Weekly Journal Scan: a penULTIMATE frontier for optimal antiplatelet therapy after drug-eluting stenting in acute coronary syndromes?

Comment on ‘Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial’ published in The Lancet; https://doi.org/10.1016/S0140-6736(24)00473-2. ULTIMATE-DAPT is a randomized, placebo-controlled, double-blind clinical trial, funded by national and local institutions in China. Patients with an acute coronary syndrome (ACS) who completed the IVUS (intravascular ultrasound)-ACS trial and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy (DAPT with ticagrelor and aspirin) were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning ∼1 month and ending at 12 months after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents (DES).1 The trial had two primary endpoints. The primary superiority endpoint was the occurrence of clinically relevant bleeding [Bleeding Academic Research Consortium (BARC) types 2, 3, or 5]. The primary non-inferiority endpoint was the occurrence of MACCE [i.e. the composite of cardiac death, myocardial infarction (MI), ischaemic stroke, stent thrombosis, and clinically driven target-vessel revascularization], with an expected event rate of 6.2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2.5% points between 1 month and 12 months after PCI. The key secondary endpoints were the time to first occurrence of composite net adverse clinical events (defined as any MACCE or any BARC bleeding) and percentage of switching from ticagrelor to clopidogrel in each group. All principal analyses were performed in the intention-to-treat population. Recruitment took place at centres in China (54 of 58), Pakistan, Italy, and the UK. From September 2019 through October 2022, 3505 patients with an ACS were randomly assigned to IVUS- or angiography-guided PCI and subsequently discharged on DAPT. Then, 3400 patients who remained event-free on DAPT (median age 63 years; 74% men; 32% with diabetes; 60% presenting with acute MI; 25% with a TIMI flow score in the culprit vessels < 3 before the index procedure) underwent a second randomization at 1 month (median 31 days, interquartile range 30–34) to receive either ticagrelor plus placebo (n = 1700) or ticagrelor plus aspirin (n = 1700). Randomization was stratified by ACS type, diabetes, IVUS-ACS randomization, and site. Follow-up was completed by 3399 participants. Between months 1 and 12 after PCI, the primary superiority endpoint of clinically relevant bleeding occurred in 35 patients (2.1%) treated with ticagrelor plus placebo and in 78 patients (4.6%) treated with ticagrelor plus aspirin [hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.30–0.66; P < .0001]. Major bleeding (BARC types 3 or 5) also occurred less frequently with ticagrelor plus placebo compared with ticagrelor plus aspirin, as did other measures of bleeding. Results were consistent across a number of pre-specified subgroups. The primary non-inferiority endpoint of MACCE occurred in 61 participants (3.6%) treated with ticagrelor plus placebo and 63 (3.7%) treated with ticagrelor plus aspirin [absolute difference −0.1% (95% CI, −1.4%–1.2%); HR, 0.98 (95% CI, 0.69–1.39); Pnon-inferiority < .0001, Psuperiority = .89]. The rates of the individual components of MACCE were not significantly different between the two groups, as were other composite ischaemic outcomes, though with a trend for more frequent MIs in the ticagrelor monotherapy group. Results were consistent in all subgroups except for age, whereby ticagrelor monotherapy was more favourable in patients younger than 65 years and long-term DAPT was more favourable in patients aged 65 years or older (P for interaction = .016). The key secondary endpoint of net clinical adverse events occurred less frequently in the ticagrelor plus placebo group than in the ticagrelor plus aspirin group (5.7% vs. 8.2%; HR, 0.68; 95% CI, 0.53–0.88). Conversion from ticagrelor to clopidogrel was required in 22 (1.3%) patients in the ticagrelor plus placebo group and 19 (1.1%) patients in the ticagrelor plus aspirin group. In patients with ACS undergoing PCI with DES implantation, 12-month DAPT with aspirin and prasugrel or ticagrelor is the only strategy with a class I recommendation according to 2023 ESC guidelines.2 However, an increased likelihood of bleeding might require adjustments to the duration of DAPT or a different choice of antiplatelet agent.3 Randomized clinical trials and meta-analyses of individual patient data (IPD) have evaluated the efficacy and safety of P2Y12 inhibitor monotherapy after 1–3 months of DAPT. The GLOBAL LEADERS trial of ∼16 000 patients undergoing PCI for stable coronary artery disease (CAD) or ACS found no superiority in terms of death or MI (the primary endpoint) of a strategy involving 1-month DAPT followed by ticagrelor monotherapy over standard 12-month DAPT followed by aspirin after DES implantation.4 Bleeding risk was reduced in the ACS subgroup with 1-month DAPT.5 The TWILIGHT study of selected high-risk patients including ACS showed that after 3 months of DAPT, ticagrelor monotherapy was safer (in terms of BARC 3 or 5 bleeding) and non-inferior in terms of MACE compared to the standard 12-month DAPT.6 The SIDNEY-2 Collaboration IPD meta-analysis, involving over 38 000 patients