Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study

Abstract

Introduction: Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis.

Methods and analysis: A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5 mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017.

Ethics and dissemination: The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598 f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals.

Trial registration numbers: NCT02933697,Pre-results.

Keywords: anticoagulation; arial fibrillation; cardiovascular morbidity; cardiovascular mortality; hemodialysis.

Conflict of interest statement

Competing interests: HR has received speaker honoraria from BMS, MedUpdate, NephroUpdate, and Pfizer. He has acted as a consultant for BMS, Pfizer and Pluristem receiving in part also financial compensations for this work. He has received research grants from the German Federal Ministry for Education and Research (BMBF). His division within the University Hospital of Muenster has taken or is still taking part in multicentre trials of BARD, Bayer, BIOTRONIK, and Pluristem receiving patient fees and financial compensation for these efforts. PK has received grants and non-financial support from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research and from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies. He is listed as inventor on two patents held by the University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). During preparation of this trial, GB has received speaker honoraria from BMS and Pfizer, he has been a member of the Scientific Advisory Boards for BMS and Pfizer, and Bayer Health Care. During his chairmanship of the Atrial Fibrillation NETwork, this institution has received funding for investigator-initiated trials from various companies (for details, please consult http://www.kompetenznetz-vorhofflimmern.de/en/research). RB has received consulting / lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. CW does not report conflicts of interest in respect to the present work. Outside this area of research he has received speaker honoraria from Amgen, Boehringer-Ingelheim, Genzyme-Sanofi and Shire.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Patients’ enrolment and allocation in accordance to the Consolidated Standards of Reporting Trials (CONSORT) stand is displayed. Of note, two stratifications are implemented in the randomisation procedure: first, for patients who suffered from a previous stroke or systemic thromboembolic (TE) event which must have occurred at least 3 months before enrolment without residual limitations (only value of 0 or 1 on the modified Rankin scale). Second, for patients who were already assigned to an oral anticoagulation whose proportion will be limited to 50% of the entire study cohort. INR, international normalised ratio.

Figure 2

Timelines and regular visits during the study period are presented. After screening visit, two qualifying ECGs showing atrial fibrillation must be sent to a central appraisal and, if all other inclusion and exclusion criteria match, randomisation and inclusion can be performed within 7 days. Afterwards, monthly visits during the regular dialysis sessions will have to be documented. When the last recruited patient has been on treatment for 6 months, the study will be terminated (end of treatment). All patients will be followed up for another 30 days after which the study will be completed (end of study).

Figure 3

The design of a pharmacokinetic (PK) substudy is given here. In total, 28 patients who must give additional written informed consent will be examined regarding their apixaban levels before and after dialysis. Of these, apixaban levels will be assessed in 14 patients after the 3-day-long dialysis-free interval, and in another 14 patients after the short 2-day dialysis-free interval. Since patients on haemodialysis are regularly treated in two shifts (AM and PM), the 14 patients will be splitted again and apixaban levels will be assessed in 7 patients of the AM shift and another 7 patients of the PM shift. This might be of interest since patients will be instructed to take their apixaban between 07:00 to 08:00 AM and PM, independent from the start of their dialysis shifts, so plasma levels may vary between the groups.