A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke

A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke
Kelly Beneke, PharmD, New Ulm Medical Center

Background: Limited evidence is available to support a specific low-density lipoprotein (LDL) cholesterol target level following ischemic stroke or transient ischemic attack (TIA). According to the 2018 American College of Cardiology and American Heart Association (ACC/AHA) guidelines, high-intensity or maximal intensity statins are recommended in patients with clinical atherosclerotic cardiovascular disease (ASCVD), and the addition of ezetimibe in very high-risk ASCVD patients is reasonable if LDL levels are >70 mg/dL. According to the American Heart Association and the American Stroke Association (AHA-ASA), intense statin therapy is recommended after an ischemic stroke of atherosclerotic origin however no specific LDL target levels are listed.

Objective: The objective of this study was to determine if an LDL cholesterol target of <70 mg/dL resulted in fewer overall cardiovascular events compared to those with an LDL cholesterol target range of 90–110 mg/dL in patients with evidence of atherosclerosis who recently had an ischemic stroke or TIA.

Study Design: The Treat Stroke to Target trial was a randomized, parallel-group, event-driven trial conducted in France and South Korea. Adult patients with atherosclerotic disease were eligible for the trial if they had an ischemic stroke within the past 3 months or a TIA within the past 15 days. The primary endpoint was a composite of major cardiovascular events (adjudicated nonfatal cerebral infarction or stroke of undetermined origin, nonfatal myocardial infarction, hospitalization for unstable angina, TIA treated with urgent carotid revascularization, or cardiovascular death). Primary efficacy analysis of the intention to treat population was assessed using a Cox proportional-hazards regression model. An enrollment of 3,786 patients followed for three years was estimated to result in 385 primary end-point events, which would achieve a power of 80% to detect a 25% lower relative risk of major cardiovascular events in the lower-target group (<70 mg/dL) than in the higher-target group (90-110 mg/dL). Alpha was set to 0.05. Patients were randomized in a 1:1 ratio to either the lower-target or higher-target group. Investigators were allowed to prescribe any statin and additional lipid-lowering agents such as ezetimibe in order to reach the assigned LDL cholesterol target.

Results: The primary composite endpoint occurred in 121 of 1430 patients in the lower-target group and in 156 of 1430 patients in the higher-target group (adjusted HR 0.78 [95% CI 0.61 – 0.98] P=0.04). Intracranial hemorrhage occurred in more patients in the lower-target group (18) compared to the higher-target group (13) (HR 1.38 [95% CI 0.68 – 2.82]). The percentage of time that patients were in assigned therapeutic range of LDL cholesterol in the lower-target group and higher-target group were 52.8% and 32.2%, respectively. The addition of ezetimibe to statin therapy occurred in 33.8% of patients in the lower-target group and 5.8% of patients in the higher-target group. Of note, recruitment was extended to include more patients as a result of slow enrollment, and the trial was stopped early due to lack of funding.  Although the study was stopped early with fewer patients and fewer primary end-points than estimated, the follow up duration was extended from three years to the duration of the trial allowing sufficient power to detect a 25% lower relative risk in the lower-target group.

Conclusion:In patients with recent ischemic stroke or TIA and evidence of atherosclerosis, a lower-target LDL level of <70 mg/dL resulted in fewer composite cardiovascular events compared to a higher-target LDL range of 90-110 mg/dL, with no significant difference in intracranial hemorrhages. Study limitations include early discontinuation of the trial due to lack of funding and low external validity with the patient population consisting of French and Korean patients.

Key Points: Treatment with a statin +/- ezetimibe towards an LDL target of <70 mg/dL reduced the risk of cardiovascular events compared to an LDL target of 90-110 mg/dL in patients with evidence of atherosclerosis who recently had an ischemic stroke or TIA. This study supports the ACC/AHA recommendation to consider the addition of ezetimibe to maximally tolerated statin therapy in patients with very high-risk ASCVD and LDL ≥70 mg/dL.

Reference:  

  1. Amarenco, Pierre, Kim, Jong S, Labreuche, Julien, et al. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. N Engl J Med. 382(1). doi:10.1056/NEJMoa1910355