Abstract and Introduction

Abstract

Background: Evidence from randomized, controlled trials suggests that reduction of low-density lipoprotein cholesterol with hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) therapy in patients at high risk for cardiovascular disease reduces the incidence of ischemic stroke; however, data from large epidemiologic observational studies suggest an inverse relationship between risk of hemorrhagic stroke and cholesterol levels.
Objective: To perform a meta-analysis of randomized controlled trials to assess the effect of statin therapy on all cerebrovascular events (CVEs), ischemic stroke, and hemorrhagic stroke.
Methods: A systematic literature search of MEDLINE, EMBASE, Cumulative Index to Nursing & Allied Health Literature, and Web of Science citations from June 1975 through September 2006 was performed to identify randomized controlled trials of statin therapy. Trials were included if they met the following criteria: (1) controlled clinical trials of statin therapy versus placebo, (2) well-described protocol, and (3) data reported on incidence of all CVEs, ischemic stroke, or hemorrhagic stroke. All data were independently extracted by 3 investigators.
Results: Weighted averages are reported as relative risk with 95% confidence intervals. A total of 26 trials (N = 100,560) reported incidence on all CVEs. Six trials (n = 37,292) reported incidence of ischemic stroke and 9 trials (n = 57,895) were included in the hemorrhagic stroke analysis. Statin therapy significantly reduced the risk of all CVEs (RR 0.83; 95% CI 0.76 to 0.91) and the risk of ischemic stroke (RR 0.79; 95% CI 0.63 to 0.99). Statin therapy did not significantly reduce risk of hemorrhagic stroke (RR 1.11; 95% CI 0.77 to 1.60).
Conclusions: Statin therapy significantly reduces risk of developing all CVEs and ischemic stroke; however, it is associated with a nonsignificant increase in risk of hemorrhagic stroke.

Introduction

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are well known to block the production of cholesterol and have a profound effect of lowering both total cholesterol and low-density lipoprotein cholesterol (LDL-C).^[1] Ample epidemiologic and experimental data have suggested that hypercholesterolemia is a statin-modifiable risk factor for coronary heart disease (CHD).^[2] However, the effect of statins on cerebrovascular disease is less clear.^[3] Stroke is the leading cause of serious, long-term disability and the third most common cause of death in the US.^[3,4] Although several limitations (eg, nonuniform reporting methods and lack of diagnostic differentiation) exist, multiple clinical trials suggest that statins protect against stroke. In fact, several prospective studies have demonstrated that statins reduce overall stroke occurrence by 19-25%.^[5-7]

Evidence from randomized controlled trials suggests that cholesterol (particularly LDL-C) reduction by statins in patients at high risk for cardiovascular disease reduces the incidence of ischemic stroke; however, data from large epidemiologic observational studies suggest an inverse relationship between risk of hemorrhagic stroke and serum cholesterol levels, creating a stroke paradox.^[8-11] In fact, in vitro analyses suggest that low cholesterol in the absence of modifiers (eg, statins) may impair platelet function or cell membrane integrity.^[12]

Epidemiologic data also show that serum cholesterol levels are inversely related to stroke death.^[9] The MRFIT (Multiple Risk Factor Intervention Trial) follow-up and the Honolulu Heart Study demonstrated a positive correlation between higher baseline cholesterol levels and nonhemorrhagic stroke; however, there was a negative association between higher baseline cholesterol and intracerebral hemorrhage.^[11,13,14] Several Japanese cohorts have reported increases in cerebral hemorrhage in patients with low cholesterol levels.^[15-17] Both hemorrhagic stroke and angionecrosis (destruction of blood vessels that may increase hemorrhagic risk) are more prevalent in Japan where residents have lower dietary cholesterol intake versus Japanese residents of Hawaii who have typically higher cholesterol dietary intake,^[18] suggesting a J-curve phenomenon with naturally occurring low cholesterol levels.^[19]

The mechanism by which statins elicit stroke protection is likely multifactorial, not only due to atheroma stabilization in extracranial arteries and reduction of source of thromboembolism (ie, CHD), but also due to direct neuroprotection (largely independent of cholesterol reduction). Neuroprotection may be linked to reduction of cholesterol-independent (pleiotropic) isoprenoid intermediates in the mevalonate pathway.^[20] The role for statins in neuroprotection is still controversial, especially in recovery following acute ischemic stroke.^[21]

We conducted a meta-analysis to elucidate the effect of statin therapy on all cerebrovascular events (CVEs), ischemic stroke, and hemorrhagic stroke.