Antiplatelet therapy on top of anticoagulation in atrial fibrillation: when less may be more

The combination of oral anticoagulants (OAC) and antiplatelet therapy (APT), mostly required in patients with both atrial fibrillation (AF) and coronary syndromes, has consistently been associated with an increased risk of bleeding with relevant prognostic implications [1]. Despite evidence from randomized controlled trials (RCTs) and guideline recommendations [2] favoring OAC monotherapy in most patients with AF outside specific high ischemic risk conditions, the concomitant use of APT remains common.

In a recent issue of IJC Heart & Vasculature, Matsuoka and colleagues provide important real-world data addressing this question through the pooled DIRECT-Extend registry, which includes more than 7,000 anticoagulated AF patients from three Japanese cohorts [3]. By excluding patients within one year of percutaneous coronary intervention (PCI) or coronary artery bypass grafting, the authors focus on a population in whom long-term combination therapy is often continued despite growing supporting evidence.

They show that patients receiving OAC plus APT experienced higher risks of both bleeding and ischemic events compared with those receiving OAC alone. These results provide compelling real-world confirmation of what previous registries and subsequent RCTs have already suggested — namely, that outside specific high-ischemic risk conditions, combining antiplatelet agents with anticoagulation may offer little benefit and substantial harm [4], [5], [6], [7], [8], [9].

Optimal antithrombotic therapy in patients with AF remains a clinical balancing act between thromboembolic protection and bleeding risk. RCTs comparing triple antithrombotic therapy (TAT) vs. dual antithrombotic therapy (DAT) in AF patients after PCI have consistently shown a significant reduction in bleeding with DAT [10], [11], [12], [13]. Although these studies were underpowered for ischemic efficacy endpoints, no overall increase in thrombotic events was observed, except among patients at particularly high thrombotic risk. This highlights the importance of careful individual risk stratification when considering discontinuation of APT [14]. Further, in RCTs including patients with AF and chronic coronary syndromes (CCS), remote from PCI or acute coronary events, OAC monotherapy was associated not only with a significant reduction in bleeding but also with similar or even lower thrombotic event rate compared with combined OAC plus APT.

For these reasons, in AF patients, the duration of TAT is recommended to be ≤1 week to 1 month after an acute coronary syndrome or PCI, contingent on the evaluation of bleeding and stent thrombosis risk; the duration of the subsequent DAT should be 6 to 12 months, according to ischemic and bleeding risk; APT beyond 12 months is not recommended [2].

The study by Matsuoka et al. addresses the persistent gap between guidelines and clinical practice. Approximately 17% of patients in the registry were treated with combined OAC and APT, reflecting the continued use of this strategy in real-world settings.

The most intriguing aspect of the study is the observation that patients receiving APT had higher rates of a composite outcome including all-cause mortality and ischemic events, consistently with some evidence from RCTs [5], [6], [7]. This finding, apparently paradoxical, confirms the relationship between bleeding and subsequent ischemic complications. Bleeding episodes can trigger discontinuation of antithrombotic therapy and create a pro-thrombotic environment which may translate into an increased risk of ischemic events [1]. In the present study, the temporal clustering of ischemic events after bleeding suggests that bleeding may act as a catalyst for downstream cardiovascular events.

A subgroup analysis of the registry showed no significant advantage of APT in patients with vascular disease treated with OAC, but significantly worse outcomes among patients without vascular disease. One might expect patients with established vascular disease to benefit most from combined antithrombotic therapy, since they could be less protected by OAC alone. Conversely, this finding raises the mechanistic hypothesis that OAC itself may exert clinically relevant platelet-inhibitory effects by interfering with the generation or activity of thrombin [15]. Therefore, in patients treated with OAC, additional APT beyond the initial period after PCI, while causing a higher risk of bleeding, might not provide any further benefit to adequately protect from ischemic events, and it might be harmful for patients without any vascular disease (Fig. 1).

Fig. 1.

Time-dependent balance between ischemic and bleeding risk after PCI in AF patients receiving OAC.

Observational analyses are inherently vulnerable to confounding by indication, whereby patients receiving APT may have a higher burden of comorbidities or more advanced vascular disease. Although the authors used propensity-based weighting to mitigate this bias, residual confounding cannot be fully excluded. Further, the exclusively Japanese cohort may limit generalizability of the results due to differences in bleeding risk, prescribing patterns, and cardiovascular disease profiles. Moreover, the definition of vascular disease was relatively broad, encompassing heterogeneous clinical conditions, and the indication for APT in patients without vascular disease is not specified.

Beyond its methodological limits and strengths, the study highlights an important clinical reality: APT often coexists with OAC in AF patients long after the original indication has faded. This phenomenon reflects a form of therapeutic inertia, where treatments initiated during an acute phase persist indefinitely without systematic reassessment. Additionally, about 43% of patients treated with OAC + APT pictured in the registry do not have a strict indication for APT because they do not present with vascular diseases, showing an even weaker reason to continue a DAT.

Taken together, the findings from the DIRECT-Extend registry reinforce the growing consensus that, outside specific high ischemic risk conditions, routine combination therapy with OAC plus APT in AF patients may be difficult to justify, while OAC monotherapy is recommended.

In our view, this work highlights the need to actively reassess antithrombotic strategies over time. Rather than asking whether antiplatelet therapy should be added to anticoagulation, clinicians should first ask whether it is still necessary.

The key message may be simple but important: when it comes to antithrombotic therapy in atrial fibrillation, less may indeed be more.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giulia Renda reports a relationship with Bayer AG that includes: funding grants, speaking and lecture fees, and travel reimbursement. Giulia Renda reports a relationship with Bristol-Myers Squibb Company that includes: funding grants. Giulia Renda reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants. Giulia Renda reports a relationship with Daiichi Sankyo Inc that includes: travel reimbursement. Giulia Renda reports a relationship with Menarini France SA that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.