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Risk Factors for Appropriate Cardioverter-Defibrillator Shocks, Inappropriate Cardioverter-Defibrillator Shocks, and Time to Mortality in 549 Patients With Heart Failure
Risk Factors for Appropriate Cardioverter-Defibrillator Shocks, Inappropriate Cardioverter-Defibrillator Shocks, and Time to Mortality in 549 Patients With Heart Failure Harit Desai, MDa, Wilbert S. Aronow, MDa,*, Chul Ahn, PhDb, Kaushang Gandhi, MDa, Sadaf Hussain, MDa, Hoang M. Lai, MDa, Mala Sharma, MDa, William H. Frishman, MDa, Martin Cohen, MDa, and Carmine Sorbera, MDa We investigated the risk factors for appropriate and inappropriate implantable cardioverterdefibrillator (ICD) shocks and mortality in 549 patients (mean age 74 years) with heart failure and ICDs. During a mean follow-up of 1,243 ⴞ 655 days, of the 549 patients, 163 (30%) had appropriate ICD shocks, 71 (13%) had inappropriate ICD shocks, and 63 (12%) died. Stepwise logistic regression analysis showed that significant independent prognostic factors for appropriate ICD shocks were smoking (odds ratio 3.7) and statins (odds ratio 0.54). The significant independent prognostic factors for inappropriate ICD shocks were atrial fibrillation (odds ratio 6.2) and statins (odds ratio 0.52). Finally, those for the interval to mortality were age (hazard ratio 1.08/1-year increase), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (hazard ratio 0.25), atrial fibrillation (hazard ratio 4.1), right ventricular pacing (hazard ratio 3.6), digoxin (hazard ratio 2.9), hypertension (hazard ratio 5.3), and statins (hazard ratio 0.32). In conclusion, in patients with heart failure and ICDs, smoking increased and statins reduced appropriate ICD shocks, atrial fibrillation increased and statins reduced inappropriate ICD shocks, and the interval to mortality was increased by age, atrial fibrillation, right ventricular pacing, hypertension, and digoxin and reduced by angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and statins. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1336 –1338) Smoking is associated with a greater incidence of appropriate implantable cardioverter-defibrillator (ICD) shocks in patients with ICDs,1,2 and statin use reduces the incidence of appropriate ICD shocks in these patients.2–5 In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, one or more inappropriate ICD shocks occurred in 83 (12%) of 719 patients.6 Atrial fibrillation triggered 44% of inappropriate ICD shocks and supraventricular tachycardia (36%) of inappropriate ICD shocks in that study.6 We report on the risk factors for appropriate ICD shocks, inappropriate ICD shocks, and the interval to all-cause mortality during 1,243 days of follow-up for 549 patients (mean age 74 years) with heart failure and ICDs. Methods We investigated, in an observational, single-center study, the risk factors for appropriate ICD shocks, inappropriate ICD shocks, and interval to all-cause mortality in 434 men and 115 women (mean age 74 years) with heart failure and ICDs. Of the 549 patients, 322 (59%) had ischemic cardiomyopathy and 227 (41%) had nonischemic cardiomyopathy. a
