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new england journal of medicine

The
established in 1812

january 20 , 2005

vol. 352

no. 3

Amiodarone or an Implantable Cardioverter–Defibrillator for Congestive Heart Failure
Gust H. Bardy, M.D., Kerry L. Lee, Ph.D., Daniel B. Mark, M.D., Jeanne E. Poole, M.D., Douglas L. Packer, M.D., Robin Boineau, M.D., Michael Domanski, M.D., Charles Troutman, R.N., Jill Anderson, R.N., George Johnson, B.S.E.E., Steven E. McNulty, M.S., Nancy Clapp-Channing, R.N., M.P.H., Linda D. Davidson-Ray, M.A., Elizabeth S. Fraulo, R.N., Daniel P. Fishbein, M.D., Richard M. Luceri, M.D., and John H. Ip, M.D., for the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators*

abstract
background

Sudden death from cardiac causes remains a leading cause of death among patients with congestive heart failure (CHF). Treatment with amiodarone or an implantable cardioverter–defibrillator (ICD) has been proposed to improve the prognosis in such patients.
methods

We randomly assigned 2521 patients with New York Heart Association (NYHA) class II or III CHF and a left ventricular ejection fraction (LVEF) of 35 percent or less to conventional therapy for CHF plus placebo (847 patients), conventional therapy plus amiodarone (845 patients), or conventional therapy plus a conservatively programmed, shockonly, single-lead ICD (829 patients). Placebo and amiodarone were administered in a double-blind fashion. The primary end point was death from any cause.
results

From the Seattle Institute for Cardiac Research (G.H.B., C.T., J.A., G.J.) and the University of Washington, Seattle (J.E.P., D.P.F.); Duke University, Durham, N.C. (K.L.L., D.B.M., S.E.M., N.C.-C., L.D.D.-R., E.S.F.); the Mayo Clinic, Rochester, Minn. (D.L.P.), the National Heart, Lung, and Blood Institute, Bethesda, Md. (R.B., M.D.), Florida Arrhythmia Consultants, Fort Lauderdale, Fla. (R.M.L.), and Ingham Medical Center, Lansing, Mich. (J.H.I.). Address reprint requests to Dr. Bardy at the Seattle Institute for Cardiac Research, 7900 East Greenlake Dr. North, No. 300, Seattle, WA 98103, or at gbardy@ sicr.org. *A complete list of investigators is provided in the Appendix. N Engl J Med 2005;352:225-37.
Copyright © 2005 Massachusetts Medical Society.

The median LVEF in patients was 25 percent; 70 percent were in NYHA class II, and 30 percent were in class III CHF. The cause of CHF was ischemic in 52 percent and nonischemic in 48 percent. The median follow-up was 45.5 months. There were 244 deaths (29 percent) in the placebo group, 240 (28 percent) in the amiodarone group, and 182 (22 percent) in the ICD group. As compared with placebo, amiodarone was associated with a similar risk of death (hazard ratio, 1.06; 97.5 percent confidence interval, 0.86 to 1.30; P=0.53) and ICD therapy was associated with a decreased risk of death of 23 percent (0.77; 97.5 percent confidence interval, 0.62 to 0.96; P=0.007) and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population. Results did not vary according to either ischemic or nonischemic causes of CHF, but they did vary according to the NYHA class.
conclusions

In patients with NYHA class II or III CHF and LVEF of 35 percent or less, amiodarone has no favorable effect on survival, whereas single-lead, shock-only ICD therapy reduces overall mortality by 23 percent.

n engl j med 352;3

www.nejm.org

january 20, 2005

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The New England Journal of Medicine Downloaded from nejm.org at VANCOUVER COASTAL HEALTH on July 18, 2011. For personal use only. No other uses without permission. Copyright © 2005 Massachusetts Medical Society. All rights reserved.

