Hassanain Toma, MD

Woo D, Deka R, Falcone GJ, Flaherty ML, Haverbusch M, Martini SR. Apolipoprotein E, Statins, and Risk of Intracerebral Hemorrhage. Stroke. 2013


The evidence supporting the association between statins and intracranial hemorrhage (ICH) is contradictory. Woo et al. hypothesized that one explanation for this is unmeasured confounding variables. These include hypercholesterolemia (HC) and ApoE genotypes. According to prior studies, HC is inversely related to the risk of ICH, and Apolipoprotein (Apo) E2 and ApoE4 are associated with a higher risk of lobar ICH compared with the more common E3 allele (wild type). Armed with these facts, the authors hypothesized that an unstudied interaction between ApoE/statin or ApoE/HC may have confounded the impact of statins on ICH. For this reason they sought to determine if a possible interaction exists between HC, statin use, and ApoE genotypes.


Their prospectively designed case-control study revealed that (1) having a history of HC was associated with decreased risk of lobar ICH, in both statin and non-statin users; (2) a history of HC did not appear to modify the association of either ApoE2 or ApoE4 with lobar ICH; and (3) Statins were associated with an increased risk of lobar ICH in patients with Apo E4/E4, and Apo E2/E4, as compared to Apo E3/E3 controls, but not in non-lobar hemorrhage.

The findings were validated in a separate population, which adds to the strength and credibility of the study. Unfortunately, the sample size decreased when patients were stratified based on their ApoE genotypes, and as a result only a trend between statin use and Apo E2/E4 and E4/E4 was observed on formal testing for the interaction. The authors concluded that if their findings are confirmed by future studies, there may be a rationale for genetic testing in lobar ICH patients who are on or are being considered for statin therapy.

Based on the data presented, the authors might have engaged in further speculation. Some physicians are concerned about statin use in the setting of non-lobar hemorrhage, such as those that occur in the setting of uncontrolled hypertension. The results of this study did not show an association between non-lobar ICH and statin use, regardless of ApoE genotype. Therefore, such patients would benefit best from optimal medical management, including control of hypercholesterolemia. Changing clinical practice, eg, stopping statins in patients with non-lobar hemorrhages, is not evidence-based and at this point may disallow patients from receiving the benefits of statin therapy.