Fewer major vascular events with statin/ezetimibe combination therapy plus lower LDL-c target after stroke or TIA
Yield of Dual Therapy With Statin and Ezetimibe in the Treat Stroke to Target Trial
Introduction and methods
For patients who had a TIA or an ischemic stroke of atherosclerotic origin, the 2021 American Heart Association/American Stroke Association Guideline for the Prevention of Stroke in Patients with Stroke and TIA recommends intensive statin therapy and an LDL-c target level of <70 mg/dL using a statin, and ezetimibe as needed . This advice was in part based on the results of the TST (Treat Stroke to Target) trial, which showed a 22% reduction in major vascular events in patients with an LDL-c target level of <70 mg/dL compared with those who had an LDL-c target level of 100±10 mg/dL .
In patients with coronary atherosclerosis, dual therapy with a statin and ezetimibe has shown benefit over statin monotherapy . However, the effect of this dual therapy on achieving an LDL-c target level of <70 mg/dL and reducing the occurrence of major vascular events has not been studied in patients with stroke.
Aim of the study
In a post-hoc analysis of the TST trial, the authors sought to evaluate the relative efficacy of dual therapy with a statin and ezetimibe versus statin monotherapy in achieving the LDL-c target level and reducing the risk of major vascular events, in a group of patients with LDL-c target <70 mg/dL compared with a patient group with LDL-c target 100±10 mg/dL.
The TST trial was a parallel-group, event-driven study conducted in South Korea and France in which 2860 patients with an ischemic stroke of atherosclerotic origin within the previous 3 months or a TIA within the previous 15 days were randomly assigned to a lower-target group (i.e., LDL-c <70 mg/dL (1.8 mmol/L)) or higher-target group (i.e., LDL-c range: 90–110 mg/dL (2.3–2.8 mmol/L)).
Trial patients had to have atherosclerotic disease, or aortic arch atherosclerotic plaques ≥4 mm in thickness, or a known history of coronary artery disease. They received a statin (any type and at any dose) to reach the assigned LDL-c target. Three weeks after randomization, the statin dose was adjusted or other lipid-lowering agents, including ezetimibe, were added if needed ; no patient was treated with an PCSK9i. LDL-c levels were measured every 6 months. The median follow-up duration was 3.5 years.
The primary endpoint was a composite outcome of nonfatal cerebral infarction or stroke of undetermined source, nonfatal MI, hospitalization for unstable angina followed by urgent coronary artery revascularization, TIA requiring urgent carotid revascularization, or CV death including unexplained sudden death.
Prespecified secondary composite endpoints were MI or urgent coronary revascularization following new symptoms; cerebral infarction or urgent carotid or cerebral artery revascularization following TIA; cerebral infarction or TIA; any revascularization procedures (both urgent and elective); vascular death; all-cause mortality; cerebral infarction or intracranial hemorrhage; intracranial hemorrhage; newly diagnosed DM; and a composite outcome of the primary endpoint and intracranial hemorrhage.
- In the lower-target group, the mean (± SD) baseline LDL-c level was higher in patients receiving dual therapy (i.e., statin plus ezetimibe) compared with those on statin monotherapy (i.e., statin plus lipid-lowering agent other than ezetimibe if needed) (141 ± 38 vs. 131 ± 36 mg/dL; P<0.001).
- During follow-up, the mean LDL-c level in the lower-target group was 66.2 mg/dL for patients on dual therapy and 64.1 mg/dL for patients on statin monotherapy.
- Patients in the lower-target group who were receiving dual therapy (n=529) had a lower risk of the primary endpoint compared with all patients in the higher-target group (n=1424), regardless of whether they were on dual therapy or statin monotherapy (hazard ratio (HR): 0.59; 95%CI: 0.38–0.90; P=0.016). However, this beneficial effect was not seen for patients on statin monotherapy in the lower-target group (n=896) when compared with the entire higher-target group (HR: 0.92; 95%CI: 0.70–1.22; P=0.52).
- Patients on dual therapy whose LDL-c level was <70 mg/dL during 50%–100% of the time of the follow-up had an even larger reduction in the risk of the primary endpoint compared with all patients in the higher-target group (HR: 0.51; 95%CI: 0.30–0.84; P=0.009). Again, statin monotherapy had no effect (HR: 0.91; 95%CI: 0.66–1.26; P=0.57).
- Compared with the higher-target group, patients in the lower-target group on dual therapy also showed a reduced risk of cerebral infarction and urgent carotid or cerebral artery revascularization (HR: 0.57; 95%CI: 0.33–0.97; P=0.037) and the composite outcome of the primary endpoint and intracranial hemorrhage (HR: 0.62; 95%CI: 0.41–0.94; P=0.023). There were no differences for the other secondary endpoints, nor between the lower-target group on statin monotherapy and the higher-target group.
In this post-hoc analysis of the TST trial, targeting an LDL-c level of <70 mg/dL with dual therapy consisting of a statin and ezetimibe reduced the risk of major vascular events compared with a higher LDL-c target of 90–110 mg/dL in patients following an atherosclerotic ischemic stroke or a TIA. Combining a lower LDL-c target of <70 mg/dL with statin monotherapy had no effect, although both treatment groups achieved a similar mean LDL-c level.
The authors believe the different outcomes within the lower-target group for patients treated with dual therapy or statin monotherapy may be explained by the higher mean baseline LDL-c level seen in those with dual therapy, with consequently a greater reduction in LDL-c level from baseline.