All patients were followed until October 31. The dose was based partly on weight. For personal use only.The new england journal of medicine p atients with congestive heart failure (CHF) can die suddenly and unpredictably from arrhythmia despite the use of proven medical therapies. Ischemic CHF was defined as left ventricular systolic dysfunction associated with at least 75 percent narrowing of at least one of the three major coronary arteries (marked stenosis) or a documented history of a myocardial infarction. Every patient provided written informed consent. single-lead therapy. study drug methods study design From September 16. Despite findings in earlier clinical trials. An NHLBI-appointed data-monitoring and safetymonitoring board oversaw the conduct of the trial. amiodarone (Cordarone. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)11 was designed to evaluate the hypothesis that amiodarone or a conservatively programmed shock-only. and Blood Institute (NHLBI). The goal was to treat only rapid. liver.9 kg) received 400 mg daily. 2001. 24-hour ambulatory electrocardiography. No other uses without permission. as well as aldosterone. Patients had to be at least 18 years of age and have New York Heart Association (NYHA) class II or III chronic. To minimize excessively rapid intervention in the event of nonsustained ventricular tachycardia.nejm. The primary end point of the trial was death from any cause. given the unknown fre- 226 n engl j med 352. Most of the mortality data on amiodarone and ICD therapy have been obtained in clinical trials performed after myocardial infarction in patients without CHF or those with ventricular arrhythmias. Additional clinical and research funding was also provided by these companies.2 kg) received 200 mg daily. Copyright © 2005 Massachusetts Medical Society.2 to 90. single-lead ICD would decrease the risk of death from any cause in a broad population of patients with mild-to-moderate heart failure.1. No dual-chamber or biventricular devices were permitted.and thyroidfunction studies. 2003. Lung.4 and also remains unproven.3 www. to July 18. The trial was funded after peer review. Sponsorship and oversight of the trial were by the National Heart.11 Study drugs and ICDs were provided free of charge by the manufacturers (Wyeth–Ayerst and Medtronic. icd therapy ICD therapy was intentionally selected to consist of shock-only. or interpretation of the study. 1997. aspirin.5-10 Such data have not been judged sufficiently relevant to guide therapy for patients who do not meet these criteria. respectively).2 The ability of an ICD to limit mortality in patients with CHF without prior cardiac arrest has been evaluated in small trials focused on patients with nonischemic cardiomyopathy3. After a loading dose of 800 mg daily was given for one week and 400 mg daily for three weeks. we randomly assigned 2521 patients in equal proportions to receive placebo. Two approaches have been developed specifically to prevent sudden death among patients with CHF: therapy with amiodarone and therapy with an implantable cardioverter–defibrillator (ICD). all patients underwent electrocardiography. A detailed review of SCD-HeFT methods has been published previously. stable CHF due to ischemic or nonischemic causes and a left ventricular ejection fraction (LVEF) of no more than 35 percent. the ability of amiodarone to reduce the risk of death among patients with CHF remains uncertain. Medtronic). when appropriate. Physicians could lower the loading or maintenance dose if a patient had bradycardia. patients weighing more than 200 lb (90.org at VANCOUVER COASTAL HEALTH on July 18. 2011. Neither company had any role in the design. 2005 The New England Journal of Medicine Downloaded from nejm.org january 20 . All rights reserved. analysis. The study was approved by the human- Placebo and amiodarone were administered in a double-blind fashion with the use of identicalappearing 200-mg tablets produced by Wyeth– Ayerst Pharmaceuticals. The ICD was uniformly programmed to have a detection rate of 187 beats per minute or more. and chest radiography. or a single-chamber ICD programmed to shock-only mode (model 7223. antitachycardia pacing therapies were not permitted.9 kg) received 300 mg daily. sustained ventricular tachycardia or ventricular fibrillation. and patients weighing less than 150 lb (68. to receive treatment with a beta-blocker and an angiotensin-converting–enzyme inhibitor. subjects’ committee of each participating institution. such as beta-blockade. . a 6-minute walk test. Wyeth– Ayerst Pharmaceuticals). and statins. if such treatment was clinically reasonable. Nonischemic CHF was defined as left ventricular systolic dysfunction without marked stenosis. All patients were required. patients weighing 150 to 200 lb (68. baseline assessments and background medical therapies Before randomization.

amiodarone or icd therapy for heart failure quency of sustained ventricular tachycardia or fibrillation in the population at the time.3 www. ICD testing could not exceed two inductions of ventricular fibrillation. 2005 227 The New England Journal of Medicine Downloaded from nejm. Permuted-block randomization with stratification according to the clinical site. The median follow-up for all surviving patients was 45.12 Event (or censoring) times for all patients were measured from the time of randomization (time zero).5 months. the level of significance required for each major treatment comparison at the completion of the study was 0. symmetric O’Brien–Fleming boundaries generated with the Lan–DeMets alphaspending-function approach to group-sequential testing. No other uses without permission. no further testing or lead configurations were recommended.6 months.org at VANCOUVER COASTAL HEALTH on July 18.025 for the two main treatment comparisons. Demographic and clinical data for the three treatment groups are shown in Table 1. The longest follow-up was 72. a 10-J shock was tested and no further inductions were recommended. Some patients may have had ICD discharges that were either not recorded or not reported to the ICD core laboratory. All rights reserved. as compared with placebo. Vital status was known for all 2521 patients at the time of the last scheduled follow-up visit. 847 were randomly assigned to placebo. Outpatient implantation of the device was encouraged. If an initial 20-J shock terminated induced ventricular fibrillation (as occurred 84 percent of the time). Copyright © 2005 Massachusetts Medical Society. the lowest trigger limit possible in the ICD model (Medtronic model 7223) used. Among the 2521 patients.001). Six interim analyses of the data were performed and reviewed by the independent data and safety monitoring board appointed by the NHLBI.16 Because of the sequential monitoring. 70 percent had NYHA class II CHF. with block size randomly chosen to be either three or six. Interim treatment comparisons were monitored with the use of two-sided. Patients were followed every three months with alternating clinic visits and telephone calls. 97. nonischemic). For personal use only. and 829 to ICD therapy. the use of antitachycardia pacing was considered to pose more risk than benefit. If both 20-J and 30-J shocks were unsuccessful. results study population The study was based on the assumption that the placebo group would have an annual mortality rate of 10 percent. The device was to be inserted without further delay given the risk associated with a prolonged procedure. Cumulative mortality rates were calculated according to the Kaplan–Meier method.nejm. The significance of differences in mortality rates between treatment groups was assessed with the log-rank test. Because of the potential for antibradycardia pacing to worsen CHF. Pairwise comparisons of amiodarone with placebo and ICD with placebo were performed according to the intention-to-treat principle. All statistical tests were two-tailed. the low likelihood of improving defibrillation thresholds. and the lack of a clear relation between the results of tests at implantation and long-term efficacy.5 percent confidence intervals are reported for the hazard ratios. No rate-responsive pacing was allowed. thus limiting our ability to know the true rate of ICD events. n engl j med 352. the cause of CHF (ischemic vs. on the basis of an a level for each comparison of 0.023.025. except in the use of beta-blockers at the time of the last follow-up visit (P<0. If the 20-J shock was unsuccessful.15. and 30 percent had class III CHF.14 Consistent with the choice of an a value of 0. two to five). statistical analysis and NYHA class (II vs. with adjustment for the NYHA class and the cause of CHF. The study was powered at 90 percent to detect a 25 percent reduction in death from any cause by amiodarone or ICD therapy. it was initiated only if the intrinsic rate decreased to less than 34 beats per minute. All surviving patients were followed at least two years. The Cox model was also used to test the significance of interactions between the NYHA class and treatment and between the cause of CHF and treatment. . Patients assigned to ICD therapy received their device a median of three days after randomization (interquartile range. There were no significant differences among the three groups. initiation of therapy and follow-up Patients assigned to amiodarone or matching placebo began therapy as outpatients immediately after randomization. 845 to amiodarone. a 30-J shock was administered at the next induction. the median LVEF of patients was 25 percent. Data from the ICD memory log were regularly downloaded at these visits. 2011.org january 20. Because of the potential for the acceleration of ventricular tachycardia and the resulting increased sensitivity to transient ventricular tachycardia.13 Relative risks were expressed as hazard ratios with associated confidence intervals and were derived from the Cox proportional-hazards model. At baseline. III) was used.

