Ticagrelor and Aspirin Most Effective in First Week Poststroke for CYP2C19 Loss-of-Function Allele Carriers

Yongjun Wang, MD

Secondary analysis data from the CHANCE-2 randomized clinical trial (NCT0407837) suggest that the benefit of dual antiplatelet therapy (DAPT) using ticagrelor (Brilinta; AstraZeneca) and aspirin is most predominant in the first week, with a smaller benefit in the following weeks for patients with minor ischemic stroke or transient ischemic attack (TIA) carrying CYP2C19 loss-of-function (LOF) alleles.

In a cohort of 6412 patients randomized to either ticagrelor and aspirin (n = 3205) or clopidogrel (Plavix; Sanofi) and aspirin (n = 3207), the reduction of major ischemic events in the ticagrelor group mainly occurred in the first week (absolute risk reduction [ARR], 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]).

Senior investigator Yongjun Wang, MD, associate professor, Chinese Academy of Medical Sciences, and colleagues concluded that the benefits observed from ticagrelor and aspirin in the first week may outweigh the risk of bleeding throughout the 21-day period of DAPT. Additionally, they wrote that the analysis does not support shortening the 21-day regimen of this approach, which, in the original analysis, was shown to modestly lower the risk of stroke over a 90-day period relative to those on clopidogrel and aspirin.²

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. Cumulative analysis showed that the reduction of major ischemic events in the ticagrelor group remained throughout the entire 90-day treatment period.¹

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Between the 2 treatment groups, there were 2 fewer moderate to severe bleeding events among those treated with ticagrelor, with a risk that was relatively constant throughout the study period. The absolute increase in any bleeding event in the first week (2.1% vs 1.2%; absolutely risk increase, 0.87%; 95% CI, 0.25-1.50) remained in the next 3 weeks (second week: 1.21% [95% CI, 0.75-1.68]; third week: 0.33% [95% CI, –0.05 to 0.72]; fourth week: 0.23% [95% CI, –0.03 to 0.49).

The absolute increase in any bleeding event seen during the first week remined relatively constant in the following weeks. Between the ticagrelor and clopidogrel groups, the reduction of major ischemic events (4.7% vs 6.3%; ARR, 1.56%; 95% CI, 0.44-2.67) and increase in any bleeding event (4.3% vs 1.9%; absolute risk increase, 2.37%; 95% CI, 1.52-3.22) was observed at 21 days, but not during the period from day 22 to day 90 (single antiplatelet therapy in both arms).

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.

Throughout the 90-day treatment period, treatment with ticagrelor and aspirin resulted in positive net clinical benefit, mainly observed in the first week and was regardless of the weight of a moderate to severe bleeding event (between 0.5- to 1.2-fold greater) and the weight of a mild bleeding event (between 0- to 0.5-fold greater) compared with a major ischemic event. Notably, from day 22 to day 90, DAPT approach with ticagrelor and aspirin showed a negligible net benefit, regardless of the weights of the moderate to severe and mild bleeding events.

REFERENCE
1. 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
2. Wang Y, Meng X, Wang A, et al. Ticagrelor vs clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA. N Engl J Med. 2021;385:2520-2530. doi:10.1056/NEJMoa2111749