**4. Statins (3 hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors) and sudden cardiac death prevention**

isosorbide dinitrate on mortality in patients with NYHA class II-III. After randomization, double blind treatment was instituted with Enalapril (n= 403) versus hydralazine/isosorbide dinitrate (n=401). Interestingly the mortality curves of the treatment arms separate early after randomization. There was a 28% relative risk reduction with Enalapril compared to hydrala‐ zine and isosorbide dinitrate (p=0.16).The overall reduction in mortality associated with

**3.3. Effect of Angiotensin-Receptor Blockers (ARBs) on sudden cardiac death prevention in**

*The Evaluation of Losartan in the Elderly Study (ELITE)* is the only ARB trial to demonstrate a reduction in sudden death. This prospective, double-blind, randomized, parallel group controlled clinical trial compared the safety and efficacy in the treatment of CHF with the use of Losartan vs Captopril. Patients were randomly assigned to losartan (n=352) versus captopril (n=370). Follow up at 48 weeks showed a 45% reduction in all-cause mortality with a relative

*ELITE II* was designed to compare the effects of losartan and captopril on all-cause mortality and sudden death or resuscitated cardiac arrest. Similar to ELITE patients were randomly assigned to losartan (n=1578) or captopril (n=1574). After 1.5 years of follow there was no statistically difference in all-cause mortality, sudden death or resuscitated cardiac arrest

**3.4. Effect of Aldosterone antagonists on sudden cardiac death prevention in post MI**

*The Randomized Aldactone Evaluation Study (RALES)* was a randomized double-blind place‐ bo controlled trial. This trial hypothesized that daily treatment with Spirinolactone would reduce the risk of death from all causes among patients who had severe heart failure. Patients enrolled had class III or IV heart failure and were being treated with an ACE-I inhibitor, loop diuretic and had an EF ≤ 35%. They were randomly assigned to ei‐ ther Spirinolactone (n=822) or placebo (n=841). This trial was ended prematurely when analysis found that Spirinolactone demonstrated a 31% reduction in cardiac death. This reduction was due to a 36% in death related to progressive heart failure and a 29% re‐

*The Eplerone Post Myocardial Heart Failure Efficacy and Survival Study (EPHESUS)* was con‐ ducted to evaluate the effect of aldosterone blocker, Eplerenone on morbidity and mor‐ tality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. In this double-blind, placebo-controlled study patients were randomly assigned to Eplerenone (n=3313) versus placebo (n=3319) in addition to optimal medical therapy. Eplerenone demonstrated a reduction in death from cardiovas‐ cular causes or hospitalization for cardiovascular events (relative risk, 0.83; 95% CI, 0.72-0.94; p=0.005). There was also a reduction in sudden death from cardiac causes (rela‐

Enalapril was due to a reduction in the incidence of sudden death [40].

risk reduction of 36% in the incidence of sudden cardiac death [41].

(losartan 9% versus captopril 7.3%, p= 0.08) between the two groups[42].

**patients and in patients with congestive heart failure**

duction in sudden cardiac death [43].

tive risk, 0.79; 95% CI 0.64-0.97; p=0.03) [44].

**patients with congestive heart failure**

220 Cardiomyopathies

#### **4.1. Potential mechanisms of 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on sudden cardiac death prevention**

Statins (3 Hydroxy-3-Methylglutaryl Coenzyme-A Reductase inhibitors) have been shown to decrease cardiovascular morbidity and mortality in both primary and secondary prevention trials. Statins are known to stabilize the plaque and to even promote plaque regression[45].This stabilization improves myocardial perfusion, oxidative stress and reduces the risk of plaque rupture[46]. This leads to decreased ischemic events and arrhythmic events, since even small areas of ischemia can promote reentry, induce ventricular arrhythmias and lead to sudden cardiac death. Statins improve endothelial function by increasing nitric oxide production from endothelial cells and they reduce ischemia mediated oxidative stress and intracellular calcium overload [47, 48]. They also have anti-inflammatory actions and reduce C-reactive protein, and they decrease endothelin-1 secretion [49]. All these effects will decrease myocardial ischemia, limit myocardial injury and prevent myocyte hypertrophy [50, 51].

#### **4.2. Effect of statin therapy on shock burden and sudden cardiac death in post MI patients and in patients with congestive heart failure**

Statins are widely accepted as preventing coronary heart disease death and MI; however their effect on sudden cardiac death prevention is unclear.

Randomized trial in post myocardial infarction patients showed the benefits of statins on overall mortality but failed to show benefit on sudden cardiac death prevention [52-54]. However, observational data from hospitalized patients with myocardial infarction showed that early statin administration (within 24 hours) of an acute MI led to a decrease in the incidence of VT/VF [55].

Furthermore, statins appear to decrease appropriate shocks in patients who have ICDs whether or not they received them for primary or secondary prevention of sudden cardiac death. In a subanalysis of AVID trial, a secondary prevention trial which compared anti-arrhythmic drugs to ICDs in patients who survived a cardiac arrest, patients who received statins had a lower risk of ventricular arrhythmias compared to those who are not on statins [56]. This was also demonstrated in the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II). Post hoc analysis of MADIT-II showed that patients receiving statin therapy > 90% of the time had a significantly reduced cumulative rate of ICD therapy for VT/VF or cardiac death[57].

Subsequently, an analysis of SCD-HeFT trial data was undertaken to evaluate the impact of statin use in heart failure. SCD-HeFT studied 2521 functional class II and III heart failure patients with left ventricular ejection fractions ≤ 35%. The cause of CHF was ischemic in 52% of the study patients. Statin use was reported in 965 (38%) of 2521 patients at baseline and 1187 (47%) at last follow-up with the median time to follow up of 45.5 months. This analysis revealed that mortality reduction related to statin therapy (HR= 0.70, 95% CI: 0.58-0.83] was identical in both ischemic and non-ischemic cardiomyopathy (HR 0.69 vs 0.67 respectively) [58].