as compared with the placebo group.2 190 (23) 189 (23) Amiodarone (N=845) Placebo (N=847) ICD Therapy (N=829) compliance and crossovers The median dose of amiodarone and placebo was 300 mg per day three months after randomization and remained so throughout the study. (%) Nonsustained ventricular tachycardia — no.0–30. P=0. the only complications observed in the amiodarone group.org at VANCOUVER COASTAL HEALTH on July 18.1 0.4 51.0 20. No other uses without permission. 228 n engl j med 352.9–1.9–1. (%) Nonwhite race — no. The noncompliance rate for study-drug therapy. (%) Ejection fraction Median Interquartile range Diabetes — no. (%)* Hypertension — no.3 www.4 139 137–141 139 137–141 139 137–141 72 64–82 73 64–84 74 65–84 70 62–80 70 62–80 70 61–80 118 106–130 120 108–132 118 104–131 190 164–216 190 163–221 190 163–220 25. were increased tremor (4 percent. Characteristic Age — yr Median Interquartile range Female sex — no. defined as the discontinuation of either placebo or amiodarone for any period. and amiodarone was discontinued in 269 of 845 patients (32 percent). At the time of the last follow-up visit.0–30.7 51. Copyright © 2005 Massachusetts Medical Society. (%) Hypercholesterolemia — no.0 20.3 206 (24) 196 (23) 59.4 1. (%) Atrial fibrillation or flutter — no. 2011.001).The new england journal of medicine Table 1.0 19. (%) Weight — lb‡ Median Interquartile range Systolic blood pressure — mm Hg Median Interquartile range Diastolic blood pressure — mm Hg Median Interquartile range Heart rate — beats/min Median Interquartile range Serum sodium — mEq/liter Median Interquartile range Serum creatinine — mg/dl§ Median Interquartile range 1. Characteristics of the Patients at Baseline or at the Last Follow-up Visit.1 0.9–69. 2005 The New England Journal of Medicine Downloaded from nejm. Place- bo was discontinued in 189 of 847 patients (22 percent). P<0.0 271 (32) 158 (19) 456 (54) 478 (56) 117 (14) 180 (21) 56 (7) 130 (15) 24.9–1.02) and increased hypothyroidism (6 percent.8 192 (23) 204 (24) 60.1 51. For personal use only.7–68. All rights reserved. (%) Pulmonary disease — no. (%) Electrophysiological study — no.org january 20 .0–30.nejm.0 243 (29) 147 (17) 442 (52) 469 (56) 132 (16) 193 (23) 54 (6) 148 (18) 25.0 253 (31) 175 (21) 431 (52) 453 (55) 141 (17) 210 (25) 52 (6) 129 (16) 60.3 1. . (%)† Syncope — no. was 27 percent (458 patients).1 0.2–67.

