Atrial FibrillationPhase 3SAFE-D2NCT07779746
Strategies for the Management of Atrial Fibrillation in patiEnts Receiving Dialysis 2 (SAFE-D2)
A Phase 3 study testing Eliquis and No oral anticoagulation in people with Atrial Fibrillation and Atrial Flutter, run by Unity Health Toronto.
Trial summary
People receiving dialysis are more likely to develop atrial fibrillation (AF), an irregular heartbeat that increases the risk of stroke. Blood-thinning medications (anticoagulants) are commonly used to prevent strokes in people with AF, but it is not known whether they are beneficial for people receiving dialysis… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Atrial Fibrillation, Atrial Flutter, End Stage Kidney Disease (ESRD)
- What is being tested?
- Eliquis and No oral anticoagulation
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 848 participants
- Where
- No sites listed yet
- Study dates
- Nov 2026to Nov 2032
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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)
Who cannot join
- 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.
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- 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.
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
People receiving dialysis are more likely to develop atrial fibrillation (AF), an irregular heartbeat that increases the risk of stroke. Blood-thinning medications (anticoagulants) are commonly used to prevent strokes in people with AF, but it is not known whether they are beneficial for people receiving dialysis because this group has not been well represented in previous clinical trials. As a result, healthcare providers do not have clear evidence to guide treatment decisions.
The SAFE-D2 study will compare two approaches to preventing stroke in adults receiving maintenance hemodialysis or peritoneal dialysis who have non-valvular AF and are at increased risk of stroke. Participants will be randomly assigned (by chance) to receive either apixaban, an oral blood thinner, or no oral anticoagulant, while continuing to receive their usual dialysis and medical care.
Read more
The main goal of the study is to determine whether apixaban is more effective than no oral anticoagulant at reducing the risk of stroke or blood clots traveling to other parts of the body (systemic embolism). The study will also compare the two approaches with respect to survival, heart-related complications, major bleeding and other bleeding events, hospitalizations, dialysis access complications, quality of life, and the overall balance of benefits and risks.
Approximately 848 participants from Canada, Brazil, and Israel will take part in the study. The results of SAFE-D2 are expected to provide important evidence to help patients, families, and healthcare providers make informed decisions about stroke prevention for people receiving dialysis who have atrial fibrillation.
Read the detailed description
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.
- Being tested
- Eliquis, No oral anticoagulation
- Keywords
- atrial fibrillation, end stage renal disease, end stage kidney disease, dialysis, oral anticoagulation, apixaban, no oral anticoagulation
- Medical subject headings
- Atrial Fibrillation, Atrial Flutter, Kidney Failure, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EliquisDrug
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 anticoagulationOther
No oral anticoagulation
| Study group | Role | What they receive |
|---|---|---|
| Apixiban | Active comparator | 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 Receives: Drug: Eliquis |
| No oral anticoagulation | Active comparator | Individuals in this arm will be exposed to a treatment strategy in which no oral anticoagulation is prescribed. Receives: Other: No oral anticoagulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Stroke or systemic embolism
The primary outcome is time to first confirmed ischemic stroke or systemic embolism.
Measured: 5 years
Secondary outcomes (16)
Time to all-cause death
Measured: 5 years
Time to first occurrence of ischemic stroke, systemic embolism, or all-cause death
Time from randomization to the first occurrence of confirmed ischemic stroke, systemic embolism, or death from any cause.
Measured: 5 years
Time to first occurrence of ischemic stroke, systemic embolism, or cardiovascular death
Time from randomization to the first occurrence of confirmed ischemic stroke, systemic embolism, or cardiovascular death.
Measured: 5 years
Time to first occurrence of ischemic stroke, systemic embolism, myocardial infarction, or all-cause death
Time from randomization to the first occurrence of confirmed ischemic stroke, systemic embolism, myocardial infarction, or death from any cause.
Measured: 5 years
Time to first ischemic stroke
Time from randomization to the first adjudicated ischemic stroke.
Measured: 5 years
Time to first systemic embolism
Time from randomization to the first adjudicated systemic embolism.
Measured: 5 years
Time to cardiovascular death
Measured: 5 years
Time to first myocardial infarction
Measured: 5 years
Net clinical benefit defined as the composite of stroke, systemic embolism, or major bleeding (ISTH definition).
Time to first occurrence of ischemic stroke, systemic embolism, or major bleeding (ISTH definition).
Measured: 5 years
Time to first dialysis vascular access thrombosis
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.
Measured: 5 years
Time to first major bleeding event
Time from randomization to the first major bleeding event meeting International Society on Thrombosis and Haemostasis (ISTH) criteria.
Measured: 5 years
Time to first major or clinically relevant non-major bleeding event
Time from randomization to the first occurrence of major bleeding or clinically relevant non-major bleeding according to ISTH definitions.
Measured: 5 years
Time to first clinically relevant non-major bleeding event
Time from randomization to the first clinically relevant non-major bleeding event according to ISTH criteria.
Measured: 5 years
Time to first intracranial hemorrhage
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.
Measured: 5 years
Time to fatal bleeding
Time from randomization to the first fatal bleeding event.
Measured: 5 years
Number of all-cause unplanned hospitalizations
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.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Aug 2026
- Study startNov 2026 (estimated)
- Primary completionNov 2031 (estimated)
- Study completionNov 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Atrial FibrillationStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 848 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Unity Health Toronto
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR)
- Responsible party
- Principal investigator, Ziv Harel, Unity Health Toronto
- Investigators
- Ziv Harel, MD, Principal investigator, Unity Health Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07779746
- Sponsor's protocol ID
- SAFE-D-02
- Acronym
- SAFE-D2
- Status last verified
- Aug 2026
- First submitted
- 15 Jun 2026
- Last updated
- 21 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes