By Matthew E. Fink, MD
Louis and Gertrude Feil Professor and Chair, Department of Neurology, Associate Dean for Clinical Affairs, NYP/Weill Cornell Medical College
SOURCES: Pan Y, Meng X, Jin A, et al. Time course for 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 clinical trial. JAMA Neurol 2022;79:739-745.
Kim AS. Optimizing the time course of risks and benefits of acute dual antiplatelet therapy for stroke prevention. JAMA Neurol 2022;79:736-738.
Secondary prevention of acute ischemic stroke is continuing to evolve, with great interest in using dual antiplatelet treatment early in the course. The most common recommended protocol has been aspirin with clopidogrel, with varying duration of treatment, from 21 days to 90 days, based on various clinical trials.
A complicating factor has been the role of the CYP2C19 loss-of-function gene that interferes with the conversion of clopidogrel to its active antiplatelet metabolite. This genetic variation is common in the Chinese population, where several pivotal trials were performed (CHANCE-1 and CHANCE-2). The true prevalence of this gene mutation is uncertain in the U.S. population.
Ticagrelor has a similar mechanism of action to clopidogrel, but it is not a prodrug and does not require metabolism for its antiplatelet activity. Therefore, ticagrelor recently has been studied as an alternative to clopidogrel in the CHANCE-2 study.1 CHANCE-2 demonstrated that in comparing clopidogrel and aspirin to ticagrelor and aspirin for 21 days, there was a lower risk of subsequent ischemic stroke without a higher risk of severe bleeding at 90 days. However, there was an overall higher risk of bleeding in the ticagrelor group. The authors conducted a further analysis of the data, which included an examination of the week-by-week risk of recurrence of ischemic stroke and hemorrhage for the first several weeks after the initiation of treatments.
The authors randomized 6,412 patients to ticagrelor and aspirin or clopidogrel and aspirin. The median age was 65 years, and 66% of patients were men. The reduction of major ischemic events with ticagrelor and aspirin was greatest during the first week, with an absolute risk reduction of 1.34%. Risk reduction declined in the next three weeks, but there continued to be a small risk reduction for ischemic stroke. The risk of moderate to severe bleeding was low, but there was a higher risk for all bleeding episodes (minor, moderate, or severe) over the next three weeks. The greatest benefit for treatment with ticagrelor and aspirin together was in the first week because of ongoing risks of bleeding from dual antiplatelet therapy. Overall, the net benefits for reduction of ischemic stroke favored continued use of dual antiplatelet therapy for 21 days for secondary stroke prevention.
In the United States, it will be important to determine the actual frequency of the CYP2C19 loss-of-function gene. We should consider point-of-care testing for patients before selecting and initiating dual antiplatelet therapy.
REFERENCE
1. Wang Y, Meng X, Wang A, et al. Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA. N Engl J Med 2021;385:2520-2530.
It will be important to determine the actual frequency of the CYP2C19 loss-of-function gene. Clinicians should consider point-of-care testing for patients before selecting and initiating dual antiplatelet therapy.
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