822). 2005 229 The New England Journal of Medicine Downloaded from nejm. 838. § To convert values for creatinine to micromoles per liter. Clinically significant ICD complications. † Nonsustained ventricular tachycardia was defined as 3 or more consecutive ventricular beats at a heart rate of more than 100 beats per minute. Crossover to some form of ICD therapy during n engl j med 352. Among the 829 patients in the ICD group. including 44 in the amiodarone group and 81 in the placebo group.4. ¶ Data for follow-up medication were available for 2500 patients (amiodarone. Of the 829 patients assigned to ICD therapy. ACE denotes angiotensin-converting enzyme.001 for the comparison among the groups. Defibrillation-testing data were reported in 716 patients. and ARB angiotensin II–receptor blocker. multiply by 88.amiodarone or icd therapy for heart failure Table 1. 2011. (Continued. A total of 125 patients (7 percent) in the drug groups crossed over to open-label treatment with amiodarone at some point. ‡ To convert weight to kilograms.2. 840. ¿ P<0. occurred in 5 percent of the patients at the time of implantation and in 9 percent later in the course of the trial. (%)¶ ACE inhibitor at enrollment ACE inhibitor at last follow-up ARB at enrollment ARB at last follow-up ACE inhibitor or ARB at enrollment ACE inhibitor or ARB at last follow-up Beta-blocker at enrollment Beta-blocker at last follow-up¿ Diuretic Loop at enrollment Loop at last follow-up Potassium-sparing at enrollment Potassium-sparing at last follow-up Thiazide at enrollment Thiazide at last follow-up Digoxin at enrollment Digoxin at last follow-up Aspirin at enrollment Aspirin at last follow-up Warfarin at enrollment Warfarin at last follow-up Statin at enrollment Statin at last follow-up 696 (82) 665 (79) 174 (21) 236 (28) 52 (6) 95 (11) 614 (73) 496 (59) 461 (55) 474 (56) 310 (37) 272 (32) 334 (40) 405 (48) 692 (82) 674 (80) 165 (19) 278 (33) 60 (7) 88 (11) 589 (70) 524 (62) 477 (56) 451 (54) 281 (33) 300 (36) 319 (38) 387 (46) 676 (82) 649 (79) 168 (20) 261 (32) 63 (8) 80 (10) 552 (67) 512 (63) 477 (58) 449 (55) 266 (32) 279 (34) 312 (38) 395 (48) 731 (87) 594 (71) 118 (14) 152 (18) 822 (97) 718 (85) 581 (69) 605 (72) 718 (85) 619 (74) 132 (16) 145 (17) 827 (98) 740 (88) 581 (69) 662 (79) 684 (83) 576 (70) 114 (14) 144 (18) 783 (94) 706 (86) 576 (69) 672 (82) Amiodarone (N=845) Placebo (N=847) ICD Therapy (N=829) * Hypercholesterolemia was defined as a low-density lipoprotein cholesterol level at enrollment of more than 130 mg per deciliter (3.org january 20. divide by 2. Copyright © 2005 Massachusetts Medical Society. and ICD. 113 (14 percent) received open-label amiodarone during some part of follow-up. the maximal device output. An additional 32 patients (4 percent) had their ICD removed during follow-up.4 mmol per liter) after an overnight fast. For personal use only. or new and otherwise unanticipated drug therapy. defined as clinical events requiring surgical correction.3 www. 17 (2 percent) declined to undergo implantation and implantation was unsuccessful in 1 (less than 1 percent).nejm. hospitalization. All rights reserved.org at VANCOUVER COASTAL HEALTH on July 18. No other uses without permission.) Characteristic Medication use — no. None of these patients required more than a 30-J shock for defibrillation. . placebo.

5-yr event rate.007 Placebo (244 deaths. P=0. All rights reserved. CI denotes confidence interval. Among pa- 230 n engl j med 352. 0. The interaction between amiodarone and NYHA class was significant (P=0. 2005 The New England Journal of Medicine Downloaded from nejm.5 percent confidence interval. P=0.004).The new england journal of medicine Hazard Ratio (97.5 percent. 5-yr event rate.30) 0. 97. Mortality curves and hazard ratios for the comparison of placebo with amiodarone and with ICD therapy according to the prespecified subgroups defined by the cause of CHF and NYHA class are shown in Figures 2 and 3. 97.68) with the cause of CHF. 0.3 Mortality Rate Amiodarone (240 deaths. As compared with placebo. 5-yr event rate.1 percent.e. primary outcome prespecified subgroups A total of 666 patients died: 244 (29 percent) in the placebo group. The median time from randomiza. respectively. 240 (28 percent) in the amiodarone group. there was a relative 44 percent increase in the risk of death among patients in the amiodarone group. 1.86 to 1. 0. 1.001).org january 20 .nejm. During five years of follow-up.0 0 12 24 36 48 60 Months of Follow-up No. Kaplan–Meier Estimates of Death from Any Cause. sustained ventricular tachycardia or fibrillation)..289) 0. 0.65 to 1. 0.007). .44. the average annual rate of ICD shocks was 5. or 21 percent of the ICD group) receiving shocks for rapid ventricular tachycardia or fibrillation. follow-up occurred in 188 patients (11 percent) in Kaplan–Meier mortality curves are shown in Figure the drug groups.62 to 0.96) P Value 0.53 0. 0. no excess risk of death was associated with amiodarone therapy.53) and ICD therapy was associated with a decreased risk of death (hazard ratio. Among patients with NYHA class II CHF.11). 0.86–1. as compared with those in the placebo group (hazard ratio. 0.77. placebo ICD therapy vs.5 percent confidence interval. amiodarone therapy was associated with a similar risk of death (hazard ratio.2 0. No other uses without permission. and the absolute reduction at five years was 7.97). placebo 0. 259 (31 percent) were known to have received shocks from their device for any cause.06.361) ICD therapy (182 deaths. at Risk Amiodarone Placebo ICD therapy 845 847 829 772 797 778 715 724 733 484 505 501 280 304 304 97 89 103 Figure 1.96.30.1. The interaction between ICD therapy and NYHA class was also significant (P<0.62–0.org at VANCOUVER COASTAL HEALTH on July 18. The relative risk reduction of ICD therapy as comtion to crossover was 26. Copyright © 2005 Massachusetts Medical Society.4 1. icd shocks Of the 829 patients in the ICD group.5% CI) Amiodarone vs.340) 0. the average annual rate of ICD shocks was 7. as compared with placebo (hazard ratio. For appropriate shocks only (i.1 0. Among patients with NYHA class III CHF.06 (0.5 percent confidence interval. with 177 (68 percent of those shocked.05 to 1.5 percent confidence interval.3 www. There was no interaction of either amiodarone therapy (P=0. 2011.7 months. and 182 (22 percent) in the ICD group. 97. shocks for rapid. 1. 97.93) or ICD therapy (P=0.2 percentage points.77 (0. For personal use only. pared with placebo was 23 percent.85.

279) 0.76–1. placebo ICD therapy vs.51) 0.79 (0. For personal use only.04) P Value 0. tients with NYHA class II CHF.3 www. 97.3 Amiodarone (5-yr event rate.1 0.40 to 0.16.0 0 12 24 36 48 60 Months of Follow-up No.60–1.5% CI) Amiodarone vs. Patients with NYHA class III CHF had no apparent reduction in the risk of death with ICD therapy. 0.9 percent at five years. 0.2 0.1 0. placebo ICD therapy vs. Copyright © 2005 Massachusetts Medical Society.05 (0. n engl j med 352.36) 0.5 percent confidence interval.2 ICD therapy (5-yr event rate. 0. . 2011. 0.0 0 12 24 36 48 60 Months of Follow-up No. 0.07 (0.74).3 ICD therapy (5-yr event rate. CI denotes confidence interval. 0. All rights reserved.432) 0.66 0. The absolute reduction in mortality among patients in NYHA class II was 11.417) 0. 0.4 Mortality Rate Amiodarone (5-yr event rate. 0.359) 0. No other uses without permission.50–1. as compared with placebo (hazard ratio. 2005 231 The New England Journal of Medicine Downloaded from nejm.4 Mortality Rate 0.54.05 Placebo (5-yr event rate. there was a 46 percent relative reduction in the risk of death (hazard ratio.org january 20. placebo 0.org at VANCOUVER COASTAL HEALTH on July 18.5% CI) Amiodarone vs.5 1. 1. at Risk Amiodarone Placebo ICD therapy 426 453 431 384 415 395 346 370 365 227 244 244 130 152 144 46 48 48 B Nonischemic CHF Hazard Ratio (97.07) P Value 0.amiodarone or icd therapy for heart failure A Ischemic CHF Hazard Ratio (97.5 1.65 0.nejm. at Risk Amiodarone Placebo ICD therapy 419 394 398 388 382 383 369 354 368 257 261 257 150 152 160 51 41 55 Figure 2. Kaplan–Meier Estimates of Death from Any Cause for the Prespecified Subgroups of Ischemic CHF (Panel A) and Nonischemic CHF (Panel B). placebo 0.81–1.258) Placebo (5-yr event rate.06 0.214) 0.73 (0.

97) 1.6 0.484) Mortality Rate Placebo (5-yr event rate. 0.5% CI) Amiodarone vs.44 (1.010 0.2 0. at Risk Amiodarone Placebo ICD therapy 601 594 566 563 563 550 536 522 531 378 367 371 222 218 236 76 72 80 B NYHA Class III Hazard Ratio (97. placebo 0. 0.74) Mortality Rate Placebo (5-yr event rate. 2011.0 0 12 24 36 48 60 P Value 0.17 <0. .3 www.61) Amiodarone ( 5-yr event rate. placebo ICD therapy vs.2 0. All rights reserved. 0. placebo 0. 0.85 (0. CI denotes confidence interval.1 0. 0.264) ICD therapy (5-yr event rate.201) Months of Follow-up No. For personal use only.3 0.0 0 12 24 36 48 60 P Value 0.5 0.84–1.4 0.40–0.org january 20 .456) Months of Follow-up No.5% CI) Amiodarone vs.001 0. No other uses without permission.528) ICD therapy (5-yr event rate. placebo ICD therapy vs. 2005 The New England Journal of Medicine Downloaded from nejm.16 (0.11) 0. 232 n engl j med 352.nejm. Kaplan–Meier Estimates of Death from Any Cause for the Prespecified Subgroups of NYHA Class II (Panel A) and Class III (Panel B).3 0.org at VANCOUVER COASTAL HEALTH on July 18. 0.65–1.30 1.5 0.4 0.The new england journal of medicine A NYHA Class II Hazard Ratio (97.320) Amiodarone (5-yr event rate.6 0.1 0.54 (0. at Risk Amiodarone Placebo ICD therapy 244 253 263 209 234 228 179 202 202 106 138 130 58 86 68 21 17 23 Figure 3. Copyright © 2005 Massachusetts Medical Society.05–1.

