Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA

N Engl J Med. 2021 Dec 30;385(27):2520-2530. doi: 10.1056/NEJMoa2111749. Epub 2021 Oct 28.


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.).

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aspirin / therapeutic use
  • Clopidogrel / adverse effects
  • Clopidogrel / therapeutic use*
  • Cytochrome P-450 CYP2C19 / genetics*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Incidence
  • Ischemic Attack, Transient / drug therapy*
  • Ischemic Attack, Transient / genetics
  • Ischemic Stroke / drug therapy*
  • Ischemic Stroke / epidemiology
  • Ischemic Stroke / genetics
  • Ischemic Stroke / prevention & control
  • Loss of Function Mutation*
  • Male
  • Middle Aged
  • Platelet Aggregation Inhibitors / therapeutic use
  • Purinergic P2Y Receptor Antagonists / adverse effects
  • Purinergic P2Y Receptor Antagonists / therapeutic use*
  • Secondary Prevention
  • Ticagrelor / adverse effects
  • Ticagrelor / therapeutic use*


  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Clopidogrel
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Ticagrelor
  • Aspirin

Associated data

  • ClinicalTrials.gov/NCT04078737