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Published on: November 8, 2024
Ticagrelor Compared to Clopidogrel in Acute Coronary Syndromes trial (TC4): a Bayesian pragmatic cluster randomized
Stephen A Kutcher1, Nandini Dendukuri1, Sonny Dandona1
1Department of Epidemiology, Biostatistics and Occupational Health (Kutcher, Brophy), McGill University; Centre for Outcomes Research and Evaluation (Dendukuri, Nadeau, Brophy), McGill University Health Centre Research Institute; Department of Medicine (Dendukuri, Dandona, Brophy), McGill University, Montréal, Que.
Insights
Ticagrelor did not show superiority over clopidogrel for acute coronary syndrome patients in North America. This study found no significant difference in effectiveness or safety between the two antiplatelet therapies.
Area of Science:
- Cardiology
- Clinical Trials
- Pharmacology
Background:
- Dual antiplatelet therapy is standard for acute coronary syndrome (ACS).
- Optimal antiplatelet regimen in North America remains uncertain.
- Previous studies may not fully represent North American patient populations.
Purpose of the Study:
- To compare the effectiveness and safety of ticagrelor versus clopidogrel in North American ACS patients.
- To provide evidence for optimizing antiplatelet therapy selection.
- To inform clinical guidelines regarding antiplatelet choice.
Main Methods:
- Pragmatic, open-label, randomized controlled trial (RCT) with time-clustered randomization.
- Primary end points: composite of all-cause mortality, nonfatal myocardial infarction, or ischemic stroke (effectiveness); hospital admissions for bleeding (safety).
- Bayesian analysis with informed and vague priors, using Quebec universal electronic health databases for 12-month outcomes.
Main Results:
- 1005 patients randomized: 450 to ticagrelor, 555 to clopidogrel.
- No significant difference in major adverse cardiovascular events between groups (RR 0.95; 95% CI 0.67-1.35).
- Bayesian analysis indicated a 57% probability of ticagrelor harm (RR ≥ 1.1) versus 2% probability of benefit (RR < 0.9). No consistent safety signals were observed.
Conclusions:
- This trial found no strong evidence for ticagrelor's superiority over clopidogrel in North American ACS patients.
- Current guidelines favoring ticagrelor may need re-evaluation based on this evidence.
- Further research may be warranted to clarify optimal antiplatelet strategies in this region.
Background:
Dual antiplatelet therapy is the standard of care for acute coronary syndrome, but uncertainty exists regarding the optimal regimen for patients in North America. We sought to compare the effectiveness and safety of acetylsalicylic acid (ASA) and ticagrelor or clopidogrel in patients with acute coronary syndrome from a single tertiary academic centre in Montréal, Canada.
Methods:
We conducted a pragmatic, open-label, time-clustered (bimonthly between October 2018 and March 2021), randomized controlled trial. The primary effectiveness end point was a composite of all-cause mortality, nonfatal myocardial infarction, or ischemic stroke. The primary safety end point was hospital admissions for bleeding. We ascertained 12-month outcomes from the Quebec universal electronic health databases. We designed and analyzed the study within a Bayesian paradigm to supplement existing knowledge. The primary analysis was a Bayesian logistic regression model with an informed focused prior from previously randomly assigned North American patients. Robustness was evaluated with vague and other prespecified informative priors, spanning reasonable pre-existing beliefs. We defined clinically important benefits and harms as risk reductions exceeding a 10% difference.
Results:
We randomly assigned 1005 patients with acute coronary syndrome to ticagrelor (n = 450) or clopidogrel (n = 555). Major acute cardiovascular events occurred in 50 (11.1%) patients assigned to ticagrelor and 64 (11.5%) assigned to clopidogrel (relative risk [RR] 0.95, 95% credible interval 0.67-1.35, with a vague prior). The primary analysis with an informed focused prior resulted in probabilities of a clinically meaningful ticagrelor benefit (RR < 0.9), equivalence (0.9 ≤ RR ≤ 1.1) or harm (RR ≥ 1.1) of 2%, 41%, and 57%, respectively. For the safety end point, there was no consistent signal of benefit or harm with ticagrelor. Sensitivity analyses with a range of prior beliefs gave generally consistent results.
Interpretation:
Whether we analyzed this trial with a vague or a range of reasonable informed priors, we found no strong evidence for the superiority of ticagrelor over clopidogrel in North American patients. Current guidelines favouring ticagrelor over clopidogrel might take this new evidence into future consideration.
Trial Registration:
Clinicaltrials.gov no. NCT04057300.
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