- Open Access
Debate: Do all patients with heart failure require implantable defibrillators to prevent sudden death?
© Current Controlled Trials Ltd 2000
- Received: 3 August 2000
- Accepted: 22 September 2000
- Published: 11 October 2000
Sudden death is a major cause of mortality in patients with ventricular dysfunction. The highest risk occurs among patients with less severe functional impairment. Current methods of risk stratification are inadequate, and a rational therapy for prevention of sudden death is not available. The implantable cardioverter-defibrillator (ICD) has proven to be more effective than drugs in reducing sudden-death risk in some subsets of patients. Empiric ICD therapy, targeting the general population with mild to moderate heart failure, will maximize the impact of such a strategy to prevent sudden death and improve long-term survival.
- heart failure
- sudden death
The causes of sudden death in heart failure are complex and poorly understood. A rational therapeutic strategy based on physiologic mechanisms is not available at this time. Recommendations for prevention of sudden death in patients with left ventricular dysfunction have evolved largely from the results of clinical trials [4,7]. Patient populations have, however, been highly diverse among these different studies, and formulating a consensus on a management strategy has therefore been difficult. Although several clinical variables have been associated with an increased cardiac mortality in patients with heart failure [8,9], major limitations remain in identifying the individual at highest risk of sudden death.
Risk stratification for sudden death using non-invasive methods or programmed stimulation is inadequate and, at best, limited to patients with coronary artery disease and non-sustained ventricular arrhythmia [10,11,12]. Importantly, preliminary analysis of outcomes in this subset of patients who participated in the Multicenter Unsustained Tachycardia Trial (MUSTT) and the Multicenter Automatic Defibrillator Implantation Trial (MADIT) suggests persistent high risk, even in those patients without inducible ventricular tachycardia. Moreover, ventricular programmed stimulation has proven to be of no value in patients with non-ischemic cardiomyopathy . Prevention of sudden death in patients with left ventricular dysfunction should thus be based on a logical strategy that optimizes effective pharmacologic and non-pharmacologic therapies.
The efficacy of angiotension-converting enzyme (ACE) inhibitors in decreasing overall mortality has been well established in populations with various degrees of myocardial systolic impairment. However, the impact of ACE inhibitors on sudden death rate is probably minimal [1,14,15].
Most trials using anti-arrhythmic drugs have resulted in worsening outcomes in the drug treatment arms , especially in patients with left ventricular dysfunction . The possible exception to this rule is amiodarone, which does not appear to have an adverse effect on either survival or heart failure. In the Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy (CHF-STAT), amiodarone did not reduce the incidence of sudden death or prolong survival . The Argentinean GESICA trial did show a reduction of total mortality with amiodarone compared with placebo. The relative risk reduction of sudden death was, however, insignificant . Other studies such as EMIAT  and CAMIAT  focused on patients with ischemic heart disease and prior myocardial infarction. These results suggested amiodarone may reduce arrhythmic death, but failed to improve survival. The conflicting outcomes of the studies evaluating amiodarone suggest that the protective beta-blocking effects of the drug may be offset by its pro-arrhythmia properties. The only drug class that convincingly reduces total mortality as well as the risk of sudden death has been beta-blockers. Relative reductions of cardiac death and sudden death in some trials ranged from 30 to 50%, and may involve mechanisms related to anti-ischemic, anti-fibrillatory effects of beta-blockade, neuro-endocrine deactivation or ventricular remodeling [21,22]. Previous studies involving high-risk patients, however, had consistently showed low rates of beta-blocker use (<50%) [11,12,23,24]. The utility of beta-blockers may be limited by bradyarrhythmias or worsening heart failure in patient populations with heart failure.
