Introduction: CHANCE-2 study of the team of Prof. Wang Yongjun, Beijing Tiantan Hospital, Capital Medical University was published on The New England Journal of Medicine on October 28, 2021. Among patients with minor ischemic stroke (MIS) or transient ischemic attack(TIA) who were carriers of CYP2C19 loss-of-function alleles the risk of stroke was modestly lower with ticagrelor combined with aspirin than with clopidogrel.
Study background
In case of patients with MIS and TIA, dual antiplatelet therapy of (Clopidogrel + Aspirin) or (Ticagrelor and Aspirin) is more effective than use of Aspirin alone in secondary prevention of stroke. However, there was no direct comparison between those two combinations. Comparisons between ticagrelor and clopidogrel for the secondary prevention of stroke in CYP2C19 loss-of-function allele carriers have not been extensively performed..
Carriers of CYP2C19 loss-of-function allele: refer to patients carry at least one *2 or *3 deficiency allele.
Study purpose
It compares efficacy of Ticagrelor and Clopidogrel in secondary prevention of stroke of carriers of CYP2C19 loss-of-function allele.
Study objects
Patients with MIS or TIA and carry CYP2C19 loss-of-function allele.
Sample size: a randomized, double-blind, placebo-controlled trial was conducted at 202 research centers in China, 11,255 patients received screening, 6,412 patients were included in the trial, 3,205 of them were assigned to Ticagrelor group, and 3,207 of them were assigned to Clopidogrel group.
Study endpoints
Primary efficacy outcome: New stroke; primary safety outcome: severe or moderate bleeding. Both are assessed for events within 90 days.
Treatment protocol
Patients are divided into groups at the ratio of 1:1 within 24h
Ticagrelor group: Ticagrelor (180 mg qd on day 1, 90 mg bid twice daily on days 2 to 90) + clopidogrel placebo treatment + aspirin 75 mg qd on day 21.
Clopidogrel group: Clopidogrel (300 mg qd on day 1 and 75 mg qd once daily on days 2 to 90) + placebo treatment with tegretol + aspirin 75 mg qd on day 21.
Study results
191 patients in Ticagrelor group (6.0%) and 243 patients in Clopidogrel group (7.6%) had stroke in 90 days (HR，0.77；95%CI，0.64~0.94；P=0.008)
9 patients in Ticagrelor group (0.3%) and 11 patients in Clopidogrel group (0.3%) had severe or moderate bleeding; 170 patients (5.3%) and 80 patients (2.5%) in the two groups had bleeding, respectively.
Conclusions
Among Chinese patients with minor ischemic stroke or TIA who were carriers of loss-of-function alleles, the risk of stroke was modestly lower with ticagrelor than with clopidogrel, the former has a 23% lower rate of stroke recurrence within 90 days than the latter. The risk of severe or moderate bleeding did not differ between the two treatment groups, but ticagrelor was associated with more total bleeding events than clopidogrel.
According to the different genotypes of CYP2C19, patients can be divided into ultra-rapid, extensive, intermediate and poor metabolizers.In Asia, the proportion of patients with intermediate and slow metabolic types reached about 45% and 19%, respectively [1], much higher than in Europe and the United States. CHANCE-2 is so far the first prospective, multi-center, double-blind, randomized and controlled Phase Ⅲ clinical trial based on genotyping of CYP2C19 in the field of cerebrovascular diseases throughout the world. Hence this study is of great value to secondary prevention of stroke among Asian population
Zeesan Biotech’s CYP2C19 gene polymorphism detection solution, based on multi-color fluorescence melting curve technology, enables rapid detection of CYP2C19*2, CYP2C19*3 and CYP2C19*17 loci within 3.5h. It provides diagnostic evidence for precise individualized antiplatelet therapy.
[1] Consolidated Analysis on Frequency of CYP2C19 Genotype Among Healthy Asian Population, Chinese Journal of Evidence-Based Medicine 2014, 14(4): 427～434
[2] Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA