Long-term treatment of patients with non-valvular AF (nvAF) undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation remains a therapeutic dilemma: how long should antiplatelet therapy be combined with lifelong oral anticoagulation? How to prevent atherothrombotic and cardioembolic recurrence at an acceptable bleeding risk? Beyond 12 months post-PCI, contemporary guidelines recommend oral anticoagulation alone, preferably with direct oral anticoagulants (DOACs) over vitamin K antagonists. However, the randomised evidence underpinning this recommendation is limited.
Most available data come from historical vitamin K-antagonist-based cohorts and from three randomised trials, all conducted in East Asia: OAC-ALONE and AFIRE from Japan and EPIC-CAD from South Korea.1–3 The OAC-ALONE trial was terminated prematurely because of slow recruitment; a total of 696 patients were enrolled over 38 months instead of the planned 2,000 in 12 months.1 The AFIRE non-inferiority trial included 2,236 Japanese patients with nvAF and stable coronary artery disease (CAD), defined as ≥12 months after PCI or coronary artery bypass grafting, or angiographically documented disease, assigned to rivaroxaban monotherapy or rivaroxaban combined with a single antiplatelet agent, predominantly aspirin (75%).2 The trial had distinct efficacy (stroke, systemic embolism, MI, unstable angina requiring revascularisation or all-cause death) and safety (International Society on Thrombosis and Haemostasis [ISTH]-defined major bleeding) endpoints. AFIRE met its non-inferiority criterion for the composite efficacy endpoint, even though the trial was stopped 2 months earlier because of an unexpected excess of all-cause, largely non-cardiovascular, mortality in the combined therapy group, an observation that remains unexplained and has not been replicated in subsequent trials. The primary efficacy endpoint event occurred in 89 patients (4.14% patient-year) and in 121 patients (5.75% patient-year) receiving monotherapy and combined therapy, respectively (HR 0.72; 95% CI [0.55–0.95], p<0.001 for non-inferiority and p<0.02 for superiority). ISTH-defined major bleeding occurred in 1.62% and 2.76% patient-year in the rivaroxaban monotherapy and combination therapy, respectively (HR 0.59; 95% CI [0.39–0.89]; p=0.01 for superiority). More recently, the EPIC-CAD superiority trial randomised nearly 1,050 patients with stable CAD and nvAF to edoxaban alone or combined with a single antiplatelet agent (largely low-dose aspirin), with a primary outcome merging efficacy and safety outcomes with different intensities: all-cause death, MI, stroke, systemic embolism, major bleeding, together with unplanned urgent revascularisation or clinically relevant non-major (CRNM) bleeding.3 The superiority of edoxaban monotherapy was largely driven by a lower incidence of major or CRNM bleeding (4.7% versus 14.2%, HR 0.34, 95% CI [0.22–0.53] in the monotherapy and combined arms), with no signal of increased mortality in the combination arm and a very low rate of serious vascular events to allow any strong conclusion on efficacy.
Against this fragmented background, the ADAPT AF-DES trial provides additional randomised evidence.4 This open-label, multicentre, non-inferiority trial enrolled fewer than 1,000 South Korean patients with AF and clinically stable CAD with a DES implanted ≥12 months earlier. Participants were randomised to DOAC (largely rivaroxaban or apixaban) alone or combined with clopidogrel. The primary composite endpoint comprised both ischaemic and bleeding outcomes, including death from any cause, MI, stent thrombosis, stroke, systemic embolism or major or clinically relevant non-major bleeding (ISTH-defined). At 12 months, the primary endpoint occurred in 46 patients (9.6%) in the monotherapy group and in 82 patients (17.2%) in the combination therapy group (HR 0.54, 95% CI [0.37–0.77]), meeting both non-inferiority and superiority. This difference was driven almost entirely by fewer major and CRNM bleeding with monotherapy (n=25, 5.2%, in the monotherapy group and n=63, 13.2%, in the combination therapy group (HR 0.38; 95% CI [0.24–0.60]), with no difference in all-cause and/or cardiovascular deaths. The absolute number of MIs, stent thromboses and strokes (ischaemic or haemorrhagic) was too low to allow any meaningful analysis on efficacy.
The results of ADAPT AF-DES align with prior trials, showing that in patients with nvAF and stable CAD, long-term DOAC monotherapy, mostly with a direct factor Xa inhibitor starting from ≥12 months since successful revascularisation (PCI or coronary artery bypass grafting), is associated with less major and/or CRNM bleeding than an anti-FXa DOAC plus an antiplatelet agent, irrespective of the type of antiplatelet agent used.4 In ADAPT AF-DES, all patients were on clopidogrel; in the previous AFIRE and EPIC-CAD trials, the majority of patients were on low-dose aspirin.2–4 The reduced bleeding diathesis was observed in trials with populations with slightly different risk profiles. This effect is consistent with the pathophysiological and pharmacological notion that blocking primary and secondary haemostasis together confers a profound iatrogenic bleeding diathesis. Reduced bleeding may also translate into practical downstream benefits, including simplified regimens, improved adherence and fewer treatment interruptions. However, none of those trials has demonstrated a clear reduction in all-cause or cardiovascular mortality attributable to antiplatelet withdrawal.
What the ADAPT AF-DES trial does not definitively establish is whether improved safety comes at no cost in terms of ischaemic protection from severe atherothrombotic vascular complications, i.e. cardiovascular death, MI, stroke, transient ischaemic attack and stent thrombosis. Although ADAPT AF-DES met its prespecified non-inferiority criterion, the overall incidence of events – particularly ischaemic events – was substantially lower than anticipated at the design stage: 18% predicted versus 9.6% observed in the monotherapy group, 23% predicted versus 17.2% observed in the combination therapy group.5 In recent years, there has been a progressive reduction in recurrent ischaemic events thanks to more aggressive recommendations for LDL cholesterol reduction and improved coronary revascularisation. The intracoronary imaging techniques available today allow for the optimisation of the positioning of stents, which are also more advanced.
A rate of observed events lower than those predicted and used to design the study and define the sample size is especially problematic in non-inferiority trials. The absolute non-inferiority margin of 3.0% in the ADAPT AF-DES was selected based on higher expected event rates. When event rates are lower than expected, absolute non-inferiority margins become proportionally more permissive, limiting the ability to exclude clinically meaningful differences.5 Consistent with this concern, confidence intervals for MI, stroke and stent thrombosis are wide, with upper limits that do not rule out increased risk for monotherapy. Thus, the trial does not provide any definitive proof of ischaemic equivalence or superiority.
Additional limitations also warrant consideration. This trial population was restricted to East Asia, where bleeding and ischaemic risk profiles may differ from those in Western populations. Follow-up was limited to 12 months, precluding assessment of later ischaemic events. Moreover, patients with particularly high atherothrombotic risk, such as those with complex PCI, prior stent thrombosis or recurrent ischaemic events, were underrepresented.
Thus, the findings of ADAPT AF-DES should be interpreted with caution. This small trial provides further randomised data that, in a broadly stable population with nvAF more than one year after DES implantation, discontinuation of clopidogrel reduces bleeding. Whether this strategy provides equivalent or superior long-term protection against major atherothrombotic events remains unproven. Rather than closing the debate, this trial sharpens the clinical trade-off, reinforces the need for more convincing trial designs and calls for individualised decision-making, particularly in patients at heightened ischaemic risk.