CHANCE
Clopidogrel with aspirin in acute minor stroke or transient ischemic attack
Clinical Question
Among patients with acute TIA or minor ischemic stroke, does early administration of aspirin/clopidogrel reduce recurrent stroke compared to aspirin alone?
Study Overview
Objective
Clopidogrel plus aspirin versus aspirin alone in reducing the risk of recurrent stroke in patients with minor stroke or high-risk TIA.
Study Summary
The CHANCE trial demonstrated that clopidogrel plus aspirin initiated within 24 hours of symptom onset significantly reduced the risk of recurrent stroke within 90 days, without increasing the risk of major bleeding, compared to aspirin monotherapy..
Intervention
Both arms received open-label aspirin 75–300 mg on day 1 (clinician-determined). Clopidogrel + aspirin arm: clopidogrel 300 mg loading dose on day 1, then clopidogrel 75 mg/day on days 2–90 plus aspirin 75 mg/day on days 2–21 (placebo aspirin days 22–90). Aspirin-alone arm: aspirin 75 mg/day on days 2–90 plus placebo clopidogrel on days 1–90.
Patients per Arm
Clopidogrel + Aspirin: 2584, Aspirin Alone: 2586
Bottom Line
Early dual antiplatelet therapy reduced 90-day stroke recurrence without increasing major bleeding risk.
Major Points
- Landmark trial establishing dual antiplatelet therapy (DAPT) for acute minor stroke and high-risk TIA. 5170 patients randomized within 24 hours of symptom onset at 114 Chinese centers.
- DAPT regimen: clopidogrel 300 mg loading dose on day 1 + aspirin, then clopidogrel 75 mg/day for 90 days. Aspirin was given at 75–300 mg on day 1, then 75 mg/day for the first 21 days only — discontinued at day 21 (CHANCE uniquely tapered aspirin early).
- Primary outcome (any stroke at 90 days): 8.2% vs 11.7% (HR 0.68, 95% CI 0.57–0.81, P<0.001). ARR = 3.5%, RRR = 32%, NNT = 29.
- No significant increase in major or moderate bleeding (0.3% vs 0.3% for moderate or severe hemorrhage, P=0.73). Any bleeding events: 2.3% vs 1.6% (HR 1.41, 95% CI 0.95–2.10, P=0.09).
- Exclusively Chinese population — the authors note a higher prevalence of genetic polymorphisms affecting clopidogrel metabolism in this population, though specific CYP2C19 allele frequencies are not reported in this paper.
- POINT trial (NCT00991029), sponsored by the NIH and enrolling at the time of publication primarily in the United States, was designed to test a higher clopidogrel loading dose (600 mg) and a narrower 12-hour treatment window than CHANCE used.
Design
Study Type: Randomized, double-blind, placebo-controlled
Randomization: 1
Blinding: Double-blind
Enrollment Period: October 2009 – July 2012
Follow-up Duration: 90 days
Centers: 114
Countries: China
Sample Size: 5170
Analysis: Intention-to-treat
Inclusion Criteria
- Age ≥40 years.
- Minor ischemic stroke defined as NIHSS ≤3 at randomization, OR high-risk TIA defined as ABCD2 score ≥4.
- Symptom onset within 24 hours prior to randomization.
- Able to be randomized and start study drug within 24 hours of symptom onset.
- CT or MRI excluding intracranial hemorrhage.
Exclusion Criteria
- Hemorrhage or other major nonischemic brain disease (vascular malformation, tumor, abscess) on imaging.
- Isolated sensory symptoms, isolated visual changes, or isolated dizziness/vertigo without imaging evidence of acute infarction.
- Modified Rankin Scale score >2 before the index event (moderate disability or worse at baseline).
- NIHSS score ≥4 at randomization.
- Clear indication for anticoagulation (e.g., atrial fibrillation, prosthetic cardiac valve) or contraindication to clopidogrel or aspirin.
- History of intracranial hemorrhage.
- Anticipated requirement for long-term nonstudy antiplatelet drugs or NSAIDs affecting platelet function.
- Heparin therapy or oral anticoagulation within 10 days before randomization.
- Gastrointestinal bleeding or major surgery within the previous 3 months.
- Planned or probable revascularization (any angioplasty or vascular surgery) within 3 months after screening.
- Planned surgery or interventional treatment requiring cessation of study drug.
- TIA or minor stroke caused by angiography or surgery.
