Percutaneous coronary intervention (PCI) is increasingly used for the treatment of chronic and acute coronary artery disease, driven by its minimally invasive nature and rapid post-procedural recovery. The placement of metal-based stents has become the cornerstone of treating significant coronary artery stenosis, based on a superior efficacy profile compared to plain-balloon angioplasty and improved outcomes across consecutive generations of drug-eluting stents, particularly in terms of thrombotic and restenosis events.1
However, PCI with the use of drug-eluting stents is associated with several potential early and long-term complications. Target-vessel revascularisations and future acute coronary syndromes, along with stent thrombosis, stand as the most harmful thrombotic events. However, the antiplatelet regimens needed to decrease the risk of thrombotic events elevate the risk of bleeding and haemorrhagic events.
AF is the most common cardiac arrhythmia, and its prevalence increases with age and concomitant cardiovascular disease. Therefore, coronary disease and PCI are intimately linked to the management of AF. Approximately one in nine patients undergoing PCI exhibits concomitant AF, and this proportion is expected to rise substantially given population ageing and the increase in life expectancy for patients with coronary disease.2
Oral anticoagulants (OACs) have been used for decades to diminish the risk of stroke among patients with AF. Over the past decade, direct OACs (DOACs) have largely replaced vitamin K antagonist (VKA) agents, given their better safety profile; they are associated with at least a non-inferior performance in terms of efficacy.3
However, in the setting of PCI, the concomitant use of antiplatelet therapy substantially increases bleeding risk in patients receiving OAC, which has been a major reason for treatment discontinuation and has stimulated interest in alternative stroke-prevention strategies, such as left atrial appendage occlusion. Moreover, it has been well established that the risk of bleeding events increases proportionally to the number of antithrombotic therapies used, including both OACs and antiplatelets.
To mitigate this risk, tailored antithrombotic regimens are required for AF patients with an indication for oral anticoagulation undergoing PCI.
First, discontinuation of OAC during dual antiplatelet therapy (DAPT) after PCI was considered. However, patients who discontinued OAC owing to AF experienced a significant increased risk of stroke, ultimately reducing their quality of life and functional prognosis.4
Therefore, recent research has primarily focused on evaluating different antiplatelet combinations and treatment durations in conjunction with OACs, rather than on strategies to discontinue them on a temporary or permanent basis.
Studies: Antithrombotic Regimens
The main randomised trials that have evaluated antithrombotic regimes in AF patients undergoing PCI are summarised in Table 1.
The first published trial was WOEST, in which dual antithrombotic therapy with clopidogrel and an OAC (mainly VKA as DOACs were not widely available during the study period) resulted in a lower rate of bleeding events than triple therapy (VKA + acetyl salicylic acid + clopidogrel) without significant differences in efficacy events including target-vessel revascularisation and stent thrombosis.5
The ISAR-TRIPLE trial compared triple therapy for 6 weeks versus 6 months after PCI, and failed to show significant differences in a combined endpoint encompassing both bleeding and thrombotic events.6
Each DOAC has been evaluated in a randomised trial in AF patients undergoing PCI. Overall, these studies were designed for a primary endpoint that included exclusively clinically relevant bleeding without thrombotic events. Moreover, the intervention strategies were mainly based on dual antithrombotic therapies with DOAC and P2Y12 inhibitors and the control strategies were mainly based on VKA anticoagulants and triple therapy regimens for at least 1 month after PCI. Therefore, the combination of a higher number of antithrombotics and the use of VKA over DOAC clearly penalised those in the control groups.7–10
In the AFIRE trial, it was clearly established that prolonging dual antithrombotic therapies beyond 12 months after PCI in patients with AF resulted in no clinical benefit, but there was potential harm in terms of bleeding events.11 Hence, single antithrombotic regimens with OACs are robustly recommended after the first year.
However, several controversies remained, such as whether triple therapy for a short period of time is needed when DOACs are used over VKA, and the optimal duration of dual antithrombotic therapy during the first year before full antiplatelet discontinuation.
OPTIMA-AF
Early results of the OPTIMA-AF trial were presented at the 2025 American Heart Association (AHA) Scientific Sessions.12,13 This was a prospective, investigator-initiated, randomised, hybrid non-inferiority-superiority Japanese trial that evaluated, in patients with AF undergoing PCI, two strategies of dual antithrombotic therapy (DAT) with DOAC and a P2Y12 inhibitor over 1 month versus 12 months. Patients presenting with MI were excluded, although unstable angina patients were admitted. The primary efficacy endpoint was a composite of death and thromboembolic events, whereas the primary safety endpoint encompassed any major or clinically relevant bleeding. Non-inferiority was assessed for the primary efficacy endpoint and, if achieved, superiority for the primary safety endpoint was studied. Finally, if the latter was also achieved, superiority for the primary efficacy endpoint was also evaluated.
