Lower LDL Cholesterol Target Reduces Cardiovascular Events After Ischemic Stroke

Pierre Amarenco, MD

Findings from a large-scale study demonstrated that patients who lowered their low-density lipoprotein (LDL) cholesterol level to less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events after ischemic stroke than those who acheived a target LDL range of 90 mg to 110 mg per deciliter.

The parallel-group trial (NCT01252875) enrolled 2860 patients who had an ischemic stroke in the previous 3 months or a transient ischemic attack (TIA) within the previous 15 days and who had atherosclerotic disease; patients were followed for a median of 3.5 years. Investigators randomly assigned participants to 2 target LDL cholesterol level groups: a lower-target group of less than 70 mg per deciliter (1.8 mmol per liter) and a higher-target group with a range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter).

The primary endpoint consisted of a composite of major cardiovascular events such as ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death related to cardiovascular causes. Within the lower-target group, 65.9% of patients received only a statin compared with 94.0% in the higher-target group; 33.8% in the lower-target group and 5.8% in the higher target group received ezetimibe in addition to statin therapy.

Among the patients observed, the mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter). At 3.5 year follow-up, the lower-target group achieved a mean LDL cholesterol level of 65 mg per deciliter (1.7 mmol per liter), while the higher-target group achieved a mean LDL cholesterol level of 96 mg per deciliter (2.5 mmol per liter).

Fewer patients in the lower-target group experienced the primary endpoint (8.5%) compared with those in the higher-target group (10.9%; adjusted HR, 0.78; 95% CI, 0.61-0.98; P=.04). The majority of the end-point events were cerebral infarctions or strokes of undetermined origin. The trial concluded early due to administrative reasons when patients reached 277 of 385 anticipated endpoints.

Ultimately, results showed that a target level of less than 70 mg per deciliter was the most effective level to lower risk of subsequent cardiovascular events in patients who suffered an ischemic stroke or TIA. Overall, the 277 events provided sufficient power to detect a 25% lower relative risk in the lower-target group. The benefits of reducing LDL levels to below 50 mg per deciliter is not yet known but could be tested in other studies, the investigators suggested.

Adverse events observed included intracranial hemorrhage, which occurred in 18 patients (1.3%) in the lower-target group and 13 (0.9%) in the higher-target group (HR, 1.38; 95% CI, 0.66-2.82). Notably, 103 patients (7.2%) in the lower-target group and 82 in the higher-target group developed a new diagnosis of diabetes (HR, 1.27; 95% CI, 0.95-1.70).

“Given the established relationship between LDL cholesterol levels and cardiovascular events, our results support the findings from meta-analyses of lipid-lowering trials suggesting that a lower level of LDL cholesterol is associated with better outcomes than higher LDL cholesterol targets,” the investigators concluded.

Reference:

Amarenco P, Kim JS, Labreuche H, et al. A comparison of two ldl cholesterol targets after ischemic stroke. N Engl J Med. Published online November 18, 2019. doi: 10.1056/NEJMoa1910355.