When less is more: dual antiplatelet therapy in elective percutaneous coronary intervention

Comment on ‘Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS): a randomised, open-label, phase 3b trial’, which was presented at the 2020 Scientific Sessions of the American Heart Association and published in The Lancet (doi.org/10.1016/S0140-6736(20)32236-4). ALPHEUS1 is a company-funded, multicentre, randomized, open-label trial including a total of 1910 stable chronic coronary syndrome (CCS) patients undergoing elective percutaneous coronary intervention (PCI) with at least one high-risk feature. Once the coronary anatomy was known, eligible patients were randomly assigned (1:1) to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days) or clopidogrel (300–600 mg loading dose, 75 mg daily thereafter for 30 days) to investigate whether more effective and faster platelet inhibition by ticagrelor could reduce periprocedural atherothrombotic complications in this setting. Cardiac troponin levels were measured at baseline, 6 and 24 h after PCI or at discharge, and peak levels were used for outcome assessment. Clinical outcomes were evaluated at 48 h and 30 days. At 48 h, the primary outcome, a composite of PCI-related type 4 (a or b) myocardial infarction (MI) or major myocardial injury (according to the third universal definition of MI) occurred in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group [odds ratio (OR) 0.97; 95% confidence interval (CI) 0.80–1.17; P = 0.75). At 48 h, the primary safety outcome, major bleeding according to the Bleeding Academic Research Consortium (BARC 3 or 5), did not differ between the two groups. However, minor bleeding events were more frequently observed with ticagrelor than clopidogrel at 30 days [105 (11%) of 941 patients in the ticagrelor group vs. 71 (8%) of 942 patients in the clopidogrel group; OR 1.54; 95% CI 1.12–2.11; P = 0.0070]. None of the secondary clinical outcomes differed between groups at 30-day follow-up. The 2019 European Society of Cardiology guidelines for the management of CCS recommend clopidogrel for coronary stenting in stable patients, without pre-treatment before the patient’s coronary status and indication for revascularization are known. However, considering that most of these procedures are performed on an ad hoc basis and that a substantial proportion of patients are at high risk, the more effective P2Y12 inhibitors ticagrelor and prasugrel received a class IIb recommendation, while acknowledging the lack of supportive data.2 Uncertainty has led to large variations in practice. Off-label use of ticagrelor and prasugrel is increasingly common in elective PCI, especially when patients are undergoing high-risk procedures (left main stent, bifurcations, multiple stenting, or any situation identified as being at high risk for stent thrombosis) or present with high-risk characteristics for ischaemic events [advanced age, renal failure, diabetes, history of acute coronary syndromes (ACS) within the past 12 months, heart failure]. Why do interventional cardiologists believe stronger P2Y12 inhibition is desirable in elective PCI? PCI-related MI or myocardial damage are frequent clinical problems diagnosed with the help of high-sensitivity troponins with a rate of approximately 30%. Several reports have shown that such periprocedural complications are closely associated with major adverse cardiac events. In particular, elevations in troponin ≥5 × 99th percentile upper reference limit (URL), used in the ALPHEUS trial to define Type 4a MI and major procedural myocardial injury in the absence of procedural complications or evidence of new myocardial ischaemia, are associated with a poorer prognosis.3 Prasugrel and ticagrelor are more effective than clopidogrel in patients with ACS, given their higher level of platelet inhibition and faster onset of action.4,5 Based on these considerations, ticagrelor and prasugrel have been suggested as better choices in high-risk elective PCI. ALPHEUS is the first adequately sized trial to test the superiority of ticagrelor over clopidogrel to prevent periprocedural MI and myocardial injury in the setting of elective PCI, based on the extent of reduction in periprocedural MI achieved in previous studies of ACS.4–6 Although more profound P2Y12 inhibition was observed with ticagrelor compared to clopidogrel in the pharmacodynamic sub-study,1 this superiority did not translate into a reduction of PCI-related MI or myocardial damage within 48 h. Pooled analysis of ALPHEUS and SASSICAIA,7 a previously published study testing intensified antiplatelet therapy with prasugrel prior to elective PCI, showed that there was no difference in the risk of periprocedural complications with ticagrelor or prasugrel vs. clopidogrel.1 ALPHEUS has several limitations: it was an open-label trial; peri-procedural MI and myocardial damage were used as surrogates for hard clinical endpoints, which are rare in elective PCI; patients on chronic clopidogrel therapy were admitted to recruitment; different troponin assays were used, and this may have caused heterogeneity in prognostic thresholds. However, these limitations are unlikely to explain the neutral results of its randomized comparison, in the short term. The simple answer we can obtain from ALPHEUS is that early ischaemic events after elective PCI are unlikely to be improved by more effective P2Y12 inhibition than achieved with clopidogrel, possibly reflecting non-platelet-related mechanisms.8 These findings suggest that clopidogrel should remain the standard of care for elective PCI in addition to aspirin, and provide a rationale for investigating other strategies to lower periprocedural myocardial necrosis in this setting. Conflict of interest: Prof. LIUZZO reports grants from the Italian National Health Service and from the Italian Minister of Education University and Research, outside the submitted work. Prof. PATRONO reports personal fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline, Tremeau, Zambon, and grants from AIFA (Italian Drug Agency), Bayer, Cancer Research UK and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation, outside the submitted work.