ACS = acute coronary syndrome; AF = atrial fibrillation; BARC= Bleeding Academic Research Consortium; BMS = bare metal stent; CABG = coronary Artery Bypass Graft; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; HBR = high bleeding risk; ISTH = International Society on Thrombosis and Haemostasis; MACCE = major adverse cardiac and cerebrovascular event; MI = myocardial infarction; NACE = net adverse clinical events; OAC = oral anticoagulation therapy; P2Y₁₂I = P2Y₁₂ inhibitors; PCI = percutaneous coronary intervention; SAPT = single antiplatelet therapy; TIMI = Thrombolysis In Myocardial Infarction; VKA = vitamin K antagonists.

3.1. Randomized Trials of Antithrombotic Strategies within One Year after PCI

The WOEST trial [10] (What is the Optimal antiplatElet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing) randomized 573 PCI patients on OAC for AF (69%) or other medical conditions (31%) to receive clopidogrel alone (DAT group) or clopidogrel plus aspirin (TAT group) using an open-label design. The primary outcome of any bleeding episode within one year post-PCI occurred in 19.4% of patients receiving DAT and in 44.4% of those receiving TAT (HR: 0.36; 95% CI: 0.26–0.50; p < 0.0001). DAT was also associated with a lower incidence of the composite secondary endpoint of death, myocardial infarction (MI), stroke, target-vessel revascularization, and stent thrombosis compared to TAT (HR: 0.60; 95% CI: 0.38–0-94; p = 0.025). The ISAR-TRIPLE [18] (Intracoronary Stenting and Antithrombotic Regimen-Testing of a 6-Week Versus a 6-Month Clopidogrel Treatment Regimen in Patients With Concomitant Aspirin and Oral Anticoagulant Therapy Following Drug-Eluting Stenting) trial was designed to evaluate whether reducing the duration of TAT from six months to six weeks by discontinuing clopidogrel in patients receiving concomitant aspirin and OAC after PCI with a drug-eluting stent (DES), improved the net clinical outcome of death, MI, definite stent thrombosis, stroke, or major bleeding at nine months. The trial randomized 614 patients to 6-week TAT versus 6-month TAT and showed no significant difference between the two treatment strategies in terms of the primary net clinical outcome (HR: 1.14; 95% CI: 0.68–1.91; p = 0.63). Similarly, no difference was observed in the key efficacy endpoint of cardiac death, MI, definite stent thrombosis, and ischemic stroke or the key safety endpoint of major bleeding. Starting the DOAC era, the PIONEER-AF PCI [13] (Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention) trial randomized 2124 patients with non-valvular AF undergoing PCI into three groups: rivaroxaban 15 mg once daily plus a P2Y12 inhibitor for 12 months (group 1); rivaroxaban 2.5 mg twice daily plus DAPT for 1, 6, or 12 months (group 2); standard therapy with a VKA plus DAPT for 1, 6, or 12 months (group 3). Rivaroxaban 15 mg or 2.5 mg plus a P2Y12 inhibitor for 12 months was associated with lower rates of clinically significant bleeding (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; HR for group 1 vs. group 3: 0.59, 95% CI: 0.47–0.76, p < 0.001; HR for group 2 vs. group 3: 0.63; 95% CI: 0.50–0.80, p < 0.001) with similar efficacy in terms of major adverse cardiovascular events (6.5% in group 1, 5.6% in group 2, and 6.0% in group 3; p values were not significant for all comparisons). In the RE-DUAL PCI [12] (Randomised Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, 2725 patients with AF-PCI were randomized to receive TAT with warfarin plus clopidogrel or ticagrelor and aspirin for 1–3 months or DAT with clopidogrel or ticagrelor plus dabigatran 110 mg or 150 mg twice daily. The incidence of the primary endpoint (major or clinically relevant non-major bleeding event, defined by the International Society on Thrombosis and Hemostasis (ISTH)) was 15.4% in the DAT group with dabigatran 110 mg compared to 26.9% in the TAT group (HR: 0.52; 95% CI: 0.42–0.63; p < 0.001 for non-inferiority; p < 0.001 for superiority) and 20.2% in the DAT group with dabigatran 150 mg compared to 25.7% in the TAT group (HR: 0.72; 95% CI: 0.58–0.88; p < 0.001 for non-inferiority). In addition, DAT was not inferior to TAT for preventing