The post hoc analyses of GLOBAL LEADERS study by Dr. Hara, published in Circulation: Cardiovascular Quality and Outcomes reported that in multiple statistical analyses considering the total number and severity of bleeding and ischemic events, ticagrelor monotherapy consistently decreased the risk of these events by 5% to 8% compared to 1-year conventional dual antiplatelet therapy. This analysis supported the beneficial effects of ticagrelor monotherapy after percutaneous coronary intervention.
Dual antiplatelet therapy after the percutaneous coronary intervention (PCI) decreases the risk of stent-related and spontaneous recurrent ischemic events but increases the risk of bleeding complications. Multiple randomized clinical trials have been conducted to determine the optimal dose and duration of antiplatelet drug regimen after PCI. The previous report of GLOBAL LEADERS study showed that 2-year ticagrelor monotherapy (in combination with aspirin for 1 month) was not superior to 12 months of conventional dual antiplatelet therapy (DAPT) followed by 12 months of aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction post PCI. Given that the previous report applied a time-to-first-event statistical analysis that has its potential limitation on considering the severity and recurrence of the events, multiple analytical approaches were performed to reevaluate the results of this study.
The GLOBAL LEADERS study was a prospective randomized, open-label superiority trial done at 130 sites in 18 countries. The trial compared two different strategies of antiplatelet therapy after PCI in all-comers population. Patients were randomized to receive either ticagrelor 90 mg twice daily (in combination with aspirin 75 to 100 mg once daily for one month), for 2 years or the standard DAPT (with clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily with aspirin 75 to 100 mg daily) for 12 months, followed by aspirin 75 to 100 mg once daily alone for the following 12 months. In the post hoc analysis of this trial, the statistical methods included all-cause mortality, any stroke, myocardial infarction, revascularization, or Bleeding Academic Research Consortium grade 2 or 3 bleeding as the composite endpoint. Win ratio analysis that considers the priority of the composite endpoint in terms of clinical importance, as well as negative binomial regression and Andersen-Gill analyses which include the repeated events, were performed.
In the traditional time-to-first-event analysis, ticagrelor monotherapy 2 years after PCI decreased the composite endpoints of the study by 6 % compared with the conventional 12-month DAPT (hazard ratio (HR): 0.94 [95% CI: 0.88–1.01]; log-rank P=0.10). In win ratio analysis, the win ratio was 1.05 (95% CI: 0.97–1.13; P=0.20). Negative binomial regression and
Andersen-Gill analyses demonstrated statistically signifcant benefit for ticagrelor monotherapy (rate ratio: 0.92 [95% CI: 0.85–0.99; P=0.020] and HR: 0.92 [95% CI: 0.85–0.99; P=0.028], respectively). In weighted composite endpoint analysis, the HR was not statistically significant (HR: 0.93 [95% CI: 0.84–1.04; log-rank P=0.22]).
There are several caveats that should be considered when interpreting the results. The present study is the posthoc analysis of the GLOBAL LEADERS study. Clinical endpoints other than death were site-reported.
As we mentioned earlier the time-to-first-event analysis has limitations as it only considers the first event regardless of its clinical significance. Antiplatelet therapy may lead to repeated bleeding and or ischemic complications with various severity that should be taken into account while comparing different antiplatelet regimens. The present study provided evidence for the superiority of ticagrelor monotherapy compared with conventional 1-year DAPT after PCI using multiple analytical approaches.