Significant reduction in the LDL cholesterol increases the risk of intracerebral hemorrhage: a systematic review and meta-analysis of 33 randomized controlled trials.

The dose-dependent pleiotropic effects of statin therapy may have unwanted side effects such as increasing the risk of intracerebral hemorrhage (ICH). The relationships among statin therapy, LDL-cholesterol levels, and ICH risk remain controversial. Here, we conduct a systematic review and meta-analysis of dose-dependent statin therapy and ICH risk. Eligible articles were identified by searching MEDLINE from inception up to December 1, 2018. Reference lists of previous meta-analyses were manually searched to retrieve all relevant publications. Statin doses were allocated into one of two groups according to the observed reduction of LDL cholesterol: doses that lowered LDL-cholesterol levels ≥35% were regarded as high-dose statin therapy, whereas those that lowered LDL-cholesterol levels <35% were regarded as low-dose statin therapy. We retrieved 33 studies involving 203,305 subjects. The pooled analysis indicated that high-dose statin treatment significantly increased the risk of ICH [relative risk (RR), 1.35; 95% confidence interval (CI), 1.08-1.68] and reduced the risk of all stroke (RR, 0.85; 95% CI, 0.78-0.92), ischemic stroke (RR, 0.79; 95% CI, 0.72-0.87), and all-cause mortality (RR, 0.94; 95% CI, 0.90-0.98). The analyses did not detect any association between low-dose statin treatment and ICH (RR, 1.05; 95% CI, 0.88-1.25). Low-dose statin therapy significantly reduced the incidence of all stroke (RR, 0.84; 95% CI, 0.79-0.89), ischemic stroke (RR, 0.81; 95% CI, 0.76-0.86), and all-cause mortality (RR, 0.94; 95% CI, 0.92-0.97). Our data indicate that low-dose statin therapy is a safe and effective ICH treatment, whereas high-dose statin therapy is associated with increased ICH risk. Hence, our meta-analysis suggests that the dose-dependent pleiotropic effects of statin therapy are related to the measured reduction in LDL cholesterol.