undergoing complex and non-complex PCI for both stable CAD and ACS, supported P2Y12 inhibitor monotherapy to reduce BARC type 3 or 5 bleeding events, and demonstrated its non-inferiority for MACE compared to standard DAPT, with notable benefits for bleeding in ACS patients7 and those undergoing complex PCI.8 A more recent systematic review and IPD meta-analysis of six randomized trials including ∼26 000 patients undergoing PCI (64% for ACS) found that ticagrelor monotherapy was non-inferior to DAPT for all-cause death, MI, or stroke and superior for major bleeding.9 Although clopidogrel monotherapy was similarly associated with reduced bleeding, it was not non-inferior to DAPT for all-cause death, MI, or stroke.9 The ULTIMATE-DAPT trial reinforces the findings of previous studies by showing that ticagrelor monotherapy after 1 month reduced the risk of clinically relevant bleeding by 55% compared to DAPT for 12 months, with a non-inferior rate of ischaemic outcomes.1 However, some limitations and a major concern should be outlined. Firstly, the primary efficacy endpoint included minor bleeding (BARC type 2). Although lower rates of major bleeding (BARC types 3 or 5) were also observed with ticagrelor monotherapy, the study was not powered to assess differences in major bleeding. Secondly, non-inferiority for MACCE was tested with an absolute margin of 2.5%. Given the 40% lower-than-expected rate of observed ischaemic events in the ticagrelor plus aspirin group (3.7% observed vs. 6.2% expected), this non-inferiority margin is extremely wide, representing 68% of the observed MACCE rate. In fact, the upper limit of the 95% CI of the HR for the MACCE comparison is compatible with up to a 39% increased risk with ticagrelor alone vs. DAPT. Additionally, cardiac death and MI data trend towards an increased risk (by 15% and 45%, respectively) with ticagrelor alone. The inclusion of clinically driven target-vessel revascularization in the MACCE co-primary endpoint (which accounted for about two-thirds of all MACCE events in both groups) is also questionable, as it severely limits the statistical power to analyse hard ischaemic endpoints. Thirdly, within the limitations of subgroup analysis, patients aged ≥65 years had higher rates of MACCE in the ticagrelor plus placebo group (5.3%) compared to the ticagrelor plus aspirin group (3.7%), in contrast to younger patients (P for interaction = .016). As age is also a risk factor for bleeding events,10 this finding should be considered hypothesis generating. Fourthly, ∼40% of patients had unstable angina with negative biomarkers. The authors believe that because hs-troponin assays were not widely available in China and Pakistan during the enrolment period, it is likely that many of these patients actually had NSTEMI. Overall, the ULTIMATE-DAPT population was a low thrombotic risk population: 70% of patients had single vessel-disease and <10% had severe calcium score or thrombus. This was reflected in the overall low rates of ischaemic events. Given the recognized higher bleeding risk observed in East Asian patients,11 it would be necessary to evaluate the applicability of a 1-month regimen of DAPT followed by ticagrelor monotherapy to other populations. Finally, the present findings are specific to a ticagrelor monotherapy regimen and cannot be extrapolated to other antiplatelet strategies (i.e. with prasugrel or clopidogrel alone). In conclusion, ULTIMATE-DAPT appears to bring limited new evidence to the belief that many ACS patients who have successfully undergone PCI with contemporary DES should now be managed with a single antiplatelet drug after a DAPT course of 1 month. This may be especially relevant for patients, like those in the ULTIMATE-DAPT study, who have a low thrombotic risk profile. However, similarly to previous studies, ULTIMATE-DAPT did not include an arm with aspirin plus placebo to verify whether ticagrelor or aspirin is safer to withdraw. In support of the choice to discontinue aspirin, the authors refer to the hypothesis that, following PCI with contemporary DES in ACS patients, the ischaemic protection from DAPT would mostly derive from the P2Y12 inhibitor, while aspirin would be responsible for many of the bleeding complications.1 However, this hypothesis has no mechanistic basis and is not supported by the available clinical evidence, since low-dose aspirin and ticagrelor have a comparable efficacy and safety profile in head-to-head randomized trials.12 Another open question is related to the appropriate therapy 12 months after PCI. These concerns will need to be addressed by future independent studies of different antiplatelet strategies targeting the early and late atherothrombotic complications with an adequate trial design. G.L. reports personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis; G.L. reports grant support (to the Institution) for investigator-initiated research from the American Heart Association, the Italian Ministry of University and Research, and the Italian Ministry of Health (grant: ‘Ricerca Corrente’). C.P. reports personal fees from AbbVie, Eli Lilly, and Tremeau, and past grant support (to the institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chaired the Scientific Advisory Board of the International Aspirin Foundation.