Ticagrelor Compared to Clopidogrel in Acute Coronary Syndromes trial (TC4): a Bayesian pragmatic cluster randomized controlled trial

Abstract

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.

Figure 1:

Recruitment timeline for randomization of group assignments from October 2018 to March 2021. See Related Content tab for accessible version.

Figure 2:

Flow chart of the study participants. See Related Content tab for accessible version.

Figure 3:

Kaplan–Meier survival curves for the clopidogrel and ticagrelor arms from the Ticagrelor Compared to Clopidogrel in Acute Coronary Syndromes trial (TC4) showing no difference in survival outcomes for major adverse cardiac events between the 2 treatments. The shaded areas represent 95% confidence intervals.

Figure 4:

Graphical display showing the posterior distribution as a weighted mean of the prior and new data from this trial. The probabilities for clinically meaningful harm, benefit, or equivalence are directly proportional to the area under the posterior probability density. Note: PLATO = Platelet Inhibition and Patient Outcomes trial, prior = focused prior limited to PLATO patients in North America, RR = relative risk, TC4 = Ticagrelor Compared to Clopidogrel in Acute Coronary Syndromes trial.