Editor's Note: this Article of the Month is based on Buber J, Goldenberg I, Moss AJ, Wang PJ, McNitt S, Hall WJ, Eldar M, et al. Reduction in Life-Threatening Ventricular Tachyarrhythmias in Statin-Treated Patients With Nonischemic Cardiomyopathy Enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). J Am Coll Cardiol 2012; 60:749-755.¹

Summary

Numerous studies have described a protective effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase-inhibitors (statins) against ventricular arrhythmias and sudden cardiac death. Since most statin trials have included predominantly patients with ischemic disease it is difficult to differentiate whether the improvements in SCD and/or arrhythmia reflect an anti-ischemic effect with decreases in ischemica-mediated arrhythmia, or a true anti-arrhythmic effect. In this study which is a post-hoc subanalysis of the MADIT-CRT study, only patients with non-ischemic cardiomyopathy were included. A composite endpoint of ICD-treated ventricular tachycardia, ventricular fibrillation, or death was compared between statin users and those not on statins.

Methods

The MADIT-CRT study² randomized patients with ischemic cardiomyopathy and NYHA class I or II heart failure, or non-ischemic CM and class II heart failure, with decreased EF (</=30%) and wide QRS (>130msec). Statin therapy was prescribed at the discretion of the treating physicians. ICD therapy programming was standardized, with a fast VT zone at 170 bpm and a VF zone at 230 bpm. VF was defined at >250 bpm with disorganized ventricular electrograms. The primary endpoint of this subanalysis in the non-ischemic group subgroup (N=821) was first appropriate defibrillator therapy for VT/VF or death, with individual secondary endpoints. In the Kaplan-Meier analyses, patients were censored when they changed statin status (discontinued or initiated the drug), and in the multivariable Cox proportional hazards regression, statin use was assessed in a time-dependent manner.

Results

Statin users (n = 499) were older and had a higher prevalence of diabetes and hypertension yet were less frequently smokers. Multivariate analysis showed that time-dependent statin therapy was independently associated with a significant 77% reduction in the risk of fast VT/VF or death (p <0.001) and with a significant 46% reduction
in the risk of appropriate implantable cardioverter defibrillator shocks (p < 0.01). Consistent with these findings, the cumulative probability of fast VT/VF or death at 4 years of follow-up was significantly lower among patients who were treated with statins (11%) as compared with study patients who were not treated with statins (19%; p < 0.006 for the overall difference during follow-up).

Conclusion

In this large subanalysis of the MADIT-CRT trial, statin use was associated with a significant decrease in ICD-treated ventricular arrhythmias among patients with non-ischemic cardiomyopathy and class II heart failure.

Perspective

While defibrillators are very effective at preventing death from ventricular arrhythmias, shocks for arrhythmia are painful and decrease quality of life,^{3, 4} leading to trials of both pharmacological and ablative techniques to decrease shocks in this population. This study suggests statins may provide another avenue to decrease arrhythmias in patients with non-ischemic cardiomyopathy and ICDs.

Prior studies have suggested that statins decrease sudden cardiac death. In a recent meta-analysis⁵ of twenty-nine trials of statin vs. control totaling 113,568 participants, use of statins was associated with a 10% reduction in sudden cardiac death, highly significant although of smaller magnitude than the 22% reduction in non-sudden (mostly atherosclerotic) cardiac deaths. However, these studies included predominantly patients with either known coronary artery disease, or risk-factors for CAD. The only study to investigate patients with heart failure including those with non-ischemic causes was GISSI-HF,⁶ which failed to show improvement in outcome with a statin; however, only 35% of the subjects had a non-ischemic etiology, and it has been noted that a small dose of statin (rosuvastatin 10mg) was used.¹ Similarly, some studies in patients with ICDs have shown a decrease in subsequent arrhythmias in those on statins, but most of these have focused on patients with underlying CAD.^{7, 8} The DEFINITE trial in patients with non-ischemic cardiomyopathy showed a decrease in shocks among those randomized to ICD arm who were taking statins,⁹ but this post-hoc subanalysis included just 56 patients on statins, of just 229 in the ICD arm, and the finding was non-significant. Thus, prior to this study, it has remained unclear whether the beneficial effects of statin were related to known effects on decreasing ischemia, or whether statins may act to decrease arrhythmias via other mechanisms.

