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PLATO's trial results, presented in Barcelona by
Lars Wallentin, were reported simultaneously
by the New England Journal of Medicine
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PLATO (a study of Platelet Inhibition and Patient Outcomes) found that the benefits were achieved without significantly increasing the risk of major bleeding.
“PLATO has redefined what is possible in the prevention of recurrent events in patients with ACS,” said Professor Lars Wallentin, chair of the PLATO Executive Committee, from Uppsala Clinical Research Center, Sweden, who reported the results yesterday. “This is a unique finding,” he said. “Over the last 10 to 15 years we have not seen any other trial with an antithrombotic compound that lowers total mortality.”
Current guidelines recommend that patients with ACS, with or without ST-elevation, receive dual antiplatelet treatment with aspirin and clopidogrel. The efficacy of clopidogrel, however, is hampered by both the slow transformation of the prodrug to the active metabolite and its modest and variable platelet inhibition.
Ticagrelor is a reversible inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.
In the study 18,624 patients hospitalised for ACS (with or without ST elevation) from 893 sites in 43 countries were randomised to ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-600 mg loading dose, 75 mg thereafter). All patients received aspirin at a dose of 75 mg to 100 mg a day, unless they could not tolerate it.
Results showed that at 12 months the composite of death from vascular causes, MI or stroke occurred in 9.8% of patients receiving ticagrelor compared with 11.7% receiving clopidogrel (HR 0.84, 95% CI 0.77-0.92, P<0.0001).
Furthermore, results showed that the rate of death from any cause was also reduced – 4.5% in the ticagrelor group versus 5.9% in the clopidogrel group (p<0.001). No significant difference in the rates of major bleeding were found between ticagrelor and clopidogrel – 11.6% versus 11.2% respectively (P=0.43).
Dyspnea, however, was more common among those taking ticagrelor, occurring in 14.2% of patients taking ticagrelor compared with 9.2% taking clopidogrel; 1% of patients taking ticagrelor discontinued treatment because of dyspnea compared to 0.3% taking clopidogrel.
Results also showed that non-CABG-related major bleeding was found to be more frequent with ticagrelor than with clopidogrel (4.5% vs 3.8%, P=0.03).
In an editorial accompanying publication of the study in the New England Journal of Medicine, Dr Albert Schomig alluded to the striking differences in outcome in trials of three antiplatelet agents: CURE with clopidogrel, Triton-TIMI 38 with prasugrel, and PLATO with ticagrelor. “In both CURE and TRITONTIMI 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 wrote.
But the side effect of dyspnea, he added, has not been observed with clopidogrel or prasugrel and “may have a negative effect on quality of life”.