Does statin increase the risk of intracerebral hemorrhage in stroke survivors? A meta-analysis and trial sequential analysis

Abstract

Background: It remains debatable whether statin increases the risk of intracerebral hemorrhage (ICH) in poststroke patients. Methods: We systematically searched PubMed, EMBASE, and CENTRAL for randomized controlled trials. Trial sequential analysis (TSA) was conducted to assess the reliability and conclusiveness of the available evidence in the meta-analysis. To evaluate the overall effectiveness, the net composite endpoints were derived by totaling ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), myocardial infarction, and cardiovascular mortality. Results: A total of 17 trials with 11,576 subjects with previous ischemic stroke, TIA, or ICH were included, in which statin therapy increased the risk of hemorrhagic stroke (risk ratio [RR], 1.42; 95% confidence interval [CI], 1.07–1.87), but reduced the risk of ischemic stroke (RR, 0.85; 95% CI, 0.75–0.95). For the net composite endpoints, statin therapy was associated with a 17% risk reduction (95% CI, 12–21%; number needed to treat = 6). With a control event rate 2% and RR increase 40%, the TSA suggested a conclusive signal of an increased risk of hemorrhagic stroke in stroke survivors taking statin. However, with the sensitivity analysis by changing assumptions, the conclusions about hemorrhagic stroke risk were less robust. Conclusions: Statin therapy in poststroke patients increased the risk of hemorrhagic stroke but effectively reduced ischemic stroke risk. Weighing the benefits and potential harms, statin has an overall beneficial effect in patients with previous stroke or TIA. However, more studies are required to investigate the conclusiveness of the increased hemorrhagic stroke risk revealed in our study.

Efficacy of statin treatment based on cardiovascular outcomes in elderly patients: a standard meta-analysis and Bayesian network analysis

“…A recent study indicated that statin therapy in post-stroke patients increased the risk of hemorrhagic stroke; however, when weighing the benefits and potential harms, statins had an overall beneficial effect in patients with a history of stroke. 51 Therefore, the risk of stroke for elderly patients who are taking statins needs to be studied further.…”

Abstract P623: Lipid-Lowering Therapy and Intracerebral Hemorrhage Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors

“…For statins, these findings are perforce consistent with prior studies, as the data is abstracted from the three most comprehensive meta-analyses of all-patient/all-dose, high dose, and prior ischemic stroke RCTs and the one salient trial for prior hemorrhagic stroke. 3,10,12,13 For each of the meta-analyses, there was no-to-moderate heterogeneity and none with high heterogeneity, indicating good consistency of results across trials. The findings of these meta-analyses contrast with some meta-analyses by other groups that did not find elevated hemorrhagic stroke risk with statins, but those studies were limited by: (1) less comprehensive inclusion of relevant RCTs and (2) analysis not only of RCTs, but also observational studies, which are vulnerable to confounding by indication.…”

Ovary and uterus related adverse events associated with statin use: an analysis of the FDA Adverse Event Reporting System

“…Although these uterine bleeding AEs of statins have not been previously reported, the bleeding risk at other sites associated with statins has already been identified. For example, several epidemiologic studies indicated that statin use was associated with increased risk of intracerebral hemorrhage and gastrointestinal hemorrhage [33][34][35] . The underlying mechanisms by which statins increase bleeding risk may include the following points: first, lower serum cholesterol levels induced by statins may increase risk of rupture and hemorrhage by reducing vessel resistance to tension 36 ; second, statins could inhibit the prenylation of small GTP-binding proteins (GTPases), such as CDC42 and Rac1, resulting in alteration of vascular permeability 37 ; third, statins also have antithrombotic effects, decrease platelet activity, inhibit platelet aggregation, have anticoagulant activity, affect blood viscosity and RBC deformability, and 'improve' von Willebrand factor activity 33 .…”