Statins and the Reduction of Sudden Cardiac Death: Antiarrhythmic or Anti-Ischemic Effect?

Abhimanyu Beri; Tahmeed Contractor; Atul Khasnis; Ranjan Thakur

Disclosures

Am J Cardiovasc Drugs. 2010;10(3):155-164. 

In This Article

4. Clinical Studies Reporting Sudden Cardiac Death Reduction with Statins

A literature search for clinical studies evaluating the relationship between statins and ventricular arrhythmias/sudden cardiac death revealed only two pertinent RCTs. Most of the published literature on this topic consists of observational studies or sub-analyses from other original studies.[68] Clinical studies reporting the effect of statins on sudden cardiac death and related outcomes are summarized in table II.

4.1 In Patients with Ischemic Disease

The initial RCTs using statins showed significant benefits in lowering cardiovascular as well as all-cause mortality for both primary[70] and secondary[69,71] prevention. Sudden death outcomes were not analyzed in these studies. However, there was no difference between statin users and non-users in noncoronary cardiac events and deaths in the 4S trial and a metaanalysis of five RCTs.[69,72]

As sudden cardiac death became a recognized problem, investigators specifically started reporting the effect of statins on this phenomenon. An initial retrospective analysis evaluating the effect of early statin therapy in new-onset heart failure after myocardial infarction did not show a significant reduction in resuscitated cardiac arrest/sudden cardiac death in statin users compared with controls. This study had significant baseline differences between the two groups, including age, hyperlipidemia, and smoking status.[73]

In a later observational study of 2130 patients with acute myocardial infarction, statins started immediately after myocardial infarction showed a trend towards lowering sudden cardiac death.[74] A meta-analysis that included ten RCTs found a significant risk reduction in sudden cardiac death (odds ratio 0.81; p = 0.003) with statins after an average of 4.4 years' follow-up.[34] Although this meta-analysis did not give an exact percentage of the patients with ischemic cardiomyopathy, 69% of the patients in the included studies had a history of myocardial infarction.

Vrtovec et al.[76] conducted a small RCT using atorvastatin that included patients with ischemic and non-ischemic heart failure. They demonstrated a benefit of statin therapy in sudden cardiac death reduction (5% vs 22% without statin therapy; p = 0.012). However, the statin group had a higher proportion of patients with ischemic cardiomyopathy than the control group (65% vs 53%; p= 0.17). The CORONA[75] and GISSIHF[77] trials did not demonstrate any benefit with statins in overall cardiovascular mortality or sudden cardiac death. This could be attributed to a low event rate of sudden cardiac death in a population with advanced heart failure, who were more likely to have pump failure-related mortality. A post hoc analysis of the CORONA trial[86] concluded that only subjects with ischemic heart failure and elevated hs-CRP levels had a significant reduction in cardiovascular mortality. Sudden cardiac death outcomes were not separately reported in this analysis. Thus the exact mechanism of sudden cardiac death prevention by statins remained unclear with anti-ischemic effects emerging as the most plausible explanation for reducing VT/VF events.

Later studies reported the incidence of sudden cardiac death as well as VT/VF and shock therapy in patients with ICDs. Two observational studies in patients with underlying coronary artery disease (with associated cardiomyopathy in one of the studies) demonstrated a significant decrease in ventricular arrhythmias and frequency of ICD therapy in patients on statins,[78,80] while a similar study in patients with coronary artery disease failed to demonstrate this benefit.[81] All of these studies were performed in patients with coronary artery disease at high risk for arrhythmias and meeting the criteria for ICD implantation.

The AVID trial[79] compared patients with coronary artery disease treated with an ICD versus antiarrhythmics for secondary prevention of VT/VF. A sub-analysis of the ICD group comparing those who received lipid-lowering agents (including statins) with those who did not demonstrated a lower probability of VT/VF recurrence with lipid-lowering agents. In this study, the lipid-lowering agent group was significantly more likely to be young and Caucasian than the controls. Also, the lipid-lowering agent group had more episodes of sustained VT than controls, but had less VF. After adjustment for these baseline differences, there was a significant increase in VT-/VF-free survival (adjusted p = 0.003) and reduction in the relative hazard ratio (HR) for VT/VF recurrence (HR 0.40; 95% CI 0.15, 0.58) with use of lipid-lowering drug therapy. The MADIT-II trial[13] similarly randomized patients with ischemic cardiomyopathy to ICD versus pharmacotherapy. In a subanalysis of the 654 ICD patients, the cumulative rate of ICD therapy for VT/VF or cardiac death was significantly reduced with statin use (HR 0.65; p < 0.01). These effects were noted with a time delay of zero days, suggesting a more immediate primary antiarrhythmic rather than a delayed anti-ischemic effect (related to lipid lowering or atherosclerosis regression) as the underlying mechanism.[87]

The CLARIDI trial[82] was the only RCT primarily designed to evaluate the reduction of VT/VF with statin therapy. This trial randomized normocholesterolemic patients with underlying coronary artery disease and an ICD (n = 106) into atorvastatin (n = 53) and placebo (n = 53) groups. Over a follow-up period of 12 months, statin therapy significantly reduced the recurrence of appropriate ICD therapy for VT/VF (HR 0.47; p = 0.040), further demonstrating the reduction of ventricular arrhythmias with statins in patients with ischemic disease.

4.2 In Patients with Non-ischemic Cardiomyopathy

The studies mentioned in section 4.1 either solely included patients with coronary artery disease or did not separately report outcomes in non-ischemic patients. The JUPITER trial[65] evaluated the potential benefits of statin therapy in apparently healthy people without coronary artery disease or hyperlipidemia. Though there was a significant reduction in overall cardiovascular mortality, sudden cardiac death outcomes were not separately analyzed. A cohort study and sub-analyses of two RCTs were performed to evaluate the effects of statins in patients with non-ischemic cardiomyopathy.[83–85] In the SCD-HeFT,[84] cardiovascular mortality was assessed separately in patients with ischemic and non-ischemic cardiomyopathy based on statin use. This substudy did not comment on sudden cardiac death outcomes. However, there was no difference in cardiovascular mortality in the head-to-head comparison between the two groups.

In a large cohort of ICD patients (n = 1204) with ischemic or non-ischemic cardiomyopathy, statins were found to reduce overall mortality (HR 0.67; p < 0.01) but not the incidence of VT/VF (HR 0.85; p = 0.14).[85] This study did not compare the relative benefits between ischemic and non-ischemic cardiomyopathy groups. The percentage of patients with ischemic cardiomyopathy in the statin group was disproportionately higher than in the control group (83.8% vs 58.5; p < 0.01) and thus a primary anti-ischemic effect may explain most of the mortality benefit.

The DEFINITE trial[83] was an RCT designed to compare outcomes with medications versus ICD in non-ischemic cardiomyopathy patients. A sub-analysis that used death from any cause as the primary endpoint showed a significant reduction in all-cause mortality in statin users compared with non-users. There was also a clear but non-significant trend in the reduction of arrhythmic sudden death with statins compared with statin non-users. However, there was no difference in the rate of appropriate shock therapy between statin users and non-users among the patients randomized to ICD therapy. As pointed out by the authors, this could be due to a limited power to detect a difference between the two groups.

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