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

Abhimanyu Beri; Tahmeed Contractor; Atul Khasnis; Ranjan Thakur

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

Abstract and Introduction

Abstract

Sudden cardiac death is an important cause of cardiovascular mortality with the majority of cases occurring in low-risk groups. HMG-CoA reductase inhibitors (statins) have recently been shown to reduce the incidence of ventricular tachycardia (VT)/fibrillation (VF) and sudden cardiac death, and this has been attributed to their pleiotropic effects. However, it is unclear whether this occurs through an 'indirect' anti-ischemic or 'direct' antiarrhythmic effect. We systematically reviewed articles published on MEDLINE between January 1996 and December 2009 focusing on the reduction of VT/VF and sudden cardiac death by statins and the potential mechanisms. Studies reporting sudden cardiac death or VT/VF outcomes with statin use (n = 23) or the pathophysiology of sudden cardiac death reduction by statins (n = 19) were included. We found that statins have been shown to reduce VT/VF and sudden cardiac death only in subjects with underlying coronary artery disease or ischemic cardiomyopathy. No definite benefits were seen with statins in sudden cardiac death and VT/VF in patients with non-ischemic cardiomyopathy. There is insufficient evidence to point toward a benefit in populations at low risk for VT/VF. In conclusion, an anti-ischemic rather than a primary antiarrhythmic effect emerges as the likely mechanism of sudden cardiac death reduction with statins.

Introduction

Sudden cardiac death is defined as unexpected death from a cardiac etiology after cardiac arrest within 1 hour of the onset of acute symptoms.^[1] Though significant developments have occurred in the management of cardiovascular disease, sudden cardiac death remains an important global health concern with more than 3 million worldwide deaths annually.^[2] The estimated incidence in the US is about 1 per 1000 person-years in the general population,^[3] with similar numbers reported from other parts of the world.^[4–7]

Arrhythmias are the most common cause of sudden cardiac death,^[8] with ventricular tachycardia (VT)/fibrillation (VF) being responsible for the vast majority (83.4%) of cases.^[9] Coronary artery disease is the underlying etiology for approximately 80% of these fatal ventricular arrhythmias, the remainder being accounted for by hypertrophic or dilated cardiomyopathy, congenital heart disease, primary electrophysiological abnormalities, valvular heart disease, and infiltrative myocardial disorders.^[10] A smaller fraction (16%) of sudden cardiac death is attributed to bradyarrhythmias and electromechanical dissociation.^[9]

Certain groups have been identified as being at high risk for sudden cardiac death, but the majority of the sudden death burden exists in the larger, lower risk population.^[10,11] Given the low incidence in this low-risk population, any attempt at reducing sudden cardiac death would require specific screening and risk-stratifying strategies as well as safe, effective yet economical interventions.

A protective effect of HMG-CoA reductase inhibitors (statins) in sudden cardiac death has been demonstrated in recent studies. This has been partly attributed to their 'pleiotropic' (i.e. beyond lipid-lowering) effects, such as atherosclerotic plaque stabilization, reduction in systemic inflammation and thrombogenicity,^[12] as well as changes in membrane ion channel conduction.^[13] We conducted a systematic review of published literature on the efficacy of statins in lowering the incidence of sudden cardiac death and explored the underlying mechanisms.

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Table I. Trial names
Acronym	Name
AFCAPS/TexCAPS	Air Force/Texas Coronary Atherosclerosis Prevention Study
AVID	Antiarrhythmics Versus Implantable Defibrillators Trial
CLARIDI	Cholesterol Lowering and Arrhythmias Recurrences after Internal Defibrillator Implantation
CORONA	Controlled Rosuvastatin Multinational Trial in Heart Failure
DEFINITE	Defibrillators in Non-ischemic Cardiomyopathy Treatment Evaluation
GISSI-HF	GISSI-Heart Failure
JUPITER	Justification for the Use of statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin
LIPID	Long-term Intervention with Pravastatin in Ischaemic Disease
MADIT-II	Multicenter Automatic Defibrillator Implantation Trial
OPTIMAAL	Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan
SDC-HeFT	Sudden Cardiac Death in Heart Failure Trial
4S	Scandinavian Simvastatin Survival Study

