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CHANCE-2

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

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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.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2111749

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2111749

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

CharacteristicTicagrelor-Aspirin (N=3,205)Clopidogrel-Aspirin (N=3,207)
Age median (IQR)65.0 (57.0-71.7)64.6 (56.9-71.1)
Female1,090 (34.0%)1,080 (33.7%)
Hypertension2,356 (73.5%)2,374 (74.0%)
Diabetes1,033 (32.2%)1,009 (31.5%)
Dyslipidemia888 (27.7%)895 (27.9%)
Previous ischemic stroke669 (20.9%)681 (21.2%)
Current smoker995 (31.0%)986 (30.7%)
CYP2C19 intermediate metabolizer2,486 (77.6%)2,515 (78.4%)
CYP2C19 poor metabolizer719 (22.4%)692 (21.6%)
Qualifying — Ischemic stroke2,577 (80.4%)2,581 (80.5%)
Qualifying — TIA628 (19.6%)626 (19.5%)
NIHSS median (stroke)2 (IQR 1-3)2 (IQR 1-3)
Time onset to randomization median13.5h (IQR 9.0-20.3)14.3h (IQR 8.9-20.7)
Symptomatic intracranial stenosis841/2,969 (28.3%)798/2,951 (27.0%)

Arms

FieldTicagrelor + AspirinControl
InterventionTicagrelor 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.
Duration90 days90 days

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
New ischemic or hemorrhagic stroke at 90 daysPrimary243/3,207 (7.6%)191/3,205 (6.0%)0.770.008
Stroke within 30 days | 95% CI: 0.61-0.93Secondary205 (6.4%)156 (4.9%)HR 0.75
Vascular composite (stroke/TIA/MI/vascular death) | 95% CI: 0.65-0.92Secondary293 (9.2%)229 (7.2%)HR 0.77
Ischemic stroke | 95% CI: 0.65-0.95Secondary238 (7.4%)189 (5.9%)HR 0.78
Disabling stroke (mRS >1) | 95% CI: 0.77-1.36Secondary92 (2.9%)97 (3.1%)HR 1.02
Ordinal stroke/TIA shift | 95% CI: 0.66-0.94Secondary——Common OR 0.79
Severe/moderate bleeding (GUSTO)Adverse11 (0.3%)9 (0.3%)HR 0.820.66
Any bleedingAdverse80 (2.5%)170 (5.3%)HR 2.18
Mild bleedingAdverse69 (2.2%)161 (5.0%)HR 2.41
All-cause deathAdverse18 (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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