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.

• Eliquis (Drug): The default starting dose of apixaban is 5 mg twice daily. Dose reduction to 2.5 mg twice daily is mandatory for participants who meet either of the following criteria at baseline or at any point during follow-up: * Age ≥80 years * Dialysis target (dry) weight ≤60 kg
• No oral anticoagulation (Other): No oral anticoagulation

Primary outcomes

• Stroke or systemic embolism [5 years]: The primary outcome is time to first confirmed ischemic stroke or systemic embolism.

Secondary outcomes

• Time to all-cause death [5 years]
• Time to first occurrence of ischemic stroke, systemic embolism, or all-cause death [5 years]: Time from randomization to the first occurrence of confirmed ischemic stroke, systemic embolism, or death from any cause.
• Time to first occurrence of ischemic stroke, systemic embolism, or cardiovascular death [5 years]: Time from randomization to the first occurrence of confirmed ischemic stroke, systemic embolism, or cardiovascular death.
• Time to first occurrence of ischemic stroke, systemic embolism, myocardial infarction, or all-cause death [5 years]: Time from randomization to the first occurrence of confirmed ischemic stroke, systemic embolism, myocardial infarction, or death from any cause.
• Time to first ischemic stroke [5 years]: Time from randomization to the first adjudicated ischemic stroke.
• Time to first systemic embolism [5 years]: Time from randomization to the first adjudicated systemic embolism.
• Time to cardiovascular death [5 years]
• Time to first myocardial infarction [5 years]
• Net clinical benefit defined as the composite of stroke, systemic embolism, or major bleeding (ISTH definition). [5 years]: Time to first occurrence of ischemic stroke, systemic embolism, or major bleeding (ISTH definition).
• Time to first dialysis vascular access thrombosis [5 years]: Time from randomization to the first clinically adjudicated thrombosis of an arteriovenous fistula or graft requiring surgical or endovascular intervention, such as thrombectomy or angioplasty, or resulting in permanent access loss.
• Time to first major bleeding event [5 years]: Time from randomization to the first major bleeding event meeting International Society on Thrombosis and Haemostasis (ISTH) criteria.
• Time to first major or clinically relevant non-major bleeding event [5 years]: Time from randomization to the first occurrence of major bleeding or clinically relevant non-major bleeding according to ISTH definitions.
• Time to first clinically relevant non-major bleeding event [5 years]: Time from randomization to the first clinically relevant non-major bleeding event according to ISTH criteria.
• Time to first intracranial hemorrhage [5 years]: Time from randomization to the first adjudicated intracranial hemorrhage, including intracerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma, or other primary intracranial hemorrhage confirmed by neuroimaging or autopsy.
• Time to fatal bleeding [5 years]: Time from randomization to the first fatal bleeding event.
• Number of all-cause unplanned hospitalizations [5 years]: Total number of all-cause unplanned hospitalizations occurring during study follow-up, including recurrent hospitalizations. An all-cause unplanned hospitalization is defined as any non-elective admission to an acute care hospital lasting ≥24 hours, regardless of cause. Elective or planned admissions or procedures, routine day procedures or outpatient visits not requiring overnight admission, protocol-mandated assessments, routine health evaluations, and admissions solely for social, administrative, or logistical reasons are excluded. Transfers between hospital units or facilities as part of the same episode of care are considered a single hospitalization.

Sex: All, ages: 18 Years to any

Inclusion criteria

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

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

   1. AF/AFL on an ECG at enrollment.
   2. ≥2 episodes of AF/AFL on cardiac diagnostics with each episode lasting ≥30 seconds and occurring ≥24 hours apart.
   3. One episode of AF/AFL on cardiac diagnostics lasting ≥30 seconds, plus ≥1 separate documented episode in the medical record.
   4. 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
   5. AF/AFL documented on one occasion in a cardiologist report.
4. 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:

1. Mitral stenosis described as moderate or severe.
2. Anticoagulation indicated for a reason other than atrial fibrillation.
3. Receipt of aspirin at a dose of >160 mg daily.
4. Ongoing requirement at screening for a strong CYP3A4/P-gp inhibitor or inducer that cannot be discontinued, substituted, or otherwise managed safely.
5. 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.
6. Known clinically significant coagulopathy, or other bleeding risk that, in the judgment of the treating physician, renders oral anticoagulation unsafe.
7. A major bleeding event in the 30 days prior to study enrollment, or any active and clinically significant bleeding.
8. Current pregnancy or breastfeeding.
9. Anticipated life expectancy < 6 months.
10. A scheduled live donor kidney transplant in the next 6 months.
11. 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
12. 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.
13. 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.

• Ziv Harel, MD, Principal investigator, Unity Health Toronto