ORLANDO — The investigational reversible oral antiplatelet drug ticagrelor proved superior to clopidogrel in all-cause mortality and other key end points in a major randomized trial involving 8,430 patients with ST-elevation MI.
“We believe that ticagrelor may become a new standard of care for the management of patients with STEMI intended for primary PCI,” Dr. P. Gabriel Steg declared in presenting the results of the Platelet Inhibition and Patient Outcomes (PLATO) STEMI subanalysis at the annual scientific sessions of the American Heart Association.
The primary end point in the new PLATO STEMI prespecified subanalysis was a composite of cardiovascular death, MI, or stroke during 1 year of treatment with aspirin and either twice-daily ticagrelor or once-daily clopidogrel (Plavix), the current standard therapy. The composite end point occurred in 9.3% of the ticagrelor group and 11.0% of those on clopidogrel, for a significant 15% relative risk reduction.
Ticagrelor was also associated with significant advantages over clopidogrel in key secondary end points in PLATO STEMI, including reductions of 18% in all-cause mortality and 39% in definite stent thrombosis. (See box.) Moreover, there was no increase in major bleeding with ticagrelor, reported Dr. Steg, professor of cardiology at the University of Paris and director of the coronary care unit at Bichat-Claude Bernard Hospital.
Ticagrelor is a reversible blocker of the P2Y12 platelet receptor with considerably more potent and consistent antiplatelet activity than clopidogrel. It's the first in a new class of agents known as the cyclo-pentyl-triazolo-pyrimidines that is chemically distinct from thienopyridines such as clopidogrel or prasugrel.
In PLATO STEMI, the number of patients who needed to be treated for 1 year with ticagrelor rather than clopidogrel to prevent one additional cardiovascular death, MI, or stroke was 59, Dr. Steg said.
He drew particular attention to the reduction in all-cause mortality with ticagrelor compared with clopidogrel, an advantage that grew over time. “We don't come across treatments in cardiovascular care that reduce all-cause mortality often. It sets ticagrelor apart from other oral inhibitors of platelet function. The mortality reduction here is new, it is important quantitatively, and it may have several explanations,” he said.
For one thing, ticagrelor is probably not solely a platelet inhibitor. It is also an adenosine agonist. “Adenosine has myriad physiologic functions that may be beneficial in the context of acute myocardial ischemia and vascular disease. It improves platelet function and vascular function and may have myocardial protection properties. This is very speculative, but given that other antiplatelet agents that have reduced MI have not decreased mortality, the fact that we see here a decrease in MI and cardiovascular events, and a decrease in mortality, raises the question of whether there are other mechanisms at play,” he said.
Discussant Lisa K. Jennings, Ph.D., a vascular biologist at the University of Tennessee, Memphis, noted that another possible contributor to ticagrelor's all-cause mortality advantage may be its faster onset of action. Unlike the thienopyridines, ticagrelor is not a pro-drug. And PLATO STEMI participants were randomized relatively early—within the first 24 hours after symptom onset, when their risk of cardiac events was especially high and a mortality difference favoring a faster-acting drug would be particularly evident.
The chief side effect associated with ticagrelor was dyspnea, occurring in 12.9% of patients, compared with 8.3% of patients on clopidogrel. The dyspnea was mild, usually occurred early in the course of treatment, and then resolved.
The reduction in cardiovascular events seen with ticagrelor could be expected to result in considerable financial savings through reduced post-STEMI hospitalizations. In addition, the drug's stronger and more consistent antiplatelet activity compared with clopidogrel could conceivably do away with the need to perform platelet function assays in patients undergoing PCI, as is now guideline-recommended with clopidogrel. That possibility will require further studies.
AstraZeneca, which sponsored PLATO, recently applied for European marketing approval for ticagrelor (Brilinta) for treatment of patients with acute coronary syndrome.
Dr. Steg disclosed that he is a consultant to and on the speakers bureau for AstraZeneca. Dr. Jennings is also a consultant to the company.
Elsevier Global Medical News