Statins and the risk of Intracranial hemorrhage. Is there a link?
Amarenco P, et al; Treat Stroke to Target Investigators. Intracranial Hemorrhage in the TST Trial. Stroke. 2022 Feb;53(2):457-462. DOI: 10.1161/STROKEAHA.121.035846
Statins are recommended after a transient ischemic attack (TIA) or an ischemic stroke of atherosclerotic origin according to the AHA/ASA guidelines. The SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Level) found patients with an ischemic event on statins had lower risk of recurrent strokes but an increase in the five year risk of hemorrhagic strokes. Despite multiple met analysis having shown no significant increase in intracerebral hemorrhages (ICH) among statin users, there continues to be concern. In the current ‘Treat Stroke to Target’ (TST) trial, patients with an ischemic stroke that underwent aggressive LDL lowering had a significant cardiovascular event reduction. The trial investigators, in a prespecified analysis, evaluated predictors of incident ICH.
This was a randomized, event-driven trial. Patients were recruited in two countries over eight years. Adult patients with a recent ischemic stroke (30 days) or TIA (15 days) with at least one arterial stenosis of an intracerebral artery or carotid artery or coronary artery atherosclerosis were enrolled. Patients were randomized in 1:1 fashion to an LDL less than 70 mg/dL or 100 mg/dL using statins and ezetimbe. The primary outcome was a composite of non-fatal cerebral infarction, nonfatal myocardial infarction, hospitalization for unstable angina followed by urgent coronary artery revascularization, TIA requiring carotid revascularization or cardiovascular death including unexplained sudden death. However, ICH was a prespecified adjudicated safety outcome and for the purpose of this trial the outcome of interest was ICH. The ICH events were adjudicated by a group that were unaware of the LDL cholesterol group.
Among 2860 patients who were followed for a median of 3.5 years, 1430 were assigned to LDL<100 mg/dL and achieved a mean LDL of 96 mg/dL; 1430 were assigned to LDL< 70 mg/dL and achieved a mean LDL of 65 mg/dL. In this prespecified analysis of only patients with stroke associated with atherosclerotic stenosis, 31 patients had an ICH over the course of the trial (absolute risk of incident ICH 1.08%). There were 18 ICH events in the low LDL group and 13 in the control group. None of the baseline characteristics were significantly associated with incident ICH. Only patients with uncontrolled hypertension during the trial (HR 2.51 [1.01–6.31]; p=0.041) and being treated with oral anticoagulant (HR 2.36 [1.00–5.62]; p=0.047) were significant predictors of ICH with an almost 3-fold increase in risk.
The key findings of this study are that in patients with stroke and atherosclerotic disease, an aggressive lowering of LDL to < 70 mg/dL did not increase the risk of ICH. The study clearly prespecified a subgroup analysis and the investigators reviewing ICH being blinded to the cholesterol groups. There are among the strengths of this study. However, there were many limitations to this study as well. Although, there was a prespecified analysis, it was still an analysis of subgroup from the original trial, thereby limiting its statistical power. In addition, there was no formal power calculation and was not powered to assess any changes in mortality. Due to these factors, the results of the study should be considered with caution.
The patient population in TST were those with atherosclerotic disease. The SPARCL trial only had one-fifth (approximately) of its cohort with atherosclerotic disease. In the subgroup analysis of the atherosclerotic group from SPARCL, there was no increased incidence of ICH. These observations may suggest that a larger trial, including patients without atherosclerotic disease, may be required to investigate the association between ICH and statin therapy. Further trials with statistical power are needed to confirm the findings of the current article. Noetheless, this is another study to suggest that statins are safe, and aggressive LDL lowering may not be associated with increased incidence of ICH.
Bilal Butt, MD
Assistant Professor of Neurology
Southern Illinois University School of Medicine