Duration of triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: A single-center retrospective review

INTRODUCTION

Atrial fibrillation (AF) and acute coronary syndrome (ACS) frequently coexist in clinical practice, given shared risk factors that contribute to both arrhythmias and atherosclerotic cardiovascular disease. AF is the most commonly treated cardiac arrhythmia. According to the Centers of Disease Control and Prevention, its prevalence is expected to increase, with an estimated 12.1 million people diagnosed with AF by 2030.^[1] In addition, approximately 805,000 Americans experience an ACS event annually.^[2] Given the prevalence of both ACS and AF, it is unsurprising that 6.5% of patients admitted for acute myocardial infarction (MI) also have coexisting AF.^[3]

Management of concomitant AF and ACS is complicated by the need for both anticoagulant and antiplatelet therapy. Oral anticoagulation is indicated for most patients with AF for the prevention of cardioembolic stroke. Anticoagulation is most commonly provided with a direct oral anticoagulant (DOAC) or alternatively, warfarin, a vitamin K antagonist (VKA).^[4] Following ACS, especially when treated with PCI, dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor, is required to prevent recurrent MI and stent thrombosis. Current guidelines recommend continuing DAPT for 12 months after ACS in most patients at low risk of bleeding following PCI, with reduced durations as short as 1 month in patients at high bleeding risk. Following this period, single antiplatelet therapy is typically continued lifelong.^[5] For those patients presenting with ACS who also require anticoagulation for AF, TAT is indicated, including an oral anticoagulant, aspirin, and a P2Y12 inhibitor. This strategy significantly increases the risk of bleeding compared to either oral anticoagulation or DAPT alone, requiring careful consideration of both the agents utilized and the duration of each therapy.

Given the high risk of bleeding with TAT therapy, clinicians must consider both bleeding and thrombotic risk when tailoring therapeutic decisions. Several clinical practice guidelines and guidance documents have been recently published regarding the utilization of TAT. In 2021, a North American Consensus Statement was released regarding antithrombotic therapy in patients with AF requiring anticoagulation undergoing PCI. The panel recommended initiating TAT with a DOAC plus DAPT for the duration of the peri-procedural period, defined as the time from PCI to hospital discharge up to 1-week post-PCI. For patients at high thrombotic risk, defined as a history of stent thrombosis or complex PCI, TAT may be extended up to 1 month. Thereafter, aspirin should be discontinued, and the DOAC and P2Y12 inhibitor should be continued for 6–12 months.^[6] Similarly, the 2025 American College of Cardiology (ACC) and American Heart Association (AHA) guidelines for the management of ACS state that patients who require oral anticoagulation should receive TAT for 1–4 weeks, followed by single antiplatelet therapy with a P2Y12 inhibitor, preferably clopidogrel, in combination with an oral anticoagulant.^[5] Finally, the 2023 European Society of Cardiology guidelines for the management of ACS recommend that TAT be continued for up to 1 week for most patients, but as long as 1 month in patients at high thrombotic risk.^[7] Data supporting these recommendations stems from subgroup and secondary analyses of historical randomized controlled trials, which were not powered to detect differences in individual ischemic outcomes. With such variable recommendations regarding optimal duration of TAT, ranging from less than 1 week up to 1 month, further research is necessary to determine the optimal duration. Given this large discrepancy in current guideline recommendations, this study aimed to explore the effect of short TAT duration (7 days or less) versus longer durations on bleeding and ischemic outcomes in patients with AF who experience ACS.

