CHANCE-2 Trial: Ticagrelor vs Clopidogrel DAPT in CYP2C19 Loss-of-Function Carriers
In CYP2C19 loss-of-function carriers with minor ischemic stroke (NIHSS ≤3) or high-risk TIA within 24 hours, does ticagrelor + aspirin outperform standard clopidogrel + aspirin for 90-day stroke recurrence?
Wang Y, et al. (NEJM 2021) · doi:10.1056/NEJMoa2111749 · 6,412 patients
Population
Included
- Age ≥40
- Acute nondisabling ischemic stroke (NIHSS ≤3) OR high-risk TIA (ABCD² ≥4)
- Within 24 hours of symptom onset
- Confirmed CYP2C19 *2 or *3 loss-of-function allele (point-of-care genotyping)
Eligible patients
- Carried a CYP2C19 loss-of-function allele (at least one *2 or *3 allele) by point-of-care testing
- 40 years of age or older
- An acute nondisabling ischemic stroke with an NIHSS score of 3 or less (range 0 to 42)
- Or a high-risk TIA with an ABCD2 score of 4 or higher (range 0 to 7)
- Could start the trial drug within 24 hours from the time last known normal
Excluded
- IV thrombolysis or mechanical thrombectomy
- mRS 3–5 at baseline
- ICH or amyloid angiopathy history
- DAPT in prior 72h
- Anticoagulation indication (AF, prosthetic valve, endocarditis)
- Contraindication to ticagrelor, clopidogrel, or aspirin
Prior acute treatment
- Received intravenous thrombolytic therapy or mechanical thrombectomy
- Surgery or interventional treatment requiring trial-drug cessation had been scheduled
Disability / bleeding history
- Moderate-to-severe disability (modified Rankin scale score of 3 to 5)
- A history of intracranial hemorrhage or amyloid angiopathy
Antithrombotic / anticoagulation
- Dual antiplatelet treatment in the 72 hours before randomization
- Current heparin or oral anticoagulation (presumed cardiac source of embolus, such as atrial fibrillation, prosthetic valve, known or suspected endocarditis)
Contraindication
- A contraindication to ticagrelor, clopidogrel, or aspirin
Source: Wang Y et al., N Engl J Med 2021· Retrieved 2026-06-09
Primary Outcome
Negligible absolute difference
Stroke-free at 90 Days
Study Arms
- Agent
- Ticagrelor plus aspirin
- Dose
- Ticagrelor 180 mg loading on day 1, then 90 mg twice daily on days 2 to 90; aspirin 75 to 300 mg loading then 75 mg daily for 21 days; plus placebo clopidogrel
- Route
- Oral
- Frequency
- Ticagrelor twice daily; aspirin once daily
- Duration
- Ticagrelor days 1 to 90; aspirin days 1 to 21
- Co-interventions
- Open-label aspirin (75 to 300 mg loading, then 75 mg daily for 21 days) in both groups; after 3 months, standard of care at investigator discretion
Restricted to CYP2C19 loss-of-function carriers; double-blind, double-dummy
- Agent
- Clopidogrel plus aspirin
- Dose
- Clopidogrel 300 mg loading on day 1, then 75 mg daily on days 2 to 90; aspirin 75 to 300 mg loading then 75 mg daily for 21 days; plus placebo ticagrelor
- Route
- Oral
- Frequency
- Once daily
- Duration
- Clopidogrel days 1 to 90; aspirin days 1 to 21
- Co-interventions
- Open-label aspirin (75 to 300 mg loading, then 75 mg daily for 21 days) in both groups; after 3 months, standard of care at investigator discretion
Active comparator (ticagrelor+aspirin is the intervention); double-blind, double-dummy
Safety
Severe/moderate bleeding (GUSTO) at 90d
0.3%
0.3%
HR 0.82 (95% CI 0.34–1.98, P=0.66). No significant difference in major bleeding between ticagrelor and clopidogrel arms.
Any adverse event
16.8%
13.3%
Dyspnea and arrhythmia more frequent with ticagrelor (class effect). Mild bleeding also increased (5.3% vs 2.5%) but severe bleeding unchanged.
Trial Design
Type
- Randomized double-blind placebo-controlled trial
- 202 centers in China
- 1:1 allocation (ticagrelor+aspirin vs clopidogrel+aspirin)
- CYP2C19 *2 or *3 LOF allele required for enrollment
- Rapid point-of-care bedside genotyping (30–60 min)
Timeline
Enrolled 2019–2021; published NEJM 2021
N
6,412
Enrollment
6,412 CYP2C19 LOF carriers at 202 centers in China. Rapid point-of-care genotyping required. Enrolled 2019–2021. Published NEJM 2021.
ClinicalTrials.gov
NCT04078737Bedside Pearl
In confirmed CYP2C19 loss-of-function carriers with minor stroke (NIHSS ≤3) or high-risk TIA within 24h, ticagrelor + aspirin × 21 days then ticagrelor alone outperforms standard clopidogrel DAPT (NNT 63). If rapid genotyping is unavailable, use clopidogrel DAPT now. Do NOT delay treatment for testing.