The GLOBAL LEADERS trial, simultaneously published in the Lancet and presented at the 2018 European Society of Cardiology (ESC) Congress (25–29 August, Munich, Germany), shows that a regimen of ticagrelor and aspirin for one month after percutaneous coronary intervention (PCI) followed by 23 months of ticagrelor monotherapy is not superior to the current standard approach of dual antiplatelet therapy (DAPT) for 12 months followed by aspirin monotherapy for 12 months.
Study authors Pascal Vranckx (Hartcentrum Hasselt, Faculty of Medicine and Life Sciences, Hasselt UniversityHasselt, Belgium) and colleagues say that the results “do not support a change to practice at this time”. In an accompanying comment article in the Lancet, Deepak L Bhatt (Brigham and Women’s Hospital Heart and Vascular Centre, Boston, USA) concurs: “Compared with standard treatment, the experimental regimen had no clear benefits and no clear harms either. However, in view of the higher rates of discontinuation, the increased frequency of dyspnoea, and the higher cost associated with the experimental regimen than with the control group, as well as the necessity of twice daily dosing with ticagrelor, aspirin should remain the preferred antiplatelet therapy for secondary prevention.”
Vranckx et al hypothesised that a shorter DAPT regimen might provide a more favourable balance. GLOBAL LEADERS, an open-label superiority trial at 130 sites in 18 countries, randomised 15,968 patients (1:1) undergoing PCI for stable coronary artery disease or acute coronary syndromes to either aspirin daily plus ticagrelor twice daily for one month, followed by 23 months of ticagrelor monotherapy (7,980) or to standard DAPT (7,988). Standard DAPT, in this study, consisted of aspirin plus either clopidogrel (stable coronary artery disease) or ticagrelor (acute coronary syndrome) for 12 months, followed by aspirin monotherapy for 12 months
In the experimental group, 304 (3.81%) participants had died or had had a non-fatal centrally adjudicated new Q-wave myocardial infarction at two years, compared with 349 (4.37%) in the control group (p=0.073). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndrome and stable coronary artery disease (p=0.93). The frequency of major bleeding according to the Bleeding Academic Research Consortium criteria was similar between groups (163 participants [2.04%] in the experimental group and 169 [2.12%] in the control group; p=0.77).
Although the rate of serious adverse events did not differ significantly between the two groups, discontinuation of the treatment regimen was more common in the experimental group than in the control group. The investigators suggest that this could “stem from the fact that aspirin constitutes the default (background) therapy for patients with established atherothrombotic cardiovascular disease, whereas the experimental treatment strategy has not been established. Additionally, we cannot exclude that pleiotropic effects of aspirin other than the antiplatelet effect could be beneficial and could have affected the outcome of our trial.”
GLOBAL LEADERS is believed to be the largest trial so far of one month of DAPT with aspirin and ticagrelor followed by ticagrelor monotherapy vs. a standard DAPT regimen after implantation of a drug-eluting stent. The trial is also unique in its sole use of ticagrelor, a P2Y12 receptor antagonist, as an antiplatelet regimen rather than aspirin after cessation of DAPT. Also, Vranckx et al comment, GLOBAL LEADERS is the only randomised trial to date in which randomisation was done at PCI and in which two antiplatelet strategies were compared, with up to two years of follow-up. The data, they said, “provided reassuring information with respect to the safety and efficacy of ticagrelor monotherapy”.