Ticagrelor Versus Clopidogrel in CYP2C19 Loss-of-Function Carriers With Stroke or TIA - CHANCE-2

Nov 15, 2022
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC ; Neil Keshvani, MD
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:
11/01/2022
Date Updated:
11/15/2022
Original Posted Date:
11/24/2021
References

Contribution To Literature:

Highlighted text has been updated as of November 15, 2022.

The CHANCE-2 trial showed that among Chinese patients with an ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel.

Description:

The goal of the trial was to assess ticagrelor and aspirin versus clopidogrel and aspirin in reducing risk of subsequent stroke among patients with stroke or high-risk transient ischemic attack (TIA) who were CYP2C19 loss-of-function carriers.

Study Design

Patients with history of stroke or TIA and CYP2C19 loss-of-function alleles were randomized in 1:1 fashion to receive ticagrelor-aspirin (n = 3,205) or clopidogrel-aspirin (n = 3,207) within 24 hours after symptom onset. Ticagrelor (180 mg loading dose) was dosed at 90 mg twice daily, while clopidogrel (300 mg loading dose) was dosed at 75 mg daily. Aspirin was initiated with 75-300 mg loading dose followed by 75 mg daily for 21 days. After 3 months, patients were treated at the discretion of the local investigator and followed for another 9 months.

  • Total screened: 11,255
  • Total number of enrollees included in intention-to-treat analysis: 6,412
  • Total number included in per-protocol analysis: 5,799
  • Mean patient age: 64.8 years
  • Percentage female: 33.8%

Inclusion criteria:

  • CYP2C19 loss-of-function allele as determined by point-of-care genotyping
  • Age >40 years
  • Acute disabling stroke with National Institutes of Health Stroke Scale (NIHSS) of 3 or less or high-risk TIA (ABCD2 of 4 or higher)

Exclusion criteria:

  • Receipt of intravenous thrombolytic therapy or mechanical thrombectomy
  • Surgery or procedure planned requiring trial-drug cessation
  • Moderate-to-severe disability (modified Rankin scale of 3-5)
  • History of intracranial hemorrhage or amyloid angiopathy
  • Current anticoagulation
  • Dual antiplatelet therapy 72 hours before randomization

Other salient features/characteristics:

  • Ischemic stroke on presentation: 80.5%
  • TIA on presentation: 19.6%
  • Intermediate metabolizers: 78%
  • Poor metabolizers: 22%
  • Han Chinese: 98%
  • Current smokers: 31%

Principal Findings:

The primary outcome, new ischemic or hemorrhagic stroke at 90 days, for ticagrelor-aspirin versus clopidogrel-aspirin, was 6.0% vs. 7.6% (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.64-0.94; p = 0.008).

Secondary outcomes for ticagrelor-aspirin vs. clopidogrel-aspirin:

  • New stroke within 30 days: 4.9% vs. 6.4%
  • Vascular event: 7.2% vs. 9.2%
  • Ischemic stroke: 5.9% vs. 7.4%

Safety outcomes for ticagrelor-aspirin vs. clopidogrel-aspirin:

  • Moderate or severe bleeding: 0.3% vs. 0.3%
  • Any bleeding: 5.3% vs. 2.5%

Ticagrelor-aspirin vs. clopidogrel-aspirin (hazard ratio [HR] for recurrent stroke) according to baseline renal function:

  • Estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m2: HR 0.63 (95% CI 0.49-0.81)
  • eGFR 60-89 mL/min/1.73 m2: HR 0.98 (95% CI 0.69-1.39)
  • eGFR ≤60 mL/min/1.73 m2: HR 1.31 (95% CI 0.48-3.55)

Interpretation:

The results of this trial indicate that among patients with CYP2C19 loss-of-function allele carriers, patients treated with ticagrelor and aspirin had a lower risk of stroke at 90 days than those treated with clopidogrel and aspirin. Patients with normal renal function derived more benefit for ticagrelor-aspirin vs. clopidogrel-aspirin. There were no increases in moderate or severe bleeding with ticagrelor, although rates of overall bleeding and adverse events such as dyspnea were higher with ticagrelor. In patients with acute coronary syndrome, a genotype-guided strategy to determine antiplatelet therapy has yielded mixed results, with later trials showing no benefit in reduction of major adverse cardiac events. However, the current trial provides strong evidence of the use of ticagrelor over clopidogrel in patients with loss-of-function carrier status, although the availability and cost of rapid genotyping and the predominant Han Chinese population significantly limit the generalizability of this trial. Additionally, the known adverse events of ticagrelor such as dyspnea and bleeding may still be cause for concern in some patients.

References:

Wang A, Xie X, Tian X, et al. Ticagrelor–Aspirin Versus Clopidogrel–Aspirin Among CYP2C19 Loss-of-Function Carriers With Minor Stroke or Transient Ischemic Attack in Relation to Renal Function: A Post Hoc Analysis of the CHANCE-2 Trial. Ann Intern Med 2022;Nov 1:[Epub ahead of print.

Wang Y, Meng X, Wang A, et al., on behalf of the CHANCE-2 Investigators. Ticagrelor Versus Clopidogrel in CYP2C19 Loss-of-Function Carriers With Stroke or TIA. N Engl J Med 2021;385:2520-30.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiac Surgery, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Anticoagulation Management and ACS, Cardiac Surgery and Heart Failure, Interventions and ACS, Interventions and Vascular Medicine

Keywords: Acute Coronary Syndrome, Anticoagulants, Asian Continental Ancestry Group, Aspirin, Brain Ischemia, Clopidogrel, Cytochrome P-450 CYP2C19, Dyspnea, Genotype, Hemorrhagic Stroke, Intracranial Hemorrhages, Ischemic Attack, Transient, Ischemic Stroke, Platelet Aggregation Inhibitors, Smokers, Thrombectomy, Thrombolytic Therapy, Vascular Diseases


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