CHANCE-2
Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA
Year of Publication: 2021
Authors: Yongjun Wang, Xia Meng, Anxin Wang, ..., for the CHANCE-2 Investigators
Journal: The New England Journal of Medicine
Citation: N Engl J Med 2021;385:2520-30.
PDF: Clinical Question
In patients with minor ischemic stroke or high-risk TIA who carry CYP2C19 loss-of-function alleles, does ticagrelor + aspirin reduce 90-day stroke risk compared with clopidogrel + aspirin?
Bottom Line
Among 6,412 Chinese patients with minor stroke/TIA who were CYP2C19 LOF carriers, ticagrelor-aspirin reduced 90-day stroke from 7.6% to 6.0% (HR 0.77; 95% CI 0.64-0.94; P=0.008). Severe/moderate bleeding was identical (0.3% vs 0.3%), but total any-bleeding doubled (5.3% vs 2.5%). Point-of-care genotyping averaged 80.3 minutes — operationally feasible.
Major Points
- 23% relative risk reduction: ticagrelor-aspirin reduced stroke from 7.6% to 6.0% (HR 0.77; 95% CI 0.64-0.94; P=0.008).
- Genotype-guided selection feasible at scale: 11,255 screened, 57% were LOF carriers, POC genotyping averaged 80.3 minutes.
- Consistent across metabolizer subgroups: intermediate (HR 0.78; 0.63-0.97) and poor metabolizers (HR 0.77; 0.50-1.18).
- No increase in severe/moderate bleeding: 0.3% vs 0.3% (HR 0.82; P=0.66).
- Any bleeding doubled: 5.3% vs 2.5% (HR 2.18; 95% CI 1.66-2.85) — mostly mild/nuisance.
- 30-day stroke also reduced: 4.9% vs 6.4% (HR 0.75; 0.61-0.93). Curves diverged in first week.
- Vascular composite reduced: stroke/TIA/MI/vascular death 7.2% vs 9.2% (HR 0.77; 0.65-0.92).
- No benefit in prior stroke/TIA patients: HR 1.07 (0.72-1.60) vs HR 0.70 (0.57-0.88) without prior events.
- Aspirin limited to 21 days in both arms, then monotherapy through Day 90.
- 6,412 patients, 202 Chinese sites, double-blind, placebo-controlled. 100% 90-day follow-up.
Design
Study Type: Randomized, double-blind, placebo-controlled superiority trial
Randomization: 1
Blinding: Double-blind with matching placebos. 1:1 within 24h of symptom onset.
Enrollment Period: September 23, 2019 to March 22, 2021
Follow-up Duration: 90 days (primary); 12 months total planned
Centers: 202
Countries: China
Sample Size: 6412
Analysis: Intention-to-treat. Cox proportional hazards with centers as random effect. 90% power to detect 25% RRR. Alpha 0.048 (adjusted for one interim analysis, O'Brien-Fleming).
Inclusion Criteria
- Age ≥40 years.
- CYP2C19 loss-of-function allele (*2 or *3) carrier confirmed by point-of-care genotyping.
- Acute nondisabling ischemic stroke (NIHSS ≤3) OR high-risk TIA (ABCD² ≥4).
- Able to start trial drug within 24 hours of last known normal.
Exclusion Criteria
- Received IV thrombolysis or mechanical thrombectomy.
- Surgery requiring drug cessation scheduled.
- mRS 3-5 (moderate-severe disability).
- History of intracranial hemorrhage or amyloid angiopathy.
- DAPT in prior 72 hours.
- Current heparin or oral anticoagulation.
- Presumed cardiac source of embolus (AF, prosthetic valve, endocarditis).
- Contraindication to ticagrelor, clopidogrel, or aspirin.
