A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study

Abstract

Background: Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known.

Methods: From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA.

Results: Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHA₂DS₂-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex] score, 4.5; baseline characteristics balanced between groups): 48 to apixaban and 49 to VKA. The median follow-up time was 429 days (range, 37 to 1370) versus 506 days (range, 101 to 1379), respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio, 0.93 [95% CI, 0.53-1.65]; P_{noninferiority}=0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA (P=0.51; log rank). There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% versus 24.5%; major bleeding, 10.4% versus 12.2%; and myocardial infarction, 4.2% versus 6.1%, respectively).

Conclusions: In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT02933697.

Keywords: atrial fibrillation; randomized controlled trial; renal dialysis; stroke.

Figure 1.

Outline of the AXADIA–AFNET 8 study according to the CONSORT guideline. The included patients and their allocation to the 2 treatment arms are shown in accordance with the CONSORT (Consolidated Standards of Reporting Trials) criteria. AXADIA–AFNET 8 indicates Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease; FU, follow-up; INR, international normalized ratio; and TE, thromboembolism.

Figure 2.

Cumulative incidence of the composite primary safety and efficacy outcome. A, Cumulative incidence (inverse Kaplan-Meier) for the primary composite safety outcome (major bleeding, clinically relevant nonmajor bleeding, or all-cause death) in the intention-to-treat population. According to the null hypothesis, the 1-sided noninferiority P value P_{noninferiority} is given. B, Cumulative incidence for the primary composite efficacy outcome (myocardial infarction, ischemic stroke, all-cause death, cardiovascular death, and deep vein thrombosis [DVT] or pulmonary embolism [PE]) is shown and compared with a 2-sided log-rank test. C and D, The same results for the on-treatment analysis.