Department of Medicine, Cardiology Division, New York Medical College, Valhalla, New York; and bDepartment of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas. Manuscript received October 12, 2009; revised manuscript received and accepted December 4, 2009. *Corresponding author: Tel: (914) 493-5311; fax: (914) 235-6274. E-mail address: [email protected] (W.S. Aronow). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.057
The left ventricular ejection fraction was measured from 2-dimensional echocardiograms, as previously described.7 At follow-up every 3 months, the ICD was interrogated to determine whether any shocks had occurred. The shocks were further evaluated by 2 electrophysiologists viewing the intracardiac electrocardiograms for appropriate shocks (ventricular tachycardia/ventricular fibrillation) or inappropriate shocks (shocks not resulting from ventricular tachycardia/ventricular fibrillation) and their causes. The mean follow-up was 1,243 ⫾ 655 days. Student’s t tests were used to analyze continuous variables. A p value ⬍0.05 by 2-sided t tests was considered significant. Chi-square tests and Fisher’s exact tests were used to analyze dichotomous variables. Stepwise logistic regression analysis was performed for appropriate ICD shocks, and inappropriate ICD shocks, and stepwise Cox regression analysis for the interval to mortality using the variables age, gender, ischemic cardiomyopathy, nonischemic cardiomyopathy, atrial fibrillation, left ventricular ejection fraction, biventricular pacing, right ventricular pacing, dual chamber pacing, QRS duration, New York Heart Association class, smoking, systemic hypertension, diabetes mellitus, dyslipidemia, and the use of statins,  blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, amiodarone, sotalol, and digoxin. Results Of 549 patients, 163 (30%) had appropriate ICD shocks, 71 (13%) had inappropriate ICD shocks, and 63 (12%) died. Table 1 lists the baseline characteristics of patients with and www.AJConline.org
Heart Failure/ICD Shocks and Mortality Table 1 Baseline characteristics Variable
Inappropriate Shocks Yes (n ⫽ 71)
Gender Women Men Age (years) Ischemic cardiomyopathy Nonischemic cardiomyopathy Atrial fibrillation Left ventricular ejection fraction Biventricular pacing Right ventricular pacing Dual chamber pacing QRS duration (ms) New York Heart Association class II or III IV Smoker Systemic hypertension Diabetes mellitus Dyslipidemia* Statins  Blockers Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers Amiodarone Sotalol Digoxin Follow-up (days)
p Value
NS 16 (23%) 55 (77%) 75 ⫾ 6 45 (63%) 26 (37%) 29 (41%) 28 ⫾ 8
99 (21%) 379 (79%) 73 ⫾ 10 277 (58%) 201 (42%) 41 (9%) 29 ⫾ 7
23 (32%) 48 (62%) 45 (63%) 117 ⫾ 21
186 (39%) 292 (61%) 322 (67%) 118 ⫾ 19
49 (69%) 22 (31%) 17 (24%) 37 (52%) 13 (18%) 39 (55%) 22 (31%) 49 (69%) 50 (70%)
328 (69%) 150 (31%) 92 (19%) 214 (45%) 99 (21%) 285 (60%) 257 (54%) 324 (68%) 304 (64%)
18 (25%) 5 (7%) 25 (35%) 1,241 ⫾ 555
0.038 NS NS ⬍0.0001 NS NS NS NS NS NS
NS NS NS NS ⬍0.0001 NS NS
94 (20%) 19 (4%) 137 (29%) 1,243 ⫾ 670
NS NS NS NS
* Dyslipidemia indicated by serum total cholesterol ⱖ200 mg/dl, serum low-density lipoprotein cholesterol ⱖ100 mg/dl, serum high-density lipoprotein cholesterol ⬍40 mg/dl, serum triglycerides ⱖ150 mg/dl, or use of lipid-lowering drug therapy.