MATERIALS AND METHODS

This study was a single-center, retrospective cohort evaluation conducted at an academic medical center in San Antonio, Texas. The patient population was obtained based on International Classification of Diseases-10 codes for PCI and AF. The initial list was then screened for study inclusion based on an independent chart review. Adult patients admitted to the hospital with AF between July 1, 2020, and January 31, 2023, were screened for study inclusion. Patients were included if they had undergone a PCI with a bare metal stent and/or a drug-eluting stent (DES) within one week and were prescribed TAT. TAT was defined as a DOAC for stroke prevention in paroxysmal, persistent, or permanent AF for at least 1 month, in addition to a P2Y12 inhibitor and aspirin. Diagnosis of AF was verified based on the chart review of the patient’s problem lists. The primary exclusion criteria were evaluated based on chart review and included an indication for long-term anticoagulation other than AF (i.e., pulmonary embolism, deep vein thrombosis, and valvular heart disease), those undergoing coronary artery bypass graft during the index admission, history of hemorrhagic stroke or other conditions known to increase bleeding risk such as hemophilias, Factor V deficiency, von Willebrand disease or history of gastrointestinal bleeding within 1 year, and acute decompensated liver failure. Patients were also excluded if they were prescribed a VKA to align with guideline recommendations to utilize a DOAC in the setting of TAT due to the increased risk of bleeding with a VKA.

Patients were stratified into three groups based on TAT duration following PCI, including <1 week (ultra-short), between 1 week and 1 month (short), and >1 month to1 year (extended). While it was anticipated that the extended group would be small, this definition was selected to reflect guideline recommendations, as TAT therapy beyond 1 month falls outside of current recommendations. Baseline risk was evaluated with the CHA₂DS₂-VASc score for stroke, score for bleeding, and history of ischemic events.

The primary outcome was the composite of International Society of Thrombosis and Hemostasis (ISTH) major or clinically relevant non-major bleeding within 1 year after initiation of TAT. Secondary outcomes included ISTH major bleeding and ISTH clinically relevant non-major bleeding within 1 year. Thrombosis outcomes evaluated were new ischemic events within 1 year, rehospitalization for revascularization within 1 year, and all-cause mortality within 1 year. All outcomes were ascertained via chart review. Antithrombotic regimens after de-escalation of TAT were also collected and compared between groups for exploratory purposes.

RESULTS

Between July 01, 2020, and January 31, 2023, 185 patient charts were screened for inclusion. Of these, 39 patients were included in this study. Reasons for exclusion are shown in Table 1, primarily driven by a lack of PCI during the index admission. Given the lower-than-expected population size, a consecutive sample of all available patients in the study period was included. The ultra-short, short, and extended groups included 10 patients (25.6%), 24 patients (61.5%), and 5 patients (12.8%), respectively. Table 2 describes the baseline characteristics of those included. Overall, about half the subjects were male (56.5%), most were white (84.6%), and the most common ACS event type was non-ST-segment elevation MI (43.6%). All stents were DES, with second-generation DES being the most common stent type placed (71.8%). Clopidogrel and apixaban were the most frequently prescribed P2Y12 inhibitor and DOAC, respectively, with 37 patients (94.9%) receiving clopidogrel and 33 patients (84.6%) receiving apixaban. The median CHA₂DS₂-VASc score for the entire cohort was 4 (interquartile range (IQR) 3–5) and did not differ between groups. There was a significant difference in age between groups. The mean (SD) ages in years for the ultra-short, short, and extended groups were 70.2 (15.3), 74.5 (11.6), and 58 (1.6), respectively (P = 0.0276). The median HAS-BLED score was also significantly different between groups; for the ultra-short, short, and extended groups, the median HAS-BLED score was 2 (IQR 1.8–2.3), 2 (IQR 2–2), and 1 (IQR 1–1.5), respectively (P = 0.0290).

Results of the study are summarized in Table 3. There was no significant difference in the primary outcome, with ISTH major bleeding or clinically relevant non-major bleeding occurring in 1 (10%), 1 (4%), and 1 (20%) in the ultra-short, short, and extended groups, respectively (P = 0.326). One patient in the ultra-short group experienced ISTH major bleeding versus no patients in the short and extended groups (P = 0.385). No patients in the ultra-short group (0%) experienced ISTH clinically relevant non-major bleeding compared to 1 patient in the short group (4%) and 1 patient in the extended group (20%) (P = 0.304). In addition, there were no ischemic events within 1 year of PCI in any of the groups. After being treated with TAT, therapy was de-escalated to a DOAC and P2Y12 inhibitor in 38 of 39 patients, aligning with guideline recommendations. The final patient was transitioned to aspirin monotherapy.

