Impact of Statins on Risk of Stroke: A Meta-Analysis

Nickole N Henyan, PharmD; Daniel M Riche, PharmD BCPS; Honey E East, MD; Pamela N Gann, PharmD


The Annals of Pharmacotherapy. 2007;41(12):1937-1945. 

In This Article


This meta-analysis illustrates that statins significantly reduce the risk of all CVEs (17%) and ischemic stroke (21%), although there was a nonsignificant increased risk of hemorrhagic stroke (11%). Although the increased risk of hemorrhagic stroke seen in this meta-analysis was driven predominately by results of the SPARCL trial, the LIPID, CARDS, and MEGA trials each contributed a nonsignificant increase in incidence of hemorrhagic stroke to the totality of data. Whether increased risk of hemorrhagic stroke is a direct class effect of statins or is dependent on the degree of cholesterol reduction remains unknown.

A meta-analysis performed by Amarenco et al.[46] concluded that statins may reduce the incidence of all strokes without any increase in hemorrhagic strokes. In that meta-analysis, not all trials were placebo-controlled (eg, ACAPS, ALLHAT-LLT, KLIS). To minimize the potential for bias introduced with active control groups, these trials were excluded in our meta-analysis. Amarenco et al. used a fixed-effects model versus a random-effects model. Since the choice between fixed and random effects remains debatable, we reported our data using both models.[47] Additionally, several trials (eg, SPARCL, CARDS, MEGA) were not published at the time of the previous meta-analysis.

Consistent with previously published observations, risk of all CVEs and ischemic stroke is significantly reduced with statin use. Both the 4D and ALERT trials evaluated patients with severe renal complications and reported an increase in the incidence of all CVEs in patients receiving statin therapy.[24,34] The 4D study further defined specific types of stroke, indicating an increase in ischemic stroke with statin therapy, which contributed to the observation of statistical heterogeneity in the ischemic analysis.[24] The 4D investigators did not have a basis of explanation for this finding; however, routine use of statins in patients receiving hemodialysis is not currently recommended.

Among trials exhibiting a nonsignificant increase in risk of hemorrhagic stroke, LIPID and MEGA evaluated pravastatin, while SPARCL and CARDS evaluated atorvastatin.[7,23,25,44] Among trials with a nonsignificant reduction in risk of hemorrhagic stroke, MIRACL and 4D evaluated atorvastatin, and CARE evaluated pravastatin.[24,26,27] Both trials evaluating simvastatin (4S and HPS) demonstrated a nonsignificant reduction in risk of hemorrhagic stroke.[5,6] The SPARCL and LIPID trials included patients with a previous history of CVE.[7,23] Since SPARCL evaluated statins as secondary prevention of stroke, the majority of patients were receiving antiplatelet therapy (87%).[23] Although LIPID included only 4% of patients with a previous CVE, the greater part of this population (83%) was also receiving antiplatelet treatment for secondary cardiovascular disease prevention.[7] Interestingly, only SPARCL and LIPID demonstrated an increase of 40% or more in hemorrhagic stroke compared with the increase shown with placebo.[7,23] On the other hand, CARE and MIRACL (evaluating the same statins at equivalent doses) also included a large percentage of patients (> 80%) on antiplatelet therapy and demonstrated a nonsignificant reduction in hemorrhagic stroke.[26,27] Therefore, an increased risk of hemorrhagic stroke with concurrent antiplatelet and statin therapy cannot be ruled out.

A recent study by Bang et al.[48] evaluated the effect of statin use and cholesterol level on the risk of symptomatic hemorrhagic transformation (sHT) in patients post acute ischemic stroke. Multivariable analysis did not find an association between statin use and increased likelihood of sHT (p = 0.566) but did demonstrate an association between lower LDL-C levels (mean ± SD 77.9 ± 40.5 mg/dL) and sHT (p = 0.02). The SPARCL and CARDS trials reached similar LDL-C levels and demonstrated an increased risk of hemorrhagic stroke.[23,25] Of note, study patients in the lower third percentile of LDL-C values were more likely to be on statins and antiplatelet/anticoagulant therapy, possibly increasing sHT risk.[48] Although this study was retrospective and had a relatively small sample size, it does provide some interesting insights into a possible association of hemorrhagic stroke and lower cholesterol levels in patients immediately following an ischemic stroke.[48]

The most recent guidelines from the National Cholesterol Education Panel state that patients with coronary heart disease (CHD) or a CHD risk equivalent should achieve a goal LDL-C less than 100 mg/dL, with a therapeutic option of less than 70 mg/dL in patients with significant CHD or CHD risk.[49] Although symptomatic carotid artery disease is a CHD risk equivalent, patients with a history of cerebrovascular disease (regardless of type) are not specifically defined as a high-risk group, and LDL-C goals for these patients can be based on Framingham risk calculation. The results of SPARCL and meta-analyses comparing high- and low-dose statins are likely to change LDL-C goals and increase the use of statins in patients with a history of ischemic stroke.[50,51,52] To achieve LDL-C levels lower than those currently recommended, aggressive statin therapy may be necessary. Considering epidemiologic evidence of an association between the increased risk of intracerebral hemorrhage and naturally occurring low cholesterol levels, the use of high-dose statins with concomitant antiplatelet therapy and risk of hemorrhagic stroke (especially in patients with lower baseline total cholesterol levels) should be assessed on an individual basis. Gradual reduction in LDL-C shortly after stroke may provide typical long-term benefit against recurrent ischemic stroke, while minimizing risk of intracranial hemorrhage.

In addition to lowering cholesterol levels, statins have cholesterol-independent effects known as pleiotropism.[20,53,54] Pleiotropic effects can be grouped into 4 categories: (1) effects explained by the influence of statins on nitric oxide bioavailability, (2) antiinflammatory effects, (3) antithrombotic effects, and (4) antioxidant effects.[20] The critical pleiotropic effect of statins relating to hemorrhagic complications is their influence on both platelet activity and fibrinolysis. Statins elicit an increase in tissue-type plasminogen activator levels promoting fibrinolysis, while platelet activator inhibitor-1 levels fall, possibly destabilizing the extracellular matrix.[20,21] Unfortunately, limited evidence exists to suggest the extent of pleiotropic effect among statins.[55]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: