients with a MI, a low ejection fraction, and nonsustained VT would be required to undergo electrophysiologic testing. A subgroup of these patients would have inducible VT, and only a subgroup of this subgroup would not have VT suppressed by procainamide infusion and would benefit from ICD implantation. The number of patients predicted to qualify for such a therapeutic strategy is tiny.l, 29 CABG Patch Trial The Coronary Artery Bypass Graft (CABG) Patch Trial" tested the hypothesis that the prophylactic implantation of a defibrillator at the time of bypass surgery would improve longterm survival in patients at high risk for sudden death. The high-risk patients had a low ejection fraction and an abnormal signal-averaged ECG (SAECG). An abnormal SAECG predicts mortality twice as high at two years as that among patients with a normal SAECG. Patients were eligible for the study if they had a left-ventricular ejection fraction less

than 0.36 and an abnormal SAECG. Of the patients screened, 5% were excluded because of age older than 80 years and 74% were excluded because their ejection fraction was at least 0.36. There were 1422 eligible patients, of whom 1055 (74%) gave consent. There were 900 patients randomized either to the implantation of an epicardial defibrillator system (n = 446) or to the control group (n = 454). In the patients who were enrolled but not randomized, 67 were found subsequently to have criteria for exclusion at the time of randomization and 88 were not randomized because intraoperative events made ICD implantation too risky. The use of antiarrhythmic drugs for asymptomatic ventricular arrhythmias was prohibited. The primary endpoint was total mortality rate. The baseline characteristics of the two groups were nearly identical. Heart failure was present in 50% of the patients. The mean left-ventricular ejection fraction was 0.27. The majority (55%)of the patients had three-vessel coronary artery disease demonstrated on coronary angiography, and 83% had a prior MI. Prophylactic ICD implantation did not improve survival. There were 24 deaths in the ICD group and 20 deaths in the control group in the first 30 days after randomization. During an average follow-up of 32 months, there were 101 deaths in the defibrillator group and 95 deaths in the control group. Crossovers occurred in 70 patients: Eighteen patients in the control group had an ICD implanted; 12 patients in the defibrillator group never re-

LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

ceived an ICD because of death or hemodynamic instability in the operating room; 40 patients had their defibrillator removed for infection, battery depletion, or patient preference. The rates of use of cardiac drugs were similar between the two groups. Over 60% were taking ACE inhibitors and almost 20% were taking p-blockers in each group at 1 year after coronary bypass surgery. The rates of use of amiodarone, sotalol, or class I antiarrhythmic drugs were low. In the patients with an ICD, 57% received a shock within the first 2 years after surgery. There are several potential explanations for the results of the CABG Patch Trial. First, coronary revascularization may have reduced or eliminated the sudden death risk in these patients.30This may be the case if coronary bypass grafting reduces ischemia and improves left-ventricular function. Second, the SAECG may be a good marker for an increased risk of sudden death but a poor marker for death resulting from ventricular arrhythmia. This points out the weaknesses in the assumption that all sudden deaths are caused by tachyarrhythmias and can be prevented with ICDs. Finally, despite superficial similarities between the patients in this trial and the patients in MADIT, the overall mortality rate was lower in this trial. This may reflect the advantages of revascularization and appropriate medical therapy and the differences between arrhythmia markers, that is, SAECG versus electrophysiologic testing.

The Multicenter Unsustained Tachycardia Trial (MUSTT)6evaluated the utility of therapy guided by electrophysiologic testing to reduce the mortality rate in patients at high risk of sudden death from ventricular arrhythmia. The study included patients with coronary artery disease, left-ventricular. dysfunction, and nonsustained VT. Thus, the patients were very similar to MADIT patients except that more information was obtained regarding patients who were either noninducible or inducible but responsive to antiarrhythmic drug therapy. Eligible patients had coronary artery disease, a left-ventricular ejection fraction no more than 0.40, and asymptomatic nonsustained VT. Enrolled patients underwent an electrophysiologic study with the following endpoints: reproducible induction of sus-