thromboembolic events (HR: 1.04; 95% CI: 0.84–1.29; p = 0.005 for non-inferiority). The ENTRUST-AF PCI [11] (Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial randomized 1506 AF-PCI patients to DAT with edoxaban 60 mg once daily plus a P2Y12 inhibitor for 12 months or TAT with a VKA for 1–12 months. The edoxaban-based regimen was not inferior to the VKA-based regimen regarding bleeding (HR: 0.83; 95% CI: 0.65–1.05; p = 0.001 for non-inferiority), with no significant differences in ischemic events. In the AUGUSTUS trial [15] (An Open-label, 2-by-2 Factorial, Randomized Controlled Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention), the only DOAC trial with a 2-by-2 factorial design, 4614 patients were randomized to receive apixaban or a VKA plus aspirin or placebo for six months. Major and clinically relevant bleeding events were observed in 10.5% of the patients receiving apixaban compared to 14.7% of those receiving VKA (HR: 0.69; 95% CI: 0.58–0.81; p < 0.001 for non-inferiority and superiority) and in 16.1% of patients receiving aspirin compared to 9.0% of those receiving placebo (HR: 1.89; 95% CI: 1.59–2.24; p < 0.001). Patients on apixaban had a lower incidence of death or hospitalization than those in the VKA group (23.5% vs. 27.4%; HR: 0.83; 95% CI: 0.74–0.93; p = 0.002) and a similar incidence of ischemic events. In summary, the antithrombotic regimen with apixaban without aspirin resulted in less bleeding and fewer hospitalizations, with no significant differences in the incidence of ischemic events, compared with regimens with a VKA, aspirin, or both. In the MASTER DAPT trial [16] (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation with an Abbreviated Versus Standard DAPT Regimen), 4579 patients at HBR were randomized after 1-month DAPT to abbreviated or standard antiplatelet therapy. Randomization was stratified by concomitant OAC indication. In the population with an OAC indication (N = 1666), at one month from PCI, patients changed immediately to single antiplatelet for five months (abbreviated regimen) or continued ≥ 2 months of dual antiplatelet and single antiplatelet (standard regimen). No difference was observed for the co-primary endpoints of net adverse clinical outcomes of death, MI, stroke, or Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding (HR: 0.83; 95% CI: 0.60–1.15); nor were differences observed in the major adverse cardiac and cerebral events (MACCE) of death, MI, or stroke (HR: 0.88; 95% CI: 0.60–1.30), and BARC type 2, 3, or 5 bleeding (HR: 0.83; 95% CI: 0.62–1.12) between abbreviated versus standard antiplatelet regimens in addition to long-term OAC. Of note, in the per-protocol analysis of the trial, including the MASTER DAPT adherent OAC population, discontinuation of single antiplatelet therapy six months after PCI was associated with similar MACCE and lower BARC type 2, 3, or 5 bleeding (HR: 0.47; 95% CI: 0.22–0.99) than single antiplatelet therapy continuation, suggesting the potential benefit of this strategy [22]. Several issues should be considered when interpreting these findings. None of the trials discussed above were powered to draw definitive conclusions about the anti-ischemic efficacy of DAT versus TAT, especially for relatively rare events, such as stent thrombosis ^[7][13][18][7,13,18]. In all DOAC trials, aspirin was not discontinued at the time of PCI; therefore, patients in the DAT groups also received TAT after PCI for variable periods (up to 72 h in PIONEER-AF PCI, 120 h in RE-DUAL PCI, 14 days in AUGUSTUS, and 5 days in ENTRUST-AF PCI). There is also no conclusive evidence on whether aspirin or clopidogrel should be part of the DAT, and data on potent P2Y12 inhibitors are limited ^[4][12][4,12]. Finally, it should be noted that the evidence in high-risk patients, including those undergoing complex PCI or presenting with ACS, is derived from subgroup analyses of randomized trials and remains exploratory. In particular, specific subsets, such as patients with ST-segment elevation MI, were underrepresented in these trials (i.e., less than 10% of the trial populations); therefore, caution should be exercised when extending these results to these patients.

