https://orcid.org/0000-0002-5714-0907
-
PDF
- Split View
-
Views
-
Cite
Cite
Giovanna Liuzzo, Carlo Patrono, Weekly Journal Scan: An EPIC comparison of edoxaban vs. dual antithrombotic therapy in atrial fibrillation and stable coronary artery disease, European Heart Journal, Volume 46, Issue 7, 14 February 2025, Pages 669–671, https://doi.org/10.1093/eurheartj/ehae787
Close - Share Icon Share
This comment refers to ‘Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease’, which was presented at ESC Congress 2024 in London and simultaneously published in The New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2407362.
The Edoxaban vs. Edoxaban with Antiplatelet Agent in Patients with Atrial Fibrillation and Chronic Stable Coronary Artery Disease (EPIC-CAD) trial was a company-funded, investigator-initiated, open-label trial with adjudicator-masked outcomes, designed to compare edoxaban monotherapy vs. edoxaban plus a single antiplatelet agent. The study recruited patients with both high-risk atrial fibrillation (AF) and stable CAD, defined as no acute coronary event within the last 12 months for those who had undergone prior revascularization or after ≥6 months for patients with chronic stable angina. The trial was conducted in 18 high-volume cardiac centres in South Korea.1
A total of 1040 patients were randomized in a 1:1 ratio to receive a standard dose of edoxaban (60 mg once daily or 30 mg according to dose reduction criteria) or dual antithrombotic therapy (DAT), which consisted of the same dose of edoxaban combined with aspirin or clopidogrel. Eligible patients were those with a CHA2DS2-VASc score ≥ 2 (scores range from 0 to 9, with higher scores indicating a greater risk of stroke), along with stable CAD. The mean age was 72 years, with 23% of female participants, the mean CHA2DS2-VASc score was 4.3 ± 1.5, and the mean HAS-BLED score (which ranges from 0 to 9, with higher scores indicating a greater risk) was 2.2 ± 0.8, thus indicating a relatively low bleeding risk. Two-thirds of patients had undergone prior revascularization, with a median time from the procedure of 53 months, and one-third had anatomically confirmed CAD. A total of 55% of the patients had paroxysmal AF, and 45% had prevalent (persistent or permanent) AF. The choice of the antiplatelet agent in the DAT group was left to the discretion of the treating physician, whereby 62% of patients received aspirin and 38% clopidogrel.
Patients were followed up over a 12-month period. The primary endpoint was net adverse outcomes (i.e. efficacy and safety events), defined as the composite of death from any cause, myocardial infarction (MI), stroke, systemic embolism, unplanned urgent revascularization or major bleeding or clinically relevant non-major bleeding (as defined by the International Society on Thrombosis and Haemostasis) at 12 months. Secondary endpoints included individual components of the primary outcome, a composite of major ischaemic events, and the safety outcome of major bleeding or clinically relevant non-major bleeding.
The overall rate of the primary endpoint was 6.8% (34 patients) in the monotherapy group vs. 16.2% (79 patients) in the DAT group [hazard ratio (HR), 0.44; 95% confidence interval (CI), 0.30–0.65; P < .001], a difference entirely accounted for by fewer bleeding events in the monotherapy arm [4.7% (23 patients), compared with 14.2% (70 patients) in the DAT group]. The cumulative incidence of major ischaemic events (a composite of death, MI, ischaemic stroke, or systemic embolism) at 12 months was similarly low with either treatment (eight patients in each group). A post hoc composite outcome of any ischaemic events (that also included unplanned urgent revascularization) occurred in 15 patients (3%) in the edoxaban group and 11 patients (2.4%) in the DAT group (HR, 1.40; 95% CI, 0.67–2.93) The estimated cumulative incidence of major bleeding at 12 months was 1.3% in the edoxaban monotherapy group and 4.5% in the DAT group (HR, 0.32; 95% CI, 0.14–0.73).
