This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, D. S. Articles by Alter, D. A. Search for Related Content PubMed PubMed Citation Articles by Lee, D. S. Articles by Alter, D. A.

CLINICAL STUDY

Effectiveness of implantable defibrillators for preventing arrhythmic events and death

A Meta-Analysis

Douglas S. Lee, MD, FRCPC^*, Lawrence D. Green, MD^*, Peter P. Liu, MD, FRCPC, Paul Dorian, MD, MSc, FRCPC^||, David M. Newman, MD, FACC^||, F. Curry Grant, MD, MSc, FRCPC, Jack V. Tu, MD, PhD, FRCPC^*¶ and David A. Alter, MD, PhD, FRCPC^#,*

^* Department of Health Policy, Management and Evaluation/Clinical Epidemiology, Toronto, Canada
Institute for Clinical Evaluative Sciences, Toronto, Canada
Division of Cardiology, University Health Network-Toronto General Hospital, Toronto, Canada
Heart and Stroke/Richard Lewar Centre of Excellence and Toronto General Hospital, Toronto, Canada
^|| Electrophysiology and Arrhythmia Service, Division of Cardiology, St. Michael’s Hospital, Toronto, Canada
^¶ Department of Medicine, Sunnybrook and Women’s College Health Science Centre, Toronto, Canada
^# Division of Cardiology, Schulich Heart Centre, Sunnybrook and Women’s College Health Science Centre, Toronto, Canada

Manuscript received June 11, 2002; revised manuscript received January 1, 2003, accepted January 30, 2003.

^* Reprint requests and correspondence: Dr. David A. Alter, Institute for Clinical Evaluative Sciences, G-106, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
david.alter{at}ices.on.ca

	Abstract

Top Abstract Methods Results Discussion References

 
OBJECTIVES: The aim of this study was to compare the effectiveness of the implantable cardioverter defibrillator (ICD) and medical strategies for prevention of arrhythmic events and death.

BACKGROUND: The ICD is a potential strategy to reduce mortality in patients at risk of sudden death.

METHODS: The MEDLINE, EMBASE, and Cochrane Library electronic databases were searched from January 1966 to April 2002. All published randomized controlled trials comparing ICD implantation with medical therapy were reviewed. Four independent reviewers extracted data on all-cause mortality, nonarrhythmic death, and arrhythmic death using a standardized protocol.

RESULTS: Nine studies including over 5,000 patients were synthesized using both fixed-effects and random-effects models. The primary and secondary prevention trials showed a significant benefit of the ICD with respect to arrhythmic death, with relative risks (RR) of 0.34 and 0.50, respectively (both p < 0.001). The mortality benefit of the ICD was entirely attributable to a reduction in arrhythmic death (all trials: p < 0.00001). Whereas the secondary prevention trials exhibited a robust decrease in all-cause ICD mortality (RR 0.75; p < 0.001), the pooled primary prevention trials demonstrated decreased all-cause ICD mortality (RR 0.66; p < 0.05) which was dependent on selected individual trials. The disparity in ICD-related mortality reductions in the primary prevention trials was related to variability in the incidence of arrhythmic death between individual studies.

CONCLUSIONS: Although the ICD decreases the risk of arrhythmic death, its impact on all-cause mortality is related to the underlying risk of arrhythmia-related death relative to competing causes. Given the cost of the device strategy, policies of targeted intervention based on the future risk of arrhythmia are warranted.

Abbreviations and Acronyms   AAD = antiarrhythmic drugs   AVID = Antiarrhythmics Versus Implantable Defibrillators study   CABG Patch = Coronary Artery Bypass Graft Patch trial   CASH = Cardiac Arrest Study Hamburg   CAT = Cardiomyopathy Trial   CI = confidence interval   CIDS = Canadian Implantable Defibrillator Study   ICD = implantable cardioverter defibrillator   LV = left ventricular   LVEF = left ventricular ejection fraction   MADIT = Multicenter Automatic Defibrillator Implantation Trial   MUSTT = Multicenter Unsustained Tachycardia Trial   RCT = randomized controlled trial   RD = risk difference   RR = relative risk

The ICD strategy is appealing because of its ability to terminate ventricular arrhythmias reliably, to provide early defibrillation, and perhaps to decrease or eliminate the need for concomitant antiarrhythmic medications and their associated adverse effects. Observational studies have shown that the ICD provides a survival advantage over AAD in patients with symptomatic arrhythmias, particularly in patients with depressed LV function (11–13). However, the ICD is associated with substantial costs and, therefore, precise estimates of device effectiveness are required. The objective of this study was to compare the effectiveness of medical therapy with the ICD in patients who are at risk of future episodes of sudden arrhythmic death and to clarify the issue of competing risks by analysis of the mode of death.