- Severe noncardiovascular coexisting condition with life expectancy <3 months.
- Women of childbearing age not practicing reliable contraception or without documented negative pregnancy test.
- Concurrent participation in other investigational drug/device studies.
Arms
| Field | Control | Arm2: Aspirin + Clopidogrel |
|---|---|---|
| Intervention | Aspirin 75–300 mg on Day 1 (open-label, clinician-determined dose), then aspirin 75 mg/day on days 2 through 90 + placebo clopidogrel on days 1 through 90. Risk factor management per standard care (BP, lipids, diabetes) without specific mandated targets. | Clopidogrel 300 mg loading dose + aspirin 75–300 mg on Day 1, then clopidogrel 75 mg/day for 90 days + aspirin 75 mg/day for first 21 days only. After day 21, aspirin was discontinued (placebo aspirin days 22–90) and only clopidogrel continued through day 90. No proton pump inhibitor mandated. Same risk factor management as control arm. |
| Duration | 90 days | Clopidogrel 90 days, Aspirin 21 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Stroke (ischemic or hemorrhagic) at 90 days | Primary | 11.7% | 8.2% | 0.68 | <0.001 |
| Stroke, MI, or death from cardiovascular causes (composite) | Secondary | 11.9% | 8.4% | 0.69 | <0.001 |
| Ischemic Stroke | Secondary | 11.4% | 7.9% | 0.67 | <0.001 |
| Hemorrhagic Stroke | Secondary | 0.3% | 0.3% | 1.01 | 0.98 |
| Myocardial Infarction | Secondary | 0.1% | 0.1% | 1.44 | 0.69 |
| Cardiovascular Death | Secondary | 0.2% | 0.2% | 1.16 | 0.81 |
| All-cause Death | Secondary | 0.4% | 0.4% | 0.97 | 0.94 |
| Transient Ischemic Attack | Secondary | 1.8% | 1.5% | 0.82 | 0.36 |
| Moderate or Severe Hemorrhage (Primary Safety Outcome, GUSTO) | Adverse | 0.3% (8) | 0.3% (7) | 0.73 | |
| Severe Bleeding | Adverse | 0.2% | 0.2% | 0.94 | 0.94 |
| Moderate Bleeding | Adverse | 0.2% | 0.1% | 0.73 | 0.68 |
| Mild Bleeding | Adverse | 0.7% | 1.2% | 1.57 | 0.12 |
| Any Bleeding | Adverse | 1.6% | 2.3% | 1.41 | 0.09 |
Subgroup Analysis
The benefit of clopidogrel + aspirin was consistent across the 11 prespecified subgroups tested in Figure 2, with no significant treatment-by-subgroup interactions (all P>0.10): age (<65 vs ≥65 yr), sex, index event (minor stroke vs TIA), ABCD2 score (4 vs >4), previous stroke (yes/no), previous TIA (yes/no), history of hypertension (yes/no), previous diabetes (yes/no), systolic pressure (<140 vs ≥140 mm Hg), time to randomization (<12h vs ≥12h), and aspirin taken within 24 hours before randomization (yes/no). CYP2C19 genotype was not tested in this trial.
Criticisms
- Exclusively Chinese population — limits generalizability to non-Asian populations. The authors note a higher prevalence of genetic polymorphisms affecting clopidogrel metabolism in this population, but no CYP2C19 genotyping was performed.
- Short follow-up (90 days) — cannot assess long-term bleeding risk of extended DAPT.
- Aspirin maintenance dose was low (75 mg/day), lower than doses used in some Western trials and clinical practice.
- No mandatory vascular imaging — stroke etiology (large artery vs lacunar vs cardioembolic) not systematically classified, raising concern about mixed etiologies.
- Under-treatment of comorbidities in this population — only 10.9% of the aspirin arm had documented hypercholesterolemia at baseline despite a median age of 62 years and a smoking rate of 43.0%.
- High TIA proportion (27.9%) with ABCD2 ≥4 threshold — ABCD2 has modest predictive accuracy for stroke recurrence.
- No CYP2C19 genotyping in the trial — clopidogrel efficacy may differ in loss-of-function carriers, but this trial cannot address the question.
Funding
Ministry of Science and Technology of the People's Republic of China
Based on: CHANCE (The New England Journal of Medicine, 2013)
Authors: Wang Y, et al.
Citation: Wang Y, et al. N Engl J Med. 2013;369(1):11–19.
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