Baseline Characteristics
| Characteristic | Ticagrelor-Aspirin (N=3,205) | Clopidogrel-Aspirin (N=3,207) |
|---|---|---|
| Age median (IQR) | 65.0 (57.0-71.7) | 64.6 (56.9-71.1) |
| Female | 1,090 (34.0%) | 1,080 (33.7%) |
| Hypertension | 2,356 (73.5%) | 2,374 (74.0%) |
| Diabetes | 1,033 (32.2%) | 1,009 (31.5%) |
| Dyslipidemia | 888 (27.7%) | 895 (27.9%) |
| Previous ischemic stroke | 669 (20.9%) | 681 (21.2%) |
| Current smoker | 995 (31.0%) | 986 (30.7%) |
| CYP2C19 intermediate metabolizer | 2,486 (77.6%) | 2,515 (78.4%) |
| CYP2C19 poor metabolizer | 719 (22.4%) | 692 (21.6%) |
| Qualifying — Ischemic stroke | 2,577 (80.4%) | 2,581 (80.5%) |
| Qualifying — TIA | 628 (19.6%) | 626 (19.5%) |
| NIHSS median (stroke) | 2 (IQR 1-3) | 2 (IQR 1-3) |
| Time onset to randomization median | 13.5h (IQR 9.0-20.3) | 14.3h (IQR 8.9-20.7) |
| Symptomatic intracranial stenosis | 841/2,969 (28.3%) | 798/2,951 (27.0%) |
Arms
| Field | Ticagrelor + Aspirin | Control |
|---|---|---|
| Intervention | Ticagrelor 180 mg loading Day 1, then 90 mg BID Days 2-90. Open-label aspirin 75-300 mg Day 1, then 75 mg/day for 21 days. Ticagrelor monotherapy Days 22-90. | Clopidogrel 300 mg loading Day 1, then 75 mg/day Days 2-90. Open-label aspirin 75-300 mg Day 1, then 75 mg/day for 21 days. Clopidogrel monotherapy Days 22-90. |
| Duration | 90 days | 90 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| New ischemic or hemorrhagic stroke at 90 days | Primary | 243/3,207 (7.6%) | 191/3,205 (6.0%) | 0.77 | 0.008 |
| Stroke within 30 days | 95% CI: 0.61-0.93 | Secondary | 205 (6.4%) | 156 (4.9%) | HR 0.75 | |
| Vascular composite (stroke/TIA/MI/vascular death) | 95% CI: 0.65-0.92 | Secondary | 293 (9.2%) | 229 (7.2%) | HR 0.77 | |
| Ischemic stroke | 95% CI: 0.65-0.95 | Secondary | 238 (7.4%) | 189 (5.9%) | HR 0.78 | |
| Disabling stroke (mRS >1) | 95% CI: 0.77-1.36 | Secondary | 92 (2.9%) | 97 (3.1%) | HR 1.02 | |
| Ordinal stroke/TIA shift | 95% CI: 0.66-0.94 | Secondary | — | — | Common OR 0.79 | |
| Severe/moderate bleeding (GUSTO) | Adverse | 11 (0.3%) | 9 (0.3%) | HR 0.82 | 0.66 |
| Any bleeding | Adverse | 80 (2.5%) | 170 (5.3%) | HR 2.18 | |
| Mild bleeding | Adverse | 69 (2.2%) | 161 (5.0%) | HR 2.41 | |
| All-cause death | Adverse | 18 (0.6%) | 9 (0.3%) | HR 0.50 |
Subgroup Analysis
Consistent across intermediate (HR 0.78; 0.63-0.97) and poor metabolizers (HR 0.77; 0.50-1.18). Age <65: HR 0.68 (0.51-0.90); ≥65: HR 0.88 (0.67-1.14). No benefit in prior stroke/TIA: HR 1.07 (0.72-1.60). No benefit in prior antiplatelet: HR 1.30 (0.69-2.44). Without intracranial stenosis: HR 0.62 (0.47-0.81).
Criticisms
- Chinese population only (98% Han) — lower CYP2C19 LOF prevalence in Western populations (~25% vs ~60%).
- Excluded cardioembolic, moderate-severe stroke, thrombolysis/thrombectomy patients.
- Any bleeding doubled (5.3% vs 2.5%) — driven by mild bleeding, dyspnea, arrhythmias.
- 12-month data not yet published; only 90-day outcomes reported.
- Benefit driven by early first-week divergence.
- Cost-effectiveness of genotype-guided strategy not evaluated.
- No direct comparison to genotype-unselected DAPT (original CHANCE).
- Higher premature discontinuation with ticagrelor (357 vs 256).
Funding
Ministry of Science and Technology of China; Beijing Municipal Science and Technology Commission; Chinese Stroke Association. Shenzhen Salubris Pharmaceuticals provided drugs (no role in trial).
Based on: CHANCE-2 (The New England Journal of Medicine, 2021)
Authors: Yongjun Wang, Xia Meng, Anxin Wang, ..., for the CHANCE-2 Investigators
Citation: N Engl J Med 2021;385:2520-30.
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