Comment
Management strategies for patients with AF and stable CAD have typically leaned towards recommending a combination of a direct oral anticoagulant (DOAC) with an antiplatelet agent (mostly, aspirin, or clopidogrel). The rationale for this combination stemmed from the need to prevent thromboembolic events, such as stroke or systemic embolism, and reduce the risk of MI in a population at high risk due to both AF and CAD.2,3 Dual antithrombotic therapy is beneficial immediately after percutaneous coronary intervention (PCI) or an acute coronary syndrome (ACS), but its prolonged use raises the risk of bleeding complications.4–6 Bleeding events can significantly impact morbidity and mortality in high-risk populations, particularly the elderly, at least in part because a bleeding event often necessitates the discontinuation of anticoagulation, which increases the risk of subsequent thromboembolic events. Thus, choosing the appropriate antithrombotic strategy for patients with both AF and stable CAD is challenging because ischaemic and bleeding risks vary over time.2,3
Guidelines7,8 have increasingly recommended DOAC monotherapy after an initial phase of DAT, particularly beyond 1-year post-PCI or for those with stable CAD who no longer require intensive antiplatelet therapy. Previous trials, such as AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease)9 and OAC-ALONE (Optimal Antiplatelet Therapy in Combination with Oral Anticoagulants Alone),10 suggested that monotherapy with a DOAC may offer a safer alternative to DAT. This result influenced guidelines by supporting the move towards DOAC monotherapy in select patient populations. However, the OAC-ALONE trial was prematurely terminated, and thus, it was underpowered and inconclusive; moreover, warfarin was predominantly used.10 The AFIRE trial showed that rivaroxaban monotherapy was non-inferior to combination therapy with rivaroxaban plus antiplatelet therapy for ischaemic outcomes and superior for bleeding outcomes; however, it did not use the globally approved standard dose of rivaroxaban.9
The EPIC-CAD trial1 contributes to the growing body of research on the optimal antithrombotic strategy for patients with AF and stable CAD. Its most striking finding was the 66% lower rate of bleeding events among patients receiving edoxaban monotherapy compared with those on DAT. The trial did not show any detectable difference in the low rate of major ischaemic events between the two groups. This finding might be interpreted to suggest that withholding antiplatelet therapy in stable CAD patients does not lead to an increased risk of atherothrombotic events, which challenges the conventional wisdom that the addition of antiplatelet therapy is necessary to protect against myocardial ischaemia in these patients.
However, the EPIC-CAD results should be interpreted within the broader framework of existing knowledge, current guidelines, and the trial's major limitations. These include the fact that the entire 9.4% absolute difference in the primary composite outcome between the two treatment groups was accounted for by the reduction in bleeding events, with no difference in ischaemic outcomes. While this finding strongly supports the safety of edoxaban monotherapy, it also underscores a potential limitation in the trial design. The study was not powered to evaluate major ischaemic events or major bleeding events as separate outcomes, which limits the possibility of reliably assessing the relative risks of these events. As acknowledged by the authors, the relatively higher incidence of bleeding compared with ischaemic events might introduce a bias favouring monotherapy, as the ‘net clinical outcome’ is more heavily influenced by bleeding events than by ischaemic complications.
While the difference in ischaemic events was not statistically significant, there was a 23% numerical increase in major ischaemic events and a 40% numerical increase in all ischaemic events in the monotherapy group compared with the DAT group. Although the overall incidence was low, the trial was not sufficiently powered to exclude the possibility of a substantially higher risk of ischaemic events with monotherapy that would only become apparent with a larger study population and longer-term follow-up. Unfortunately, none of the available trials were designed to assess meaningful differences in serious ischaemic events and mortality.
Another important consideration is the temporally dynamic nature of ischaemic and bleeding risks in patients with AF and stable CAD.2,3 The risk of ischaemic events tends to be higher in the initial months following PCI or an ACS but decreases over time. Conversely, bleeding risks tend to accumulate with prolonged antithrombotic therapy.2,3 Moreover, none of the current trials, including EPIC-CAD, were designed to assess the optimal timing for transitioning from DAT to monotherapy. This leaves an important gap in our understanding of how best to tailor antithrombotic therapy over time to balance bleeding and ischaemic risks. A personalized approach based on individual risk profiles may be especially beneficial in the era of modern drug-eluting stents, which reduce ischaemic risks and potentially allow for shorter DAT duration. As bleeding risks increase with age, personalized anticoagulation strategies that balance thrombotic and haemorrhagic risks are crucial for safer long-term management.11
Finally, the trial only included an East Asian population, which is known to have a different propensity for ischaemic and bleeding complications as compared with Western populations,12 and women were underrepresented, which may limit the generalizability of the current findings.
In conclusion, the EPIC-CAD trial contributes new evidence supporting the safety of DOAC monotherapy in patients with AF and stable CAD, particularly for reducing bleeding complications during the first year of follow-up. However, the trial's major limitations—such as its lack of statistical power to reliably assess ischaemic outcomes— imply that its findings should be integrated into clinical practice cautiously. Future independent research should focus on refining the timing and patient selection for monotherapy vs. DAT, within the context of much larger pragmatic trials with longer-term follow-up, in order to fill the important gaps in current knowledge. The MATRIX-2 trial (NCT05955365) will compare DOAC monotherapy vs. DAT starting 30-day post-PCI in patients requiring oral anticoagulation, with a sample size three-fold larger than previous studies.
Declarations
Disclosure of Interest
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.
