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 (NOACs) have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of NOACs in patients on hemodialysis is not well known. Methods: From June 2017 until May 2022, the investigator-initiated, prospective, randomized, open, blinded outcome assessment 'A Safety Study Assessing Oral Anticoagulation with ApiXAban versus Vitamin K-Antagonists in Patients with Atrial Fibrillation and End-Stage Kidney Disease on Chronic HemoDIAlysis Treatment' (AXADIA) trial randomized patients with AF on chronic hemodialysis to either apixaban 2.5 mg bid or the vitamin K antagonist (VKA) phenprocoumon (INR 2.0-3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically-relevant non-major bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis and/or pulmonary embolism. Our hypothesis was that apixaban is non-inferior to VKA. Results: Thirty-nine sites randomized 97 patients (30% women, mean age 75 years, mean CHA2DS2-VASc score 4.5, baseline characteristics balanced between groups), 48 to apixaban and 49 to VKA. The median follow-up time was 429 (range 37-1,370) vs. 506 (range 101-1,379) days, 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 (45.8%) patients on apixaban and in 25 (51.0%) patients on VKA (HR 0.93, 95% CI 0.53-1.65, p(noninferiority)=0.157). Composite primary efficacy outcome events occurred in 10 (20.8%) patients on apixaban and in 15 (30.6%) patients on VKA (p=0.51, log rank). There were no significant differences regarding individual outcomes (all-cause mortality 18.8% vs. 24.5%; major bleedings 10.4% vs. 12.2%; myocardial infarctions 4.2% vs. 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. Clinical Trial Registration: EudraCT No. 2015-005503-84, NCT02933697

Pharmacology and Clinical Development of Factor XI Inhibitors

“…74 Still, evidence is accruing on the use of direct factor Xa inhibitors in patients with severe chronic kidney disease or on dialysis. 75,76 Two phase 2 randomized trials of IONIS-FXI Rx and xisomab 3G3 have been conducted and completed (Table 4). IONIS-FXI Rx is a promising compound for the ESRD population because of its predictable pharmacokinetics and no evidence of drug accumulation.…”

“…74 Still, evidence is accruing on the use of direct factor Xa inhibitors in patients with severe chronic kidney disease or on dialysis. 75,76…”

Vorhofflimmern und Antikoagulation bei Niereninsuffizienz

“…Diese letztere Beobachtung ließ sich einerseits auf eine erhöhte Quote intrakranieller Blutungen und hämorrhagischer Schlaganfälle zurückführen, weist aber andererseits gleichwohl auf den weiter oben schon einmal dargestellten Umstand hin, dass es keinerlei kontrollierte Studiendaten gibt, aufgrund derer eine Reduktion des Schlaganfallrisikos bei Dialysepatient*innen mit Vorhofflimmern durch Antikoagulation als zweifelsfrei gesichert betrachtet werden kann. Die AXADIA-Studie randomisierte schließlich 97 Dialysepatient*innen (Apixaban-Arm mit 2 × 2,5 mg), wobei es im Vergleich der beiden Gruppen zu keinen signifikanten Unterschieden hinsichtlich der Wirksamkeits-und Sicherheitsendpunkte kam, was aber u. U. an "Underpowerment" lag (numerisch Apixaban vs. VKA: Schlaganfälle: 20,8 vs. 30,6 %; Blutungen: 10,4 vs. 12,2 %) [30]. Die RE-NAL-AF-Studie randomisierte 154 Dialysepatient*innen mit Vorhofflimmern zu Apixaban (2 × 5 mg, bzw.…”

Left atrial appendage occlusion in patients suffering from advanced chronic kidney disease (stage 4 and 5). Long‐term follow‐up

“…14 Recently, two trials have not reported positive results comparing apixaban versus warfarin for dialysis patients. 15,16 Left atrial appendage occlusion (LAAO) has emerged as a nonpharmacological alternative to prevent thromboembolic events in nonvalvular AF patients. 17,18 Around 90% of left atrial thrombi are located in the left atrium appendage, 19,20 this is even higher in CKD patients, due to its influence on the prothrombotic state.…”

“…In fact, it has been demonstrated that benefits from some therapies cannot be extrapolated from non‐CKD to CKD cohorts, such as statins in CKD stage 5 14 . Recently, two trials have not reported positive results comparing apixaban versus warfarin for dialysis patients 15,16 …”