Table 2 Stepwise logistic regression analysis for inappropriate implantable cardioverter-defibrillator (ICD) shocks in patients with heart failure Prognostic Factor Atrial fibrillation Statins
Table 3 Stepwise logistic regression analysis for appropriate implantable cardioverter-defibrillator (ICD) shocks in patients with heart failure Prognostic Factor
No (n ⫽ 478)
Parameter Estimate
SE
p Value
Odds Ratio
95% Confidence Interval
0.915 ⫺0.323
0.150 0.144
⬍0.0001 0.025
6.238 0.524
3.470–11.22 0.298–0.922
without inappropriate shocks and the levels of statistical significance. The mean follow-up was 1,243 ⫾ 655 days. Appropriate ICD shocks occurred in 33 (46%) of 71 patients who had inappropriate ICD shocks and in 130 (27%) of 478 patients who had no inappropriate ICD shocks (p ⬍0.0001). Of the 71 patients with inappropriate ICD shocks, 16 (23%) died and of the 478 patients who had no inappropriate ICD shocks, 47 (10%) died (p ⫽ 0.002). A total of 187 inappropriate shocks occurred in the 71 patients with inappropriate shocks. Of the 187 inappropriate shocks, 109 (58%) were triggered by atrial fibrillation with
1337
Smoking Statins
Parameter Estimate
SE
p Value
Odds Ratio
95% Confidence Interval
0.648 ⫺0.307
0.113 0.098
⬍0.0001 0.002
3.656 0.542
2.352–5.682 0.368–0.797
a rapid ventricular rate, 64 (34%) were triggered by supraventricular tachycardia and 14 (7%) by sinus tachycardia with a ventricular rate ⬎150 beats/min. The data listed in Table 2 showed that atrial fibrillation (odds ratio 6.2) and statins (odds ratio 0.54) were significant independent risk factors for inappropriate ICD shocks. The data listed in Table 3 showed that smoking (odds ratio 3.7) and statins (odds ratio 0.54) were significant independent risk factors for appropriate ICD shocks. The data listed in Table 4 showed that significant independent risk factors for the interval to all-cause mortality were age (hazard ratio 1.08/1-year increase), ACE inhibitors/angiotensin receptor blockers (hazard ratio 0.25), atrial fibrillation (hazard ratio 4.1), right ventricular pacing (hazard ratio 3.6), digoxin (hazard ratio 2.9), systemic hypertension (hazard ratio 5.3), and statins (hazard ratio 0.32). Discussion In the present study of 549 patients with heart failure and ICDs, smoking significantly increased the incidence of appropriate ICD shocks 3.7 times, and the use of statins significantly reduced appropriate ICD shocks by 46%. In the MADIT II trial, smoking significantly increased the incidence of appropriate ICD shocks 2.1 times and inappropriate ICD shocks 2.9 times.1 In 209 patients with heart failure and combined cardiac resynchronization-ICD therapy, smoking significantly increased the incidence of appropriate ICD shocks by 3.5 times.2 The use of statins significantly reduced the incidence of appropriate ICD shocks by 54%,2 by 34% in MADIT II,3 by 60% in 362 patients with coronary artery disease treated with an ICD for ventricular tachycardia/ventricular fibrillation,4 and from 57% to 22% in 78 patients with coronary artery disease treated with an ICD for life-threatening ventricular arrhythmias.5 The potential mechanisms for statins reducing appropriate ICD shocks for ventricular tachycardia/ventricular fibrillation could include their numerous beneficial pleiotropic effects, in addition to their favorable effects on serum lipids.8 By reducing high serum low-density lipoprotein cholesterol levels and increasing low serum high-density lipoprotein cholesterol levels, statins can slow the rate of progression of coronary atherosclerosis, can occasionally cause regression of coronary atherosclerosis, and can cause stabilization of atherosclerotic plaques that are prone to rupture. Statins improve endothelial dysfunction. Statins reduce platelet aggregation and deposition and maintain a favorable balance between prothrombotic and fibrinolytic mechanisms. Statins reduce myocardial ischemia. In addition, statins can decrease the inflammatory component of atherosclerosis progression, in which oxidized low-density lipoprotein cholesterol exerts an adverse effect on endothelial cells, smooth muscle cells, and macrophages.
