The existing treatment paradigm for preventing thrombotic events after implantation of an intracoronary stent is dual antiplatelet therapy with aspirin and an inhibitor of the platelet P2Y12 receptor.
The recommended duration of such therapy is at least six to 12 months. However, results from the DAPT (Dual antiplatelet therapy) trial indicated that certain patients may benefit from much longer courses of therapy. Regardless of the potential benefits (ie. reducing thrombotic events) of a longer course of therapy, prolonged exposure to antiplatelet therapy is associated with an increased risk of bleeding—a complication that may confer a comparable mortality hazard with that of recurrent myocardial infarction. Therefore therapeutic strategies after percutaneous coronary intervention (PCI) that lower bleeding while simultaneously maintaining anti-ischaemic efficacy have emerged as a major area of intense clinical investigation.
One such study is the multinational, randomised double-blinded TWILIGHT (Ticagrelor with aspirin or alone in high-risk patients after coronary intervention) trial, which is funded by an investigator-initiated grant from AstraZeneca (the manufacturers of ticagrelor, Brilique) and is sponsored by the Icahn School of Medicine at Mount Sinai (New York, USA). The aim of the study (ClinicalTrials.gov identifier: NCT02270242) is to test the hypothesis that ticagrelor monotherapy is superior to ticagrelor plus aspirin at reducing clinically relevant bleeding among high-risk patients undergoing PCI who have already received a three-month course of ticagrelor plus aspirin. The key secondary hypothesis is that ticagrelor monotherapy is non-inferior to ticagrelor plus aspirin at reducing major ischaemic events.
Led by global principal investigator Roxana Mehran (The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA), the TWILIGHT investigators aim to enroll a high-risk PCI population that is characterised by a clinical and angiographic phenotype that is associated with above average risks for both thrombotic and bleeding events after PCI. For example, the inclusion criteria require patients to have at least one clinical high-risk factor (such as diabetes mellitus, chronic kidney disease or older age) and at least one angiographic risk factor (including but not limited to thrombotic target lesions, multivessel coronary artery disease or bifurcation lesions requiring multiple stents). Residual atherothrombotic risk in such patients is substantial despite conventional treatment with aspirin and clopidogrel, thereby providing a rationale for a strategy that involves the more potent P2Y12 inhibitor ticagrelor. As these parameters also correlate with bleeding propensity, withdrawal of aspirin may simultaneously reduce haemorrhagic complications and, therefore, optimise the overall net clinical benefit according to the trial hypothesis.
TWILIGHT is a unique and innovative study in that the experimental intervention is to withdraw rather than add to existing background pharmacotherapy. In this manner, conventional notions of safety and efficacy are switched as bleeding represents an efficacy endpoint while thrombotic events constitute the safety endpoint. The trial is the first specifically designed to examine the safety and efficacy of aspirin withdrawal in a high-risk PCI population that is statistically powered for a primary bleeding endpoint. Withdrawal studies testing therapeutic strategies that focus on simplifying, rather than adding to existing treatment, are also advocated by major thought leaders in the fields of clinical trial design and analysis. The results of this trial are expected to provide novel and highly clinically relevant insight that may change clinical practice with respect to long-term antiplatelet pharmacotherapy after PCI.
Usman Baber, The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA