N Engl J Med 2021 Oct 28
Ticagrelor versus Clopidogrel in Loss-of-Function Carriers with Stroke or TIA.
Abstract
Background
Comparisons between ticagrelor and clopidogrel for the secondary prevention of stroke in CYP2C19 loss-of-function carriers have not been extensively performed.
Methods
We conducted a randomized, double-blind, placebo-controlled trial at 202 centers in China involving patients with a minor ischemic stroke or transient ischemic attack (TIA) who carried CYP2C19 loss-of-function alleles. Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel or to receive 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. The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days.
Results
A total of 11,255 patients were screened and 6412 patients were enrolled, with 3205 assigned to the ticagrelor group and 3207 to the clopidogrel group. The median age of the patients was 64.8 years, and 33.8% were women; 98.0% belonged to the Han Chinese ethnic group. Stroke occurred within 90 days in 191 patients (6.0%) in the ticagrelor group and 243 patients (7.6%) in the clopidogrel group (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P = 0.008). Secondary outcomes were generally in the same direction as the primary outcome. Severe or moderate bleeding occurred in 9 patients (0.3%) in the ticagrelor group and in 11 patients (0.3%) in the clopidogrel group; any bleeding occurred in 170 patients (5.3%) and 80 patients (2.5%), respectively.
Conclusions
Among Chinese patients with minor ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel. 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. (Funded by the Ministry of Science and Technology of the People's Republic of China and others; CHANCE-2 ClinicalTrials.gov number, NCT04078737.).
Related Questions
Is there a risk of CYP2C19 gene testing only being adopted by wealthier health systems, thereby creating a disparity gap in treatment?
I do not believe this test is widely available for use in clinical practice. There is a serum platelet assay that checks for P2Y12 receptor inhibition that is widely available and could be an alternative to CYP2C19 testing.
Does the overall conclusion of the CHANCE-2 trial make ticagrelor + ASA a worthwhile transition given the data showing cumulative hazard of stroke diverged during the first week and was subsequently similar, which suggests the benefit of ticagrelor over clopidogrel is seen predominantly soon after stroke?
Given the fact that clopidogrel costs 11 cents a day and ticagrelor costs almost $8/day and the fact that most patients will not be tested for slow CYP2c19 metabolizer (or have the results back in a timely fashion), it seems that the combination of ASA plus clopidogrel is the best option from a publ...
Would you generalize the data from the CHANCE-2 trial to a broader clinic population given that the study was specific to Han Chinese patients?
I would not generalize to a broader population at this time but it is probably relevant in slow metabolizers of any ethnicity.
Do you recommend genetic testing after a patient on clopidogrel has a stroke based on the results of the CHANCE-2 trial?
No, the data from CHANCE-2 (Wang et al., PMID 34708996) was based on a strictly Asian population and results need to be validated elsewhere for it to change practice.