(Circulation. 2007;115:2983-2989.)
© 2007 American Heart Association, Inc.
Controversies in Cardiovascular Medicine |
From the Heart Institute, Good Samaritan Hospital, and Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California (R.A.K.), and Cardiology Division, Good Samaritan Hospital, and Cardiology Division, University of California at Los Angeles School of Medicine (D.S.C.), Los Angeles.
Correspondence to Robert A. Kloner, MD, PhD, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017. E-mail rkloner{at}goodsam.org
| Introduction |
|---|
|
|
|---|
Response by Pitt and Pitt p 2989
Ventricular arrhythmias can occur in both the acute and chronic phases of acute myocardial infarction and can lead to sudden cardiac death (SCD). Reentrant arrhythmias may arise at the border zone of infarcts, causing monomorphic ventricular tachycardia that may occur years after the index infarction. Recurrent myocardial ischemia resulting in an unstable substrate may contribute to polymorphic ventricular tachycardia or ventricular fibrillation. Agents such as β-blockers that are anti-ischemic may reduce sudden death by quieting this unstable substrate. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable defibrillators were shown to reduce mortality in post–myocardial infarction patients with left ventricular dysfunction entirely due to a reduction in SCD.2 It is likely that these devices did not primarily improve the arrhythmic substrate. However, long-term cardiac resynchronization will encourage reverse remodeling that might reduce the substrate for arrhythmia.
| ACE Inhibitors and Angiotensin Receptor Blockers After Myocardial Infarction |
|---|
|
|
|---|
| β-Blockers After Myocardial Infarction |
|---|
|
|
|---|
2 years. Total mortality was 7.2% in the propranolol group and 9.8% in the placebo group (26% reduction). Sudden cardiac death occurred in 3.3% of the propranolol patients versus 4.6% of the placebo patients (28% reduction).14 A subset of 826 of these patients also had paired ambulatory ECG monitoring at baseline and after 6 weeks of therapy. An increase in ventricular arrhythmias over the 6-week period was blunted by propranolol.15 Some but not all studies in which other β-blockers were administered after myocardial infarction showed a reduction in SCD.16 Hjalmarson17 postulated that the more lipophilic β-blockers (timolol, metoprolol, propranolol) were more likely to demonstrate this benefit because they could penetrate the brain and maintain high vagal tone during stress, thus reducing ventricular fibrillation. Of course, it is also possible that the β-blockers are primarily reducing postinfarction ischemia, which would explain why they are antiarrhythmic. Although these findings represented a major advance, as pointed out by Fonarow et al,18 many of the earlier studies with β-blockers did not include patients with heart failure. The Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) study determined the effects of carvedilol added to standard therapy (including ACE inhibitors) for patients with an acute myocardial infarct who had an ejection fraction <0.40.19 More than 1900 patients with a mean ejection fraction of 0.33 were randomized to placebo or carvedilol and followed up for 15 months. Total mortality was reduced from 15.3% in the placebo group to 11.9% with carvedilol. SCD was reduced as well (Table 1). In the CAPRICORN study, sudden death occurred in 5% of carvedilol patients versus 7% of placebo patients (P=0.098).
