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(2020)Objective
Determine whether targeting a lower LDL cholesterol level (<70 mg/dL) reduces the risk of cardiovascular events compared to a higher LDL target (90–110 mg/dL) in patients with recent ischemic stroke or TIA and evidence of atherosclerosis.
Study Summary
Intervention
Randomized, open-label, event-driven trial across 77 sites (France and South Korea). • Patients (N=2860) within 3 months of ischemic stroke or 15 days of TIA were randomized to LDL target <70 mg/dL or 90–110 mg/dL. • Statins and ezetimibe were used to achieve LDL targets. • Follow-up: median 3.5 years • Statin dose adjustments and lipid monitoring were performed at regular intervals.
Study Design
Arms: Array
Outcome
• Intracranial hemorrhage: 1.3% vs. 0.9% (HR 1.38; p=NS)
• Newly diagnosed diabetes: 7.2% vs. 5.7% (HR 1.27; p=NS)
• Trial stopped early after 277 of 385 expected events due to funding
• No difference in all-cause mortality or secondary endpoints
• Results support a target LDL <70 mg/dL in patients with stroke or TIA due to atherosclerosis.
Bottom Line
Patients with ischemic stroke or TIA of atherosclerotic origin who achieved an LDL cholesterol target of less than 70 mg per deciliter (1.8 mmol per liter) had a significantly lower risk of subsequent major cardiovascular events compared to those with a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter), with no significant difference in intracranial hemorrhage or newly diagnosed diabetes.
Major Points
- 2860 patients with ischemic stroke (previous 3 months) or TIA (previous 15 days) and evidence of cerebrovascular or coronary-artery atherosclerosis were randomized.
- Patients were assigned to a target LDL cholesterol of less than 70 mg/dL (lower-target group, n=1430) or 90-110 mg/dL (higher-target group, n=1430).
- Mean achieved LDL cholesterol was 65 mg/dL in the lower-target group and 96 mg/dL in the higher-target group.
- The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred, with a median follow-up of 3.5 years.
- The composite primary end point of major cardiovascular events occurred in 8.5% (121 patients) in the lower-target group and 10.9% (156 patients) in the higher-target group (adjusted HR, 0.78; 95% CI, 0.61 to 0.98; P=0.04).
- The incidence of intracranial hemorrhage (1.3% lower-target vs 0.9% higher-target; HR 1.38; 95% CI 0.68 to 2.82) and newly diagnosed diabetes (7.2% lower-target vs 5.7% higher-target; HR 1.27; 95% CI 0.95 to 1.70) did not differ significantly between the two groups.
Study Design
- Study Type
- Randomized, parallel-group, event-driven trial
- Randomization
- Yes
- Blinding
- Outcome adjudicators were unaware of trial-group assignments or LDL cholesterol levels reached.
- Sample Size
- 2860
- Follow-up
- Median 3.5 years
- Centers
- 77
- Countries
- France, South Korea
Primary Outcome
Definition: Composite of major cardiovascular events including ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 156 (10.9%) patients (2.98 per 100 person-years) | 121 (8.5%) patients (2.27 per 100 person-years) | 0.78 (0.61 to 0.98) | 0.04 |
Limitations & Criticisms
- The trial was stopped prematurely due to a shortage of funds, preventing it from reaching the planned 385 primary endpoint events, although the observed 277 events were deemed sufficient to detect the hypothesized effect size.
- Although adjudicators were blinded, investigators and research assistants were aware of the assigned LDL targets, which could introduce bias in patient management or data collection.
- Secondary endpoints could not be formally tested due to the failure of the hierarchical analysis, meaning their reported confidence intervals should not be used for causal inference.
- The median follow-up time differed significantly between French (5.3 years) and South Korean (2.0 years) patients, potentially impacting the generalizability of results to the Korean population.
- The trial found a numerically higher incidence of intracranial hemorrhages in the lower-target group, similar to some previous studies, though not statistically significant in this trial.
- The effect size, while positive, may not be large enough to be considered highly impactful, as indicated by the 95% CI just barely crossing the significance threshold.
Citation
N Engl J Med 2020;382:9-19.