Changing paradigms in antiplatelet therapy after coronary intervention

This editorial refers to ‘P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: a meta-analysis of randomized clinical trials including 29 089 patients’, by M. Bianco et al. pp. 196--205. In the era of percutaneous coronary intervention (PCI) and stent implantation in patients presenting with coronary artery disease, antiplatelet treatment strategies occupy a central position in the pharmacotherapeutic approach to prevent recurrent myocardial ischaemia. While dual antiplatelet therapy (DAPT) for 1 year mirrors a guideline-supported standard of care after acute coronary syndrome (ACS), a duration of at least 6 months is recommended in individuals undergoing elective coronary interventions.1,2 We need to be aware that the evidence for the duration of DAPT after stenting is based on trials conducted more than a decade ago showing that DAPT is superior to an aspirin-based single antiplatelet therapy in terms of efficacy, but not using stent generations with current antithrombotic characteristics and standards. Since a major downside of a prolonged DAPT is the associated risk of major bleeding events, strategies to de-escalate antiplatelet therapy and the respective duration of DAPT after stent implantation have become a major focus in the scientific field. Facing this dilemma in terms of a favourable net benefit, several trials addressed the clinical imperative of lowering the risk of bleeding while balancing the atherothrombotic risk and preserving the ischaemic benefit, via reducing the duration of aspirin during DAPT and subsequently allowing a prolonged use of more potent P2Y12 inhibitors. Four recently published trials are available in the literature that aimed to fill this specific gap of knowledge, i.e. the GLOBAL LEADERS trial, the SMART-CHOICE trial, the STOPDAPT-2 trial, and the TWILIGHT trial.3–6 The GLOBAL LEADERS trial was the first open-label, randomized study to elucidate the efficacy and safety of a shortened DAPT followed by a potent P2Y12 inhibitor in individuals undergoing PCI—investigating the effect of 1-month DAPT followed by 23 months of P2Y12 inhibitor monotherapy compared with 1 year of DAPT followed by 12 months of aspirin monotherapy.3 The 1-month DAPT approach followed by P2Y12 inhibitor monotherapy was found non-inferior to 12 months of DAPT followed by aspirin monotherapy in terms of both efficacy and safety. In agreement with this, the GLOBAL LEADERS Adjudication Sub-StudY (GLASSY) revealed that a 1-month DAPT strategy was non-inferior to a 12-month duration of DAPT considering the reduction of all-cause mortality, myocardial infarction, ischaemic stroke, and urgent target vessel revascularization. The SMART-CHOICE trial randomized patients in a 1:1 fashion to either 3 months of DAPT followed by P2Y12 inhibitor monotherapy or a 1-year DAPT arm.4 The results indicated that a 3-month period of DAPT is non-inferior to a 1-year DAPT therapy for major adverse cardiac and cerebrovascular events (all-cause death, myocardial infarction, or stroke) in an unselected patient population undergoing coronary intervention, including individuals presenting with ACS. As expected, the risk of bleeding was significantly lower in the short-term DAPT arm. As a multicentre, open-label, adjudicator-blinded randomized clinical trial, the design of STOPDAPT-2 was similar to that of GLOBAL LEADERS comparing a 1-month DAPT followed by P2Y12 inhibitor monotherapy with a 1-year DAPT approach.5 Within this investigation, a 1-month DAPT was found to be superior in the reduction of the defined composite of cardiovascular adverse events (cardiovascular death, myocardial infarction, ischaemic or haemorrhagic stroke, definite stent thrombosis, or major or minor bleeding) as compared with a 1-year DAPT approach. Additionally, the 1-month DAPT arm was non-inferior to the 12-month DAPT group in terms of preventing ischaemic events, but was superior in preventing TIMI major and minor bleeding events. The most recently published TWILIGHT trail aimed to compare the safety and efficacy of a 3-month DAPT approach followed by P2Y12 inhibitor monotherapy compared with 12 months of DAPT in individuals undergoing PCI in a 1:1 double-blind fashion.6 The provided data indicated that a 3-month period of DAPT has a lower rate of bleeding events compared with the 12-month DAPT arm. Moreover, in terms of