PLATO CABG Cohort: Ticagrelor Cuts Total and CV Mortality in Half

In patients with acute coronary syndromes (ACS) who undergo coronary artery bypass grafting (CABG), the novel antiplatelet agent ticagrelor reduces total and cardiovascular death by about 50% compared with clopidogrel, according to an analysis from the PLATO trial published online December 29, 2010, ahead of print in the Journal of the American College of Cardiology. The mortality benefit is not accompanied by any increase in major bleeding.

The multicenter PLATO trial, which was published in the New England Journal of Medicine last September, randomized 18,624 ACS patients to ticagrelor (180-mg loading dose, then 90 mg twice daily) or clopidogrel (300- to 600-mg loading dose, then 75 mg once daily). All patients also received aspirin. At 12-month follow-up, the primary efficacy endpoint (composite of CV death, MI, or stroke) was reduced with ticagrelor (9.8% vs. 11.7% with clopidogrel; P < 0.001).

Major Reduction in Death After CABG

For the new analysis, researchers led by Claes Held, MD, PhD, of Uppsala Clinical Research Center (Uppsala, Sweden), looked at the subgroup of 1,261 patients in PLATO who underwent CABG within 7 days after the last study drug intake.

By 12 months, CABG patients receiving ticagrelor saw a relative reduction in the primary endpoint (CV death, MI, or stroke) that was consistent with the original PLATO trial. Furthermore, reductions in total mortality, CV death and non-CV death for the ticagrelor group were significantly greater than in the original trial. Rates of MI and stroke did not differ between the 2 treatments (table 1).

Table 1. Outcomes at 12 Months

 
Although a likely explanation for the mortality difference would be reduced bleeding with ticagrelor, bleeding complications and transfusion rates were similar between the ticagrelor and clopidogrel groups (table 2).

Table 2. CABG-Related Bleeding

In fact, ticagrelor and clopidogrel produced similar levels of protocol-defined major/fatal/life-threatening CABG-related bleeding and GUSTO severe bleeding regardless of the time span between the last intake of the study drug and surgery. This held true even when the drug was stopped just 1 day prior to surgery.

Bleeding Equal Across the Board

“Because of the rigorous application of the bleeding definitions in the PLATO study, the criteria for major bleeding were fulfilled in > 80% of the CABG-treated patients,” Dr. Held and colleagues write. But the study’s observation of equivalent CABG-related bleeding and reoperation rates between the 2 drugs held true even with thorough analyses using different definitions.

The findings hint that ticagrelor might achieve more bang for its buck, with “relatively lower risk of bleeding in relation to platelet activity” in CABG patients, than prasugrel, also a P2Y12 inhibitor. In the TRITON trial, prasugrel was associated with a fourfold higher rate of CABG-related TIMI major bleeding over clopidogrel among ACS patients.

In an editorial accompanying the study, David J. Schneider, MD, of the University of Vermont (Burlington, VT), says potential mechanisms related to the primary action of ticagrelor may ultimately explain the mortality difference.

“Two characteristics of ticagrelor that merit additional study are reversibility of its binding to P2Y12 and its inhibition of adenosine uptake into erythrocytes,” he concludes.

 

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Sources:
1. Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: Results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol. 2010;Epub ahead of print.

2. Schneider DJ. Mechanisms potentially contributing to the reduction in mortality associated with ticagrelor therapy. J Am Coll Cardiol. 2010;Epub ahead of print.

 

 

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