Anticoagulant and Antiplatelet Therapy in Stented Patients with Atrial Fibrillation Combining Oral Anticoagulants With Platelet Inhibitors in Patients With Atrial Fibrillation and Coronary Disease

In an article published in the Journal of the American College of Cardiology, authored by Caroline Sindet-Pederson, MSc, and colleagues in the Department of Cardiology at Copenhagen University Hospital Herlev and Gentofte in Hellerup, Denmark, evaluating a real-world population of AF patients with MI and/or after PCI, the use of direct oral anticoagulants (DOAC) as compared to VKA reduced the risk of bleeding in patients also taking dual antiplatelet therapy (DAPT).

AF patients experiencing an MI or undergoing a PCI are concomitantly treated with an antiplatelet, such as aspirin, clopidogrel or both, because of an increased risk of coronary vascular events. Dual or triple antithrombotic therapy may be effective in reducing the risk of thromboembolic events, but the risk of bleeding inherent to treatment has been shown to increase with combinations of antiplatelets and oral anticoagulants. Therefore, the optimal treatment strategy when combining antiplatelets with oral anticoagulants in patients with atrial fibrillation (AF) and myocardial infarction (MI) or undergoing percutaneous coronary intervention (PCI) is unknown. In the light of this, the authors conducted an observational study to investigate the risk of bleeding, ischemic stroke, MI, and all-cause mortality associated with direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in combination with aspirin, clopidogrel, or both in patients with AF following MI and/or PCI.

To ascertain the risks of adverse events for patients with atrial fibrillation (AF) and myocardial infarction (MI) or percutaneous coronary intervention (PCI) taking an anticoagulant in addition to antiplatelet therapy, Danish nationwide registries were used to identify patients with AF who were admitted with a MI and/or underwent PCI, between August 2011 and June 2017, treated with OAC in combination with antiplatelet(s). Patients were followed for 12 months or until an outcome, study end, or death. Standardized absolute risks were estimated on the basis of outcome-specific Cox regression models adjusted for potential confounders. Average treatment effects were obtained as standardized absolute risk differences (ARD) in risks at 3 and 12 months of follow up.

The 3,222 individuals included in the study population were assigned to one of four treatment regimens: VKA with single antiplatelet therapy (SAPT), DOAC and SAPT, VKA and DAPT or DOAC and DAPT. Of the patients included in the study population, 27% received vitamin K antagonist (VKA) plus a single antiplatelet, 18% were treated with a direct oral anticoagulant (DOAC) plus single antiplatelet, 22% received VKA plus dual antiplatelet therapy (DAPT), and 22% received DOAC plus DAPT. At 3 months, there was a lower risk of MI in DOAC vs. VKA plus single antiplatelet (absolute risk difference, -1.53%; 95% confidence interval [CI], -3.08% to -0.11%). No difference was found for bleeding, ischemic stroke, and all-cause mortality. In adjusted models, there was a trend towards a lower risk of MI for DOAC vs. VKA treated in addition to single antiplatelet therapy (adjusted hazard ratio [aHR], 0.63; 95% confidence interval [CI], 0.40-1.00). At 3 months, the risk of bleeding was lower for DOAC vs. VKA plus DAPT (absolute risk difference, -1.96%; 95% CI, -3.46% to -0.88%). There was no difference in the risk of all-cause mortality, stroke, or MI. For patients with DAPT, use of DOAC was associated with a reduced risk of bleeding (aHR, 0.51; 95% CI, 0.33-0.78) with similar risks of ischemic stroke, MI, and all-cause mortality.

“Our data suggest that despite the lack of trial evidence on the safety and effectiveness of DOAC versus VKA in combination with antiplatelets, DOACs seem safe and effective in real-world AFib patients following MI or PCI,” noted Sindet-Pederson et al. Within the limitations of a nonrandomized, retrospective study, they demonstrated overall safety of DOAC therapy as compared to VKA for patients with AF who are also treated with antiplatelet therapy for MI and/or PCI. It was notable that bleeding risk was reduced for DOAC plus DAPT, while MI risk was reduced for DOAC plus single antiplatelet therapy. Prior randomized trials had focused on the question of single vs. DAPT for AF and PCI patients, but had primarily used VKA anticoagulation. This study suggested that DOAC therapy may be beneficial in select populations, especially those at increased risk for bleeding who require DAPT following PCI in addition to an oral anticoagulant for AF. However, in an accompanying editor’s note, Dr. C. Michael Gibson of Beth Israel Deaconess Medical Center in Boston, Massachusetts echoed a cautionary note. “Although Sindet-Peterson et al.  were able to confirm the increased bleeding risk associated with VKA-based triple therapy, a conclusion supported by prior registries and 2 RCTs, the analyses among DOAC and VKA–based dual therapies, which lack external validation from RCTs, should be interpreted with caution. These limitations re-enforce the need for randomized data from large-scale national/international registries with unselected patients to combine the strengths of randomized trials with the generalizability of registries.”

While the study validated in a real-world population the observations from the randomized PIONEER AF-PCI and REDUAL-PCI trials: a DOAC-based strategy was superior to a VKA-based strategy in the reduction of bleeding events, this result should be ‘interpreted with caution,’ he and his two co-authors stated. “First, because there was a censoring period of 7 days following hospital discharge, this analysis did not capture the in-hospital or early bleeding events during the highest-risk period following the PCI, and may have selectively cultivated out those patients who tolerated triple therapy. Second, the bleeding rate was significantly lower in the DOAC+DAPT group compared with the DOAC+ single antiplatelet therapy group. This discrepancy is biologically implausible if the 2 groups were similar and points to potential unidentified confounders as playing a role in bleeding rates.”