3.2. Randomized Trials of Antithrombotic Strategies beyond One Year after PCI

The OAC-ALONE trial [19] (Optimizing Antithrombotic Care in Patients With AtriaL fibrillatiON and Coronary stEnt) was designed to compare a single-drug strategy of OAC alone with a combination strategy of OAC plus single antiplatelet agent (aspirin or clopidogrel) in patients with AF from one year after stent implantation onwards. The study initially planned to enroll 2000 patients over 12 months but was terminated early after enrolling 696 patients over 38 months. The primary endpoint of all-cause death, MI, stroke, or systemic embolism was observed in 15.7% of patients treated with OAC alone and 13.6% of patients treated with OAC plus a single antiplatelet agent, not achieving the non-inferiority for the ischemic endpoint (HR: 1.16; 95% CI: 0.79–1.72; p = 0.20 for non-inferiority, p = 0.45 for superiority). The key secondary endpoint of all individual ischemic endpoints and ISTH major bleedings occurred in 19.5% of OAC-alone patients and 19.4% of those receiving OAC plus an antiplatelet agent (HR: 0.99; 95% CI: 0.71–1.39; p = 0.016 for non-inferiority, p = 0.96 for superiority). Overall, the trial was underpowered and inconclusive regarding the comparative efficacy and safety of the two strategies. More recently, the AFIRE [20] (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study) trial included 2236 patients with AF and established chronic coronary disease who had undergone PCI (1564 patients, 71.4% of whom with at least one DES) or coronary artery bypass grafting (252 patients, 11.4%) more than one year earlier or were managed medically. Patients were randomized to receive rivaroxaban monotherapy (15 mg daily for patients with a creatinine clearance of ≥50 mL/min, 10 mg daily for those with a creatinine clearance of 15–49 mL/min) or combination therapy with rivaroxaban plus a single antiplatelet agent. Rivaroxaban monotherapy was non-inferior to combination therapy for the primary efficacy endpoint of death, stroke, systemic embolism, MI, or unstable angina requiring revascularization (HR: 0.72; 95% CI: 0.55–0.95; p < 0.001 for non-inferiority) and was superior for the primary safety endpoint of major bleeding (HR: 0.59; 95% CI: 0.39–0.89; p = 0.01 for superiority). In the subgroup analysis by revascularization strategy, the point estimate of the treatment effect for the primary endpoint was numerically in favor of rivaroxaban monotherapy in the PCI subgroup (HR: 0.62, 95% CI: 0.45–0.85) but not in the CABG subgroup (HR: 1.19; 95% CI: 0.67–2.11). The trial was stopped early due to increased mortality with the combination therapy, and its results support current recommendations to discontinue antiplatelet therapy at 12 months after PCI and continue with OAC monotherapy. Of note, the inclusion of only East Asian patients and the Japanese-approved dose of rivaroxaban (10 mg or 15 mg once daily, depending on creatinine clearance) instead of the globally approved daily dose of 20 mg should be considered when interpreting these results.