61). are considered most credible if they are prespecified. the greater the benefit of ICD therapy. MADIT II showed a benefit of ICD therapy in terms of survival that was similar to the overall trial results when the groups were stratified according to the NYHA class (I. therapy with a conservatively programmed. the general trend in prior trials had been for the relative treatment effect to be nearly constant and. shock-only ICD therapy outweighs any shortcomings of this approach. Subgroup effects.84 to 1.6 a secondary prevention trial. 2011. and are considered biologically plausible. the findings of other trials can guide the interpretation of this particular subgroup effect. or III) (MADIT II Executive Committee: personal communication). for the treatment benefit to be larger in absolute terms for sicker patients. Moreover. Placing our findings in relation to those of other trials of ICD therapy poses some difficulties. No other uses without permission.10 Our findings raise the standard of care for many patients with CHF by substantiating evidence from earlier trials in favor of ICD therapy in patients with ischemic CHF and by providing evidence of a survival benefit associated with such therapy in patients with nonischemic CHF. the worse the ejection fraction.5 percent confidence interval. shock-only ICD significantly decreased the relative risk of death by 23 percent. The traditional view of clinical trialists is that the results of subgroup analysis are inherently misleading and should be interpreted very conservatively until replicated elsewhere. and in the Antiarrhythmics versus Implantable Defibrillators (AVID) study. as compared with those who received placebo. it is worth pointing out that this subgroup effect was not anticipated before data analysis. however. In contrast. Rather. or III who had an LVEF of 35 percent or less and had nonsustained ventricular tachycardia during ambulatory monitoring to amiodarone or dual-chamber ICDs programmed as VVI shock only (Strickberger A: personal communication).2 percentage points at five years among patients with CHF who received state-of-the-art background medical therapy. It is not surprising that ICD therapy has complications related to surgery and long-term management limitations. discussion Our study has two principal findings. The NYHA subgroups were prespecified.4 Thus. Another pertinent finding of our study was that single-lead ICDs proved beneficial despite a 5 percent rate of acute device-related complications and 9 percent rate of chronic complications.org at VANCOUVER COASTAL HEALTH on July 18. Differences in outcome between the two trials are probably due to differences in the number of patients enrolled and the duration of follow-up. Two previous studies have examined the role of ICD therapy in patients with CHF — the Amiodarone versus Implantable Cardioverter–Defibrillator Trial (AMIOVIRT)3 and the DEFINITE trial4 — but only among those with nonischemic cardiomyopathy. . thus. First. In the absence of repli- cation. II.nejm. In the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II). In the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial. the results of the sixminute walk test (Fig. Hazard ratios for other subgroups of interest pertinent to the comparison of placebo with amiodarone and with ICD therapy are shown in Figure 4.amiodarone or icd therapy for heart failure 97. we do not believe that the unanticipated subgroup effect we found is a sufficient basis for withholding ICD therapy from patients in NYHA class III. not only for ICD therapy but also for amiodarone. amiodarone had no beneficial effect on survival. but the survival benefit associated with simple.3 www. 4) support the findings with respect to NYHA class. 69 percent at randomization). The DEFINITE trial randomly assigned 458 patients to ICD or standard therapy and did not find a n engl j med 352. II. and the benefit did not vary according to the cause of CHF. Second. amiodarone therapy had no benefit in patients in NYHA class II and decreased survival among patients in NYHA class III CHF. have a significant interaction with treatment. Copyright © 2005 Massachusetts Medical Society. AMIOVIRT randomly assigned 103 patients in NYHA class I. For personal use only. 2005 233 The New England Journal of Medicine Downloaded from nejm. patients in NYHA class III derived the largest survival benefit from ICD therapy. No mortality advantage had been observed when the trial was aborted after two years.17 a study of patients who had had a myocardial infarction. Whether the treatment differences that we observed in NYHA-class subgroups are biologically plausible is uncertain.1. Background use of beta-blockers was somewhat lower in AMIOVIRT than in our trial (53 percent vs. 0. ICD therapy had a significant benefit in patients in NYHA class II but not in those in NYHA class III CHF. Nevertheless. resulting in an absolute reduction of 7.org january 20. All rights reserved. and the results of the interaction tests were significant. despite the use of appropriate dosage and reasonable compliance rates over longer periods than in other placebocontrolled trials.9. In a post hoc analysis.