Table II. Clinical studies reporting the effect of HMG-CoA reductase inhibitors (statins) on sudden cardiac death (SCD) and related outcomes
Study	Year	Study design	Population size (n)	Patient population included	SCD-related outcomes	Results (comparing statin users and non-users)
Ischemic heart disease
Overall and combined CAD mortality
4S^[69]	1994	RCT	4444	History of angina pectoris or acute MI with high cholesterol levels	Combined major coronary events including coronary deaths, resuscitated cardiac arrest, non-fatal acute MI, and silent MI	Major coronary events reduced with simvastatin (p < 0.001)
AFCAPS/TexCAPS^[70]	1998	RCT	6605	Average TC and LDL-C levels and below-average HDL-C level, no known CAD	First acute major coronary event defined as MI, unstable angina, or SCD. No separate analysis for SCD	Lovastatin reduced the risk for the first acute major coronary event (p < 0.001)
LIPID^[71]	1998	RCT	9014	Known CAD	Combined death from CAD (fatal MI, SCD, in-hospital death after possible MI or heart failure or another coronary cause)	Reduced CAD (p < 0.001) and overall mortality (p < 0.001) with statins
LaRosa et al.^[72]	1999	Meta-analysis of 5 RCTs	30817	Studies where participants were randomized to statins versus controls and the primary outcome was clinical disease or death	Combined major coronary events (unstable angina, silent MI, non-fatal MI, coronary death, resuscitated cardiac arrest or SCD)	Risk reduction in major coronary events with statins (p < 0.01)
SCD in patients without an ICD
OPTIMAAL^[73]	2004	Retrospective	5301	Acute MI with heart failure within 10 days of hospitalization	SCD/resuscitated cardiac arrest	Statins alone did not reduce SCD/resuscitated cardiac arrest
Mäkikallio et al.^[74]	2006	Prospective	2130	Acute MI	SCD	Absence of statins was a nonsignificant predictor of SCD
Levantesi et al.^[34]	2007	Meta-analysis of 10 RCTs	22 275	Studies with outcome focusing on the incidence of SCD, statin treatment compared with control	SCD	Statin treatment significantly reduced SCD (p = 0.03)
CORONA^[75]	2007	RCT	5011	Patients ≥60 years of age with ischemic systolic heart failure (NYHA II to IV)	Death from cardiovascular causes (SCD reported separately)	No reduction in mortality or SCD with rosuvastatin
Vrtovec et al.^[76]	2008	RCT	110	Patients with EF <30% (59% of patients had ischemic etiology)	SCD	Decreased incidence of SCD in the statin group (p = 0.012)
GISSI-HF^[77]	2008	RCT	4574	Patients ≥18 years of age with chronic heart failure (NYHA II to IV) irrespective of cause	Time to death due to any cause or death or hospitalization due to cardiovascular cause (SCD reported separately)	No reduction in mortality or SCD death with rosuvastatin
SCD and related outcomes in patients with an ICD
De Sutter et al.^[78]	2000	Prospective	78	History of CAD and life-threatening VT/VF treated with an ICD	Recurrences of VT/VF requiring ICD intervention	Lipid-lowering drugs independently reduced recurrence of VT/VF (p = 0.004)
AVID^[79]	2003	RCT sub-analysis	362	Patients with CAD who received an ICD for secondary prevention of VT/VF	VT/VF recurrence	Reduction in VT/VF recurrence with statins (p = 0.003)
Chiu et al.^[80]	2005	Prospective	281	CAD and ICD implantation	First appropriate ICD therapy	Statins lowered ICD therapy for ventricular arrhythmias (p = 0.01)
Riahi et al.^[81]	2005	Prospective	86	CAD diagnosed by coronary angiography, with an ICD implantation (per ACC/AHA/NASPE 2002 ICD guidelines)	VT/VF events	No significant difference in the incidence of ventricular arrhythmias
MADIT-II^[13]	2006	RCT sub-analysis	654	History of MI one month or more before entry, EF <0.30, and ICD placement	Occurrence of cardiac death or first appropriate ICD therapy for VT/VF	Statins lowered VT/VF or cardiac death (p < 0.01) and SCD (p < 0.01)
CLARIDI^[82]	2006	RCT	106	CAD patients with ICD implants and TC levels lower than 250mg/dL	Occurrence of ICD therapy for VT/VF	Statins reduced ICD therapy for VT/VF (p = 0.04)
Non-ischemic cardiomyopathy
Overall and SCD in patients with an ICD
DEFINITE^[83]	2006	RCT sub-analysis	458	Non-ischemic cardiomyopathy with an EF <35%, symptomatic heart failure	SCD from VT/VF	One arrhythmic SCD in the 110 statin patients vs 18 of 348 in the non-statin group (p = 0.04)
SCD-HeFT^[84]	2007	RCT sub-analysis	2521	Both ischemic and non-ischemic cardiomyopathy	All-cause mortality, no SCD outcome reported	Reduction in mortality in both subgroups (ischemic and non-ischemic cardiomyopathy)
Coleman et al.^[85]	2008	Prospective	1204	Both ischemic and non-ischemic cardiomyopathy	All-cause mortality and VT/VF incidence	Reduction in overall mortality (p < 0.01) but not in VT/VF (p = 0.14)

ACC = American College of Cardiology; AHA = American Heart Association; CAD = coronary artery disease; EF = ejection fraction; HDL-C = high-density lipoprotein cholesterol; ICD = implantable cardioverter defibrillator; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; NASPE = North American Society of Pacing and Electrophysiology; RCT= randomized control trial; TC = total cholesterol; VF = ventricular fibrillation; VT = ventricular tachycardia.

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

Abstract and Introduction

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