4. Synthesis of Evidence from Meta-Analyses

Pivotal AF-PCI trials, each with a relatively small sample size distributed across multiple treatment arms, were generally designed to detect superiority for bleeding events and non-inferiority for ischemic events ^{[11][12][13][15]}[11,12,13,15]. However, none had enough statistical power to explore rare events such as stent thrombosis or intracranial bleeding. To this purpose, meta-analyses are useful to enhance statistical power and more accurately determine the clinical impact of multiple antithrombotic treatment strategies on such uncommon events. Given the immense complexity of treatment decisions for AF patients undergoing PCI or with ACS—considering antithrombotic type, duration, and dosage, which could result in hundreds of thousands of possible treatment permutations—it’s unsurprising that numerous articles have been published [23]. Despite only seven randomized trials investigating the impact of DAT or TAT in these patients ^{[10][11][12][13][15][18][24]}[10,11,12,13,15,18,24], over 80 meta-analyses have been published. This abundance of meta-analyses arises because attempts to summarize evidence have been associated with various interpretations of data from the available trials. Specifically, the main differences in results from these meta-analyses are linked to diverse approaches to study inclusion, endpoint selection, timing, and treatment type and dosage. These are summarized in Table 2. In general, all published meta-analyses confirm original findings from individual trials that DAT is associated with a reduction of major or clinically relevant non-major bleeding compared with TAT. Golwala et al., in one of the first studies published in the field, confirmed that DAT, compared with TAT, was associated with a 47% reduction of TIMI (Thrombolysis in Myocardial Infarction) major and minor bleeding, maintaining a substantial equipoise in terms of trial-defined MACE [25]. This meta-analysis published in 2018 lacked the more definitive evidence provided by two additional pivotal AF-PCI trials, AUGUSTUS and ENTRUST-AF-PCI, which were available later. An updated meta-analysis by Gargiulo et al. [26] evaluated the impact of DAT compared to TAT, including all four pivotal AF-PCI trials, and encompassed 10,234 patients. In this study, DAT was associated with a 44% reduction of ISTH major or clinically relevant non-major bleeding and a 46% reduction of ISTH major bleeding [26]. Regarding ischemic endpoints, while prior meta-analyses confirmed no difference between DAT and TAT in terms of MACE, Gargiulo et al. suggested a possible increase of ischemic events in patients assigned to DAT, with a 59% increase in trial-defined stent thrombosis and a borderline increase in MI [26]. This was also confirmed by Andò et al., who found that DAT was associated with a significant 54% increase in stent thrombosis, a 23% increase in MI, a significant increase in cardiovascular mortality without impacting all-cause mortality or study-defined MACE [27]. The signal for higher rates of ischemic events with DAT was primarily driven by an excess of ischemic events in patients assigned to DAT with dabigatran 110 mg. A dedicated analysis of the AUGUSTUS trial also highlighted a possible increase in stent-related events in the first 30 days after the procedure in patients assigned to DAT [28]. This underscores, for the first time, the presence of a possible trade-off between ischemic and bleeding events to be considered in patients assigned to DAT or TAT. Notably, while a bleeding-ischemic event trade-off was observed, overall rates of bleeding events largely surpassed those of ischemic events, reflecting a lower number needed to treat with DAT to obtain a bleeding benefit compared to preventing rarer events such as stent thrombosis or MI. In this context, several elements have been suggested by international guidelines to base treatment decisions in these cases ^[29][30][31][29,30,31]. Clinical presentation has been considered a possible element to highlight a higher ischemic risk population that might benefit from a longer initial treatment with TAT. Therefore, Gargiulo et al. specifically explored the impact of DAT compared to TAT in 10,193 patients with ACS or CCS [32]. They found that irrespective of clinical presentation, DAT was associated with a similar reduction of ISTH major or clinically relevant non-major bleeding in both patients with ACS and CCS, where a reduction of 37% and 32%, respectively, was observed, with negative interaction testing [32]. In both subgroups, there was no difference between DAT and TAT for all-cause death, MACE, or stroke. However, MI and stent thrombosis were numerically higher with DAT versus TAT consistently in ACS and CCS [32].