68–1.48–1.25 0.60) 0.82 (0.30) 0.52) Hazard ratio (97.49–0.31) 1.83–1. Figure 4. .42) 0.5 1.61–1.org 1.84 (0. Placebo No.61) 0. Copyright © 2005 Massachusetts Medical Society.87–1.23) 0.50–0. All rights reserved.71–1.17 (0. 2011.08 (0.81–1.29) 1.08 (0.57 (0.69–1.72 (0.65) 1.68 (0.04 (0.91) 0.92 (0.38) 1.85–1.30) Diabetes No diabetes Beta-blocker No beta-blocker 6-Min walk test <950 ft 950–1275 ft >1275 ft 526 536 526 1157 519 524 1152 1.62) 1.org at VANCOUVER COASTAL HEALTH on July 18.65–1.80–1.73 (0.77–1. 2005 0.95 (0.24 (0.12) 1.20 (0.57–0.62–1.06 (0. 398 1294 Female sex Male sex Age <65 yr Age ≥65 yr White race Nonwhite race LVEF ≤30% LVEF >30% QRS <120 msec QRS ≥120 msec 977 699 1390 285 1283 393 0.62–1.83–1.3 517 547 545 1162 530 514 1178 2.27–0.0 2. 382 1294 Hazard ratio (97.76–1.84–1.41) 1.0 4.234 Amiodarone vs.18) 1119 573 1292 400 1407 285 999 692 1.72–1.93) 1098 578 0. For personal use only.66–2.98 (0.41) 1.0 Amiodarone Better Placebo Better ICD Better Placebo Better The New England Journal of Medicine Downloaded from nejm.78 (0.17) 0.38–0.nejm.51–0.86 (0.61 (1.93) Subgroup ICD Therapy vs.67 (0.50–0.5% CI) 0.57–2.78–1.30) No.05 (0.56–1.06 (0. Placebo The n engl j med 352. Hazard Ratios for the Comparison of Amiodarone and ICD Therapy with Placebo in Various Subgroups of Interest.84–1.88) 0.20) 0.96 (0. CI denotes confidence interval.00 (0.34) 1.13 (0.58–1. No other uses without permission.04 (0.68 (0.0 of medicine january 20 .0 new england journal www.0 4.5 1.93) 0.76) 0.46–1.90) 1.73 (0.25 0.14 (0.32) 1.92) 1.17–2.5% CI) 1.45 (0.00 (0.57–0.75 (0.00) 0.90) 0.14) 0.10 (0.33) 0.67 (0.07) 0.