	Methods

Top Abstract Methods Results Discussion References

 
Search strategy.   High-quality randomized trials of primary or secondary prevention that compared the ICD with medical therapy (with or without AAD) were identified. The strategy used to identify studies was developed in collaboration with the Cochrane Heart Group (14). The MEDLINE database was searched from January 1966 to April 2002. A previously published randomized controlled trial (RCT) filter for use with the MEDLINE electronic database was employed to optimize the search strategy (15). Keywords included: defibrillators, implantable; cardioverter; anti-arrhythmia agents. Amiodarone, sotalol, and names of other antiarrhythmic agents were searched as textwords. The EMBASE database was searched from January 1980 to April 2002. A previously published RCT filter for use with the EMBASE electronic database was used to optimize the search strategy (16). The COCHRANE Library and Controlled Trials Register (2002) was also searched. No restrictions on language, dose, or ICD type were applied. All reference lists of pertinent studies were searched by two reviewers (D.S.L. and L.D.G.). Published study protocols were evaluated to further clarify specific methodologic elements for quality assessment. Updated publications pertaining to any relevant outcomes that were not published in the primary article were also reviewed.

Study selection.   Criteria used to select studies for inclusion in this review were as follows. 1) Design: RCT comparing ICD with medical strategy. 2) Population: patients (18 years) who have had an episode of resuscitated sudden death or symptomatic ventricular tachyarrhythmia or patients who have a low left ventricular ejection fraction (LVEF) (0.40) and are thought to be at risk for development of lethal cardiac arrhythmia. 3) Intervention: ICD versus medical therapy for the prevention of sudden arrhythmic death. Studies whose primary objectives were the evaluation of defibrillation thresholds or mechanism of drug or device action and/or where the primary end point of interest was not mortality were excluded. 4) Outcome: at least one of the reported outcomes was all-cause mortality, cardiac death, arrhythmic mortality, or cardiac arrest. A QUOROM statement flow diagram (17) for included and excluded studies is shown in Figure 1.

View larger version (25K): [in this window] [in a new window]   Figure 1 QUOROM flow diagram of search results and the process of identification of randomized controlled trials (RCTs) meeting inclusion criteria. ICD = implantable cardioverter defibrillator.

Statistical analysis.   Analysis was performed using the Mantel-Haenszel method. Relative risk (RR) and risk difference (RD) with 95% confidence intervals (CI) using the fixed effects model were calculated for the primary/secondary prevention trials separately and for all the trials in the overall analysis. If a statistically significant reduction in the RD was found, the number needed to treat was calculated (18). Statistical heterogeneity between studies was identified using the chi-square statistic, and a p 0.10 was deemed statistically significant. If significant statistical heterogeneity was identified, a random effects analysis was performed. We performed an overall analysis including all randomized trials. However, we anticipated clinical heterogeneity which was addressed by the performance of separate analyses of primary and secondary prevention studies and selected sensitivity analyses. Adverse events are reported overall as weighted percentages. Fatal perioperative adverse events included deaths occurring up to 30 days after device implantation.

	Results

Top Abstract Methods Results Discussion References

 
Search results.   A total of 1,077 potentially relevant articles were screened, and 1,003 were excluded after examination of the title and abstract. Of the 74 articles retrieved for further examination, 51 were excluded for the following reasons: nonrandomized (41 articles), absence of ICD arm (2 articles), quality of life outcome (1 article), no useful outcomes (6 articles), and protocol of ongoing study (1 article). Of the remaining 23 articles, a number were publications that evaluated the mode of death in the same patient sample as the primary study publication. There were 16 discrete randomized trials that were subsequently assessed for quality.

Details of the included study designs and trial interventions are shown in Table 1 (19–27). In total, the meta-analysis represented a composite of over 5,000 patients. These studies were multicenter randomized trials spanning several countries (U.S., Canada, Netherlands, Australia, and Germany). Five trials were primary prevention studies. The primary prevention trials identified patients with poor LV function (LVEF 0.40) who were deemed to be at increased risk of sudden death (Fig. 2). Four randomized trials were secondary prevention studies that evaluated patients resuscitated from sudden cardiac death or with symptomatic ventricular tachyarrhythmias and reduced ejection fraction (Fig. 2).

View larger version (20K): [in this window] [in a new window]   Figure 2 Plot of left ventricular ejection fraction (LVEF) in the defibrillator intervention (horizontal axis) and control arms (vertical axis) of the included randomized trials. Error bars are the reported standard deviations of LVEF in trial publications. Most of the points lie on the diagonal, suggesting that the trials were balanced for LVEF in the study arms. MADIT I and CABG Patch point estimates overlap. MUSTT and Wever et al. point estimates overlap. No standard deviation of LVEF was reported in MUSTT; only the point estimate is shown. AVID = Antiarrhythmics Versus Implantable Defibrillators study; CABG Patch = Coronary Artery Bypass Graft Patch Trial; CASH = Cardiac Arrest Study Hamburg; CAT = Cardiomyopathy Trial; CIDS = Canadian Implantable Defibrillator Study; MADIT = Multicenter Automatic Defibrillator Implantation Trial; MUSTT = Multicenter Unsustained Tachycardia Trial.

Primary prevention trials.   The MADIT I and MUSTT studies showed significant reductions in arrhythmic death of 75% and 73%, respectively. In CABG Patch, there was a trend to decreased risk of arrhythmic death with the ICD; however, the CI crossed unity (RR 0.55; 95% CI 0.30 to 1.01). When the results were pooled, there was no statistical heterogeneity (p = 0.21), and a significant pooled reduction in arrhythmic death favoring the ICD (RR 0.34; 95% CI 0.23 to 0.50) was found (p < 0.00001). There was no excess of nonarrhythmic deaths in the ICD group with a pooled RR of 0.95 (95% CI 0.74 to 1.21) for this end point. For the end point of all-cause mortality, MUSTT, MADIT I, and MADIT II found significant reductions in all-cause death with relative reductions in risk ranging from 29% to 59% (absolute risk reduction 26%, 23%, and 6%, respectively). The pooled data (Fig. 3) showed significant benefits in favor of the ICD with a RR reduction of death from any cause of 34% (p = 0.03). The random effects 95% CI of the RR reduction was 4% to 54%.

View larger version (16K): [in this window] [in a new window]   Figure 3 Death from all causes in the primary prevention defibrillator trials, pooled in a random effects model. For each randomized trial, the number of deaths (n) and the number assigned (N) are shown. The rectangles represent the point estimates of the relative risk (RR) for individual studies, and the 95% confidence intervals (CI) are shown as bars. The overall pooled RR is 0.66 with a 95% CI of 0.46 to 0.96, which significantly favors treatment with the defibrillator (p = 0.03). The horizontal tips of the black diamond represent the 95% CI, and the midpoint of the diamond represents the point estimate of the RR. df = degrees of freedom; other abbreviations as in Figure 2.

View larger version (14K): [in this window] [in a new window]   Figure 4 All-cause mortality in pooled secondary prevention defibrillator trials. For each randomized trial, the number of deaths (n) and the number assigned (N) are shown. The rectangles represent the point estimates of the relative risk (RR) for individual studies, and the 95% CI are shown as bars. The overall pooled RR is 0.75 with a 95% CI of 0.64 to 0.87, which significantly favors treatment with the defibrillator (p = 0.0002). The study results were not heterogeneous (p = 0.26), and together demonstrated significant reduction in death from any cause with the implantable cardioverter defibrillator. The horizontal tips of the black diamond represent the 95% CI, and the midpoint of the diamond represents the point estimate of the RR. AVID = Antiarrhythmics Versus Implantable Defibrillators study; CASH = Cardiac Arrest Study Hamburg; CIDS = Canadian Implantable Defibrillator Study; df = degrees of freedom.

