Praveen Hariharan, MD

Sanz-Cuesta BE, Saver JL. Lipid-Lowering Therapy and Hemorrhagic Stroke Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors. Stroke. 2021.

Since the birth of statins in the late 20th century, statins have become an integral part of cardiovascular disease management. However, several studies showing increased risk of hemorrhagic stroke with statin use have raised concerns, and the risk is currently being evaluated with ongoing randomized clinical trials. PCSK9 (proprotein convertase subtilisin kexin 9) inhibitors are the most potent novel antihyperlipidemic medications and could serve as potential alternatives to statins.

In this study, Drs. Sanz-Cuesta and Saver investigated the hemorrhagic stroke rates of PCSK9 inhibitors by undertaking a meta-analysis of data available from randomized clinical trials (RCTs) comparing low or high dose statins with each other or controls, and low and high dose PCSK9 inhibitors with each other or controls. Assuming a gradient risk based on the history of ischemic or hemorrhagic stroke and medication dosing, RCTs were planned to be grouped into 4 subcategories: 1) all patients/any dose; 2) all patients/high dose; 3) history of ischemic stroke/any dose; and 4) history of hemorrhagic stroke/any dose.

After appropriate exclusion, a total of 36 RCTs were included in the statins group and 5 RCTs in the PCSK9 inhibitors group for meta-analysis. All doses of statins were significantly associated with increased risk of hemorrhagic stroke (n=33 RCTs; RR 1.15, 95% CI: 1.00 – 1.32; p=0.04), and risk was slightly more pronounced with higher doses (n=7 RCTs; RR 1.53, 95% CI: 1.16 – 2.01; p=0.002). There was increased risk of hemorrhage in patients with history of ischemic stroke (n=5 RCTs; RR 1.43, 95% CI:1.02 – 2.02; p=0.04) and nonsignificant increased risk in patients with history of hemorrhagic stroke (n=1 RCT; HR 4.06, 95% CI: 0.84 – 19.57; p=0.1).

Patients with history of hemorrhagic stroke on statins seem to be at the greatest risk of hemorrhage followed by patients with history of ischemic stroke on statins, high dose statins and any dose statins in a descending order. PCSK9 inhibitors demonstrated no increased risk of hemorrhagic stroke in any of the abovementioned subgroups, although no RCT report results on patients with history of hemorrhagic stroke. Perhaps increased risk of hemorrhage with statins could be attributed to the antithrombotic properties of statins.

Acknowledging the limitations, including shorter duration of follow up with PCSK9 inhibitors and smaller overall percentage of hemorrhagic strokes, this study outlines valuable conclusions from available data. Current ongoing trials on cessation of statins following intracerebral hemorrhage and more prospective data on head-to-head comparison of statins and PCSK9 inhibitors could provide helpful results to clinical practice.