efficacy, a 3-month DAPT treatment met the criteria for non-inferiority (for prevention of all-cause death, myocardial infarction, and ischaemic stroke) as compared with a 12-month DAPT strategy. Most interestingly, the observed effects remained consistent during subgroup analysis of individuals presenting with non-ST-elevation myocardial infarction (NSTEMI) or type-2 diabetes mellitus, and patients undergoing complex coronary intervention. Therefore, the benefit observed with P2Y12 inhibitor monotherapy after short-term DAPT is uniform across different levels of risk and regardless of NSTEMI or unstable angina presentation. In the current issue of the European Heart Journal – Cardiovascular Pharmacotherapy, Bianco and co-workers aimed to summarize and investigate available evidence coming from the four above-mentioned randomized controlled trials on early aspirin interruption after PCI in order to evaluate the safety and efficacy of a P2Y12 inhibitor monotherapy within a highly powered meta-analysis of 29 089 individuals.7 The authors found that, after 1 year of patient follow-up, the rate of major adverse cardiac and cerebrovascular events (defined as myocardial infarction, ischaemic stroke, and all-cause mortality) was similar (odds ratio [OR] 0.90; 95% confidence interval [CI] 0.79–1.03) when comparing the efficacy of short-term DAPT followed by a single P2Y12 inhibitor approach with a 12-month DAPT strategy. Interestingly, this effect remained stable when independently calculated for myocardial infarction (OR 1.06; 95% CI 0.90–1.26), ischaemic stroke (OR 1.12; 95% CI 0.82–1.53), and all-cause mortality (OR 0.87; 95% CI 0.71–1.06). Most importantly, while the frequency of definite/probable stent thrombosis was comparable between P2Y12 inhibitor monotherapy and the 12-month DAPT approach (OR 1.17; 95% CI 0.83–1.64), BARC 3 or 5 major bleeding was significantly lower for the P2Y12 inhibitor monotherapy group (OR 0.70; 95% CI 0.58–0.86). The present meta-analysis clearly highlighted the absence of major adverse cardiac and cerebrovascular events in individuals that discontinue aspirin within the first 3 months after PCI compared with 12 months of DAPT for both stable coronary artery disease and ACS. Aligned with those findings, an early interruption of DAPT and subsequent P2Y12 inhibitor monotherapy constitutes a significant reduction in clinically relevant bleeding, without increasing the risk of stent thrombosis. TWILIGHT, GLOBAL LEADERS, SMART-CHOICE, and STOPDAPT-2 have tested similar strategies of discontinuing aspirin either at month 1 or month 3 with subsequent P2Y12 inhibitor monotherapy in patients who were undergoing coronary intervention either for stable coronary disease or for ACS. Of note, these studies included several patients presenting with both NSTEMI and ST-elevation myocardial infarction (STEMI), and all of them followed different strategies for single P2Y12 inhibitor therapy (clopidogrel, prasugrel, or ticagrelor) after omitting aspirin. However, the first remaining question is which P2Y12 inhibitor provides the most beneficial therapeutic profile during monotherapy in terms of preserving the ischaemic risk and lowering the risk of bleeding. Considering significant interpatient variability in terms of the pharmacodynamic response—especially in clopidogrel—genotyping or platelet function testing might be appropriate in recipients before single P2Y12 inhibitor therapy. Similarly, it needs to be investigated whether aspirin could be safely discontinued even before 1–3 months after coronary intervention or whether a P2Y12 inhibitor monotherapy may be continued indefinitely beyond a 12-month period. Current evidence provided by the four randomized controlled trials and the present meta-analysis does not indicate that an early discontinuation of aspirin after a short-term DAPT leads to an increase of major adverse cardiac and cerebrovascular events. Therefore, a P2Y12 inhibitor monotherapy 1–3 months after coronary intervention seems applicable for a large population of patients in terms of efficacy and safety, but effects from a long-term perspective beyond 1 year of follow-up deserve further attention. Conflict of interest: P.S. reports grants from Daiichi Sankyo and Boehringer-Ingelheim outside the submitted work. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal – Cardiovascular Pharmacotherapy or of the European Society of Cardiology.