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Table 4 Stepwise Cox regression analysis for interval to mortality in patients with heart failure and implantable cardioverter-defibrillators (ICDs) Prognostic Factor Age Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers Atrial fibrillation Right ventricular pacing Digoxin Systemic hypertension Statins
Parameter Estimate
SE
p Value
Hazard Ratio
95% Confidence Interval
0.079 ⫺1.369
0.022 0.323
0.0002 ⬍0.0001
1.082 0.254
1.038–1.129 0.135–0.479
1.415 1.287 1.060 1.662 ⫺1.135
0.280 0.334 0.283 0.323 0.343
⬍0.0001 0.0001 0.0002 ⬍0.0001 0.0009
4.115 3.620 2.887 5.268 0.321
2.378–7.122 1.881–6.967 1.658–5.025 2.799–9.916 0.164–0.630
In the present study, atrial fibrillation significantly increased the incidence of inappropriate ICD shocks 6.2 times, and the use of statins significantly reduced the incidence of inappropriate ICD shocks by 48%. In MADIT II, atrial fibrillation was the most common trigger for inappropriate ICD shocks (44%) followed by supraventricular tachycardia (36%).6 In the present study, atrial fibrillation was the most common trigger for inappropriate ICD shocks (58%), followed by supraventricular tachycardia (34%). By decreasing the atrial fibrillation burden, statins reduce the incidence of inappropriate ICD shocks. In the present study, the interval to death was significantly increased 1.08 times for each 1-year increase in age, 4.1 times by atrial fibrillation, 3.6 times by right ventricular pacing, 5.3 times by systemic hypertension, and 2.9 times by the use of digoxin and was significantly decreased 75% by the use of ACE inhibitors or angiotensin receptor blockers and 68% by the use of statins. In 209 patients with heart failure and combined cardiac resynchronization-ICD therapy, the significant independent prognostic factors for mortality were the use of statins (risk ratio 0.05), the use of digoxin (risk ratio 4.2), systemic hypertension (risk ratio 14.2), diabetes mellitus (risk ratio 4.3), and left ventricular ejection fraction (risk ratio 1.1).2 In other ICD studies, the use of statins significantly reduced cardiac death or ventricular tachycardia/ventricular fibrillation by 35% in MADIT II,3 by 61% in 362 patients with coronary artery disease treated with an ICD for ventricular tachycardia or ventricular fibrillation,4 by 34% in 829 patients randomized to an ICD in the Sudden Cardiac Death in Heart Failure Trial,9 and by 46% in 965 patients with ICDs.10 In 286 patients with ICDs followed up for 3 years, mortality increased significantly 1.9 times by digoxin and 1.6 times by loop diuretics and significantly decreased 50% by the use of ACE inhibitors or aldosterone antagonist therapy.11 The use of ACE inhibitors or angiotensin receptor blockers also significantly reduced mortality in 965 patients with ICDs.10 At 1 year of follow-up of 506 patients with ICDs, the patients randomized to dual-chamber rateresponsive pacing at a rate of 70 beats/min had a 61% insignificantly greater mortality rate than patients randomized to ventricular backup pacing at 40 beats/min.12 Of 80 patients treated with right ventricular pacing, 22 (28%) died at 45 months of follow-up and 8 (10%) of 81 patients treated with biventricular pacing died at 53 months of follow-up (p ⬍0.01).13 Randomized clinical trials are needed to confirm the validity of previously published data1– 6,9 –13 and the data from the present study.
1. Goldenberg I, Moss AJ, McNitt S, Zareba W, Daubert JP, Hall WJ, Andrews ML; Multicenter Automatic Defibrillator Implantation Trial-II Investigators. Cigarette smoking and the risk of supraventricular and ventricular tachyarrhythmias in high-risk cardiac patients with implantable cardioverter-defibrillators. J Cardiovasc Electrophysiol 2006;17:931–936. 2. Desai H, Aronow WS, Tsai F, Ahn C, Lai HM, Amin H, Gandhi K, Frishman WH, Cohen M, Sorbera C. Statins reduce appropriate cardioverter-defibrillator shocks and mortality in patients with heart failure and combined cardiac resynchronization and implantable cardioverter-defibrillator therapy. J Cardiovasc Pharmacol Ther 2009;14:176 –179. 3. 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. 4. Mitchell LB, Powell JL, Gillis AM, Kehl V, Hallstrom AP; AVID Investigators. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the antiarrhythmics versus implantable defibrillators (AVID) trial. J Am Coll Cardiol 2003;42:81– 87. 5. De Sutter J, Tavernier R, De Buyzere M, Jordaens L, De Backer G. Lipid lowering drugs and recurrences of life-threatening ventricular arrhythmias in high-risk patients. J Am Coll Cardiol 2000;36:766 –772. 6. Daubert JP, Zareba W, Cannom DS, McNitt S, Rosero SZ, Wang P, Schuger C, Steinberg JS, Higgins SL, Wilber DJ, Klein H, Andrews ML, Hall WJ, Moss AJ; MADIT II Investigators. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II. J Am Coll Cardiol 2008;51:1357–1365. 7. 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. 8. Aronow WS, Frishman WH. Management of hypercholesterolemia in older persons. Cardiol Rev; in press. 9. Dickinson MG, Ip JH, Olshansky B, Hellkamp AS, Anderson J, Poole JE, Mark DB, Lee KL, Bardy GH; SCD-HeFT Investigators. Statin use was associated with reduced mortality in both ischemic and nonischemic cardiomyopathy and in patients with implantable defibrillators: mortality data and mechanistic insights from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Am Heart J 2007;153:573–578. 10. Lai HM, Aronow WS, Kruger A, Desai H, Amin H, Frishman WH, Cohen M, Sorbera C. Effect of beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins on mortality in patients with implantable cardioverter-defibrillators. Am J Cardiol 2008;102:77–78. 11. Thibodeau JB, Pillarisetti J, Khumri TM, Jones PG, Main ML. Mortality rates and clinical predictors of reduced survival after cardioverter defibrillator implantation. Am J Cardiol 2008;101:861– 864. 12. The DAVID Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual chamber and VVI Implantable Defibrillator (DAVID) trial. JAMA 2002;288:3115–3123. 13. Sukhija R, Aronow WS, Sorbera C, Peterson SJ, Frishman WH, Cohen M. Mortality, left ventricular ejection fraction, and prevalence of new left ventricular wall motion abnormality at long-term follow-up in patients with implantable cardioverter defibrillators treated with biventricular pacing versus right ventricular pacing. Am J Ther 2007;14: 328 –330.
Department of Medicine, Cardiology Division, New York Medical College, Valhalla, New York; and bDepartment of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas. Manuscript received October 12, 2009; revised manuscript received and accepted December 4, 2009. *Corresponding author: Tel: (914) 493-5311; fax: (914) 235-6274. E-mail address: [email protected] (W.S. Aronow). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.057
The left ventricular ejection fraction was measured from 2-dimensional echocardiograms, as previously described.7 At follow-up every 3 months, the ICD was interrogated to determine whether any shocks had occurred. The shocks were further evaluated by 2 electrophysiologists viewing the intracardiac electrocardiograms for appropriate shocks (ventricular tachycardia/ventricular fibrillation) or inappropriate shocks (shocks not resulting from ventricular tachycardia/ventricular fibrillation) and their causes. The mean follow-up was 1,243 ⫾ 655 days. Student’s t tests were used to analyze continuous variables. A p value ⬍0.05 by 2-sided t tests was considered significant. Chi-square tests and Fisher’s exact tests were used to analyze dichotomous variables. Stepwise logistic regression analysis was performed for appropriate ICD shocks, and inappropriate ICD shocks, and stepwise Cox regression analysis for the interval to mortality using the variables age, gender, ischemic cardiomyopathy, nonischemic cardiomyopathy, atrial fibrillation, left ventricular ejection fraction, biventricular pacing, right ventricular pacing, dual chamber pacing, QRS duration, New York Heart Association class, smoking, systemic hypertension, diabetes mellitus, dyslipidemia, and the use of statins,  blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, amiodarone, sotalol, and digoxin. Results Of 549 patients, 163 (30%) had appropriate ICD shocks, 71 (13%) had inappropriate ICD shocks, and 63 (12%) died. Table 1 lists the baseline characteristics of patients with and www.AJConline.org
Heart Failure/ICD Shocks and Mortality Table 1 Baseline characteristics Variable
Inappropriate Shocks Yes (n ⫽ 71)
Gender Women Men Age (years) Ischemic cardiomyopathy Nonischemic cardiomyopathy Atrial fibrillation Left ventricular ejection fraction Biventricular pacing Right ventricular pacing Dual chamber pacing QRS duration (ms) New York Heart Association class II or III IV Smoker Systemic hypertension Diabetes mellitus Dyslipidemia* Statins  Blockers Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers Amiodarone Sotalol Digoxin Follow-up (days)
p Value
NS 16 (23%) 55 (77%) 75 ⫾ 6 45 (63%) 26 (37%) 29 (41%) 28 ⫾ 8
99 (21%) 379 (79%) 73 ⫾ 10 277 (58%) 201 (42%) 41 (9%) 29 ⫾ 7
23 (32%) 48 (62%) 45 (63%) 117 ⫾ 21
186 (39%) 292 (61%) 322 (67%) 118 ⫾ 19
49 (69%) 22 (31%) 17 (24%) 37 (52%) 13 (18%) 39 (55%) 22 (31%) 49 (69%) 50 (70%)
328 (69%) 150 (31%) 92 (19%) 214 (45%) 99 (21%) 285 (60%) 257 (54%) 324 (68%) 304 (64%)
18 (25%) 5 (7%) 25 (35%) 1,241 ⫾ 555
0.038 NS NS ⬍0.0001 NS NS NS NS NS NS
NS NS NS NS ⬍0.0001 NS NS
94 (20%) 19 (4%) 137 (29%) 1,243 ⫾ 670
NS NS NS NS
* Dyslipidemia indicated by serum total cholesterol ⱖ200 mg/dl, serum low-density lipoprotein cholesterol ⱖ100 mg/dl, serum high-density lipoprotein cholesterol ⬍40 mg/dl, serum triglycerides ⱖ150 mg/dl, or use of lipid-lowering drug therapy.
Table 2 Stepwise logistic regression analysis for inappropriate implantable cardioverter-defibrillator (ICD) shocks in patients with heart failure Prognostic Factor Atrial fibrillation Statins
Table 3 Stepwise logistic regression analysis for appropriate implantable cardioverter-defibrillator (ICD) shocks in patients with heart failure Prognostic Factor
No (n ⫽ 478)
Parameter Estimate
SE
p Value
Odds Ratio
95% Confidence Interval
0.915 ⫺0.323
0.150 0.144
⬍0.0001 0.025
6.238 0.524
3.470–11.22 0.298–0.922
without inappropriate shocks and the levels of statistical significance. The mean follow-up was 1,243 ⫾ 655 days. Appropriate ICD shocks occurred in 33 (46%) of 71 patients who had inappropriate ICD shocks and in 130 (27%) of 478 patients who had no inappropriate ICD shocks (p ⬍0.0001). Of the 71 patients with inappropriate ICD shocks, 16 (23%) died and of the 478 patients who had no inappropriate ICD shocks, 47 (10%) died (p ⫽ 0.002). A total of 187 inappropriate shocks occurred in the 71 patients with inappropriate shocks. Of the 187 inappropriate shocks, 109 (58%) were triggered by atrial fibrillation with
1337
Smoking Statins
Parameter Estimate
SE
p Value
Odds Ratio
95% Confidence Interval
0.648 ⫺0.307
0.113 0.098
⬍0.0001 0.002
3.656 0.542
2.352–5.682 0.368–0.797
a rapid ventricular rate, 64 (34%) were triggered by supraventricular tachycardia and 14 (7%) by sinus tachycardia with a ventricular rate ⬎150 beats/min. The data listed in Table 2 showed that atrial fibrillation (odds ratio 6.2) and statins (odds ratio 0.54) were significant independent risk factors for inappropriate ICD shocks. The data listed in Table 3 showed that smoking (odds ratio 3.7) and statins (odds ratio 0.54) were significant independent risk factors for appropriate ICD shocks. The data listed in Table 4 showed that significant independent risk factors for the interval to all-cause mortality were age (hazard ratio 1.08/1-year increase), ACE inhibitors/angiotensin receptor blockers (hazard ratio 0.25), atrial fibrillation (hazard ratio 4.1), right ventricular pacing (hazard ratio 3.6), digoxin (hazard ratio 2.9), systemic hypertension (hazard ratio 5.3), and statins (hazard ratio 0.32). Discussion In the present study of 549 patients with heart failure and ICDs, smoking significantly increased the incidence of appropriate ICD shocks 3.7 times, and the use of statins significantly reduced appropriate ICD shocks by 46%. In the MADIT II trial, smoking significantly increased the incidence of appropriate ICD shocks 2.1 times and inappropriate ICD shocks 2.9 times.1 In 209 patients with heart failure and combined cardiac resynchronization-ICD therapy, smoking significantly increased the incidence of appropriate ICD shocks by 3.5 times.2 The use of statins significantly reduced the incidence of appropriate ICD shocks by 54%,2 by 34% in MADIT II,3 by 60% in 362 patients with coronary artery disease treated with an ICD for ventricular tachycardia/ventricular fibrillation,4 and from 57% to 22% in 78 patients with coronary artery disease treated with an ICD for life-threatening ventricular arrhythmias.5 The potential mechanisms for statins reducing appropriate ICD shocks for ventricular tachycardia/ventricular fibrillation could include their numerous beneficial pleiotropic effects, in addition to their favorable effects on serum lipids.8 By reducing high serum low-density lipoprotein cholesterol levels and increasing low serum high-density lipoprotein cholesterol levels, statins can slow the rate of progression of coronary atherosclerosis, can occasionally cause regression of coronary atherosclerosis, and can cause stabilization of atherosclerotic plaques that are prone to rupture. Statins improve endothelial dysfunction. Statins reduce platelet aggregation and deposition and maintain a favorable balance between prothrombotic and fibrinolytic mechanisms. Statins reduce myocardial ischemia. In addition, statins can decrease the inflammatory component of atherosclerosis progression, in which oxidized low-density lipoprotein cholesterol exerts an adverse effect on endothelial cells, smooth muscle cells, and macrophages.
1338
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Table 4 Stepwise Cox regression analysis for interval to mortality in patients with heart failure and implantable cardioverter-defibrillators (ICDs) Prognostic Factor Age Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers Atrial fibrillation Right ventricular pacing Digoxin Systemic hypertension Statins
Parameter Estimate
SE
p Value
Hazard Ratio
95% Confidence Interval
0.079 ⫺1.369
0.022 0.323
0.0002 ⬍0.0001
1.082 0.254
1.038–1.129 0.135–0.479
1.415 1.287 1.060 1.662 ⫺1.135
0.280 0.334 0.283 0.323 0.343
⬍0.0001 0.0001 0.0002 ⬍0.0001 0.0009
4.115 3.620 2.887 5.268 0.321
2.378–7.122 1.881–6.967 1.658–5.025 2.799–9.916 0.164–0.630
In the present study, atrial fibrillation significantly increased the incidence of inappropriate ICD shocks 6.2 times, and the use of statins significantly reduced the incidence of inappropriate ICD shocks by 48%. In MADIT II, atrial fibrillation was the most common trigger for inappropriate ICD shocks (44%) followed by supraventricular tachycardia (36%).6 In the present study, atrial fibrillation was the most common trigger for inappropriate ICD shocks (58%), followed by supraventricular tachycardia (34%). By decreasing the atrial fibrillation burden, statins reduce the incidence of inappropriate ICD shocks. In the present study, the interval to death was significantly increased 1.08 times for each 1-year increase in age, 4.1 times by atrial fibrillation, 3.6 times by right ventricular pacing, 5.3 times by systemic hypertension, and 2.9 times by the use of digoxin and was significantly decreased 75% by the use of ACE inhibitors or angiotensin receptor blockers and 68% by the use of statins. In 209 patients with heart failure and combined cardiac resynchronization-ICD therapy, the significant independent prognostic factors for mortality were the use of statins (risk ratio 0.05), the use of digoxin (risk ratio 4.2), systemic hypertension (risk ratio 14.2), diabetes mellitus (risk ratio 4.3), and left ventricular ejection fraction (risk ratio 1.1).2 In other ICD studies, the use of statins significantly reduced cardiac death or ventricular tachycardia/ventricular fibrillation by 35% in MADIT II,3 by 61% in 362 patients with coronary artery disease treated with an ICD for ventricular tachycardia or ventricular fibrillation,4 by 34% in 829 patients randomized to an ICD in the Sudden Cardiac Death in Heart Failure Trial,9 and by 46% in 965 patients with ICDs.10 In 286 patients with ICDs followed up for 3 years, mortality increased significantly 1.9 times by digoxin and 1.6 times by loop diuretics and significantly decreased 50% by the use of ACE inhibitors or aldosterone antagonist therapy.11 The use of ACE inhibitors or angiotensin receptor blockers also significantly reduced mortality in 965 patients with ICDs.10 At 1 year of follow-up of 506 patients with ICDs, the patients randomized to dual-chamber rateresponsive pacing at a rate of 70 beats/min had a 61% insignificantly greater mortality rate than patients randomized to ventricular backup pacing at 40 beats/min.12 Of 80 patients treated with right ventricular pacing, 22 (28%) died at 45 months of follow-up and 8 (10%) of 81 patients treated with biventricular pacing died at 53 months of follow-up (p ⬍0.01).13 Randomized clinical trials are needed to confirm the validity of previously published data1– 6,9 –13 and the data from the present study.
