Association Between Intensity of Low-Density Lipoprotein Cholesterol Reduction With Statin-Based Therapies and Secondary Stroke Prevention: A Meta-analysis of Randomized Clinical Trials

Abstract

Importance: The benefits and risks associated with intensive low-density lipoprotein cholesterol (LDL-C)-lowering statin-based therapies to lessen the risk of recurrent stroke have not been established.

Objective: To conduct a meta-analysis of randomized clinical trials to evaluate the association of more intensive vs less intensive LDL-C-lowering statin-based therapies with outcomes for patients with ischemic stroke.

Data sources: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1, 1970, to July 31, 2021.

Study selection: This meta-analysis included randomized clinical trials that compared more intensive vs less intensive LDL-C-lowering statin-based therapies and recorded the outcome of recurrent stroke among patients with stroke.

Data extraction and synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used for abstracting data and assessing data quality and validity. Relative risk (RR) with 95% CI was used as a measure of the association of more intensive vs less intensive LDL-C lowering with primary and secondary outcomes.

Main outcomes and measures: The primary outcome was recurrent stroke, and the secondary outcomes were major cardiovascular events and hemorrhagic stroke.

Results: The final analysis included 11 randomized clinical trials with 20 163 patients (13 518 men [67.0%]; mean [SD] age, 64.9 [3.7] years) with stroke. The mean follow-up was 4 years (range, 1-6.1 years). Pooled results showed that more intensive LDL-C-lowering statin-based therapies were associated with a reduced risk of recurrent stroke compared with less intensive LDL-C-lowering statin-based therapies (absolute risk, 8.1% vs 9.3%; RR, 0.88; 95% CI, 0.80-0.96) and that the benefit associated with these LDL-C-lowering therapies was not different among LDL-C-lowering strategies (statins vs no statins: RR, 0.90; 95% CI, 0.81-1.01; more statins or ezetimibe vs less statins or ezetimibe: RR, 0.77; 95% CI, 0.62-0.96; and proprotein convertase subtilisin/kexin type 9 inhibitors plus statins vs placebo plus statins: RR, 0.90; 95% CI, 0.71-1.15; P = .42 for interaction). More intensive LDL-C-lowering statin-based therapies were associated with a reduced risk of major cardiovascular events, but with an increased risk of hemorrhagic stroke, compared with less intensive LDL-C-lowering statin-based therapies. More intensive LDL-C-lowering statin-based therapies were associated with a reduced risk of recurrent stroke in trials with all patients having evidence of atherosclerosis (RR, 0.79; 95% CI, 0.69-0.91), but not in trials with most patients not having evidence of atherosclerosis (RR, 0.95; 95% CI, 0.85-1.07; P = .04 for interaction), compared with less intensive LDL-C-lowering statin-based therapies.

Conclusions and relevance: This study suggests that the benefits and risks of more intensive LDL-C-lowering statin-based therapies for recurrent stroke risk reduction might be more favorable than the benefits and risks of less intensive LDL-C-lowering statin-based therapies, especially for patients with evidence of atherosclerosis.

Figure 1.. Risk of Recurrent Stroke

Relative risk (RR) of recurrent stroke with more intensive vs less intensive low-density lipoprotein cholesterol–lowering statin-based therapies among patients with stroke. Different sizes of markers indicate the different weights used for pooled analysis. CARE indicates the Cholesterol and Recurrent Events Study; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk; HPS, Heart Protection Study; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; J-STARS, Japan Statin Treatment Against Recurrent Stroke; LIPID, Long-term Intervention with Pravastatin in Ischaemic Disease; ODYSSEY OUTCOMES, Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; PCSK9, proprotein convertase subtilisin/kexin type 9; PODCAST, Prevention of Decline in Cognition after Stroke Trial; SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels; and TST, Treat Stroke to Target.

Figure 2.. Risk of Hemorrhagic Stroke

Relative risk (RR) of hemorrhagic stroke with more intensive vs less intensive low-density lipoprotein cholesterol–lowering statin-based therapies among patients with stroke. Different sizes of markers indicate the different weights used for pooled analysis. FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk; HPS, Heart Protection Study; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; J-STARS, Japan Statin Treatment Against Recurrent Stroke; PCSK9, proprotein convertase subtilisin/kexin type 9; PODCAST, Prevention of Decline in Cognition after Stroke Trial; SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels; and TST, Treat Stroke to Target.

Figure 3.. Evidence of Atherosclerosis

Relative risk (RR) with 95% CI of recurrent stroke with more intensive vs less intensive low-density lipoprotein cholesterol–lowering statin-based therapies among patients with stroke having or not having evidence of atherosclerosis. Different sizes of markers indicate the different weights used for pooled analysis. CARE indicates the Cholesterol and Recurrent Events Study; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk; HPS, Heart Protection Study; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; J-STARS, Japan Statin Treatment Against Recurrent Stroke; LIPID, Long-term Intervention with Pravastatin in Ischaemic Disease; ODYSSEY OUTCOMES, Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; PODCAST, Prevention of Decline in Cognition after Stroke Trial; SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels; and TST, Treat Stroke to Target.