View larger version (18K): [in this window] [in a new window]   Figure 5 Impact of the randomized defibrillator trials on arrhythmic death. For each randomized trial, the number of arrhythmic deaths (n) and the number assigned (N) are shown. All studies showed consistent benefit in reducing arrhythmic death with the implantable cardioverter defibrillator (ICD), and there was no statistical heterogeneity between studies (p = 0.18). Over all studies reporting arrhythmic deaths, the defibrillator reduced the risk of arrhythmic death significantly (pooled relative risk 0.43; 95% CI 0.35 to 0.54). The ICD effect was a highly significant reduction in risk of arrhythmic death (p < 0.00001). The horizontal tips of the black diamond represent the 95% CI, and the midpoint of the diamond represents the point estimate of the RR. CABG Patch = Coronary Artery Bypass Graft Patch Trial; MADIT = Multicenter Automatic Defibrillator Implantation Trial; MUSTT = Multicenter Unsustained Tachycardia Trial. Other abbreviations as in Figure 4.

Treatment-related complications.   Perioperative death complicating defibrillator implantation occurred in 1.2% without concomitant thoracotomy and coronary artery bypass grafting; however, such deaths occurred in 5.5% of patients in CABG Patch. Other commonly reported adverse events (and weighted percentages) in the defibrillator arm were infection (2.4%), hematoma or seroma (3.7%), pericardial effusion or tamponade (0.6%), pneumothorax (1.6%), lead dislodgement or fracture (2.3%), and device malfunction (2.0%). Among the medical arms employing antiarrhythmic agents, amiodarone pulmonary toxicity was the most often reported adverse effect, occurring in 3.0% to 5.7% (weighted mean 4.8%) of patients by study termination.

	Discussion

Top Abstract Methods Results Discussion References

 
Our meta-analysis demonstrated a significant survival advantage with the defibrillator for patients at risk of sudden cardiac death. Pooling primary and secondary prevention studies together, defibrillators were associated with a 57% reduction in the risk of an arrhythmic death and a 30% decrease in risk of all-cause mortality as compared with medical therapy alone. When distinguishing primary from secondary prevention studies, only the latter was associated with a consistent reduction in total mortality. In contrast, the impact of defibrillators on total mortality for primary prevention was variable and heavily dependent on the patient population examined. Notwithstanding the differential effect on total mortality, both primary and secondary prevention trials were associated with a similar reduction in the risk of arrhythmic death.

Implantable defibrillator and survival benefits.   The effects of the ICD on outcomes in secondary prevention were consistent with other investigators (28). Specifically, the ICD was associated with a 50% RR reduction for arrhythmic death and a 25% RR reduction for all-cause mortality (both absolute risk reductions, 7%). The secondary prevention trial results were robust and consistent from study to study.

To our knowledge, ours is the first meta-analysis evaluating the efficacy of defibrillators in primary prevention of sudden cardiac death reporting random effects analyses in the presence of between-study heterogeneity. Primary prevention studies showed a variable effect on all-cause mortality. A factor that may have contributed to the variability in primary prevention studies may have been the underlying cardiac substrate. Whereas the majority of primary prevention studies included patients with ischemic heart disease, CAT was the only trial that included exclusively patients with nonischemic cardiomyopathy. The role of defibrillators in the latter group may be clarified by trials that address this subpopulation of patients with LV dysfunction. Yet, the effect of prophylactic defibrillators on arrhythmic death in the primary prevention population was surprisingly similar and consistent with its risk reduction for arrhythmic death in secondary prevention. Excluding the MUSTT trial, a primary prevention study for which the ICD was arguably based on selection rather than on randomization, the ICD was associated with RR reductions of 50% and 45% for arrhythmic death among the secondary and primary prevention trials, respectively. Given that defibrillators do not reduce the risk of nonarrhythmic death, the difference between the ICD outcome effects for primary prevention and secondary prevention relates to the baseline risk of life-threatening arrhythmia. In short, the attenuated and inconsistent effect of defibrillators on total mortality among primary prevention patients directly reflects a more heterogenous spectrum of risk for life-threatening arrhythmias in the months and years that follow.

Risk stratification.   If ultimately, the clinical effectiveness (and economic impact) of the ICD reflects the baseline risk of arrhythmic death in the population, it is incumbent upon researchers and clinicians to stratify patients in accordance with the risk of life-threatening arrhythmias. Our analysis crudely stratified patients into those with and without previous cardiac arrest or symptomatic ventricular tachycardia. Arguably, this is the simplest form of risk stratification. However, available evidence suggests that within each subgroup, the baseline risk of a life-threatening arrhythmia impacts upon the subsequent effectiveness of defibrillators on total mortality. For example, within a secondary prevention trial, a further high-risk subset included those with the lowest ejection fractions (29,30).

In addition to underlying ejection fraction and previous history of cardiac arrest, other important case-mix and clinical factors may predict the risk of life-threatening arrhythmic complications; these include age (30), functional status (30), the etiology of cardiac disease (2,31), residual ischemic burden (32–35), electrocardiographic indices (36–38), and inducibility of arrhythmias at electrophysiologic study (39–41). The incremental importance of other strategies that delineate and/or modify the risk of life-threatening complications (e.g., electrophysiologic study, revascularization) requires further evaluation. We believe that the magnitude of absolute survival benefit and the cost-effectiveness of the ICD will depend on the efficiency by which patients who are at high risk of arrhythmic death can be identified in the population (42).

The methodology employed for stratification of risk of arrhythmic death in future studies might include predictive models or clinical decision aids from substudies of RCTs (30,43). Simple clinical rules, such as those gleaned from electrocardiographic analysis, may be clinically useful. Ultimately, no single test may be highly predictive, and it may require a combination of predictive tests to identify a high-risk subset (44). In addition to the need for further study of the prognostic value of diagnostic tests, equally important may be the consideration of patient-related factors. This includes consideration of the cardiac substrate and comorbidities. Factors that predict high utility of the ICD in patients with ischemic heart disease may not apply to those with nonischemic cardiomyopathy. In addition, non-cardiac comorbidities may lead to mechanisms of death for which the ICD would not change the disease history and the ultimate prognosis of the patient. This concept of competing risks may diminish the effectiveness of the defibrillator on all-cause mortality (45). Studies that include patients who are similar to those that clinicians encounter in real-world practice may offer insight.

Study limitations.   There are several noteworthy limitations to our study. First, our study was limited by the relative paucity of primary prevention defibrillator trials. For example, we had only one trial in nonischemic cardiomyopathy, which may complement our primary prevention analysis of patients with coronary artery disease. Additional randomized trials of ICD strategies in patients with coronary artery disease will help to increase further the precision of the estimated benefits of the defibrillator and may lead to greater robustness of our results. A number of pending publications of randomized trials, including Amiodarone Versus Implantable Defibrillator in Patients with Nonischemic Cardiomyopathy and Asymptomatic Nonsustained Ventricular Tachycardia (AMIOVIRT), Beta-blocker Strategy plus Implantable Cardioverter Defibrillator Trial (BEST-ICD), Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE), Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), and Sudden Cardiac Death in Heart Failure Trial (SCD-HEFT), may further improve the reliability of the primary prevention estimates of ICD effect. Second, there may be other reasons for statistical and clinical heterogeneity that could not be realized from this analysis, such as the effects of variable follow-up times. An analysis of pooled survival time data may yield further insights. Third, studies with arrhythmic death end points are limited by the accuracy of death classification methods, and the further subclassification of arrhythmic deaths as bradyarrhythmic or tachyarrhythmic deaths may be limited without studies employing combined ventricular pacemaker and defibrillator. Fourth, no cost-effectiveness analysis was undertaken. Nonetheless, the robust estimates of event rates as determined by our study may set the stage for future ICD cost-benefit analysis.

Conclusions.   The defibrillator is highly effective in reducing the risk of arrhythmic death when used in either a primary or secondary prevention context. Pooled analysis of all-cause mortality showed a reduction in risk of death with defibrillator implantation. While the secondary prevention results were robust, primary prevention findings were sensitive to the contributions of individual trials. Given the fiscal implications of the primary prevention trials, we believe that the impact of device implantation strategies on health policy, cost-effectiveness, and access to this form of therapy should be further evaluated. Our results suggest that net survival benefits and cost-effectiveness of the ICD when applied to the population will depend upon efficient use of devices for those at highest risk of life-threatening arrhythmias.

	Acknowledgments

 
We thank Claus Wall and Kathy Sykora (Institute for Clinical Evaluative Sciences, Ontario, Canada) for assistance with technical German and Czech translations, respectively. We also thank Theresa Moore and Margaret Burke (Cochrane Heart Group, University of Bristol, Bristol, United Kingdom) for assistance with the search strategy.

	Footnotes

 
Dr. Lee is a research fellow of the Heart and Stroke Foundation of Canada/Canadian Institutes of Health Research. Dr. Liu is supported in part by grants from the Heart and Stroke Foundation of Ontario, the Canadian Institutes of Health Research, and the Heart & Stroke/Polo Chair Professor of Medicine at the University of Toronto. Dr. Tu is supported by a Canada Research Chair in Health Services Research and by the Canadian Institutes of Health Research. Dr. Alter is supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.

	References

Top Abstract Methods Results Discussion References

 

1. Cannom DS, Prystowsky EN. Management of ventricular arrhythmias: detection, drugs, and devices. JAMA. 1999;281:172–179[Abstract/Free Full Text]
2. Josephson ME, Callans DJ, Buxton AE. The role of the implantable cardioverter-defibrillator for prevention of sudden cardiac death. Ann Intern Med. 2000;133:901–910[Abstract/Free Full Text]
3. Saksena S, Madan N, Lewis C. Implanted cardioverter-defibrillators are preferable to drugs as primary therapy in sustained ventricular tachyarrhythmias. Prog Cardiovasc Dis. 1996;38:445–454[CrossRef][Medline]
4. Anderson J. Implantable defibrillators are preferable to pharmacologic therapy for patients with ventricular tachyarrhythmias: an antagonist’s viewpoint. Prog Cardiovasc Dis. 1996;38:393–400[CrossRef][Medline]
5. Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R. 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. 1994;344:493–498[CrossRef][Medline]
6. 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. N Engl J Med. 1995;333:77–82[Abstract/Free Full Text]
7. Sim I, McDonald KM, Lavori PW, Norbutas CM, Hlatky MA. Quantitative overview of randomized trials of amiodarone to prevent sudden cardiac death. Circulation. 1997;96:2823–2829[Abstract/Free Full Text]
8. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350:1417–1424[CrossRef][Medline]
9. Pollak PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol. 1999;84:37R–45R[Medline]
10. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol. 1997;30:791–798[Abstract]
11. Fogoros RN, Fiedler SB, Elson JJ. The automatic implantable cardioverter-defibrillator in drug-refractory ventricular tachyarrhythmias. Ann Intern Med. 1987;107:635–641[CrossRef][Medline]
12. Newman D, Sauve MJ, Herre J, et al. Survival after implantation of the cardioverter defibrillator. Am J Cardiol. 1992;69:899–903[CrossRef][Medline]
13. Powell AC, Fuchs T, Finkelstein DM, et al. Influence of implantable cardioverter-defibrillators on the long-term prognosis of survivors of out-of-hospital cardiac arrest. Circulation. 1993;88:1083–1092[Abstract/Free Full Text]
14. Lee DS, Green LD, Liu PP, Grant FC, Alter DA. Implantable defibrillators vs antiarrhythmic drugs for left ventricular dysfunction [Cochrane Protocol]. In: The Cochrane Library 2002. Oxford: Update Software
15. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ. 1994;309:1286–1291[Abstract/Free Full Text]
16. Lefebvre C, McDonald S. Development of a sensitive search strategy for reports of randomised controlled trials in EMBASE. Fourth International Cochrane Colloquium 1996. Available at: http://www.update-software.com/ccweb/cochrane/colabstr.htm
17. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999;354:1896–1900[CrossRef][Medline]
18. Mulrow C, Cook D, editors. Systematic Reviews: Synthesis of Best Evidence for Health Care Decisions. Philadelphia, PA: American College of Physicians, 1998
19. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med. 1997;337:1576–1583[Abstract/Free Full Text]
20. Coronary Artery Bypass Graft (CABG) Patch Trial InvestigatorsBigger JT Jr. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. N Engl J Med. 1997;337:1569–1575[Abstract/Free Full Text]
21. Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation. 2000;102:748–754[Abstract/Free Full Text]
22. Bansch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation. 2002;105:1453–1458[Abstract/Free Full Text]
23. Connolly SJ, Gent M, Roberts RS, et al. Canadian Implantable Defibrillator Study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. 2000;101:1297–1302[Abstract/Free Full Text]