DISCUSSION

In this retrospective cohort study, we examined the duration of TAT in patients with AF diagnosed with ACS who received PCI. This is the first study to evaluate three TAT durations, including <1 week (ultra-short), 1 week–1 month (short), and >1 month–1 year (extended). However, this study had a small sample size due to event rates that were lower than anticipated. No ischemic events occurred in any of the groups. Overall, the number of ISTH major bleeding and clinically relevant non-major bleeding events was low across all groups. These findings should be considered exploratory in nature, given the limited power of the study, but should serve as support for future studies of larger magnitude to investigate the duration of TAT.

DOACs are preferred in most AF patients for the prevention of cardioembolic stroke due to the reduced risk of hemorrhagic stroke, standardized dosing, and lack of need for routine therapeutic drug monitoring. DOACs utilized in this study included apixaban and rivaroxaban. Following ACS, especially with stent placement, ticagrelor and prasugrel are the preferred P2Y12 inhibitors to be added to aspirin for DAPT as they provide a greater reduction in major adverse cardiovascular events and stent thrombosis.^[5] However, this increased efficacy comes with an increase in major bleeding as compared to clopidogrel.^[8,9] Thus, clopidogrel is the preferred P2Y12 inhibitor when TAT is required based on the 2025 ACC/AHA guidelines, aligning with what was seen in our study.^[5] Given that 95% of the patients in this study received clopidogrel, these findings cannot be extrapolated to ticagrelor- or prasugrel-based regimens.

Clinically, it would be expected that shorter durations of TAT may be associated with a higher ischemic risk and a lower bleed risk, whereas longer durations would carry a lower ischemic risk and higher bleed risk. Multiple trials have compared dual antithrombotic therapy to TAT, and dual antithrombotic therapy has been consistently associated with lower bleeding rates.^[10-14] The RE-DUAL PCI and ENTRUST-AF PCI trials compared dual antithrombotic therapy with various DOACs to TAT with warfarin, with TAT ranging from 1 to 12 months.^[12,13] The AUGUSTUS trial compared dual antithrombotic therapy and TAT using apixaban and warfarin in a two-by-two factorial design over 6 months, finding that dual antithrombotic therapy with apixaban and a P2Y12 inhibitor reduced bleeding without increased thrombotic events compared to other strategies.^[14] However, this trial did not investigate shorter durations of TAT. Overall, these studies support the use of dual antithrombotic therapy, finding reduced bleeding without an increase in thrombotic events, but do not provide data regarding optimal duration of TAT in the immediate post-PCI period. At the time of writing, there are no other published trials comparing varying durations of TAT immediately following ACS, assessing both bleeding and ischemic risk. Based on past data as well as the mechanisms of the TAT agents, a reduction in bleeding was expected with shorter durations of TAT. This study found very low rates of ISTH major bleeding and ISTH clinically relevant non-major bleeding in the overall population. The effect of TAT duration on ischemic events was also of interest, with no ischemic events occurring in any group. While these results may seem promising, they should be interpreted with caution due to the risk of type II error with the small sample size of the study.

Overall, the results of this study must be considered within the constraints of the study limitations. As mentioned previously, this exploratory evaluation was not powered to detect differences between groups, and the lack of bleeding and thrombotic events should be seen as hypothesis-generating for future studies. The single-center design may have resulted in missed bleeding or thrombotic events since only events within one health system were evaluated. Bleeding and thrombotic outcomes were determined through chart review, which may have introduced bias compared to independent event adjudication. In addition, the retrospective design may have introduced bias. Potential selection bias is likely, as TAT duration selection was based on prescribers’ clinical decision-making. Notably, there were several differences between groups, including age and HAS-BLED scores, increasing the risk of potential confounding. This likely reflects prescribing practices to limit TAT duration in patients who are older or at high risk of bleeding. Finally, adherence to the antithrombotic therapies was not assessed.

CONCLUSION

This study found bleeding rates were low in patients with AF and concurrent ACS who received PCI prescribed ultra-short, short, or extended duration TAT. In addition, no difference in ischemic events was seen. These findings provide reassurance that shorter durations of TAT may be appropriate, but these findings need to be supported by larger prospective trials to definitively determine optimal duration. In addition, trials investigating specific patient populations, such as those at higher risk of thrombosis, are also needed.