There were 1,079 patients included in the final analysis, 542 for the 1-month and 537 for the 12-month DAT strategies, respectively. Mean ages were 75.4 ± 8.1 and 74.9 ± 8.8 years for the 1- and 12-month DAT groups, and close to 80% of the study population were men. Cardiovascular comorbidities were well-balanced between study groups.
The main indication for PCI was chronic coronary syndrome (~94%), intravascular imaging was used for guidance in >99% of patients and the PCI was categorised as complex in approximately 23% of the population in both study groups.
At discharge, edoxaban was the most frequently prescribed DOAC (approximately 47% in each group), followed by apixaban (26%) and rivaroxaban (23%). Regarding antiplatelet therapies, prasugrel (37.5 mg daily) was used in ~51% of cases and clopidogrel (75 mg daily) in 48% approximately.
The first hypothesis of non-inferiority for the efficacy endpoint was met at 12 months’ follow-up, with an incidence of 5.4% for the 1-month DAT group and 4.5% for the 12-month group (HR 1.2; 95% CI [0.7–2.07]; p=0.002 for non-inferiority). The second hypothesis of superiority for the combined endpoint was achieved, with 12-month rates of any major or clinically relevant bleeding of 9.5% and 4.8% for the 12- and 1-month DAT groups, respectively (HR 0.5; 95% CI [0.31–0.8]; p=0.004 for superiority). Notably, those differences were mainly based on the reduction in clinically relevant non-major bleeding (5.4% versus 2.5%; HR 0.27; 95% CI [0.12–0.59]) rather than major bleeding (4.3% versus 3.5%; HR 0.82; 95% CI [0.44–1.5]) events. Finally, superiority for the primary efficacy endpoint was not met (p=0.597).
Overall, the study demonstrated lower bleeding rates for the 1-month DAT strategy without a significant trade-off in terms of thrombotic events. However, certain aspects merit careful consideration.
Event Rates and Statistical Power
Event rates for both efficacy and safety endpoints were substantially lower than anticipated.
The sample size for the first hypothesis was based on an expected rate of 10% for the efficacy endpoint, and the non-inferiority margin was set at 5% in terms of absolute risk difference. Consequently, the final ~5% rate of death or thromboembolic events facilitated the attainment of the non-inferiority margin.
Similarly, the bleeding events rate was expected to be 25% for the 12-month DAT group, differing significantly from the 9.5% event rate ultimately observed. Nevertheless, the nearly 50% reduction with the shorter DAT strategy demonstrated the superiority of the first strategy. Bleeding events declined markedly over time in the intervention arms of the major AF-PCI trials (Figure 1).
Clinical Presentation
Around 95% of cases presented with stable angina, with a minority of unstable angina presentations (5%), whereas any type of MI was excluded per protocol. This is in contrast to the main DOAC and PCI trials, where acute coronary syndromes represented close to 50% of the included population.
Thrombotic risk is well known to be higher in the setting of MI and during the subsequent months, driven by the associated pro-inflammatory and pro-thrombotic cascades.
Therefore, the results of the present study cannot be extrapolated to such clinical contexts, where the complete avoidance of any triple therapy along with shortened DAT regimens could lead to greater risks of coronary stent thrombosis and cerebrovascular embolisms.
Intravascular Imaging
Despite growing evidence demonstrating the clinical benefits of intravascular imaging guidance during PCI, its overall use in clinical practice in Europe remains relatively low.14
In the OPTIMA-AF trial, intravascular guidance was mandatory and may have contributed to the low rates of further coronary events observed at 12 months’ follow-up (0.4% for spontaneous MI and 0.2% for stent thrombosis) despite the substantial proportion of complex PCI procedures included in the trial (23%). Hence, caution is warranted when extrapolating those findings to contemporary clinical practice, especially in centres with little experience in intravascular imaging.
Use of Prasugrel
The use of novel P2Y12 inhibitors (prasugrel and ticagrelor) in combination with OAC is rare in western countries, in accordance with the recommendations of clinical practice guidelines.15
In contrast, prasugrel was the main antiplatelet agent used in the OPTIMA-AF study, administered at a reduced dosage tailored to the characteristics of East Asian populations (3.75 mg instead of the 10 mg indicated in Europe), who are more susceptible to bleeding under antiplatelet treatment. Whether there were differences in bleeding outcomes between patients receiving prasugrel or clopidogrel within the OPTIMA-AF trial remains unknown. Although allocation to prasugrel or clopidogrel lacked randomisation, the relatively balanced use of both therapies might allow exploratory sub-analysis.
Conclusion
The OPTIMA-AF trial has demonstrated that, in a cohort of AF patients undergoing PCI for stable angina, the use of short 1-month DAT strategy with DOAC and one P2Y12 inhibitor (clopidogrel or prasugrel) resulted in fewer bleeding events overall, without any significant trade-off in terms of death or thromboembolic events. However, this approach cannot be extrapolated to patients presenting with any kind of MI.