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Effect of Beta Blockers, Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers, and Statins on Mortality in Patients With Implantable Cardioverter-Defibrillators
Effect of Beta Blockers, Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers, and Statins on Mortality in Patients With Implantable Cardioverter-Defibrillators Hoang M. Lai, MD, Wilbert S. Aronow, MD*, Adam Kruger, MD, Harit Desai, MD, Harshad Amin, MD, William H. Frishman, MD, Martin Cohen, MD, and Carmine Sorbera, MD Nine hundred sixty-five patients (mean age 70 years) with implantable cardioverterdefibrillator were followed for 32 ⴞ 33 months for all-cause mortality. Death occurred in 73 of 515 patients (13%) treated with  blockers (group 1), in 84 of 494 patients (17%) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (group 2), in 56 of 402 patients (14%) treated with statins (group 3), in 40 of 227 patients (18%) treated with amiodarone (group 4), in 5 of 26 patients (19%) treated with sotalol (group 5), and in 64 of 265 patients (24%) treated with no  blocker, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, statin, amiodarone, or sotalol (group 6) (p <0.001 for group 1 vs group 6 and group 3 vs group 6, p <0.02 for group 2 vs group 6). In conclusion, patients with implantable cardioverter-defibrillators should be treated with  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins to reduce mortality. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008; 102:77–78) The use of  blockers,1–3 angiotensin-converting enzyme (ACE) inhibitors,2 and statins4 has been reported in nonrandomized studies to be associated with significant reductions in the risk for cardiac death in patients with implantable cardioverter-defibrillators (ICDs). Sotalol and amiodarone had a neutral effect on survival.3 We found that appropriate ICD shocks occurred in 324 of 1,038 patients (31%) who had ICDs at 33-month follow-up.5 Here we report the association of the use of  blockers, ACE inhibitors or angiotensin receptor blockers (ARBs), statins, amiodarone, and sotalol with all-cause mortality in 965 patients with ICDs at a mean follow-up of 32 months. Methods and Results We investigated in an observational, retrospective, singlecenter study the association of use of  blockers, ACE inhibitors or ARBs, statins, amiodarone, sotalol, and no  blockers, ACE inhibitors or angiotensin receptor blockers, statins, amiodarone, or sotalol with all-cause mortality in 965 patients who received ICDs at an academic cardiology practice. There were no exclusion or inclusion criteria. The 965 patients included 778 men and 187 women (mean age 70 ⫾ 14 years). The mean follow-up period was 32 ⫾ 33 months. All 965 patients had measurements of left ventricular (LV) ejection fractions using 2-dimensional echocardiography. An LV ejection fraction ⬍50% was considered reduced.6 The manufacturers of the ICDs were Medtronic, Inc. (Minneapolis, Minnesota; 56% of the ICDs), Guidant Corporation (Indianapolis, Indiana; Department of Medicine, Cardiology Division, New York Medical College, Valhalla, New York. Manuscript received January 21, 2008; revised manuscript received and accepted February 26, 2008. *Corresponding author: Tel: 914-493-5311; fax: 914-235-6274. E-mail address: [email protected] (W.S. Aronow). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.02.103
44% of the ICDs), and St. Jude Medical, Inc. (St. Paul, Minnesota; ⬍1% of the ICDs). The use or nonuse of  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol was prescribed by the cardiologists following their patients according to their clinical judgment. Therapy was started at the beginning of the study and continued through the study. Of the 575 patients receiving  blockers, 301 (52%) were treated with carvedilol and 274 (48%) with metoprolol controlled release/ extended release. Patients were not treated with ACE inhibitors plus ARBs. There were no significant differences in clinical characteristics, cardiovascular risk factors, and LV ejection fractions between the 6 different treatment groups. Student’s t tests were used to analyze continuous variables. Chi-square tests were used to analyze dichotomous variables. Death occurred in 208 of 965 patients (22%). Death occurred in 199 of 871 patients (23%) with reduced LV ejection fractions and in 9 of 94 patients (10%) with normal LV ejection fractions (p ⬍0.005). Table 1 lists the incidence of all-cause mortality in patients treated with  blockers, with ACE inhibitors or ARBs, with statins, with amiodarone, with sotalol, and with no  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol. Table 1 also lists levels of statistical significance. Table 2 lists the incidence of all-cause mortality in patients with ischemic cardiomyopathy treated with  blockers, with ACE inhibitors or ARBs, with statins, with amiodarone, with sotalol, and with no  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol. Table 2 also lists levels of statistical significance. Table 3 lists the incidence of all-cause mortality in patients with nonischemic cardiomyopathy treated with  blockers, with ACE inhibitors or ARBs, with statins, with amiodarone, with sotalol, and with no  blockers, ACE www.AJConline.org
78
The American Journal of Cardiology (www.AJConline.org)
Table 1 Incidence of all-cause mortality in patients with implantable cardioverter-defibrillators treated with  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, sotalol, and no  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, or sotalol Drug
Mortality
 blockers (n ⫽ 575; group 1) ACE inhibitors or ARBs (n ⫽ 494; group 2) Statins (n ⫽ 402; group 3) Amiodarone (n ⫽ 227; group 4) Sotalol (n ⫽ 26; group 5) No  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol (n ⫽ 265; group 6)
73 (13%) 84 (17%) 56 (14%) 40 (18%) 5 (19%) 64 (24%)
p ⬍0.001 for group 1 versus group 6 and group 3 versus group 6; p ⬍0.02 for group 2 versus group 6. Table 2 Incidence of all-cause mortality in patients with ischemic cardiomyopathy with implantable cardioverter-defibrillators treated with  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, sotalol, and no  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, or sotalol Drug
Mortality
 blockers (n ⫽ 404; group 1) ACE inhibitors or ARBs (n ⫽ 336; group 2) Statins (n ⫽ 315; group 3) Amiodarone (n ⫽ 158; group 4) Sotalol (n ⫽ 16; group 5) No  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol (n ⫽ 162; group 6)
54 (13%) 58 (17%) 44 (14%) 29 (18%) 3 (19%) 42 (26%)
p ⬍0.005 for group 3 versus group 6; p ⬍0.01 for group 1 versus group 6; p ⬍0.025 for group 2 versus group 6. Table 3 Incidence of all-cause mortality in patients with nonischemic cardiomyopathy with implantable cardioverter-defibrillators treated with  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, sotalol, and no  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, or sotalol Drug
Mortality
 blockers (n ⫽ 171; group 1) ACE inhibitors or ARBs (n ⫽ 158; group 2) Statins (n ⫽ 87; group 3) Amiodarone (n ⫽ 69; group 4) Sotalol (n ⫽ 10; group 5) No  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol (n ⫽ 103; group 6)
19 (11%) 26 (16%) 12 (14%) 11 (16%) 2 (20%) 22 (21%)
p ⬍0.025 for group 1 versus group 6.
inhibitors or ARBs, statins, amiodarone, or sotalol. Table 3 also lists levels of statistical significance. Appropriate ICD shocks occurred in 150 of 575 patients (26%) treated with -adrenergic blockers and in 101 of 265 patients (38%) treated with no  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol (p ⬍0.001).
Discussion To the best of our knowledge, no randomized studies have investigated the incidence of all-cause mortality in patients with ICDs treated with  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol. Nonrandomized studies have shown that  blockers significantly reduce mortality in patients with ICDs by 56% to 58%,1 by 57%,2 and by 72%.3 A nonrandomized study reported that ACE inhibitors significantly reduced mortality in patients with ICDs by 22%.2 A nonrandomized study showed that statins significantly reduced cardiac death or ventricular tachycardia or ventricular fibrillation by 35%.4 Amiodarone and sotalol were found to have a neutral effect on survival.3 The data from our nonrandomized study are in agreement with the previously reported data.1– 4 We demonstrated significant reductions in all-cause mortality in our patients with ICDs of 46% in those treated with  blockers, 29% in those treated with ACE inhibitors or ARBs, and 42% in those treated with statins. Amiodarone and sotalol had no significant effect on mortality. Our patients with ischemic cardiomyopathy treated with ICDs showed a 50% significant reduction in mortality in those treated with  blockers, a 46% significant reduction in mortality in those treated with statins, and a 35% significant reduction in mortality in those treated with ACE inhibitors or ARBs. Our patients with nonischemic cardiomyopathy treated with ICDs showed a 48% significant reduction in mortality in those treated with  blockers, a 33% nonsignificant reduction in mortality in those treated with statins, and a 24% nonsignificant reduction in mortality in those treated with ACE inhibitors or ARBs. Randomized clinical trials need to be performed to confirm the validity of previously published data1– 4 and of our data. However, until these data are available, we recommend treating patients with ICDs with  blockers, ACE inhibitors or ARBs, and statins, especially those with ischemic cardiomyopathy. 1. Brodine WN, Tung RT, Lee JK, Hockstad ES, Moss AJ, Zareba W, Hall WJ, Andrews M, McNitt S, Daubert JP, for the MADIT-II Research Group. Effects of beta-blockers on implantable cardioverter defibrillator therapy and survival in the patients with ischemic cardiomyopathy (from the Multicenter Automatic Defibrillator Implantation Trial-II). Am J Cardiol 2005;96:691– 695. 2. Tandri H, Griffith LS, Tang T, Nasir K, Zardkoohi O, Reddy CV, Capps M, Calkins H, Donahue JK. Clinical course and long-term follow-up of patients receiving implantable cardioverter-defibrillators. Heart Rhythm 2006;3:762–768. 3. Ho AT, Pai SM, Timothy P, Pai RG. Effect of concomitant antiarrhythmic therapy on survival in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2005;28:647– 653. 4. Vyas AK, Guo H, Moss AJ, Olshansky B, McNitt SA, Hall WJ, Zareba W, Steinberg JS, Fischer A, Ruskin J, Andrews ML, for the MADIT-II Research Group. Reduction in ventricular tachyarrhythmias with statins in the Multicenter Automatic Defibrillator Implantation trial (MADIT)II. J Am Coll Cardiol 2006;47:769 –773. 5. Kruger A, Aronow WS, Lai HM, Desai H, Singla A, Frishman WH, Cohen M, Sorbera C. Prevalence of appropriate cardioverter-defibrillator shocks in 1,038 consecutive patients with implantable cardioverterdefibrillators. Am J Ther. In press. 6. Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure after prior myocardial infarction in older men and women with abnormal versus normal left ventricular ejection fraction. Am J Cardiol 2000;85:1382–1384.
44% of the ICDs), and St. Jude Medical, Inc. (St. Paul, Minnesota; ⬍1% of the ICDs). The use or nonuse of  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol was prescribed by the cardiologists following their patients according to their clinical judgment. Therapy was started at the beginning of the study and continued through the study. Of the 575 patients receiving  blockers, 301 (52%) were treated with carvedilol and 274 (48%) with metoprolol controlled release/ extended release. Patients were not treated with ACE inhibitors plus ARBs. There were no significant differences in clinical characteristics, cardiovascular risk factors, and LV ejection fractions between the 6 different treatment groups. Student’s t tests were used to analyze continuous variables. Chi-square tests were used to analyze dichotomous variables. Death occurred in 208 of 965 patients (22%). Death occurred in 199 of 871 patients (23%) with reduced LV ejection fractions and in 9 of 94 patients (10%) with normal LV ejection fractions (p ⬍0.005). Table 1 lists the incidence of all-cause mortality in patients treated with  blockers, with ACE inhibitors or ARBs, with statins, with amiodarone, with sotalol, and with no  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol. Table 1 also lists levels of statistical significance. Table 2 lists the incidence of all-cause mortality in patients with ischemic cardiomyopathy treated with  blockers, with ACE inhibitors or ARBs, with statins, with amiodarone, with sotalol, and with no  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol. Table 2 also lists levels of statistical significance. Table 3 lists the incidence of all-cause mortality in patients with nonischemic cardiomyopathy treated with  blockers, with ACE inhibitors or ARBs, with statins, with amiodarone, with sotalol, and with no  blockers, ACE www.AJConline.org
78
The American Journal of Cardiology (www.AJConline.org)
Table 1 Incidence of all-cause mortality in patients with implantable cardioverter-defibrillators treated with  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, sotalol, and no  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, or sotalol Drug
Mortality
 blockers (n ⫽ 575; group 1) ACE inhibitors or ARBs (n ⫽ 494; group 2) Statins (n ⫽ 402; group 3) Amiodarone (n ⫽ 227; group 4) Sotalol (n ⫽ 26; group 5) No  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol (n ⫽ 265; group 6)
73 (13%) 84 (17%) 56 (14%) 40 (18%) 5 (19%) 64 (24%)
p ⬍0.001 for group 1 versus group 6 and group 3 versus group 6; p ⬍0.02 for group 2 versus group 6. Table 2 Incidence of all-cause mortality in patients with ischemic cardiomyopathy with implantable cardioverter-defibrillators treated with  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, sotalol, and no  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, or sotalol Drug
Mortality
 blockers (n ⫽ 404; group 1) ACE inhibitors or ARBs (n ⫽ 336; group 2) Statins (n ⫽ 315; group 3) Amiodarone (n ⫽ 158; group 4) Sotalol (n ⫽ 16; group 5) No  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol (n ⫽ 162; group 6)
54 (13%) 58 (17%) 44 (14%) 29 (18%) 3 (19%) 42 (26%)
p ⬍0.005 for group 3 versus group 6; p ⬍0.01 for group 1 versus group 6; p ⬍0.025 for group 2 versus group 6. Table 3 Incidence of all-cause mortality in patients with nonischemic cardiomyopathy with implantable cardioverter-defibrillators treated with  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, sotalol, and no  blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, amiodarone, or sotalol Drug
Mortality
 blockers (n ⫽ 171; group 1) ACE inhibitors or ARBs (n ⫽ 158; group 2) Statins (n ⫽ 87; group 3) Amiodarone (n ⫽ 69; group 4) Sotalol (n ⫽ 10; group 5) No  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol (n ⫽ 103; group 6)
19 (11%) 26 (16%) 12 (14%) 11 (16%) 2 (20%) 22 (21%)
p ⬍0.025 for group 1 versus group 6.
inhibitors or ARBs, statins, amiodarone, or sotalol. Table 3 also lists levels of statistical significance. Appropriate ICD shocks occurred in 150 of 575 patients (26%) treated with -adrenergic blockers and in 101 of 265 patients (38%) treated with no  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol (p ⬍0.001).
Discussion To the best of our knowledge, no randomized studies have investigated the incidence of all-cause mortality in patients with ICDs treated with  blockers, ACE inhibitors or ARBs, statins, amiodarone, or sotalol. Nonrandomized studies have shown that  blockers significantly reduce mortality in patients with ICDs by 56% to 58%,1 by 57%,2 and by 72%.3 A nonrandomized study reported that ACE inhibitors significantly reduced mortality in patients with ICDs by 22%.2 A nonrandomized study showed that statins significantly reduced cardiac death or ventricular tachycardia or ventricular fibrillation by 35%.4 Amiodarone and sotalol were found to have a neutral effect on survival.3 The data from our nonrandomized study are in agreement with the previously reported data.1– 4 We demonstrated significant reductions in all-cause mortality in our patients with ICDs of 46% in those treated with  blockers, 29% in those treated with ACE inhibitors or ARBs, and 42% in those treated with statins. Amiodarone and sotalol had no significant effect on mortality. Our patients with ischemic cardiomyopathy treated with ICDs showed a 50% significant reduction in mortality in those treated with  blockers, a 46% significant reduction in mortality in those treated with statins, and a 35% significant reduction in mortality in those treated with ACE inhibitors or ARBs. Our patients with nonischemic cardiomyopathy treated with ICDs showed a 48% significant reduction in mortality in those treated with  blockers, a 33% nonsignificant reduction in mortality in those treated with statins, and a 24% nonsignificant reduction in mortality in those treated with ACE inhibitors or ARBs. Randomized clinical trials need to be performed to confirm the validity of previously published data1– 4 and of our data. However, until these data are available, we recommend treating patients with ICDs with  blockers, ACE inhibitors or ARBs, and statins, especially those with ischemic cardiomyopathy. 1. Brodine WN, Tung RT, Lee JK, Hockstad ES, Moss AJ, Zareba W, Hall WJ, Andrews M, McNitt S, Daubert JP, for the MADIT-II Research Group. Effects of beta-blockers on implantable cardioverter defibrillator therapy and survival in the patients with ischemic cardiomyopathy (from the Multicenter Automatic Defibrillator Implantation Trial-II). Am J Cardiol 2005;96:691– 695. 2. Tandri H, Griffith LS, Tang T, Nasir K, Zardkoohi O, Reddy CV, Capps M, Calkins H, Donahue JK. Clinical course and long-term follow-up of patients receiving implantable cardioverter-defibrillators. Heart Rhythm 2006;3:762–768. 3. Ho AT, Pai SM, Timothy P, Pai RG. Effect of concomitant antiarrhythmic therapy on survival in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2005;28:647– 653. 4. Vyas AK, Guo H, Moss AJ, Olshansky B, McNitt SA, Hall WJ, Zareba W, Steinberg JS, Fischer A, Ruskin J, Andrews ML, for the MADIT-II Research Group. Reduction in ventricular tachyarrhythmias with statins in the Multicenter Automatic Defibrillator Implantation trial (MADIT)II. J Am Coll Cardiol 2006;47:769 –773. 5. Kruger A, Aronow WS, Lai HM, Desai H, Singla A, Frishman WH, Cohen M, Sorbera C. Prevalence of appropriate cardioverter-defibrillator shocks in 1,038 consecutive patients with implantable cardioverterdefibrillators. Am J Ther. In press. 6. Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure after prior myocardial infarction in older men and women with abnormal versus normal left ventricular ejection fraction. Am J Cardiol 2000;85:1382–1384.