Wagner.08). D. M. Mendez. Mid Carolina Cardiology. S. J. M. W. G. Moreover. Consequently. Creó. Mirro. Borganelli. Dr. Charlotte. L. Keim. Ehrich. any benefit. Copyright © 2005 Massachusetts Medical Society. D. Hatter. The study used nonsustained ventricular tachycardia and frequent ectopy as entry criteria. Klahr. Vincent Medical Center. Moe. Hart. 2011. Ensley. P. Nora. Cleveland: M. In conclusion. Mich. Toronto: P. Bennett. Supported by grants (UO1 HL55766.org january 20.: I. I. Delgado. Adkisson. they may fail to realize that the same is true for ICD therapy. Chiaramonte. J. Bryan LGH Heart Institute. L. Loyola University Medical Center. Bardy reports having received research grants from Medtronic and Wyeth–Ayerst Pharmaceuticals. Wright Patterson Air Force Base. Orosco. Singer. D. J. National Institutes of Health. King. ICD therapy cannot be considered a single intervention. Thompson. Stagaman. Michaels’ Hospital. S. L. S. Fla. V. shock-only ICD therapy improves survival beyond the improvement afforded by stateof-the-art drug therapy. Stucky Research Center/Parkview Memorial Hospital. R. .18 they may not afford the same benefit or. Wyeth–Ayerst Laboratories. such as those involving dual-chamber or biventricular pacing. Mark reports having received grant support and speaking fees from Medtronic. Perreault. and having received speaking fees from Medtronic. Martin. Colo. J. M. T Eastburn. Ky. Portland. Klevan. Fisher. K. Gabris. J. Crelinsten. Lehmann.K. J. A. Lane. since. Olshansky. J. M Cishek.: M. ICDs were inserted on an outpatient basis.: S.: D. C. D. Dr. having served as a consultant to Guidant. Prystowsky. Fulton. Mathews. the death rate was higher at two years than among our patients with nonischemic CHF (14 percent vs. whether antibradycardia pacing or rateresponsive pacing is used. Colorado Springs. M. J. L. C. Memorial Hospital. Taylor. Wise. M. or triple-chamber devices are used. Louisville. Ip. Lansing. McGill University Hospital. dual-. Zilo. and Knoll Pharmaceuticals. Becher.: K. N. Matteson. Halperin. P. Montreal: M. Blaske. board member of. Dorian. Liebling. Beaudion. Brown. Talajic.: M. Pelletier. Vermaas.: R. T. C. Reddy. Lauderdale: R. Al-Mudamgha. Ft. given the finding that no patient who underwent ICD testing required more than the maximal output of the device to terminate ventricular fibrillation. O’Toole. Crockett. Lee reports having received research funding from Medtronic and Wyeth–Ayerst Pharmaceuticals and having received speaking fees from Guidant and Medtronic. Pensacola. and by Medtronic. Norfolk. Gonzalez. Although physicians understand that different drugs lead to different outcomes. Ip reports that he is a consultant for St. J. McAnulty. L. Wright Patterson Air Force Base. A. Montreal: M. Jasky. McGuire. 2005 235 The New England Journal of Medicine Downloaded from nejm. J. and equity holder in Cameron Health. Ingham Medical Center. 34 beats per minute). Mil- n engl j med 352. Kandrac. James. he is a founder of. C. H. J. M. ap p e n d i x The following investigators and institutions participated in the SCD-HeFT trial: Investigators (listed in descending order of the number of randomized patients): Florida Arrhythmia Consultants. Jude Medical and holds equity in Guidant. D. C. Dr. Moreover. Cardiology Consultants. 10 percent). Texas Cardiac Arrhythmia. P. Sweeney. Van DeGraaff. Carlson. San Diego Cardiac Center. Kowalewski. Franks. Pina. Cuny. O’Shaughnessy. Plant. New York Heart Center.3. Cardiology of Tulsa. Barackman. Teague. Ill. Norton. which detection algorithm is used. effective approach to the implantation of single-lead. M. E. Midwest Heart Research Foundation. as reported previously. suggesting that there may have been fundamental differences in the two study populations. and UO1 HL55496) from the NHLBI. Drs. Strzelecki. San Diego. M. Edwards. R. however. Parker. Enger. Curry. E.3 www. S. Snyder. S. Russo. and the heart rate prompting intervention was lower (180 vs. J. Indianapolis: M. Newell. V. and whether antitachycardia pacing maneuvers are used for ventricular tachycardia. For personal use only. D. T. Dusman. Wilber. Hockenberry. Wayne. shock-only ICDs such as ours should translate into cost savings.C. It is critical to emphasize that the effect of ICD therapy in patients with CHF may differ substantially depending on the programming of the device. Schwendeman. M. Dr. University Hospitals of Cleveland. Ohio: R. D. B.: B. considerable caution should be used in extrapolating our results to other approaches to ICD therapy. we cannot emphasize too strongly that we evaluated only very conservatively programmed ICDs with a conservative detection algorithm and shock-only therapy. R. Whisnant. Simple. D. Dr. M. Institut de Cardiologie de Montréal. DiBiase. Luceri. B. Northside Cardiology/The Care Group. Syracuse: A. D. J. Williams. L. L. No other uses without permission. D. a reasonable argument can be made that defibrillation testing is unwarranted in this population. E. Wash. E. Inland Cardiology Associates. Walsh. given the numerous possible permutations of this approach. Krone. G. Spokane. D. Poole and Packer report having received speaking fees from Guidant and Medtronic.amiodarone or icd therapy for heart failure significant survival benefit (P=0. Chilson. Calif. Tulsa. Va.org at VANCOUVER COASTAL HEALTH on July 18. Ft.8. Alcorn. Austin: R. Rogers. Pawletko-Mathews.: J. Lantz.: D. Kremers. Baxter. G. Weaver.: M. R. Oregon Health Sciences University/Providence St. B.nejm. L. Oreg. All rights reserved.: J. Nebr. Our approach to ICD therapy is widely applicable and should have a positive public health effect on the population of patients with CHF. V. Sami. Ind. Raitt. Fishbein reports having received research support from Medtronic and speaking fees from Guidant and Medtronic. Hershberger. The risk and cost of defibrillation testing are likely to outweigh the remote possibility that a rare patient might benefit from it. for that matter. R. Herre. A simplified. Canby. E. whether single-. Hicks. Rubin. Sentara Norfolk General Hospital. S. T. and 22 percent of the patients were in NYHA class I. Lombard. consultant to. UO1 HL55297. Ciriello.: J. R. A. Margiotti. Grimes. Budzon. D. Maywood. Ill. Del Priore. Krueger. M. Cardinal. C. Our findings may also be pertinent to constraining the costs of ICD therapy. Lincoln. D. Outpatient insertion is certainly less expensive than inpatient insertion and can easily be translated to routine practice. University of Louisville. 187 beats per minute). Davidenko.: M. amiodarone does not improve survival among patients with mild-to-moderate systolic CHF. In addition. Gill. the threshold for pacing was higher than in our study (40 vs. We found strong evidence that this approach works. and testing of the devices was very limited. Okla. J.

Ensley. Jr. A. St. M. V. N. Temple University Hospital. Fields. Schnitzler. Megas-Nowak. Cardiology Associates.: M. P. Hirsch. Providence Hospital. Pacetti. Brooklyn. Pa. Philadelphia: M. J. M. Al Adhamy. Cleveland Clinic Foundation. M. J. B. For personal use only. N. Waitkus. Cloutier.: C. Seattle: C. Quebec Heart Institute.: J. J. Wadsworth West Los Angeles Veterans Affairs Medical Center. Welch. T. N. E. O’Brien. Marinchak. San Francisco. Bauerlein. Deering. J. C. Butler. Ryder. Hamilton. T. S. R. Hayes. Sainte-Foy. Campagne. Pa. Warner-Stevenson.org at VANCOUVER COASTAL HEALTH on July 18. N. Louis: A. M. Calgary. L. Mikolich. J. McKelvie. Nail. Renlund. Allen. Seattle: D. Ohio: R. University of Texas Medical Branch. McNish. N. Howlett. San Antonio: D. Maine Medical Center. P. Keinanen. University of Utah Medical Center. Tuomala. Mid America Heart Institute. S. Sanders. C. Cleveland: P.: R. Aranda. Minneapolis: S. Mont. Packer. New York: L. W. Dallas: S. Nattama. J. D. M. Hordes. 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