Ticagrelor and Aspirin Combination Most Effective in CYP2C19 Carriers With Low Risk Profile

The study provided class II evidence that CYP2C19 loss of function carriers with minor stroke or transient ischemic attack at low risk, but not high risk, of recurrent stroke received greater benefit from ticagrelor and aspirin rather than clopidogrel and aspirin.

Yongjun Wang, MD, associate professor, Chinese Academy of Medical Sciences

Yongjun Wang, MD

Post-hoc findings from the CHANCE-2 trial (NCT0407837) showed that the benefit of dual antiplatelet therapy (DAPT) using ticagrelor (Brilinta; AstraZeneca) and aspirin is most effective in carriers of CYP2C19 loss of function (LOF) alleles with minor stroke or transient ischemic attack (TIA) who have low risk profiles, as defined by Essen Stroke Risk Score (ESRS).1

In a cohort of 6412 patients randomly assigned to either ticagrelor and aspirin (n = 3205) or clopidogrel (Plavix; Sanofi) and aspirin (n = 3207), ticagrelor and aspirin use was associated with a reduced risk of new stroke within 90-day follow-up, the primary outcome, in patients at low risk (hazard ratio [HR], 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel and aspirin (P = .02). Overall, these findings may help identify patient profiles who may be more suitable for this type of treatment.

In the original study, genotype data showed that the efficacy of clopidogrel and aspirin depended on CYP2C19 genotype and risk profile. In the new post-hoc analysis, senior investigator Yongjun Wang, MD, associate professor, Chinese Academy of Medical Sciences, and colleagues, compared the efficacy of both DAPT approaches in carriers of CYP2C19 LOF alleles according to risk of recurrent stroke, with scores greater than 3 on ESRS considered high-risk.

On the primary safety analysis, outcome of severe or moderate bleeding did not differ based on risk profile (P = .24 for interaction), though the incidence of total bleeding was greater with ticagrelor and aspirin vs clopidogrel and aspirin among patients with low risk profiles (P <.01). Additionally, secondary outcomes generally went in the same direction as the primary outcome, and analyses in the per-protocol population also yielded similar results.

In CHANCE-2, patients received ticagrelor 180 mg on day 1 followed by 90-mg twice daily on days 2 to 90, or clopidogrel 300 mg on day 1 followed by 75-mg daily on days 2 to 90, all while on aspirin 75 to 300 mg on day 1 followed by 75-mg daily for 21 days.

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In July 2022, a secondary analysis from CHANCE-2 published in JAMA Neurology suggested that the greatest benefit from ticagrelor and aspirin occurs during the first week after administration, with a smaller benefit in the following weeks. In the first week, the reduction of major ischemic events in the ticagrelor group resulted in absolute risk reduction [ARR] of 1.34% (95% CI, 0.29-2.39). In the following 3 weeks, the reductions remained, but were attenuated (second week: ARR, 0.11% [CI, –0.24 to 0.45]; third week: ARR, 0.14% [95% CI, –0.11 to 0.38]; fourth week: ARR, 0.04% [95% CI, –0.18 to 0.25]).2

Net clinical benefit was also evaluated using the composite outcome of major ischemic event and moderate to severe bleeding, which included the combination of ischemic stroke, moderate to severe bleeding, and death. The data continued to favor the ticagrelor group, observed in the first week (absolute risk reduction, 1.49%; 95% CI, 0.43-2.56) that remained in the next 3 weeks (second week: 0.04% [95% CI, –0.32 to 0.40]; third week: 0.10% [95% CI, –0.15 to 0.35] first week: 0.07% [95% CI, –0.16 to 0.29]). The net clinical benefit was consistently observed across the prespecified subgroups, except that greater absolute net benefit was found in those without previous ischemic stroke or TIA than those with previous ischemic stroke or TIA.

REFERENCES
1. Wang A, Meng X, Zuo X, et al. Ticagrelor-aspirin vs clopidogrel-aspirin in CYP2C19 loss-of-function carriers with minor stroke or TIA stratified by risk profile. Neurology. Published online December 19, 2022. doi:10.1212/WNL.0000000000201454
2. Pan Y, Meng X, Jin A, et al. Time course benefit and risk with ticagrelor and aspirin in individuals with acute ischemic stroke or transient ischemic attack who carry CYP2C19 loss-of-function alleles: a secondary analysis of the CHANCE-2 randomized study. JAMA Neurol. Published online June 21, 2022. doi:10.1001/jamaneurol.2022.1457
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