Ticagrelor shift from PLATO to PEGASUS: Vanished mortality benefit, excess cancer deaths, massive discontinuations, and overshooting target events

After the successful PLATO, failed both PHILO and ATLANTIC, PEGASUS trial assessed efficacy and safety of ticagrelor (120 mg/day and 180 mg/day) on top of aspirin versus aspirin alone beyond 1 year in patients with stable coronary disease. Similar to PLATO, PEGASUS revealed reduction of composite primary endpoint after ticagrelor at expense of extra bleeding. However, there were major fundamental differences between the trial outcomes. Hence, the shift of evidence with ticagrelor from PLATO to PEGASUS trials has been comprehended. In contrast to PLATO, in PEGASUS there were more premature permanent ticagrelor discontinuations (PPTD): RR = 1.35; 95%CI 1.29-1.42, p < 0.0001; significant excess of cancer deaths (RR = 1.46; 95%CI 1.02-2.06,p = 0.034), trend to more sepsis deaths (RR = 1.29; 95%CI 0.76-2.20), and most importantly identical all-cause mortality (RR = 1.00; 95%CI 0.86-1.16, p = 0.99) versus placebo. Applied conservative TIMI bleeding classification in PEGASUS did not correspond with PPTD rate, with potential heavy underreporting of hemorrhagic events. Finally, unexplained late addition of 198 primary events in PEGASUS is concerning. PEGASUS failed to confirm ticagrelor mortality benefit reported in PLATO, but rather discover additional shortcomings.