24. Multicenter Automatic Defibrillator Implantation Trial InvestigatorsMoss 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. 1996;335:1933–1940[Abstract/Free Full Text]
25. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–883[Abstract/Free Full Text]
26. Multicenter Unsustained Tachycardia Trial InvestigatorsBuxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med. 1999;341:1882–1890[Abstract/Free Full Text]
27. Wever EF, Hauer RN, van Capelle FL, et al. Randomized study of implantable defibrillator as first-choice therapy versus conventional strategy in postinfarct sudden death survivors. Circulation. 1995;91:2195–2203[Abstract/Free Full Text]
28. Connolly SJ, Hallstrom AP, Cappato R, et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. Eur Heart J. 2000;21:2071–2078[Abstract/Free Full Text]
29. AVID InvestigatorsDomanski MJ, Sakseena S, Epstein AE, et al. Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias: Antiarrhythmics Versus Implantable Defibrillators. J Am Coll Cardiol. 1999;34:1090–1095[Abstract/Free Full Text]
30. Sheldon R, Connolly S, Krahn A, Roberts R, Gent M, Gardner M. Identification of patients most likely to benefit from implantable cardioverter-defibrillator therapy: the Canadian Implantable Defibrillator Study. Circulation. 2000;101:1660–1664[Abstract/Free Full Text]
31. Stevenson WG, Ridker PM. Should survivors of myocardial infarction with low ejection fraction be routinely referred to arrhythmia specialists? JAMA. 1996;276:481–485[Abstract]
32. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol. 2002;39:1151–1158[Abstract/Free Full Text]
33. Exner DV, Klein GJ, Prystowsky EN. Primary prevention of sudden death with implantable defibrillator therapy in patients with cardiac disease: can we afford to do it? (can we afford not to?). Circulation. 2001;104:1564–1570[Free Full Text]
34. Margonato A, Mailhac A, Bonetti F, et al. Exercise-induced ischemic arrhythmias in patients with previous myocardial infarction: role of perfusion and tissue viability. J Am Coll Cardiol. 1996;27:593–598[Abstract]
35. Veenhuyzen GD, Singh SN, McAreavey D, Shelton BJ, Exner DV. Prior coronary artery bypass surgery and risk of death among patients with ischemic left ventricular dysfunction. Circulation. 2001;104:1489–1493[Abstract/Free Full Text]
36. Dabrowski A, Kramarz E, Piotrowicz R, Kubik L. Predictive power of increased QT dispersion in ventricular extrasystoles and in sinus beats for risk stratification after myocardial infarction. Circulation. 2000;101:1693–1697[Abstract/Free Full Text]
37. Armoundas AA, Osaka M, Mela T, et al. T-wave alternans and dispersion of the QT interval as risk stratification markers in patients susceptible to sustained ventricular arrhythmias. Am J Cardiol. 1998;82:1127–1129[CrossRef][Medline]
38. Fauchier L, Babuty D, Cosnay P, Fauchier JP. Prognostic value of heart rate variability for sudden death and major arrhythmic events in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1999;33:1203–1207[Abstract/Free Full Text]
39. Buxton AE, Marchlinski FE, Flores BT, Miller JM, Doherty JU, Josephson ME. Nonsustained ventricular tachycardia in patients with coronary artery disease: role of electrophysiologic study. Circulation. 1987;75:1178–1185[Abstract/Free Full Text]
40. Wilber DJ, Olshansky B, Moran JF, Scanlon PJ. Electrophysiological testing and nonsustained ventricular tachycardia: use and limitations in patients with coronary artery disease and impaired ventricular function. Circulation. 1990;82:350–358[Abstract/Free Full Text]
41. Gold MR, Bloomfield DM, Anderson KP, et al. A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification. J Am Coll Cardiol. 2000;36:2247–2253[Abstract/Free Full Text]
42. Hlatky MA, Bigger T. Cost-effectiveness of the implantable cardioverter defibrillator? Lancet. 2001;357:1817–1818[CrossRef][Medline]
43. Buxton AE, Lee KL, Hafley GE, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation. 2002;106:2466–2472[Abstract/Free Full Text]
44. Bailey JJ, Berson AS, Handelsman H, Hodges M. Utility of current risk stratification tests for predicting major arrhythmic events after myocardial infarction. J Am Coll Cardiol. 2001;38:1902–1911[Abstract/Free Full Text]
45. Welch HG, Albertsen PC, Nease RF, Bubolz TA, Wasson JH. Estimating treatment benefits for the elderly: the effect of competing risks. Ann Intern Med. 1996;124:577–584[Abstract/Free Full Text]