Non-pharmacological therapy has proven more effective in improving survival and reducing sudden death risk. The utility of the implantable defibrillators in 'secondary prevention' has been well established in patients resuscitated from cardiac arrest or syncopal ventricular tachycardia [23,24]. Those patients with highest risk appear to benefit most from ICD therapy . Importantly, the effectiveness of ICDs in primary prevention has also been established in the subgroup of patients with coronary artery disease and non-sustained ventricular tachycardia. MADIT was the first study to evaluate the prophylactic use of ICDs in patients with prior myocardial infarction, low ejection fraction, and inducible but non-suppressible ventricular arrhythmias. The use of ICDs is associated with a significant survival benefit compared with 'conventional' anti-arrhythmic drug therapy (mostly amiodarone) . MADIT has been criticized for its small sample size and the low rate of beta-blocker use in patients on 'conventional' therapy (5%) compared with the ICD arm (27%). However, this difference alone cannot mitigate the magnitude of mortality reduction (54%) observed in the defibrillator group.
The randomized, controlled MUSTT evaluated the utility of electrophysiologically guided therapy to reduce the risk of sudden death . The study included a larger patient population, but similar to that of the MADIT, and had a higher rate of beta-blockers and ACE inhibitor use among patients. MUSTT demonstrated that, in this relatively asymptomatic population, inducible sustained arrhythmia is associated with a substantial risk of dying suddenly, and therapy guided by electrophysiologic testing resulted in a significant reduction of sudden death. This survival benefit was, however, solely due to the use of defibrillators. Among patients who received defibrillators, there was no difference in sudden death rate based on beta-blocker use. It is also noteworthy that the 2-year mortality rate in patients who received defibrillators was similar in both MADIT and MUSTT, even though the rate of beta-blocker use in MUSTT was twice that in MADIT. These data confirm that the benefit of ICD therapy is independent of the beneficial effects of beta-blockers.
Other ongoing trials, such as the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation Trial (DEFINITE), will address the utility of prophylactic ICD therapy in the subset of patients with dilated cardiomyopathy and non-ischemic heart failure. The counterpart of DEFINITE for patients with coronary artery disease is the MADIT II trial, in which patients are randomized to either ICD or no anti-arrhythmic drug therapy. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) is the first heart failure trial focusing on prophylactic intervention for sudden death. It is unique because its entry criteria are based only on the presence of heart failure and low ejection fraction. Arrhythmia markers are not considered. Patients with either ischemic or non-ischemic cardiomyopathy are included in this study. Although we have been concerned that this study may not be powered sufficiently to identify a small, but nevertheless, important improvement in survival, we are optimistic, given the effectiveness of the ICD, that a positive outcome favoring ICD therapy will be forthcoming. Most of these ongoing trials included an empiric ICD arm and incorporated maximal heart failure therapy with ACE inhibitors and beta-blockers. At the conclusion of these trials, we should have a better understanding of which group of the high-risk patients will benefit most from ICD therapy.
With the current transvenous lead systems, defibrillator implantation can be now achieved with a brief (<24 h) hospital stay, and is associated with less than 1% mortality and minimal morbidity risk. Defibrillators can additionally provide sophisticated monitoring and diagnostic functions that allow one to more accurately assess arrhythmia recurrence and determine the mode of death. Furthermore, current generation devices are capable of providing a full range of physiologic pacing, which can facilitate the optimum utilization of beta-blocker therapy, potentially resulting in even greater synergistic benefits on improving survival. ICD therapy has also been shown to be cost-effective in long-term management of patients with life-threatening ventricular arrhythmias .
- Goldman S, Johnson G, Cohn JN, Cintron G, Smith R, Francis G: Mechanism of death in heart failure: The Vasodilator-Heart Failure Trial. Circulation. 1993, 87 (suppl VI): VI 24-VI 31.Google Scholar
- Kjekshus J: Arrhythmia and mortality in congestive heart failure. Am J Cardiol. 1990, 65: 421-481.View ArticleGoogle Scholar
- Groupo de Estudio de la Sobrevida en la Insufficiencia Cardiaca en Argentina (GESICA) : Randomized trial of low-does amiodarone in severe congestive heart failure. Lancet. 1994, 344: 493-498. 10.1016/S0140-6736(94)91895-3.View ArticleGoogle Scholar
- Uretsky BF, Sheahan RG: Primary prevention of sudden cardiac death in heart failure: will the solution be shocking?. J Am Coll Cardiol. 1997, 30: 1589-1597. 10.1016/S0735-1097(97)00361-6.View ArticlePubMedGoogle Scholar
- de Luna AB, Coumel P, Leclercq JF: Ambulatory sudden cardiac death: mechanism of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J. 1989, 177: 151-159.View ArticleGoogle Scholar
- Luu M, Stevenson WG, Stevenson LW, Baron K, Walden J: Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation. 1989, 80: 1675-1680.View ArticlePubMedGoogle Scholar
- Strobel JS, Epstein AE: Large clinical trials in the management of ventricular arrhythmias. In Cardiology Clinics. Edited by Miller JM. Philadelphia: W.B. Saunders,. 2000, 337-356.Google Scholar
- Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, Rector T, Smith R, Fletcher R: Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. Circulation. 1993, 87(suppl VI): VI 5-VI 16.Google Scholar
- Middlekauff HR, Stevenson WG, Stevenson LW, Saxon LA: Syncope in advanced heart failure: high risk of sudden death regardless of origin of syncope. J Am Coll Cardiol. 1993, 21: 110-116.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Moss AJ: Improved survival with an implanted defibrillator in patients with coronary artery disease at high risk for ventricular arrhythmia. N Engl J Med. 1996, 335: 1933-1940. 10.1056/NEJM199612263352601.View ArticlePubMedGoogle Scholar
- Buxton AE, Lee KL, Fisher JD, Gold MR, 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. 10.1056/NEJM199912163412503.View ArticlePubMedGoogle Scholar
- Poll DS, Marchlinski FE, Buxton AE, Josephson ME: Usefulness of programmed stimulation in idiopathic dilated cardiomyopathy. Am J Cardiol. 1986, 58: 992-997.View ArticlePubMedGoogle Scholar
- The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987, 316: 1429-1435.Google Scholar
- The SOLVD investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med. 1991, 325: 293-302.Google Scholar
- Teo KK, Yusuf S, Furberg CD: Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA. 1993, 270: 1589-1595. 10.1001/jama.270.13.1589.View ArticlePubMedGoogle Scholar
- Pratt CM, Eaton T, Francis M, Woolbert S, Mahmarian J, Roberts R, Young JB: The inverse relationship between baseline left ventricular ejection fraction and outcome of antiarrhythmic therapy: a dangerous imbalance in the risk-benefit ratio. Am Heart J. 1989, 118: 433-440.View ArticlePubMedGoogle Scholar
- Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, Massie BM, Colling C, Lazzeri D: Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med. 1995, 333: 77-82. 10.1056/NEJM199507133330201.View ArticlePubMedGoogle Scholar
- Julian DG: Randomized trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction. Lancet. 1997, 349: 667-674. 10.1016/S0140-6736(96)09145-3.View ArticlePubMedGoogle Scholar
- Cairns JA: Randomized trial of outcome after myocardial infarction in patients with frequent and repetitive ventricular premature depolarizations. Lancet. 1997, 349: 675-682. 10.1016/S0140-6736(96)08171-8.View ArticlePubMedGoogle Scholar
- Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996, 334: 1349-1355. 10.1056/NEJM199605233342101.View ArticlePubMedGoogle Scholar
- MERIT-HF Study Group: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999, 353: 2001-2007. 10.1016/S0140-6736(99)04440-2.Google Scholar
- 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. 10.1056/NEJM199711273372202.Google Scholar
- Connolly SJ: Canadian Implantable Defibrillator Study (CIDS). A randomized trial of the implantable defibrillator against amiodarone. Circulation. 2000, 101: 1297-1302.View ArticlePubMedGoogle Scholar
- Sheldon R, Connolly S, Krahn A, Roberts R, Gent M, Gardner M: Identification of patients most likely to benefit from the implantable cardioverter-defibrillator therapy: The Canadian Implantable Defibrillator Study. Circulation. 2000, 101: 1660-1664.View ArticlePubMedGoogle Scholar
- Stanton MS, Bell GK: Economic outcomes of implantable cardioverter-defibrillators. Circulation. 2000, 101: 1067-1074.View ArticlePubMedGoogle Scholar