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Study Summary

The international, randomized, open-label, phase 3b ALPHEUS trial aimed to examine if ticagrelor, a more potent antiplatelet medication than clopidogrel, was superior in reducing periprocedural myocardial necrosis for stable coronary artery disease (CAD) patients undergoing elective percutaneous coronary intervention (PCI). Patients were eligible if they had an underlying condition or were having a high-risk procedure. A total of 1,910 patients were randomized to receive a loading dose of 180mg of ticagrelor and then ticagrelor 90mg twice daily for 30 days or a loading dose of 300-600mg of clopidogrel and then clopidogrel 75mg once daily for 30 days (see accompanying Hurst’s Central Illustration). The primary outcome —PCI-related type 4a or 4b myocardial infarction (MI) or major myocardial injury within 48 hours or at discharge — occurred in 35% of the ticagrelor arm and 36% of the clopidogrel arm (OR 0.97, 95% CI 0.80–1.17; P = 0.75). At 48 hours after PCI, no excessive major bleeding was noted among the patients treated with ticagrelor compared to those assigned to clopidogrel, but minor bleeding events at 30 days and dyspnea were noted to be more frequent in the ticagrelor group.

Commentary

Study Strengths: The study was a randomized, large, international, multicenter trial. The two study groups were well balanced.

Study Limitations: Limitations of this study were its open-label design and the short follow-up, as benefits of more potent P2Y12 inhibition may occur long after the end of the study follow-up. Another limitation was the use of hard clinical end points that are rare in elective PCI cases, such as MI and myocardial injury. Additionally, using assays that measure all types of troponin may have introduced heterogeneity in the study population, as periprocedural troponin elevation may not only be a result of platelet aggregation, but could possibly be secondary to the procedure itself. Lastly patients already on chronic P2Y12 inhibition with clopidogrel were included in the study.

Next Steps/Clinical Perspective: The results of this study were surprising, as ticagrelor, with its higher level of platelet inhibition, did not reduce periprocedural MI or MI injury in the 48 hours following high-risk PCI in stable CAD patients when compared to clopidogrel. Assuming ticagrelor is a potent enough P2Y12 platelet inhibitor, these findings question whether periprocedural myocardial injury is mediated by platelet aggregation, or is secondary to plaque shifts verses direct mechanical injury following intervention, as the injury of both mechanisms may not respond to P2Y12 inhibition. At 30 days, clinical outcomes were not different amongst the two groups undergoing elective PCI; however, it would be interesting to see longer term follow-up data. This trial also paves the way for further investigation on alternative antiplatelet therapy for stable CAD in a high-risk population.

Trial Reference

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Silvain  J, Lattuca  B, Beygui  F,  et al. Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS): a randomised, open-label, phase 3b trial. Lancet doi:10.1016/S0140-6736(20)32236-4

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