Characterizing high-risk enrollment criteria and impact on clinical outcomes in a large randomized clinical trial: Insights from the TWILIGHT trial.

BACKGROUND

The TWILIGHT trial showed that, among high-risk patients who underwent percutaneous coronary intervention (PCI) and were event-free at 3 months, ticagrelor monotherapy versus ticagrelor plus aspirin reduced bleeding without increasing ischemic events.

METHODS

This posthoc analysis describes the risk profiles and outcomes of patients enrolled in the TWILIGHT trial. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, and the key secondary outcome was a composite of death, myocardial infarction, or stroke within 1 year after randomization.

RESULTS

The proportion of patients (n = 7,119) fulfilling ≤ 3, 4, 5, or ≥ 6 risk factors was 21.5%, 32.7%, 27.4%, and 18.4%, respectively. Troponin-positive acute coronary syndrome (ACS) was the most prevalent clinical criterion (64.9%), and multivessel disease (MVD) was the most prevalent angiographic criterion (66.5%). The most frequent intersection of criteria was the combination of troponin-positive ACS, atherosclerotic vascular disease, MVD, left main or proximal anterior descending lesion, and stent length > 30 mm. A stepwise increase in ischemic but not in bleeding risk was noted with an increasing number of high-risk criteria. Compared with ticagrelor plus aspirin, ticagrelor monotherapy reduced bleeding regardless of the number of risk factors (≤ 3-RF: 3.5% vs 5.8%, HR 0.59, 95% CI [0.38-0.93]; 4-RF: 3.7% vs 6.4%, HR 0.57, 95% CI [0.37-0.86]; 5-RF: 3.8% vs 8.6%, HR 0.44, 95% CI [0.29-0.66]; ≥ 6-RF: 5.3% vs 7.9%, HR 0.65, 95% CI [0.44-0.96]; p-interaction = .56) without significantly increasing the ischemic risk (≤ 3-RF: 1.6% vs 2.1%, HR 0.75, 95% CI [0.38-1.50]; 4-RF: 3.5% vs 2.2%, HR 1.58, 95% CI [0.91-2.75]; 5-RF: 4.1% vs 5.0%, HR 0.80, 95% CI [0.51-1.24]; ≥ 6-RF: 6.7% vs 6.9%, HR 0.98, 95% CI [0.67-1.43]; p-interaction = .22).

CONCLUSIONS

In the TWILIGHT trial, the high-risk features correlated more strongly with ischemic than with bleeding risk. Nonetheless, the benefits of ticagrelor compared with ticagrelor plus aspirin were consistent, irrespective of the number of high-risk features. These findings are only applicable to patients who are event-free at 3 months after PCI.

CLINICAL TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, NCT02270242.