Does abbreviated dual antiplatelet therapy after PCI provide a clinically meaningful trade-off between bleeding and ischaemic events in patients at high risk for bleeding?

MASTER DAPT was an investigator-initiated, industry-funded, randomized, open-label, noninferiority trial with sequential superiority testing, assessing the optimal duration of dual antiplatelet therapy (DAPT) in patients at high risk for bleeding (HBR) after the implantation of a biodegradable-polymer sirolimus-eluting stent.1 The trial randomized 4579 patients [mean age, 76 years; 69% men; 34% with diabetes; 36% receiving concomitant oral anticoagulation (OAC); mostly presenting with chronic coronary syndromes (CCS)] who underwent successful percutaneous coronary intervention (PCI) of all coronary artery stenoses and fulfilled one or more HBR criteria (mean, 2.1 per patient). Patients free from ischaemic and active bleeding events and who adhered to a DAPT regimen were screened for inclusion 30–44 days after PCI (median, 34 days): 2295 patients were allocated to abbreviated therapy, and immediately stopped DAPT to continue single antiplatelet therapy (SAPT, aspirin or a P2Y12 inhibitor) until completion of the trial (up to 6 months if on concomitant OAC); 2284 patients were allocated to standard therapy and continued DAPT for at least 5 more months (for at least 2 additional months if on concomitant OAC). The trial included three ranked primary outcomes whose cumulative incidence was assessed at 335 days. Net adverse clinical events [NACE, a composite of all-cause death, myocardial infarction (MI), stroke or major bleeding, i.e. Bleeding Academic Research Consortium (BARC) type-3 or -5] and major adverse cardiac or cerebral events (MACCE, a composite of all-cause death, MI, or stroke) were analysed for noninferiority in a per-protocol population of 4434 patients. Major or clinically relevant nonmajor (CRNM) bleeding (BARC type-2, -3, or -5) was analysed for superiority in the intention-to-treat population (n = 4579). NACE occurred in 7.5% of patients in the abbreviated-therapy group vs. 7.7% in the standard-therapy group [hazard ratio (HR) = 0.97; 95% confidence interval (CI), 0.78–1.20; P < 0.001 for noninferiority). MACCE occurred in 6.1% vs. 5.9% (HR = 1.02; 95% CI, 0.80–1.30; P = 0.001 for noninferiority). Major or CRNM bleeding occurred less often in the abbreviated-therapy group than in the standard-therapy group (6.5% vs. 9.4%; HR = 0.68; 95% CI, 0.55–0.84; P < 0.001 for superiority), an absolute 2.9% reduction largely driven by the 2.3% lower incidence of BARC type 2 bleeding (4.5% vs. 6.8%), while the cumulative incidence of bleeding of type-3, -4, or -5 was similar in the two groups (2.3% vs. 2.6%). Results were consistent across 10 prespecified subgroups. The results of ‘Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk’ have been presented at the 2021 European Society of Cardiology Congress and simultaneously published in the N Engl J Med. https://www.nejm.org/doi/10.1056/NEJMoa2108749. MASTER DAPT is the largest, randomized trial addressing the conundrum of DAPT duration in post-PCI patients at HBR, a population that represents up to 40% of patients undergoing PCI.1 Current guidelines recommend considering a shorter DAPT duration in HBR patients with a C level of evidence (expert opinion).2 Two major trials, GLOBAL LEADERS and STOPDAPT-2, have compared 1 month with at least 12 months of DAPT after PCI with drug-eluting stents.3,4 However, in both trials, patients were enrolled immediately after the PCI, and those at HBR were not selected. MASTER DAPT differs importantly in that it specifically enrolled patients at HBR. The predominant HBR criteria were age ≥75 years (69%), a PRECISE-DAPT score ≥25 (54%) and clinical indication for OAC ≥12 months (36%). Although the predominant clinical presentation was CCS, 48% of the patients had undergone PCI for an acute coronary syndrome, and the results were consistent regardless of the clinical presentation. The trial also did not limit the number, location, or complexity of the treated lesions including patients with coronary anatomy carrying a high risk of stent thrombosis, in whom current guidelines specify to continue DAPT for 3–6 months,2 provided that the lesions had been uniformly treated with a specific biodegradable-polymer sirolimus-eluting stent and the patients had not experienced postprocedural ischaemic events during the first month of DAPT. The latter requirements resulted in only 4% of the patients who underwent screening (22% of the eligible patients) being enrolled.1 In a subgroup analysis reported separately, stopping DAPT at 1 month and continuing with SAPT reduced clinically relevant bleeding risk significantly in patients without an indication for OAC and numerically, but not significantly, in patients with an indication for OAC (P for interaction = 0.057).5 Is MASTER DAPT a game-changing trial? There are three important caveats in the interpretation of its results. Firstly, the observed cumulative incidence of NACE was 36% lower than expected (7.7% vs. 12%).1 Because the upper limit of the two-sided 95% CI for the difference in the cumulative incidence of NACE had to exclude 3.6 percentage points to establish noninferiority, this value represented 30% of the expected incidence but almost half of the observed incidence. Similarly, the observed cumulative incidence of MACCE was 26% lower than expected (5.9% vs. 8%).1 The upper limit of the two-sided 95% CI for the difference in the cumulative incidence of MACCE had to exclude 2.4 percentage points to define noninferiority. This represented 30% of the expected incidence, but 41% of the observed incidence. This implies accepting the possibility of losing most, if not all, the benefit of DAPT vs. SAPT. Therefore, it is questionable whether the statistical uncertainty surrounding the point estimate of MACCE allows declaring an acceptable trade-off between ischaemic and bleeding events,6 as a moderate increase (up to 30%) in the former as a result of abbreviated DAPT cannot be excluded by the present findings. Second, the primary goal of such strategy, i.e. reducing bleeding complications, was not reached in terms of major bleeding (BARC type-3 to -5, with similar results when TIMI or GUSTO criteria were used).1 Last, but not least, the trial results apply to patients who received the specific biodegradable-polymer sirolimus-eluted stent (Ultimaster, Terumo) used in the present study and not necessarily to patients receiving other drug-eluting stents. In conclusion, although Valgimigli et al should be congratulated for adding another missing piece to the puzzle, we believe that an unequivocal answer to the important clinical question that MASTER DAPT was designed to address will require larger (to ensure patients’ safety through tighter boundaries for noninferiority testing) and independent (to improve the generalizability of the results) randomized trials applying novel methods to assess the benefit–risk balance of different antiplatelet strategies. It is interesting to note that to inform the regulatory decision on the 2020 supplemental new drug application for ticagrelor, based on the THEMIS trial,7 the US Food and Drug Administration applied for the first time multicriteria decision analysis, to quantitatively explore the sensitivity of the benefit–risk balance to judgements about the relative importance of individual ischaemic and major bleeding outcomes.8 Conflict of interest: G.L. received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, and Daiichi Sankyo. C.P. received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline, Tremeau, and Zambon and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation.