Ticagrelor Steps It Up for Stroke Patients With Impaired Clopidogrel Metabolism

Stroke survivors carrying CYP2C19 loss-of-function alleles had better secondary prevention when taking ticagrelor (Brilinta) versus clopidogrel (Plavix) as an add-on to aspirin, according to the Chinese CHANCE-2 trial.

Subsequent ischemic or hemorrhagic strokes at 90 days occurred in 6.0% of patients randomized to ticagrelor, which was modestly lower than the 7.6% of peers assigned to clopidogrel (HR 0.77, 95% CI 0.64-0.94, P=0.008). Ticagrelor’s efficacy was similar between intermediate and poor metabolizers of clopidogrel.

The primary safety endpoint — severe or moderate bleeding at 90 days — occurred in 0.3% of both groups. Ticagrelor was associated with an uptick in minor bleeds that bumped total bleeding up to 5.3% versus 2.5% with clopidogrel, reported Yongjun Wang, MD, of Beijing Tiantan Hospital at Capital Medical University.

Results were presented as a late-breaking abstract at the World Stroke Congress and published in the New England Journal of Medicine.

Ticagrelor’s main downside was an association with more dyspnea and arrhythmias, two adverse events that led to disproportionately more patients prematurely discontinuing the drug in the trial.

The study authors noted that the per-protocol analysis, counting individuals who stayed on their assigned drug, was similar to the primary intention-to-treat analysis.

“Ticagrelor may be clinically useful as an alternative antiplatelet agent in patients with stroke carrying CYP2C19 loss-of-function alleles for whom the efficacy of clopidogrel might be reduced, especially in East Asian populations for whom the burden of stroke recurrence and the prevalence of CYP2C19 loss-of-function alleles are high,” Wang’s group wrote.

“However, the clinical usefulness of pharmacogenomics-guided selection of antiplatelet therapy is limited by the availability of rapid CYP2C19 genotyping techniques and tool kits, and the cost-effectiveness of a genotype-guided strategy needs further investigation,” the authors acknowledged.

Clopidogrel had proved to be better than aspirin alone for secondary stroke prevention in the CHANCE and POINT trials.

The antiplatelet is a prodrug requiring hepatic conversion into its active metabolite. CYP2C19 genetic polymorphisms can make the conversion more or less effective. Loss-of-function alleles are thought to be present in 25% of white patients and 60% of Asian patients, according to Wang and colleagues.

Unlike clopidogrel, ticagrelor does not require metabolic activation for its antiplatelet effect. The THALES group had shown that early treatment with ticagrelor and aspirin was better than aspirin alone in secondary stroke prevention.

Wang’s team conducted CHANCE-2 at 202 centers in China in 2019 to 2021. They screened 11,255 patients and enrolled 6,412 who had a recent minor ischemic stroke or transient ischemic attack and carried at least one CYP2C19 loss-of-function allele on rapid genotyping.

Participants had a median age of 64.8 years, and just over one in three were women. The cohort was split between intermediate clopidogrel metabolizers (harboring one CYP2C19 loss-of-function allele; 78%) and poor metabolizers (harboring two or more such alleles; 22%).

Within 24 hours after symptom onset, patients were randomized to either a group getting ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel, or a group getting clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 through 90) and placebo ticagrelor. Both groups received aspirin for 21 days.

Since this study cohort was comprised of 98.0% Han Chinese patients, this limited CHANCE-2’s generalizability to other populations, the study authors noted.

Furthermore, the findings may not be applicable to patients excluded from the trial, namely people with cardioembolic stroke, moderate or severe stroke, or delayed presentation after stroke onset, as well as those receiving thrombolysis or thrombectomy.