Results from a phase-IIIb, open-label, multi-center, randomized clinical trial comparing the safety of dual anti-thrombotic therapy (DAT) with triple anti-thrombotic therapy (TAT) for patients with atrial fibrillation who have undergone recent (4 hours – 5 days) percutaneous coronary intervention (PCI), have shown that the DAT regimen (Edoxaban plus a P2Y12 inhibitor) is non-inferior to Vitamin K antagonist(VKA) plus a P2Y12 inhibitor and aspirin or TAT regimen.
The results of the trial were presented at the European Society of Cardiology (ESC) Congress 2019 by Dr. Pascal Vranckx, MD (Hasselt University, Belgium) and simultaneously published in The Lancet. The ENTRUST AF-PCI trial enrolled 1,506 participants ≥18 years of age (26% females) who presented with AF and had undergone successful coronary stenting in the recent past (3 hours to 5 days). Patients were randomized in 1:1 fashion to either receive either edoxaban (NOAC 60 mg-1 oral anti-coagulant) plus clopidogrel (75mg-1 anti-platelet) OR a vitamin K antagonist (VKA-1 oral anti-coagulant) plus dual antiplatelet therapy consisting of clopidogrel (75mg) and aspirin (100mg). The primary outcome was the composite of major or clinically relevant non-major (CRNM) bleeding defined according to the International Society of Thrombosis and Hemostasis (ISTH) between randomization and 12 months post-randomization.
The investigators found that the patients receiving the vitamin-K antagonist based triple therapy had a 3.3% numerically higher rate of major or CRNM bleeding (20.3% for warfarin based triple therapy vs. 17% for edoxaban based dual therapy), which statistically demonstrated non-inferiority for the edoxaban-based dual therapy in terms of the primary end-point [hazard ratio 0·83, with an upper boundary set at 1.20 (95% CI 0·65–1·05; p=0·0010 for non-inferiority; p=0·1154 for superiority)]. Fatal bleeding occurred in one (<1%) patient receiving the edoxaban regimen and seven (1%) patients receiving the VKA regimen. Intracranial bleeding occurred in four (1%; 0·6% per year) and nine (1%; 1·3% per year) patients. Secondary outcome for the trial was the composite of ischemic events (cardiovascular death, myocardial infarction, stroke, systemic embolism, or definite stent thrombosis). In terms of the secondary outcome, the main efficacy outcome occurred in 49 (7%) of 751 patients (annualized event rate 7·3%) receiving the edoxaban regimen compared with 46 (6%) of 755 (annualized event rate 6·9%) patients receiving the VKA regimen (HR for edoxaban 1·06 [95% CI 0·71–1·69, p = not significant], showing no difference in efficacy; though the trial was designed to test the safety and was underpowered to assess efficacy due to small sample size.
This trial is the fourth consecutive randomized clinical trial that has demonstrated the safety of a dual therapeutic regimen consisting of a novel or non-vitamin K oral anti-coagulant (NOAC) and one anti-platelet therapy for patients with AF and PCI in terms of bleeding. The safety of non-Vitamin K oral anti-coagulant (NOAC)-based strategies, using a NOAC plus a P2Y12 inhibitor, has been compared to vitamin K antagonist (VKA)-based triple therapy, in the PIONEER AF-PCI (Rivaroxaban) and REDUAL PCI (Dabigatran) and AUGUSTUS (Apixaban) randomized trials; all three of which have demonstrated that NOAC-based strategies are safer and provide an attractive alternative to VKA-based triple therapy among AF patients who undergo PCI during the first 12 months. ENTRUST-AF PCI stands out from rest in that edoxaban-based double therapy did not prove superior to VKA-based triple therapy in terms of bleeding, unlike the other NOAC-based regimens. The authors of explained this through conducting a posthoc landmark analysis with a landmark in the first 14 days, which revealed that the patients treated with the VKA-based triple therapy had sub-therapeutic international normalized ratios (INR < 2). Edoxaban, on the other hand, exhibits full anticoagulation effect within 2 h of drug intake. This was reflected in the Kaplan-Meier curves as an unexpectedly low event rate (bleeding rate) in the VKA group during the first two weeks. Non-significantly lower bleeding rates were noted for the VKA-based TAT versus the edoxaban-based DAT (HR for edoxaban 2·42 [95% CI 1·27–4·63]) followed by a significant reduction in the rate of the primary bleeding outcome in favor of the edoxaban regimen (HR for edoxaban 0·68 [95% CI 0·53–0·88]. Edoxaban dose (60 mg once daily) has been shown to be both safe and efficacious in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation– Thrombolysis in Myocardial Infarction) trial.
The trial results may be limited due to its open-label study methodology with potential treatment or reporting bias, which might explain why more patients withdrew from the VKA group. However, the authors account for this via monitoring for unreported events and blind adjudication. Further, the median time in therapeutic range for the patients who received VKA was modestly lower than in ENGAGE AF-TIMI 48 but similar to other NOAC AF PCI studies. Therefore, this trial must primarily be viewed as a comparison of clopidogrel-based antiplatelet therapies, which accordant with all previous NOAC AF PCI trials.
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