Genotype-Guided Dual Antiplatelet Therapy in Minor Stroke or Transient Ischemic Attack With a Single Small Subcortical Infarction

Abstract

Background and objectives: Single small subcortical infarction (SSSI) is an important stroke subtype. The optimal antiplatelet medication for patients with ischemic stroke with an SSSI is still unclear. We aimed to test the efficacy and safety of ticagrelor-aspirin in preventing stroke recurrence among patients with SSSI in the Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial.

Methods: In the CHANCE-2 trial, patients with a minor stroke or TIA who carried CYP2C19 loss-of-function (LOF) alleles were randomly assigned within 24 hours after symptom onset, to either ticagrelor-aspirin (placebo clopidogrel plus a 180 mg loading dose of ticagrelor on day 1, followed by 90 mg twice daily on days 2-90) or clopidogrel-aspirin (placebo ticagrelor plus a 300 mg loading dose of clopidogrel on day 1, followed by 75 mg daily on days 2-90). Aspirin was applied during the first 21 days. Patients who had an SSSI (diffusion-weighted imaging lesion diameter ≤20 mm) were included in this analysis and further categorized into 2 types according to whether they had the responsible intracranial artery stenosis (ICAS): SSSI + ICAS and SSSI - ICAS. The primary efficacy outcome was a new stroke at 90 days.

Results: Among 2,143 eligible patients, 340 had the responsible ICAS, and 1,803 did not. Ticagrelor-aspirin reduced stroke recurrence among all patients with SSSI (hazard ratio [HR]: 0.55; 95% CI 0.38-0.78; p = 0.001) compared with clopidogrel-aspirin. Stroke recurrence occurred in 35/901 (3.9%) patients with SSSI - ICAS on ticagrelor-aspirin and in 72/902 (8.0%) on clopidogrel-aspirin (hazard ratio [HR]: 0.45; 95% CI 0.29-0.68; p < 0.001). In patients with SSSI + ICAS, the corresponding event rates were 14/176 (8.0%) and 13/164 (7.9%), respectively (HR: 1.20; 95% CI 0.45-3.23; p = 0.71; p for interaction = 0.08). The risk of severe or moderate bleeding only occurred in patients with SSSI - ICAS (5/901 [0.6%] vs 5/902 [0.6%]).

Discussion: In this prespecified substudy, ticagrelor-aspirin was superior to clopidogrel-aspirin in reducing the risk of stroke at 90 days among patients with SSSI who carried CYP2C19 LOF allele(s). Although there was no treatment-by-heterogeneous etiology interaction, a greater absolute risk reduction of stroke was observed in patients with SSSI - ICAS than in those with SSSI + ICAS.

Classification of evidence: This study provides Class II evidence that ticagrelor and aspirin reduced the risk of stroke recurrence compared with clopidogrel with aspirin in adult patients with acute minor SSSI.

Figure 1. Flowchart of the Included Patients

CHANCE-2 = Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II; DWI = diffusion-weighted imaging; ECAS = extracranial artery stenosis; ICAS = intracranial artery stenosis; SSSI = single small subcortical infarction.

Figure 2. Cumulative Probability of Recurrent Stroke in Patients With SSSI

Kaplan-Meier curves showing the time to event for the primary efficacy outcome according to (A) treatments and (B) potential etiologies and treatments. SSSI = single small subcortical infarction; SSSI + ICAS = single small subcortical infarction with responsible intracranial artery stenosis; SSSI − ICAS = single small subcortical infarction without responsible intracranial artery stenosis.