Effect of insulin resistance on ticagrelor-versus clopidogrel-based dual antiplatelet therapy for secondary prevention of stroke in carriers of CYP2C19 loss-of-function mutations.

BACKGROUND: Insulin resistance is associated with increased platelet reactivity. We sought to investigate the effects of insulin resistance on dual antiplatelet therapy in CYP2C19 loss-of-function carriers with minor stroke or transient ischemic attack (TIA). METHODS: We conducted a post hoc analysis of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial, in which we randomized patients with minor stroke or TIA who carried CYP2C19 loss-of-function mutations to receive ticagrelor-acetylsalicylic acid (ASA) or clopidogrel-ASA. We categorized patients by insulin resistance status using a cut-off of 8 mg/kg/min in the estimated glucose disposal rate. The primary efficacy outcome was recurrent stroke. The primary safety outcome was severe or moderate bleeding within 90 days of starting the intervention. RESULTS: Among 4954 patients included, 3122 (63.0%) had high insulin resistance and 1832 (37.0%) had low insulin resistance. Compared with clopidogrel-ASA, ticagrelor-ASA reduced the risk of recurrent stroke in the low-insulin resistance group (71 [7.8%] v. 36 [3.9%]; hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.34 to 0.79), but not in the high-insulin resistance group (120 [7.7%] v. 120 [7.7%]; HR 0.96, 95% CI 0.74 to 1.24) (p = 0.01 for interaction). Results were similar among patients with and without diabetes (p for interaction = 0.3). The benefit of ticagrelor-ASA versus clopidogrel-ASA for recurrent stroke increased continuously as insulin resistance decreased (p for interaction = 0.03). Rates of severe or moderate bleeding were similar regardless of treatment or insulin resistance group (p for interaction = 0.8). INTERPRETATION: In CYP2C19 loss-of-function carriers with minor stroke or TIA, ticagrelor-ASA use was associated with reduced future stroke risk compared with clopidogrel-ASA among patients with low insulin resistance. Insulin resistance biomarkers have a potential role in optimal selection of antiplatelet therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04078737.