Clinical Pearls & Morning Reports
Wang et al. conducted a trial that tested the hypothesis that dual treatment with ticagrelor and aspirin would be superior to clopidogrel and aspirin in reducing the risk of subsequent stroke among patients with minor ischemic stroke or high-risk TIA who were CYP2C19 loss-of-function allele carriers. Read the NEJM Original Article here.
Q: Does clopidogrel require metabolic activation for its antiplatelet effect?
A: Dual antiplatelet therapy with clopidogrel and aspirin has been shown to be more effective than aspirin alone for reducing subsequent events in patients with minor stroke or TIA in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trials. However, clopidogrel is a prodrug requiring conversion into its active metabolite by hepatic cytochrome p450 (CYP). Clopidogrel is less effective for the secondary prevention of stroke in carriers of CYP2C19 loss-of-function alleles, which are present in 25% of White patients and in 60% of Asian patients.
Q: What was the basis for the hypothesis that ticagrelor would be superior to clopidogrel in the trial by Wang et al.?
A: Ticagrelor, a reversible oral antagonist that directly blocks platelet P2Y12 receptor and does not require metabolic activation for its antiplatelet effect, may yield similar or greater levels of inhibition of platelet aggregation than clopidogrel. In the PRINCE (Platelet Reactivity in Acute Stroke or Transient Ischaemic Attack) trial, patients with minor stroke or TIA who were treated with ticagrelor plus aspirin had a lower platelet reactivity than those who were treated with clopidogrel plus aspirin, particularly in CYP2C19 loss-of-function allele carriers. This finding suggests that the combination of ticagrelor and aspirin may result in a lower risk of subsequent stroke than the combination of clopidogrel and aspirin among patients with minor stroke or TIA who are carriers of CYP2C19 loss-of-function alleles.
A: In this randomized, double-blind, placebo-controlled trial conducted almost exclusively in Han Chinese participants, those with minor ischemic stroke or high-risk TIA who were CYP2C19 loss-of-function allele carriers had a lower risk of stroke at 90 days with ticagrelor and aspirin than with clopidogrel and aspirin. A primary-outcome event, new ischemic or hemorrhagic stroke within 90 days, occurred in 191 of the 3205 patients (6.0%) in the ticagrelor–aspirin group and in 243 of the 3207 patients (7.6%) in the clopidogrel–aspirin group (hazard ratio, 0.77; 95% CI, 0.64 to 0.94; P=0.008). Overall, the incidence of adverse events and total bleeding events was greater with ticagrelor–aspirin treatment, mainly owing to mild bleeding, but there was not an increased incidence of moderate or severe bleeding. Dyspnea and arrhythmias were more frequent with ticagrelor than with clopidogrel and were the primary causes of between-group differences in discontinuation.
A: The trial’s results are not generalizable to non-Han patients, because Han patients made up 98.0% of those enrolled. This population also has a higher incidence of intracranial-artery stenosis than non-Asian populations, and ticagrelor and clopidogrel may have different effects in non-Han patients with loss-of-function alleles. Despite the effort of recruiting hospitals for this trial in provinces where most minority populations reside, there were very few hospitals that were equipped to conduct clinical trials and that voluntarily participated.