Statins have pleiotropic effects, many of which may contribute to anti-arrhythmic properties. Statins decrease inflammation,¹⁰ a known risk factor for sudden death¹¹ as well as for ICD-treated ventricular arrhythmias.¹² Inflammation alters autonomic tone as measured by heart rate variability,¹³ which may in part explain these associations of inflammation and arrhythmic outcomes. Statins have documented effects on autonomic activation, improving heart rate variability,¹⁴ and in rats, atorvastatin desensitizes myocytes to beta-adrenergic stimulation.¹⁵

This study provides the strongest evidence to date that statins exert anti-arrhythmic effects beyond their effects on ischemia. While statin use was not randomized, the prospective collection of both statin data and outcome data as part of the randomized MADIT-CRT trial provides a complete database. The statistical analysis including statin use as a time-dependent variable is another strength of the study. A limitation lies in the relatively narrow inclusion criteria for MADIT-CRT, which enrolled only those non-ischemic patients with class II heart failure (as those with more severe heart failure had been previously demonstrated to have improved survival with CRT; and benefit from ICD for those with less severe heart failure has not been investigated). Similarly, only those with a wide QRS were enrolled, although it seems unlikely that QRS width would impact the effects of statins. These data should add impetus to the need for a randomized trial of statins to decrease arrhythmias in patients with non-ischemic cardiomyopathy and class II heart failure, as well as the wider population of non-ischemic patients.

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References

1. Buber J, Goldenberg I, Moss AJ, Wang PJ, McNitt S, Hall WJ, Eldar M, et al. Reduction in Life-Threatening Ventricular Tachyarrhythmias in Statin-Treated Patients With Nonischemic Cardiomyopathy Enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). J Am Coll Cardiol 2012; 60:749-755.
2. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA, 3rd, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009; 361:1329-38.
3. Irvine J, Dorian P, Baker B, O'Brien BJ, Roberts R, Gent M, Newman D, et al. Quality of life in the Canadian implantable defibrillator study (CIDS). Am Heart J 2002; 144:282-9.
4. Schron E, Exner D, Yao Q, Jenkins L, Steinberg J, Cook J, Kutalek S, et al. Quality of life in the antiarrhythmics versus implantable defibrillators. Circulation 2002; 105:589-594.
5. Rahimi K, Majoni W, Merhi A, Emberson J. Effect of statins on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of published and unpublished evidence from randomized trials. Eur Heart J 2012; 33:1571-U42.
6. Gissi HFI, Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372:1231-9.
7. Vyas AK, Guo H, Moss AJ, Olshansky B, McNitt SA, Hall WJ, Zareba W, et al. Reduction in ventricular tachyarrhythmias with statins in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II.[Erratum appears in J Am Coll Cardiol 2006 Apr 18;47(8):1739]. J Am Coll Cardiol 2006; 47:769-73.
8. 8. Mitchell LB, Powell JL, Gillis AM, Kehl V, Hallstrom AP, Investigators A. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 2003; 42:81-7.
9. 9. Goldberger JJ, Subacius H, Schaechter A, Howard A, Berger R, Shalaby A, Levine J, et al. Effects of statin therapy on arrhythmic events and survival in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol 2006; 48:1228-33.
10. 10. Albert MA, Danielson E, Rifai N, Ridker PM, Investigators P. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286:64-70.
11. 11. Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002; 105:2595-9.
12. 12. Blangy H, Sadoul N, Dousset B, Radauceanu A, Fay R, Aliot E, Zannad F. Serum BNP, hs-C-reactive protein, procollagen to assess the risk of ventricular tachycardia in ICD recipients after myocardial infarction. Europace 2007; 9:724-9.
13. 13. Lampert R, Bremner JD, Su S, Miller A, Lee F, Cheema F, Goldberg J, et al. Decreased heart rate variability is associated with higher levels of inflammation in middle-aged men. Am Heart J 2008; 156.
14. 14. Pehlivanidis AN, Athyros VG, Demitriadis DS, Papageorgiou AA, Bouloukos VJ, Kontopoulos AG. Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease. Atherosclerosis 2001; 157:463-9.
15. 15. Muhlhauser U, Zolk O, Rau T, Munzel F, Wieland T, Eschenhagen T. Atorvastatin desensitizes beta-adrenergic signaling in cardiac myocytes via reduced isoprenylation of G-protein gamma-subunits. FASEB Journal 2006; 20:785-7.

Keywords: Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Cardiomyopathies, Death, Sudden, Cardiac, Heart Conduction System, Oxidoreductases, Tachycardia, Ventricular, Ventricular Fibrillation

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