1. Goldenberg I, Moss AJ, McNitt S, Zareba W, Daubert JP, Hall WJ, Andrews ML; Multicenter Automatic Defibrillator Implantation Trial-II Investigators. Cigarette smoking and the risk of supraventricular and ventricular tachyarrhythmias in high-risk cardiac patients with implantable cardioverter-defibrillators. J Cardiovasc Electrophysiol 2006;17:931–936. 2. Desai H, Aronow WS, Tsai F, Ahn C, Lai HM, Amin H, Gandhi K, Frishman WH, Cohen M, Sorbera C. Statins reduce appropriate cardioverter-defibrillator shocks and mortality in patients with heart failure and combined cardiac resynchronization and implantable cardioverter-defibrillator therapy. J Cardiovasc Pharmacol Ther 2009;14:176 –179. 3. 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. 4. Mitchell LB, Powell JL, Gillis AM, Kehl V, Hallstrom AP; AVID Investigators. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the antiarrhythmics versus implantable defibrillators (AVID) trial. J Am Coll Cardiol 2003;42:81– 87. 5. De Sutter J, Tavernier R, De Buyzere M, Jordaens L, De Backer G. Lipid lowering drugs and recurrences of life-threatening ventricular arrhythmias in high-risk patients. J Am Coll Cardiol 2000;36:766 –772. 6. Daubert JP, Zareba W, Cannom DS, McNitt S, Rosero SZ, Wang P, Schuger C, Steinberg JS, Higgins SL, Wilber DJ, Klein H, Andrews ML, Hall WJ, Moss AJ; MADIT II Investigators. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II. J Am Coll Cardiol 2008;51:1357–1365. 7. 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. 8. Aronow WS, Frishman WH. Management of hypercholesterolemia in older persons. Cardiol Rev; in press. 9. Dickinson MG, Ip JH, Olshansky B, Hellkamp AS, Anderson J, Poole JE, Mark DB, Lee KL, Bardy GH; SCD-HeFT Investigators. Statin use was associated with reduced mortality in both ischemic and nonischemic cardiomyopathy and in patients with implantable defibrillators: mortality data and mechanistic insights from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Am Heart J 2007;153:573–578. 10. Lai HM, Aronow WS, Kruger A, Desai H, Amin H, Frishman WH, Cohen M, Sorbera C. Effect of beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins on mortality in patients with implantable cardioverter-defibrillators. Am J Cardiol 2008;102:77–78. 11. Thibodeau JB, Pillarisetti J, Khumri TM, Jones PG, Main ML. Mortality rates and clinical predictors of reduced survival after cardioverter defibrillator implantation. Am J Cardiol 2008;101:861– 864. 12. The DAVID Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual chamber and VVI Implantable Defibrillator (DAVID) trial. JAMA 2002;288:3115–3123. 13. Sukhija R, Aronow WS, Sorbera C, Peterson SJ, Frishman WH, Cohen M. Mortality, left ventricular ejection fraction, and prevalence of new left ventricular wall motion abnormality at long-term follow-up in patients with implantable cardioverter defibrillators treated with biventricular pacing versus right ventricular pacing. Am J Ther 2007;14: 328 –330.