Amarenco P, Kim JS, Labreuche H, et al. A comparison of two LDL cholesterol targets after ischemic stroke. NEJM 2020; 382:9-19.
Reviewed by Kyle Hobbs, MD
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Summary: Intensive lipid lowering therapy is recommended after ischemic stroke or TIA, but the exact LDL target is unclear. The Treat Stroke to Target trial is an international, multicenter, randomized, parallel-group, event driven trial comparing a target LDL of < 70 mg/dL to a target of 90-110 mg/dL after ischemic stroke or TIA in patients with atherosclerosis.
Adult patients were eligible for enrollment if they had had an ischemic stroke in the past 3 months with subsequent modified Rankin score of 0 to 3, or a TIA within the past 15 days involving a speech or motor deficit lasting > 10 minutes, and atherosclerosis causing stenosis of any extra- or intracranial cerebral artery, aortic arch atherosclerosis > 4mm in thickness, or a known history of coronary artery disease.
Pre-enrollment LDL of > 70 mg/dL was required for patients already on statin therapy, or > 100 mg/dL if not already on statin therapy.
Patients were randomized 1:1 to a lower LDL target (< 70 mg/dL) or higher target (LDL 90-110 mg/dL). Investigators were allowed to prescribe any type of statin to reach the target, and medications were adjusted at 3 weeks (including addition of other lipid-lowering agents including ezetimibe) to reach the assigned target. LDL was measured every 6 months and medications were further adjusted. Patients were also treated for hypertension and diabetes according to guidelines, and smoking cessation was encouraged.
The primary endpoint was a composite of major cardiovascular events (nonfatal cerebral infarction or stroke of undetermined origin, nonfatal myocardial infarction, hospitalization for unstable angina followed by urgent coronary artery revascularization, TIA treated with urgent carotid revascularization or cardiovascular death, including unexplained sudden death). The secondary end points were (1) myocardial infarction or urgent coronary revascularization after the onset of new symptoms; (2) cerebral infarction or urgent revascularization of a carotid or cerebral artery after TIA; cerebral infarction or TIA; (3) any revascularization of a coronary, cerebral, or peripheral artery (either urgent or elective); (4) cardiovascular death; (5) death from any cause; (6) cerebral infarction or intracranial hemorrhage; intracranial hemorrhage; (7) newly diagnosed diabetes; and a (8) composite of the primary end point or intracranial hemorrhage.
Results: 2860 patients were enrolled from 2010-2018 and included in the primary analysis. All patients were followed until the end of the trial. The mean LDL in both the low and high target groups was 135 before treatment. Median follow-up was 5.3 years in France and 2.0 years in Korea. In the lower-target group, 33.8% of patients required a statin and ezetimibe therapy, while only 5.8% of higher target patients required addition of ezetimibe. At a median follow up of 3.5 years, lower target mean LDL was 65 mg/dL and higher target was 96 mg/dL. The median percentage of time spent in the assigned therapeutic range was 52.8% in the lower-target group and 32% in the higher target group. In the lower- target group, 47% of patients were above target, 44% ranged from 50-70 mg/dL, and 7.7% ranged from 30-49 mg/dL, and 0.3% were below 30 mg/dL. In the higher-target group, 48% were below target (< 90 mg/dL), and 16% were above the target (> 110 mg/dL).
The primary endpoint occurred in 8.5% of lower-target patients and 10.9% of higher target patients (adjusted hazard ratio 0.78; 95% CI, 0.61-0.98; p=0.04). The majority of events were cerebral infarctions or strokes of undetermined origin. These results held true in the sensitivity analyses and after adjustment. The hazard ratios for all secondary endpoints were in the same direction as for the primary end point, but all confidence intervals included 1.0. Intracranial hemorrhage occurred in 1.3% of lower-target patients and 0.9% in higher-target patients (hazard ratio, 1.38; 95% CI, 0.68-2.82), and there were no significant differences in any adverse events.
Commentary: In the Treat Stroke to Target trial, a lipid-lowering goal of LDL < 70 mg/dL was associated with a significantly lower incidence of cardiovascular events compared to a goal of 90-110 mg/dL. This benefit was seen in a composite endpoint of major cardiovascular events.
This trial used a prespecified hierarchical analysis in which the first composite secondary endpoint of myocardial infarction or urgent coronary revascularization was not significant, resulting in a lack of formal testing of the other individual secondary endpoints; these all skewed in the direction of favoring the lower-target group, but significance was not analyzed.
In this trial, the percentage of time patients spent in the assigned therapeutic LDL range was low (52% for lower-target, and only 32% for higher-target), with a large proportion of the lower-target group being above target, with a similar percentage (48%) of the higher-target group being below target (< 90 mg/dL). It is possible that the benefit of the lower target group would have been more profound if the amount of time on target in both groups had been achieved more frequently.
This trial did not address the possibility that even lower LDL targets (< 50 mg/dL) could be beneficial. Limitations of this trial include early termination due to lack of funding. In addition, many of the lower-target patients required addition of additional medication for achievement of the LDL goal. Overall, in patients with prior stroke or TIA and atherosclerotic disease, aggressive lipid lowering appears beneficial.