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Ticagrelor not superior to clopidogrel after elective PCI

Presented by
Prof. Johanne Silvain, Sorbonne University, France
AHA 2020
Phase 3, ALPHEUS
In the ALPHEUS trial, ticagrelor was not superior to clopidogrel at reducing the incidence of periprocedural myocardial infarction (MI) for patients undergoing elective percutaneous coronary intervention (PCI). The authors concluded that aspirin/clopidogrel remains the standard of care for elective PCI and more potent P2Y12 inhibitors (i.e. ticagrelor and prasugrel) for acute coronary syndromes [1,2].

For patients undergoing elective PCI, aspirin/clopidogrel is the recommended dual antiplatelet therapy (DAPT) regimen. PCI-related MI and myocardial injury are frequent complications that impact long-term clinical prognosis. Stronger platelet inhibition could potentially lower these events and make the procedure safer, explained Prof. Johanne Silvain (Sorbonne University, France). The ALPHEUS study (NCT02617290) aimed to examine whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing high-risk elective PCI.

ALPHEUS was a phase 3b, randomised, open-label trial conducted at 48 centres in France and the Czech Republic. Participants were 1,910 troponin-negative or moderately positive patients scheduled for PCI. Mean age was 66 years, and ~20% was female. Participants were randomised 1:1 before the start of PCI to a loading dose of ticagrelor (180 mg) or clopidogrel (300 or 600 mg at the physician's discretion). After revascularisation, DAPT with either ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily was continued. Study follow-up was 30 days. The primary ischaemic endpoint was defined as PCI-related MI (type 4a or 4b) or major myocardial injury within 48 hours (or at hospital discharge if earlier) after PCI. The safety endpoint was defined as major bleeding events (i.e. BARC types 3 or 5) at 48 hours (or at discharge if earlier). Considering a total event rate (for the primary endpoint) of 30% at 48 hours in the clopidogrel arm, the hypothesis was a 20% relative risk reduction of the primary endpoint with ticagrelor versus clopidogrel.

The primary outcome of MI type 4a, 4b (i.e. stent thrombosis), or major myocardial injury at 48 hours occurred in 334 (35%) of 941 patients in the ticagrelor group compared with 341 (36%) of 942 patients in the clopidogrel group (OR 0.97; 95% CI 0.80–1.17; P=0.75). There was no difference in ischaemic events. “The observed rates of non-MI clinically apparent events including death, stroke and revascularisation were extremely low,” Prof. Silvain noted, “so the predominant endpoint was related to the periprocedural components.” Death occurred in 0.2% and 0.0% in the ticagrelor and clopidogrel group, respectively; stroke/ transient ischaemic attack in 0.2% and 0.1%. Kaplan-Meier analysis showed that almost all events occurred right at the time of the procedure, with very few events occurring afterwards. The primary safety outcome did not differ between the groups. However, minor bleeding events were more frequently observed with ticagrelor than with clopidogrel at 30 days: 105 (11%) versus 71 (8%) (OR 1.54; 1.12–2.11; P=0.007).

Prof. Silvain offered the following possible explanation of ticagrelor's lack of ischaemic benefit: “In stable patients, perhaps troponin elevation may be more related to the atherosclerotic milieu and technical factors than platelet activation and thrombosis. It would be interesting to see the troponin distribution; perhaps rates of very high troponin levels may uncover platelet-mediated events. We also know that advances in technique and technology have resulted in very low rates of definite thrombotic complications such as stent thrombosis or STEMI. Also, despite clear differences in antiplatelet effects, the timing of administration may have limited outcome differences in the highest risk period, during and immediately following PCI.”

    1. Silvain J, et al. Ticagrelor versus Clopidogrel in Elective Percutaneous Coronary Intervention : The Alpheus Trial. LBS.03, AHA Scientific Sessions 2020, 13–17 Nov.
    2. Silvain J, et al. Lancet. 2020;396(10264):1737–1744.


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