In patients who have an acute coronary syndrome with or without STEMI, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, MI or stroke without an increase in the rate of overall major bleeding, based on the PLATO trial presented Sunday at the European Society of Cardiology (ESC) Congress in Barcelona, Spain. However, researchers found an increase in the rate of non–procedure-related bleeding.
The investigators of PLATO (phase 3 PLatelet Inhibition And paTient Outcomes ), which was simultaneously published in the New England Journal of Medicine, said that ticagrelor (Brilinta, AstraZeneca), an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12, has a more rapid onset and more pronounced platelet inhibition than clopidogrel (Plavix, Bristol-Myers Squibb).
In this multicenter, double-blind, randomized trial, Lars Wallentin, MD, PhD, from the Uppsala Clinical Research Center, University Hospital in Uppsala, Sweden, and colleagues compared ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300 to 600 mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without STEMI.
The overall rate of adherence to the study drug, as assessed by the site investigators, was 82.8 percent, and the median duration of exposure to the study drug was 277 days, they wrote.
At 12 months, Wallentin reported at the ESC, the primary endpoint—a composite of death from vascular causes, MI or stroke—had occurred in 9.8 percent of patients receiving ticagrelor compared with 11.7 percent of those receiving clopidogrel.
Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8 percent in the ticagrelor group vs. 6.9 percent in the clopidogrel group) and death from vascular causes (4 vs. 5.1 percent) but not in stroke alone (1.5 vs. 1.3 percent), the authors wrote.
Wallentin also reported that the rate of death from any cause was reduced with ticagrelor (4.5 vs. 5.9 percent with clopidogrel). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6 and 11.2 percent, respectively), but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting (4.5 vs. 3.8 percent), including more instances of fatal intracranial bleeding and fewer instances of fatal bleeding of other types.
In terms of other adverse events, dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 13.8 percent of patients vs. 7.8 percent). Yet, the researchers said few patients discontinued the study drug because of dyspnea (0.9 percent of patients in the ticagrelor group and 0.1 percent in the clopidogrel group). Also, Holter monitoring detected more ventricular pauses during the first week in the ticagrelor group than in the clopidogrel group, but the episodes “were infrequent at 30 days and were rarely associated with symptoms,” the authors wrote.
In the accompanying NEJM editorial, Albert Schömig, MD, from the department of cardiology at the Deutsches Herzzentrum and First Medizinische Klinik rechts der Isar in Munich, noted that in both the “CURE trial and TRITON–TIMI 38, stronger platelet inhibition was associated with an increased risk of bleeding, whereas in PLATO, the risk of major bleeding was not increased with ticagrelor.” He said these results highlight the “important advantage of reversibility in the mechanism of action of ticagrelor.”
Likewise, he said that PLATO shows a decrease in mortality compared to clopidogrel, unlike the CURE study or TRITON–TIMI 38. However, Schömig expressed some concern in the other adverse events.
Also, he said that though the trial was “thoughtfully designed and conducted,” it could have been stronger if the drug had been administered for at least one year; if clopidogrel loading (preferably in a 600 mg dose) had been used for all patients in the clopidogrel group irrespective of whether they had been treated previously with clopidogrel; and if proton-pump inhibitors had been used less frequently after randomization.
Finally, Schömig said that the availability of three agents for antagonizing platelet ADP receptors may make it possible