Statins and Intracerebral Hemorrhage: Collaborative Systematic Review and Meta-Analysis

Study Questions:

Is the use of statins associated with intracerebral hemorrhage?


The authors reported the results of a systematic review of the literature of both randomized and observational studies, using DerSimonian-Laird random-effects models to compute summary risk ratios with 95% confidence intervals. They searched 17 electronic bibliographic databases and analyzed the identified randomized trials, cohort studies, and case-control study separately, using only adjusted risk estimates for pooling observational data. Published and unpublished data from 23 randomized trials and 19 observational studies were included. The authors tested for publication bias by inspecting funnel plots and performing Begg and Mazumdar rank correlation tests.


The author’s final data set comprised 248,391 subjects suffering 14,784 intracerebral hemorrhages. Statins were not associated with an increased risk of intracerebral hemorrhage in randomized trials (relative risk [RR], 1.10; 95% confidence interval [CI], 0.86-1.41), in cohort studies (RR, 0.94; 95% CI, 0.81-1.10), or in case-control studies (RR, 0.60; 95% CI, 0.41-0.88). There was statistical heterogeneity in the case-control studies (I2 = 66%, p = 0.01), but little in the cohort studies (I2 = 0%, p = 0.48) or randomized trials (I2 = 30%, p = 0.09). The results were not materially changed by sensitivity analyses for study design type, patient characteristics, or magnitude of cholesterol-lowering.


The authors found no evidence that statins were associated with intracerebral hemorrhage. They also opined that if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs.


The search for a ‘free lunch’ sometimes seems to be a never-ending human endeavor. The magnitude of the benefit seen from the use of statins is so great, that any finding of slightly increased risk of adverse events—however severe—should not dissuade anyone from their use. Furthermore, if randomized trials demonstrate a dramatic reduction in lives lost and strokes suffered (which clearly takes into account any intracerebral hemorrhages attributable to the medication), then the benefit is clear, and the use of the medication should be strongly recommended. An obsessive search for evidence of increased risk of adverse events associated with the use of statins therefore misses the point, does not inform clinical decision-making, and runs the very significant risk of decreasing adherence to these effective preventive therapies. Even if an increased risk of intracerebral hemorrhage was associated with statin use, the idea that this could be clinically useful information, or support the avoidance of these agents in patients perceived to be at increased risk for intracerebral hemorrhage, would remain highly speculative. Fortunately, this exhaustive, well-performed, and comprehensive study establishes that there is either no association between statin use and intracerebral hemorrhage, or the risk is so small as to be so far undetectable.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Cooperative Behavior, Cholesterol, Risk, Stroke, Case-Control Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiovascular Diseases, Databases, Bibliographic, Confidence Intervals, Publication Bias, Deoxyguanosine, Cerebral Hemorrhage

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