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Study Summary

The optimal antiplatelet therapy in the post-percutaneous coronary intervention (PCI) period remains uncertain. The GLOBAL LEADERS trial randomized 15,968 patients in a 1:1 open-label fashion to 2 years of standard of care versus an experimental therapy arm. Standard of care was defined as 1 year of dual antiplatelet therapy (DAPT) with aspirin and either clopidogrel 75 mg daily for patients with stable coronary disease or ticagrelor 90 mg twice daily in patients with acute coronary syndrome (ACS) followed by 1 year of aspirin alone. The experimental arm consisted of only 1 month of dual therapy with aspirin and ticagrelor 90 mg twice daily followed by 23 months of ticagrelor monotherapy. The groups were stratified based upon presentation as either stable coronary disease or ACS. There was no difference in the primary combined endpoint of all-cause mortality or non-fatal Q-wave myocardial infarction (3.81% vs. 4.37%; P = 0.073) (see accompanying Hurst’s Central Illustration). These findings were similar in the subgroups of ACS or stable angina. There was also no difference in the safety endpoint of BARC grade 3 or 5 bleeding (2.04% vs. 2.12%; P = 0.77).

Commentary

Study Strengths: Key strengths of this trial include the large size; minimal exclusion criteria based upon clinical or angiographic parameters; hard primary endpoint of death or Q-wave myocardial infarction and experimental strategy of antiplatelet monotherapy using ticagrelor. In this regard, GLOBAL LEADERS is the first trial to examine aspirin withdrawal in a large PCI population.

Study Limitations: The study was an open-label trial and the lack of central adjudication for all events may have led to under-reporting and an attenuated treatment effect. Non-adherence to the experimental strategy was substantial, with over 21% of patients receiving a therapy other than that prescribed. All patients received percutaneous coronary intervention with a biolimus A9-eluting stent. While uniform deployment of the same drug-eluting stent removes the effect of stent-choice on outcomes, it raises questions about the generalizability of this strategy.

Next Steps/Clinical Perspective: This trial failed to demonstrate superiority of 2-year treatment with ticagrelor monotherapy, when compared to 12 months of standard dual antiplatelet therapy followed by 12 months of aspirin alone. As this trial was not designed as a non-inferiority trial, and compares two different durations of therapy, the lack of significant difference between treatment arms does not alter the current state of clinical equipoise and further investigations will be required to identify the ideal DAPT regimen after PCI. The ongoing TWILIGHT trial will focus on whether or not elimination of aspirin from dual therapy with ticagrelor reduces bleeding in a high-risk PCI population.

Trial Reference

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Vranckx  P, Valgimigli  M, Jüni  P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. doi: 10.1016/S0140-6736(18)31858-0

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