353

tained VT, reproducible induction of more than 15 complexes of polymorphic VT or ventricular flutter, or noninducibility. Patients with inducible ventricular arrhythmias were randomized in a 1:l ratio to antiarrhythmic therapy guided by electrophysiologic (EP) testing or no antiarrhythmic therapy. Patients who refused randomization also were followed, and their treatment noted. Patients with no inducible arrhythmias were followed without antiarrhythmic therapy in a registry. Patients randomized to EP-guided therapy underwent serial drug testing. The drugs were assigned randomly, except that amiodarone could be considered only after two failed drug trials. If no drug could be found that prevented inducibility, then a drug that resulted in hemodynamic stability during induced VT could be utilized. After at least one unsuccessful drug trial, ICD therapy could be used. Antiarrhythmic drugs were given to these patients only to prevent shocks. The primary endpoint was arrhythmic death or resuscitated cardiac arrest. Secondary endpoints included death from any cause, cardiac death, and spontaneous sustained VT. There were 2202 patients enrolled, including 767 (35%)with arrhythmia inducibility, of whom 704 agreed to be randomized and 63 refused randomization. There were 1435 patients with no inducible ventricular arrhythmias. Patients had a mean left-ventricular ejection fraction of 0.29 and a mean duration of nonsustained VT of five beats. Sustained VT was the induced rhythm in 90% of patients. p-blockers were used in 40% of patients at the time of discharge and were used more frequently in patients randomized to an antiarrhythmic therapy. At the time of discharge, 45% of the patients randomized to EP-guided therapy were taking an antiarrhythmic drug based on their response to EP testing. An ICD was implanted in 46% of the EP-guided group after drug failure. Seven percent were discharged without therapy after VT remained inducible on antiarrhythmic drugs. Two percent of the patients died prior to discharge. The patients randomized to no antiarrhythmic therapy maintained good compliance, with 96% receiving no antiarrhythmic therapy at the time of discharge. Patients were followed a median of 39 months. Death or cardiac arrest occurred in 136 patients randomized to EP-guided therapy (39%)and in 168 patients randomized to no antiarrhythmic therapy (48%). Total mortality rates after 2 and 5 years were 22% and

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STROBEL & EPSTEIN

42%, respectively; for patients randomized to EP-guided therapy versus 28Y0 and 48%, respectively, for patients randomized to no antiarrhythmic therapy (P = .06). The investigators determined that the reduction in total mortality rate was attributable almost entirely to the use of an ICD in the EP-guided therapy arm. At 60 months, the total mortality rate in the El'-guided arm was 24% in the ICDtreated patients versus 55% for drug-treated patients and 48% for patients receiving no therapy. This trial has several important implications. The inclusion of an untreated group of patients demonstrated that patients with coronary artery disease, left-ventricular dysfunction, nonsustained VT, and inducible sustained VT have a substantial risk of death. It also demonstrated that this risk could be reduced markedly with ICD therapy, but not with antiarrhythmic drug therapy. The registry will provide more information about the outcomes of the patients who were noninducible at electrophysiologic study. The potential benefit of ICD therapy for these patients will be answered by ongoing trials. SCD-HeFT (Ongoing)

The next natural area of investigation is to define subsets of patients who may benefit from ICD therapy relative to drugs. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) is enrolling patients with leftventricular ejection fractions less than 0.35 and class I1 and 111 CHF of greater than 3 months' duration resulting from either ischemic or nonischemic causes. All patients will be treated with optimized heart-failure regimens including afterload reduction, p-blockers, and diuretics according to prespecified guidelines. Patients will be randomized to one of three groups for adjunctive therapy with placebo, amiodarone, or an implantable defibrillator. The primary trial endpoint is death from any cause. The trial is important for two reasons: First, the entry criterion is heart failure, and arrhythmia markers are not considered. Thus, it addresses a different problem than prior trials. Second, its design acknowledges the importance of a control group in prophylactic trials; without one, the Cardiac Arrhythmia Suppression Trial would never have been able to show the detrimental effects of antiarrhythmic drugs in the population studied.

DEFINITE (Ongoing)

The subset of patients with dilated cardiomyopathy and nonischemic heart failure are the focus of study in the Defibrillators in Non-ischemic Cardiomyopathy Treatment Evaluation Trial (DEFINITE). Patients with a nonischemic dilated cardiomyopathy, leftventricular ejection fraction less than 0.35, and either nonsustained VT on Holter or telemetry monitoring or more than 10 PVCs per hour on Holter monitoring. Consenting patients will be randomized to conventional heart-failure treatment with or without an implantable defibrillator to answer the question of whether defibrillator implantation will improve survival in this group of patients over that afforded by optimal heart-failure care. The primary endpoint is total mortality rate, and secondary endpoints are cost-effectiveness, quality of life, and cause-specific death. DINAMIT (Ongoing)

Because arrhythmic death is common in high-risk survivors of acute myocardial infarction, the Defibrillators in Acute Myocardial Infarction Trial (DINAMIT) is studying whether defibrillator therapy will reduce the risk of death compared with best medical therapy including afterload reduction with ACE inhibitors, @-blockers,lipid-lowering drugs (statins), and aspirin. Amiodarone therapy is optional. Patients eligible for enrollment will have survived an acute MI within 30 days (documented by two of three signs or symptoms including chest pain, elevated cardiac enzymes, or Q waves on electrocardiography) and have a left-ventricular ejection fraction less than 0.35 and autonomic imbalance determined by abnormal heart-rate variability. Patients will be randomized in a 1:l scheme to therapy with or without a defibrillator. BEST+ ICD Trial (Ongoing)

The Beta Blocker Strategy Plus ICD (BEST +ICD) Trial is enrolling 1500 patients at 50 European centers to determine if EP-guided therapy and defibrillator implantation improve survival compared with conventional therapy in patients who are within 5 to 21 days of MI. Patients already will be taking a p-blocker and will have a left-ventricular

LARGE CLINICAL TRIALS IN THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

ejection fraction less than 0.35 and a marker for arrhythmic death (decreased heart rate variability, more than 10 PVCs per hour, or late potentials). After a run-in phase to show tolerance to metoprolol, patients will be randomized to conventional treatment or to EP study and subrandomization to conventional therapy with or without an implantable defibrillator based on its result.

MADIT II (Ongoing)

The MADIT I1 trial will assess whether defibrillator therapy will increase overall survival in patients with coronary artery disease at high risk for sudden arrhythmic death. Ventricular arrhythmia inducibility is not a requirement for enrollment. Special attention will be given to avoiding the use of antiarrhythmic drug therapy and to optimizing pblocker and ACE-inhibitor therapy, because the first MADIT study was criticized for lack of a control group and a high use of amiodarone in the ”conventionally” treated group. Patients will be included if they have survived MI and have a left-ventricular ejection fraction less than 0.30 and more than 10 PVCs or couplets on a Holter monitor. A substudy will assess the utility of electrophysiologic study to predict implantable defibrillator use.

References 1. Andresen D, Steinbeck G, Bruggemann T, et al: Risk stratification following myocardial infarction in the thrombolytic era: A two-step strategy using noninvasive and invasive methods. J Am Coll Cardiol33:131138, 1999 2. The AVID investigators: A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 3371576-1583, 1997 3. Bigger J T Why patients with congestive heart failure die: arrhythmias and sudden cardiac death. Circulation 75:28-35, 1987 4. Bigger JT, for the Coronary Artery Bypass Graft (CABG) Patch Trial Investigators: Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. N Engl J Med 3371569-1575, 1997 5. Boutitie F, Boissel JP, Connolly SJ, et al: Amiodarone interaction with beta-blockers: Analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT

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and CAMIAT Investigators. Circulation 99:22682275, 1999 6. Bwton AE, on behalf of the MUSTT investigators: The Multicenter UnSustained Tachycardia Trial: Final results. Presented at the Annual Session of the American College of Cardiology, New Orleans, March 710, 1999 7. Cairns JA, Connolly SJ, Roberts R, et al: Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 349:675482, 1997 8. The CASCADE Investigators: Cardiac arrest in Seattle: Conventional versus Amiodarone Drug Evaluation (the CASCADE study). Am J Cardiol 67578584, 1991 9. The CASCADE Investigators: Randomized antiarrhytluruc drug therapy in survivors of cardiac arrest (the CASCADE study). Am J Cardiol72:28&287,1993 10. Connolly SJ: “An AVID dissent:” Commentary. Pacing Clin Electrophysiol 171712-1713, 1994 11. Connolly SJ, on behalf of the CIDS investigators: The CIDS study: Final results. Presented at the Annual Session of the American College of Cardiology, Atlanta, March 29-April 1, 1998 12. Dolack GL, for the CASCADE Investigators: Clinical predictors of implantable cardioverter-defibrillator shocks (results of the CASCADE trial). Am J Cardiol 73:237-241, 1994 13. Doval HC, Nu1 DR, Grancelli HO, et al: Randomised trial of low-dose amiodarone in severe congestive heart failure: Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Lancet 344:493498, 1994 14. Echt DS, Liebson PR, Mitchell LB, et al: Mortality and morbidity in patients receiving encainide, flecainide, or placebo: The Cardiac Arrhythmia Suppression Trial. N Engl J Med 324:781-788, 1991 15. Epstein AE: AVID necessity. Pacing Clin Electrophysiol 16:1773-1775, 1993 16. Epstein AE, Carlson MD, Fogoros RN, et al: Classification of death in antiarrhythmia trials. J Am Coll Cardiol27433-442, 1996 17. Epstein AE, Hallstrom AP, Rogers WJ, et al: Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction: The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA 270~2451-2455, 1993 18. Every NR, Hlatky MA, McDonald KM, et al: Estimating the proportion of the post-myocardial infarction patients who may benefit from prophylactic implantable defibrillator placement from analysis of the CAST registry: Cardiac Arrhythmia Suppression Trial. Am J Cardiol 82:683-685, 1998 19. Far& J, Romero J, Rubio JM, et al: Amiodarone and “primary” prevention of sudden death: Critical review of a decade of clinical trials. Am J Cardiol 83:55D-63D, 1999 20. Fogoros RN: An AVID dissent. Pacing Clin Electrophysiol 17:1707-1 711, 1994 21. Fogoros RN: Why the antiarrhythmics versus implantable defibrillator (AVID) trial sets the wrong precedent. Am J Cardiol 80762-765, 1997 22. Fogoros RN, Fiedler SB, Elson JJ: The automatic implantable cardioverter-defibrillator in drug-refractory ventricular tachyarrhythmias. Ann Intern Med 107635641, 1987

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