January 3rd, 2011
PLATO CABG Substudy Raises Hope and Questions
The much-anticipated CABG substudy from the PLATO (Platelet Inhibition and Patient Outcomes) trial comparing ticagrelor to clopidogrel in ACS patients has been published online in JACC. About 10% of the 18,624 patients enrolled in PLATO underwent CABG. The substudy reports on the 1,261 who received the study drug within 7 days prior to their surgery. The study protocol called for ticagrelor to be withheld for 24-72 hours and clopidogrel to be withheld for 5 days prior to CABG.
The reduction in the primary endpoint (a composite of death from vascular causes, myocardial infarction, or stroke) was not significant but, wrote the authors, “was consistent with the results of the whole trial” (10.6% in the ticagrelor group versus 13.1% in the clopidogrel group, p=0.29). There was a significant reduction in total mortality (9.7% versus 4.7%, p<0.01) and cardiovascular death (7.9% vs 4.1%, p<0.01). In addition, there was a surprising lack of any differences in CABG-related major bleeding, although in the overall trial ticagrelor was associated with more bleeding.
The authors write that the mortality findings were “striking and also explained about a quarter of the mortality reduction in the whole trial. The finding that the excess mortality with clopidogrel was unrelated to differences in the rates of bleeding raises the suspicion that clopidogrel treatment might be associated with other specific risks in association with major surgery.”
In an accompanying editorial, David Schneider speculates about the striking findings of the substudy. He writes that the difference in mortality and the lack of difference in bleeding may be explained in part by the greater antiplatelet efficacy of ticagrelor, the time difference in discontinuation of therapy, the reversability of ticagrelor’s P2Y12 binding, and inhibition of adenosine uptake into erythrocytes.