Strategies for the Management of Atrial Fibrillation in patiEnts Receiving Dialysis 2 (SAFE-D2)

Atrial fibrillation (AF) is common among people receiving maintenance dialysis and is associated with an increased risk of ischemic stroke, systemic embolism, cardiovascular events, and death. Although oral anticoagulation is recommended for many patients with AF in the general population, the benefits and risks of anticoagulation in people receiving dialysis remain uncertain because this population has been excluded from most pivotal randomized trials. Observational studies have reported conflicting findings, and current guideline recommendations differ, resulting in substantial variation in clinical practice.

The Strategies for the Management of Atrial Fibrillation in patiEnts receiving Dialysis 2 (SAFE-D2) trial is designed to address this important evidence gap. The study will evaluate whether a treatment strategy using apixaban is superior to a strategy of no oral anticoagulation for the prevention of ischemic stroke and systemic embolism in adults receiving maintenance hemodialysis or peritoneal dialysis who have non-valvular AF and an elevated risk of stroke.

SAFE-D2 is an investigator-initiated, international, multicenter, pragmatic, randomized, open-label trial with blinded adjudication of study outcomes. Approximately 848 participants will be randomly assigned in a 1:1 ratio to receive either apixaban or no oral anticoagulation, while continuing to receive standard dialysis and other routine medical care.

The trial is designed to determine whether apixaban reduces the risk of ischemic stroke or systemic embolism while evaluating the overall balance between potential benefits and harms. In addition to thromboembolic events, the study will assess mortality, cardiovascular events, bleeding complications, hospitalizations, dialysis vascular access thrombosis, and patient-reported health-related quality of life. An independent Clinical Events Committee, blinded to treatment allocation, will adjudicate all major efficacy and safety outcomes according to prespecified definitions.

SAFE-D2 builds on the feasibility established in the CIHR-funded SAFE-D pilot trial and reflects contemporary clinical practice by evaluating apixaban rather than warfarin. The results are expected to provide high-quality randomized evidence to inform clinical practice guidelines and support shared decision-making regarding stroke prevention in people receiving maintenance dialysis and atrial fibrillation.

Inclusion criteria

To be eligible to participate in this trial, participants need to satisfy ALL these inclusion criteria:

• Age ≥18 years,
• Kidney failure treated with hemodialysis or peritoneal dialysis for at least 90 days,
• A history of non-valvular AF or atrial flutter (AFL) defined as one of the following:

• AF/AFL on an ECG at enrollment.
• ≥2 episodes of AF/AFL on cardiac diagnostics with each episode lasting ≥30 seconds and occurring ≥24 hours apart.
• One episode of AF/AFL on cardiac diagnostics lasting ≥30 seconds, plus ≥1 separate documented episode in the medical record.
• One episode of AF (reported by cardiac diagnostics or documented in the medical record) plus treatment with an oral anticoagulant for stroke prevention as a result of AF/AFL; or
• AF/AFL documented on one occasion in a cardiologist report.
• Meet the CHA2DS2-VASc criteria (i.e. ≥2 for men and ≥3 for women)

Exclusion criteria

Potential participants must have NONE of the following exclusion criteria:

• Mitral stenosis described as moderate or severe.
• Anticoagulation indicated for a reason other than atrial fibrillation.
• Receipt of aspirin at a dose of >160 mg daily.
• Ongoing requirement at screening for a strong CYP3A4/P-gp inhibitor or inducer that cannot be discontinued, substituted, or otherwise managed safely.
• Ongoing requirement for dual antiplatelet therapy at the time of screening that, in the judgement of the treating clinician, is expected to remain necessary after randomization and cannot be safely de-escalated to single antiplatelet therapy in the event of randomization to apixaban.
• Known clinically significant coagulopathy, or other bleeding risk that, in the judgment of the treating physician, renders oral anticoagulation unsafe.
• A major bleeding event in the 30 days prior to study enrollment, or any active and clinically significant bleeding.
• Current pregnancy or breastfeeding.
• Anticipated life expectancy < 6 months.
• A scheduled live donor kidney transplant in the next 6 months.
• Co-enrollment in a clinical trial where the intervention is deemed to interfere with the adherence, safety or efficacy of the SAFE-D2 treatment strategies
• The treating clinical team has determined that long-term OAC is clearly indicated such that randomization to the no OAC strategy would not be clinically acceptable.
• The treating clinical team has determined that long-term OAC is clearly contraindicated such that randomization to the apixaban strategy would not be clinically acceptable.