This article has been cited by other articles:

				Authors/Task Force Members, F. Van de Werf, J. Bax, A. Betriu, C. Blomstrom-Lundqvist, F. Crea, V. Falk, G. Filippatos, K. Fox, K. Huber, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology: Eur. Heart J., December 1, 2008; 29(23): 2909 - 2945. [Full Text] [PDF]

				K.-H. Ladwig, J. Baumert, B. Marten-Mittag, C. Kolb, B. Zrenner, and C. Schmitt Posttraumatic Stress Symptoms and Predicted Mortality in Patients With Implantable Cardioverter-Defibrillators: Results From the Prospective Living With an Implanted Cardioverter-Defibrillator Study Arch Gen Psychiatry, November 1, 2008; 65(11): 1324 - 1330. [Abstract] [Full Text] [PDF]

				J. K. Triedman Should patients with congenital heart disease and a systemic ventricular ejection fraction less than 30% undergo prophylactic implantation of an ICD?: Implantable Cardioverter Defibrillator Implantation Guidelines Based Solely on Left Ventricular Ejection Fraction Do Not Apply to Adults With Congenital Heart Disease Circ Arrhythmia Electrophysiol, October 1, 2008; 1(4): 307 - 316. [Full Text] [PDF]

				H. J. Wellens Forty Years of Invasive Clinical Electrophysiology: 1967-2007 Circ Arrhythmia Electrophysiol, April 1, 2008; 1(1): 49 - 53. [Full Text] [PDF]

				S. K H Lam and A. Owen Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials BMJ, November 3, 2007; 335(7626): 925 - 925. [Abstract] [Full Text] [PDF]

				D. S. Lee, J. V. Tu, P. C. Austin, P. Dorian, R. Yee, A. Chong, D. A. Alter, and A. Laupacis Effect of Cardiac and Noncardiac Conditions on Survival After Defibrillator Implantation J. Am. Coll. Cardiol., June 26, 2007; 49(25): 2408 - 2415. [Abstract] [Full Text] [PDF]

				E. B Friedrich and M. Bohm MANAGEMENT OF END STAGE HEART FAILURE Heart, May 1, 2007; 93(5): 626 - 631. [Full Text] [PDF]

				P. H. Pun, R. W. Lehrich, S. R. Smith, and J. P. Middleton Predictors of Survival after Cardiac Arrest in Outpatient Hemodialysis Clinics Clin. J. Am. Soc. Nephrol., May 1, 2007; 2(3): 491 - 500. [Abstract] [Full Text] [PDF]

				J. J. Bailey, M. Hodges, and T. R. Church Decision to Implant a Cardioverter Defibrillator after Myocardial Infarction: The Role of Ejection Fraction v. Other Risk Factor Markers Med Decis Making, March 1, 2007; 27(2): 151 - 160. [Abstract] [PDF]

				Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): 1064 - 1108. [Full Text] [PDF]

				Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]

				D. P. Zipes, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death--executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur. Heart J., September 1, 2006; 27(17): 2099 - 2140. [Full Text] [PDF]

				Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]

				C. M. Ripplinger, V. I. Krinsky, V. P. Nikolski, and I. R. Efimov Mechanisms of unpinning and termination of ventricular tachycardia Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H184 - H192. [Abstract] [Full Text] [PDF]