Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical Trial

Abstract

Importance: Discontinuing aspirin after short-term dual antiplatelet therapy (DAPT) was evaluated as a bleeding reduction strategy. However, the strategy of ticagrelor monotherapy has not been exclusively evaluated in patients with acute coronary syndromes (ACS).

Objective: To determine whether switching to ticagrelor monotherapy after 3 months of DAPT reduces net adverse clinical events compared with ticagrelor-based 12-month DAPT in patients with ACS treated with drug-eluting stents.

Design, setting, and participants: A randomized multicenter trial was conducted in 3056 patients with ACS treated with drug-eluting stents between August 2015 and October 2018 at 38 centers in South Korea. Follow-up was completed in October 2019.

Interventions: Patients were randomized to receive ticagrelor monotherapy (90 mg twice daily) after 3-month DAPT (n = 1527) or ticagrelor-based 12-month DAPT (n = 1529).

Main outcomes and measures: The primary outcome was a 1-year net adverse clinical event, defined as a composite of major bleeding and adverse cardiac and cerebrovascular events (death, myocardial infarction, stent thrombosis, stroke, or target-vessel revascularization). Prespecified secondary outcomes included major bleeding and major adverse cardiac and cerebrovascular events.

Results: Among 3056 patients who were randomized (mean age, 61 years; 628 women [20%]; 36% ST-elevation myocardial infarction), 2978 patients (97.4%) completed the trial. The primary outcome occurred in 59 patients (3.9%) receiving ticagrelor monotherapy after 3-month DAPT and in 89 patients (5.9%) receiving ticagrelor-based 12-month DAPT (absolute difference, -1.98% [95% CI, -3.50% to -0.45%]; hazard ratio [HR], 0.66 [95% CI, 0.48 to 0.92]; P = .01). Of 10 prespecified secondary outcomes, 8 showed no significant difference. Major bleeding occurred in 1.7% of patients with ticagrelor monotherapy after 3-month DAPT and in 3.0% of patients with ticagrelor-based 12-month DAPT (HR, 0.56 [95% CI, 0.34 to 0.91]; P = .02). The incidence of major adverse cardiac and cerebrovascular events was not significantly different between the ticagrelor monotherapy after 3-month DAPT group (2.3%) vs the ticagrelor-based 12-month DAPT group (3.4%) (HR, 0.69 [95% CI, 0.45 to 1.06]; P = .09).

Conclusions and relevance: Among patients with acute coronary syndromes treated with drug-eluting stents, ticagrelor monotherapy after 3 months of dual antiplatelet therapy, compared with ticagrelor-based 12-month dual antiplatelet therapy, resulted in a modest but statistically significant reduction in a composite outcome of major bleeding and cardiovascular events at 1 year. The study population and lower than expected event rates should be considered in interpreting the trial.

Trial registration: ClinicalTrials.gov Identifier: NCT02494895.

Figure 1.. Participant Flow in the TICO Randomized Clinical Trial

^aStudy sites were not required to provide screening logs. Data regarding reasons for ineligibility are not available. ^bOutcomes of patients who were lost to follow-up or withdrew consent were included to the point of final contact. Their time-to-event measure was censored at the last contact date.

Figure 2.. Time-to-Event Curves for the Primary Outcome and Landmark Analysis at 3 Months

A net adverse clinical event was defined as a composite of major bleeding by the Thrombolysis in Myocardial Infarction criteria or major adverse cardiac and cerebrovascular event. Between 3 and 12 months, the hazard ratio (HR) was 0.41 (95% CI, 0.25-0.68; P = .001). Reported HRs are for the patients with ticagrelor monotherapy after 3-month dual antiplatelet therapy (DAPT). The median observation periods were 365 days (interquartile range, 365-365) for both study groups.

Figure 3.. Subgroup Analyses for the Primary Outcome

Numbers and percentages shown are number of patients with event/number of patients at risk and incidences at 1 year. NSTEMI indicates non–ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. ^aP values for interaction were calculated using interaction terms in a Cox proportional hazard model. ^bChronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m² of body surface area. ^cCalculated as weight in kilograms divided by height in meters squared.