|
| Aldosterone Antagonists After Myocardial Infarction |
|---|
|
|
|---|
40%). Therapy was started 3 to 14 days after acute myocardial infarction, and patients received placebo (n=3319) or eplerenone (25 mg/d; n=3313) for 4 weeks, after which the dose was increased to 50 mg/d. If the potassium concentration was >5.5 mmol/L, the dose of study drug was reduced or treatment stopped temporarily. Patients were already on standard optimal medical therapy including ACE inhibitors, angiotensin receptor blockers, β-blockers, diuretics, and reperfusion therapy. Follow-up was for 16 months. Fewer patients died in the eplerenone group (478; 14.4%) than in the placebo group (554 patients; 16.7%; relative risk [RR]=0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008). Death due to cardiovascular causes occurred in 407 patients in the eplerenone group versus 483 patients in the placebo group (RR=0.83; 95% CI, 0.72 to 0.94; P=0.005). Sudden death from cardiac causes occurred in 162 of the eplerenone group versus 201 in the placebo group (RR=0.79; 95% CI, 0.64 to 0.97; P=0.03). Death from cardiovascular causes or hospitalization for cardiovascular events, death from any cause or any hospitalization, and hospitalization for heart failure were also reduced by eplerenone. At 1 year, potassium levels increased by 0.2 mmol/L in placebo-treated patients versus 0.3 mmol/L in the eplerenone group (P<0.001). Serious hypokalemia (potassium <3.5 mmol/L) occurred in 8.4% of eplerenone patients versus 13.1% in the placebo group (P<0.001). Hyperkalemia, with a serum potassium level
6.0 mmol/L, occurred in 5.5% of eplerenone-treated versus 3.9% of placebo-treated patients (P=0.002). Twelve patients in the eplerenone group versus 3 in the placebo group were hospitalized for the condition; 1 patient in the placebo group died of the condition. A number of proposed mechanisms for the reduction in mortality in the eplerenone group were suggested, including effects of eplerenone on plasma volume and electrolyte excretion, reductions in coronary vascular inflammation, improvements in endothelial function, attenuation of platelet aggregation, improvements in ventricular remodeling with a decrease in activation of matrix metalloproteinases, and a decrease in interstitial fibrosis. Besides these direct effects on the vasculature and myocardium, the authors pointed out that aldosterone blockade decreased sympathetic drive in experimental animal studies, improved norepinephrine uptake in heart failure victims, and improved heart rate variability.
One of the simplest explanations for the benefit of eplerenone in reducing sudden death is its prevention of hypokalemia, a known trigger of ventricular arrhythmias, especially in patients also taking digitalis preparations. In a letter to the editor, Coca and Buller21 raised the issue that the 21% decrease in the rate of sudden death from cardiac causes associated with eplerenone in the EPHESUS trial may have been attributable to the reduction of hypokalemia. However, Pitt responded that "a preliminary analysis of data from EPHESUS reveals a significant reduction in the risk of sudden death from cardiac causes, which is independent of the effects of eplerenone in preventing hypokalemia." It is still conceivable that some of the benefit of eplerenone in reducing sudden death was related to preventing hypokalemia. Subsequent analyses revealed that eplerenone reduced the risk of sudden death by 33%22 in patients with baseline left ventricular ejection fraction of
30% and that eplerenone reduced the early incidence of sudden death by 37% within 30 days of randomization in this trial.23
Although the results show that eplerenone reduced sudden death in the post–myocardial infarction patients with left ventricular dysfunction, many questions in this field remain unanswered. Was this benefit primarily due to a reduction in hypokalemia? Would eplerenone provide this benefit to patients with heart failure but not in the post–myocardial infarction setting? Would eplerenone benefit patients with heart failure who had automatic implantable defibrillators and/or patients with biventricular pacing for cardiac resynchronization therapy?
| Aldosterone Antagonists in Patients With Chronic Heart Failure |
|---|
|
|
|---|
35% who were already on an ACE inhibitor, a loop diuretic, and in many cases digoxin. Patients were randomized to 25 mg of the aldosterone antagonist spironolactone (n=822) versus placebo (n=841). The study was stopped at 24 months with 386 deaths (46%) in the patients receiving placebo versus 284 deaths (35%) in the spironolactone group (RR of death=0.70; 95% CI, 0.60 to 0.82; P<0.001). Spironolactone was associated with a lower risk of death from progressive heart failure as well as a lower rate of sudden death. Sudden death due to cardiac cause occurred in 82 of 822 spironolactone-treated patients versus 110 of 841 placebo-treated patients (RR=0.71; 95% CI, 0.54 to 0.95; P=0.02). Spironolactone also reduced all cardiac causes for hospitalization as well as hospitalization for worsening heart failure. The median potassium concentration increased by 0.30 mmol/L in the spironolactone group but did not increase in the placebo group. Serious hyperkalemia was observed in 10 placebo patients (1%) and 14 spironolactone patients (2%; P=NS). Again, although the exact mechanism by which the aldosterone antagonist reduced SCD in RALES is unknown, prevention of hypokalemia cannot be ruled out entirely, despite the rather small increase in potassium levels in the treated group. In addition, it is unknown whether spironolactone could also reduce sudden death in post–myocardial infarction patients with left ventricular dysfunction with or without clinical congestive heart failure or in patients already receiving automatic implantable cardioverter-defibrillators (ICDs) and/or biventricular pacing for resynchronization therapy.
