Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events - CHANCE

Jun 27, 2016
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Ministry of Science and Technology of the People’s Republic of China
Date Published:
06/23/2016
Date Updated:
06/27/2016
Original Posted Date:
06/26/2013
References

Description:

The goal of the trial was to evaluate treatment with clopidogrel plus short-term aspirin compared with placebo plus aspirin among patients within 24 hours of a minor stroke or high-risk transient ischemic attack (TIA).

Contribution to the Literature: The CHANCE trial revealed that short-term dual antiplatelet therapy was beneficial after a nondisabling stroke.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Chinese patients at least 40 years of age within 24 hours of minor ischemic stroke or high-risk TIA

    Number of screened applicants: 41,561
    Number of enrollees: 5,170
    Duration of follow-up: 90 days
    Mean patient age: 63 years
    Percentage female: 33%

Exclusions:

  • Intracranial hemorrhage
  • Tumor, abscess, or other major nonischemic brain disease
  • Isolated sensory symptoms, visual changes, or dizziness
  • Indication for anticoagulation therapy
  • Contraindication to aspirin or clopidogrel
  • Anticoagulation therapy within the previous 10 days
  • Gastrointestinal bleeding or major surgery within the previous 3 months
  • Anticipated revascularization within the next 3 months
  • Planned surgery requiring cessation of study drug
  • Limited life expectancy (<3 months)

Primary Endpoints:

  • Ischemic or hemorrhagic stroke at 90 days

Drug/Procedures Used:

Chinese patients within 24 hours of a minor stroke or high-risk TIA were randomized to clopidogrel 300 mg, then 75 mg daily for 90 days plus aspirin 75 mg for 21 days (n = 2,584) versus placebo plus aspirin (n = 2,586).

Principal Findings:

Overall, 5,170 patients were randomized. The median age was 63 years, 33% were women, median systolic blood pressure was 150 mm Hg, median body mass index was 25 kg/m2, 21% had diabetes, and 43% were current or prior smokers.

At 90 days, the primary outcome of stroke occurred in 8.2% of the clopidogrel group versus 11.7% of the placebo group (p < 0.001). Among those with high-sensitive C-reactive protein (hsCRP) >3 mg/L versus hsCRP <1 mg/L, there was an increased risk of recurrent stroke (adjusted hazard ratio 1.46, 95% confidence interval 1.08-1.98; p = 0.039). Among those with a CYP2C19 loss of function allele, dual antiplatelet failed to reduce the risk of recurrent stroke (p for interaction = 0.02).

- Fatal or disabling stroke: 5.2% vs. 6.8% (p = 0.01), respectively
- Ischemic stroke: 7.9% vs. 11.4% (p < 0.0001), respectively
- Hemorrhagic stroke: 0.3% vs. 0.4%, respectively
- Moderate or severe hemorrhage: 0.3% vs. 0.3%, respectively
- Any bleeding: 2.3% vs. 1.6% (p = 0.09), respectively

Interpretation:

Among Chinese patients with minor stroke or TIA within 24 hours, clopidogrel for 90 days plus aspirin for 21 days was beneficial. This strategy reduced the incidence of stroke recurrence without an increase in major bleeding. Elevated hsCRP level was associated with an increased hazard of recurrent stroke, while CYP2C19 loss of function allele negated the beneficial association of dual antiplatelet therapy on recurrent stroke. These findings do not apply to patients with large ischemic stroke where the risk of hemorrhagic conversion is greater. CHANCE is distinct from other studies (for example, the MATCH trial) in that dual antiplatelet therapy was given early and for a relatively short period after ischemic stroke. The currently enrolling POINT trial will evaluate dual antiplatelet therapy among similar participants in the United States.

References:

Wang Y, Zhao X, Lin J, et al. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA 2016;Jun 23:[Epub ahead of print].

Li J, Zhao X, Meng X, et al. High-Sensitive C-Reactive Protein Predicts Recurrent Stroke and Poor Functional Outcome: Subanalysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events Trial. Stroke 2016;Jun 21:[Epub ahead of print].

Wang Y, Wang Y, Zhao X, et al., on behalf of the CHANCE Investigators. Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack. N Engl J Med 2013;369:11-9.

Keywords: Stroke, Ischemic Attack, Transient, Body Mass Index, Platelet Aggregation Inhibitors, Blood Pressure, Ticlopidine, Hemorrhage, Diabetes Mellitus, Purinergic P2Y Receptor Antagonists, United States, C-Reactive Protein


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