A small study by Ramires et al25 randomized 35 patients with class III congestive heart failure due to dilated or ischemic cardiomyopathy and mean ejection fraction of 33% to spironolactone in addition to standard medical therapy for 16 weeks. Spironolactone was initiated at 50 mg/d until week 12 and then was decreased to 25 mg/d until the end of 16 weeks. After 16 weeks, ambulatory ECG monitoring revealed a lower frequency of ventricular premature beats and episodes of nonsustained ventricular tachycardia in the spironolactone group compared with the control group. Spironolactone was also associated with an improvement in ventricular arrhythmias during treadmill exercise. The authors observed that before administration of spironolactone and after adjustment for baseline drug therapy, there was a reduction in serum sodium, potassium, and magnesium that was corrected after 16 weeks of spironolactone therapy. The authors postulated that "a possible explanation for the reduced frequency of ventricular arrhythmia could be related to electrolyte regulation promoted by spironolactone in combination with ACE inhibitors." They described the concern that hypokalemia could have contributed to increased arrhythmias in the setting of digoxin, which was then corrected by the aldosterone antagonist.
Clinical trials are currently lacking of patients with chronic heart failure (not related to the postinfarct setting) who received eplerenone. Table 1 summarizes some recent key randomized trials of nonantiarrhythmic drugs and their effect on SCD.26 Several agents used for the treatment of heart failure (as well as hypertension) have demonstrated this benefit: β-blockers, ACE inhibitors, and aldosterone antagonists. Again, a host of mechanisms have been postulated, including improvements in ventricular remodeling and endothelial function, a reduction in sympathetic tone, and improved electrolyte balance, including less hypokalemia with ACE inhibitors and aldosterone antagonists.
For all the aforementioned studies, the assessment of whether the precise cause of death is arrhythmic or due to heart failure, recurrent infarction, or other causes is very difficult. The ICD randomized trials have used total mortality as the end point precisely because retrospective analysis of an individual death is so difficult. Therefore, studies with β-blockers, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists that claim to demonstrate a reduction in sudden death need to be interpreted cautiously and with the realization that all deaths, in a sense, are sudden. It is feasible that the mechanisms of benefit of agents including eplerenone and spironolactone may be directly antiarrhythmic, indirectly antiarrhythmic (for example, preventing hypokalemia), or due to a change in the cardiac substrate (for example, an anti-ischemic effect or a reduction in ventricular remodeling). The studies with the aldosterone antagonists to date do not clarify which of these mechanisms is most likely.
| Aldosterone Antagonists in ICD and Cardiac Resynchronization Trials |
|---|
|
|
|---|
|
To conclusively determine whether aldosterone antagonists confer additional benefit on reducing SCDs in patients with ICDs, one would need to design a study in which patients with ICDs (and preferably a group without ICDs as well) were randomized to aldosterone antagonists versus placebo in addition to the usual heart failure medicines. Unfortunately, and to the best of our knowledge, such a study has not been performed. We have been able to obtain some observational retrospective data from MADIT II and the COMPANION trial that address this issue to some extent. We briefly present our findings, realizing that limitations exist that must be kept in mind when these data are viewed. The limitations of this analysis include the following: a lack of randomization for the use of spironolactone; a relatively small number of patients who were assigned to spironolactone, which resulted in the studies not being powered to definitely answer the question about a benefit of aldosterone antagonists in patients already treated with ICD, cardiac resynchronization therapy [CRT], or both; the possible presence of a type II or β error; and the possibility of confounding biases. For example, patients assigned to spironolactone may have been sicker. The analyses below are retrospective and must be considered exploratory and hypothesis generating, not definitive. However, when we were assigned the topic of presenting the "con" side of the aldosterone antagonist argument by Circulation, we tried to find all available data on this concept. Therefore, we briefly present our findings below, and we are not aware of more definitive data at the time of this writing.
Although there has been little use of spironolactone in the ICD trials, the MADIT II Investigators have kindly provided new data on the issue of the possible effects of spironolactone in this trial (S. McNit, MS, and J. Hall, PhD, written communication, 2006). MADIT II was a study of 1232 patients with a prior myocardial infarction (
8 years) and a reduced left ventricular ejection fraction (
0.30). Patients were randomized to receive an implantable defibrillator or conventional medical therapy.35 No attempt was made to risk stratify by invasive electrophysiological testing. The primary end point was death from any cause. During an average of 20 months of follow-up, the mortality rates were 14.2% in the ICD group versus 19.8% in the conventional medical therapy group, representing a 31% reduction in the risk of death in the ICD patients (hazard ratio [HR]=0.69; 95% CI, 0.51 to 0.93; P=0.016). The conclusion of these investigators was that prophylactic implantation of a defibrillator improved survival and should be considered as therapy for patients with prior myocardial infarction and poor left ventricular dysfunction.
At study commencement (in which patients were randomized in a 3:2 ratio to ICD versus conventional therapy), 101 patients (13.6%) randomized to ICD treatment were receiving spironolactone, and 57 (11.6%) in the conventional arm were receiving this drug. Spironolactone use was analyzed as a time-varying risk factor in proportional hazards regression analysis of the various end points in MADIT II. Because of the clinical suspicion that spironolactone may have been used as a result of a hospitalization for heart failure, the first occurrence of heart failure was also used as a time-dependent factor.40 The HR for all-cause mortality for patients while on spironolactone compared with patients and periods not on spironolactone was 1.13 (P=0.53). Thus, no overall effect of spironolactone use on all-cause mortality was found in MADIT II. The HR for spironolactone for all-cause mortality in the conventional medical arm was 1.43 versus 0.90 in the ICD arm (P=0.23 for difference).
The HR for spironolactone for sudden death in the conventional arm was 1.13 (P=0.76). The HR for spironolactone for first appropriate shock in the ICD arm was 1.51 (P=0.07). The HR for spironolactone for either first appropriate shock or death in the ICD arm was 1.20 (P=0.34). Most of the HRs for spironolactone exceeded unity, suggesting a trend toward an increased risk of the end point occurring when the patients were on the drug relative to being off the drug. However, drug usage could be a proxy for heart failure risk or severity of heart failure. In summary, on the basis of a retrospective analysis, the MADIT II trial produces no evidence that spironolactone provides a benefit.
Supporting evidence is provided by the COMPANION trial along similar lines. The COMPANION trial randomized >1500 New York Heart Association class III/IV heart failure patients with a prolonged QRS and ejection fraction
35% to optimal medical therapy, optimal medical therapy plus CRT, or optimal medical therapy plus CRT plus an ICD. Both CRT and CRT plus an ICD reduced combined all-cause mortality and hospitalization in heart failure patients. CRT plus an ICD reduced all-cause mortality; CRT alone had a trend toward reduced mortality.
In the COMPANION trial, 55% of patients were treated with spironolactone, and this was not associated with risk of death in any treatment group and did not protect against appropriate shocks in the patients with CRT plus an ICD. However, β-blockers and ACE inhibitors did afford such protection (L. Saxon, MD, written communication, 2006, and Saxon et al41).
| Summary |
|---|
|
|
|---|
| Acknowledgments |
|---|
Dr Kloner is a consultant and speaker for Pfizer. Dr Cannom is a consultant and speaker for Medtronic and Boston Scientific.
| References |
|---|
|
|
|---|
2. Goldenberg H, Moss AJ, Hall WJ, McNitt S, Zareba W, Andrews ML, Cannom DS; for the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II Investigators. Causes and consequences of heart failure after prophylactic implantation of a defibrillator in the MADIT II. Circulation. 2006; 113: 2810–2817.
3. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM; on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med. 1992; 327: 669–677.[Abstract]
4. St John Sutton M, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation. 1997; 96: 3294–3299.
5. Gruppo Italiano per lo Studio della Sopravvivenza nellinfarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994; 343: 1115–1122.[Medline] [Order article via Infotrieve]
6. Torp-Pedersen C, Kober L; TRACE Study Group. Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction: Trandolapril Cardiac Evaluation. Lancet. 1999; 354: 9–12.[CrossRef][Medline] [Order article via Infotrieve]
7. Kingma JH, van Gilst WH, Peels CH, Dambrink JH, Verheugt FW, Wielenga RP. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction: results from the Captopril and Thrombolysis Study (CATS). Eur Heart J. 1994; 15: 898–907.
8. van Gilst WH, Kingma JH, Peels KH, Dambrink JH, St John Sutton M. Which patient benefits from early angiotensin-converting enzyme inhibition after myocardial infarction? Results of one-year serial echocardiographic follow-up from the Captopril and Thrombolysis Study (CATS). J Am Coll Cardiol. 1996; 28: 114–121.[Abstract]
9. Hall AS, Murray GD, Ball SG. Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) Study: Acute Infarction Ramipril Efficacy. Lancet. 1997; 349: 1493–1497.[CrossRef][Medline] [Order article via Infotrieve]
10. Pfeffer MA, Greaves SC, Arnold JM, Glynn RJ, LaMotte FS, Lee RT, Menapace FJ Jr, Rapaport E, Ridker RM, Rouleau JL, Solomon SD, Hennekens CH. Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction: the healing and early afterload reducing therapy trial. Circulation. 1997; 95: 2643–2651.
11. Borghi C, Marino P, Zardini P, Magnani B, Collatina S, Ambrosioni E; FAMIS Working Party. Short- and long-term effects of early fosinopril administration in patients with acute anterior myocardial infarction undergoing intravenous thrombolysis: results from the Fosinopril in Acute Myocardial Infarction Study. Am Heart J. 1998; 136: 213–225.[CrossRef][Medline] [Order article via Infotrieve]
12. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003; 349: 1893–1906.
13. Dickstein K, Kjekshus J; OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial: Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet. 2002; 360: 752–760.[CrossRef][Medline] [Order article via Infotrieve]
14. A randomized trial of propranolol in patients with acute myocardial infarction, I: mortality results. JAMA. 1982; 247: 1707–1714.
15. Lichstein E, Morganroth J, Harrist R, Hubble E. Effect of propranolol on ventricular arrhythmia: the Beta-Blocker Heart Attack Trial experience. Circulation. 1983; 67 (6 pt 2): I5–10, 1983.
16. A multicenter study on timolol in secondary prevention after myocardial infarction. Acta Med Scand Suppl. 1983; 674: 1–129.[Medline] [Order article via Infotrieve]
17. Hjalmarson A. Effect of beta blockade on sudden cardiac death during acute myocardial infarction and the postinfarction period. Am J Cardiol. 1997; 80: 35J–39J.[CrossRef][Medline] [Order article via Infotrieve]
18. Fonarow GC, Abraham WT, Cannon CP, Gheorghiade M, Sackner-Bernstein JD, Vdelson JE. Role of β-blocker therapy in the post-myocardial infarction patient with and without left ventricular dysfunction: the post-myocardial infarction guideline committee. Rev Cardiovasc Med. 2003; 4 (suppl 3): S54–S59.[CrossRef][Medline] [Order article via Infotrieve]
19. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomized trial. Lancet. 2001; 357: 1385–1390.[CrossRef][Medline] [Order article via Infotrieve]
20. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 48: 1309–1321.
21. Coca SG, Buller GK. Eplerenone in patients with left ventricular dysfunction. N Engl J Med. 2003; 349: 88.[CrossRef][Medline] [Order article via Infotrieve]
22. Pitt B, Gheorghiade M, Zannad F, Anderson JL, van Veldhuisen DJ, Parkhomenko A, Corbalan R, Klug EQ, Mukherjee R, Solomon H; on behalf of the EPHESUS Investigators. Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction < or=30%. Eur J Heart Fail. 2006; 8: 295–301.
23. Pitt B, White H, Nicolau J, Martinez F, Gheorghiade M, Aschermann M, van Veldhuisen DJ, Zannad F, Krum H, Mukherjee R, Vincent J; EPHESUS Investigators. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. 2005; 46: 425–431.
24. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341: 709–717.
25. Ramires FJ, Mansur A, Coelho O, Maranhao M, Gruppi CJ, Mady C, Ramires JA. Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol. 2000; 85: 1207–1211.[CrossRef][Medline] [Order article via Infotrieve]
26. Richter S, Duray G, Gronefeld G, Israel CW, Hohnloser SH. Prevention of sudden cardiac death: lessons from recent controlled trials. Circ J. 2005; 69: 625–629.[CrossRef][Medline] [Order article via Infotrieve]
27. Cannom DS, Prystowsky EN. The evolution of the implantable cardioverter defibrillator. Pacing Clin Electrophysiol. 2004; 27: 419–431.[CrossRef][Medline] [Order article via Infotrieve]
28. McMurray J, Kober L, Robertson M, Dargie H, Colucci W, Lopez-Sendon J, Remme W, Sharpe DN, Ford I. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. J Am Coll Cardiol. 2005; 45: 525–530.
29. The Heart Outcomes Prevention Evaluation Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153.
30. Domanski MJ, Exner DV, Borkow CB, Geller NL, Rosenberg Y, Pfeffer MA. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 1999; 33: 598–604.
31. Teo KK, Mitchell LB, Pogue J, Bosch J, Dagennals G, Yusef S. Effect of ramipril in reducing sudden deaths and nonfatal cardiac arrests in high-risk individuals without heart failure and left ventricular dysfunction. Circulation. 2004; 110: 1413–1417.
32. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M; for the Multicenter Automatic Defibrillator Implantation Trial Investigators. 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.
33. Bigger JT; for the CABG Patch Trial Investigators. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary artery bypass graft surgery. N Engl J Med. 1997; 337: 1569–1575.
34. Lee KI, Hafley G, Fisher JD, Gold MR, Prystowsky EN, Talajie M, Josephson ME, Packer DL, Buxton AE; for the Multicenter Unsustained Tachycardia Trial Investigators. Effect of implantable defibrillators on arrhythmic events and mortality in the Multicenter Unsustained Tachycardia Trial. Circulation. 2002; 106: 233–238.
35. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML; for the Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346: 877–883.
36. Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, Fain E, Gent M, Connolly SJ; DINAMIT Investigators. Randomized trial of prophylactic implantable cardioverter defibrillator after acute myocardial infarction. N Engl J Med. 2004; 351: 2481–2488.
37. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, DeMarco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; for the Comparison of Medical Therapy Pacing and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350: 2340–2350.
38. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH; for the Sudden Cardiac Death in Heart Failure (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005; 352: 225–237.
39. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NAM, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH; for the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004; 350: 2151–2158.
40. Cox DR. Regression models with life tables (with discussion). J Roy Statist Soc B. 1972; 34: 187–220.
41. Saxon LA, Bristow MR, Boehner J, Krueger S, Kass DA, DeMarco T, Carson P, DiCarlo L, Feldman AM, Galle E, Ecklund F. Predictors of sudden cardiac death and appropriate shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial. Circulation. 2006; 114: 2766–2772.
| Footnotes |
|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2007 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |