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

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

The prevention of atrial fibrillation related thromboembolism in the dialysis population is unclear. While the practice of anticoagulation appears favorable in patients with mild-to-moderate chronic kidney disease, no patients with severe chronic kidney disease (estimated glomerular filtration rate <25 ml/min), and specifically those receiving dialysis, have been included in randomized trials.Moreover, the effect of anticoagulation in the dialysis population may fundamentally differ from those studied in clinical trials. Accordingly, characterization of the optimal management strategy to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation receiving dialysis is a priority. The overall goal of this pilot trial is to evaluate the feasibility of conducting a randomized controlled trial comparing anticoagulation strategies in patients with atrial fibrillation receiving dialysis (either hemodialysis or peritoneal dialysis).

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation; End Stage Renal Failure on Dialysis
• Intervention / Treatment: Drug: Warfarin; Drug: Apixaban; Other: No oral anticoagulation

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Sydney, Australia
    • St. George Hospital
  • New South Wales
    • Kingswood, New South Wales, Australia, 2747
      • Nepean Hospital
    • Randwick, New South Wales, Australia, 2031
      • Prince of Wales Hospital
    • Saint Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
• Canada
  • British Columbia
    • Surrey, British Columbia, Canada, V3V 0C6
      • Surrey Memorial Hospital
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2V 3M3
      • Seven Oaks General Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Nova Scotia Health Authority, QEII Health Sciences Centre
  • Ontario
    • Barrie, Ontario, Canada, L4M 6M2
      • Royal Victoria Regional Health Centre
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston Health Sciences Centre - Kingston General Hospital
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
    • Oakville, Ontario, Canada, L6M 0L8
      • Halton Healthcare - Oakville Trafalgar Memorial Hospital
    • Oshawa, Ontario, Canada, L1G 2B9
      • Lakeridge Health Oshawa
    • Ottawa, Ontario, Canada
      • The Ottawa Hospital - Riverside Campus
    • Sudbury, Ontario, Canada, P3E 5J1
      • Health Sciences North
    • Thunder Bay, Ontario, Canada, P7B 6V4
      • Thunder Bay Regional Health Sciences Centre
    • Toronto, Ontario, Canada, M4G 3E8
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • Unity Health Toronto, at its St. Michael's Hospital site
    • Toronto, Ontario, Canada, M6K3S2
      • University Health Network - Toronto General Hospital
    • Toronto, Ontario, Canada, M6R 1B5
      • St. Joseph's Health Centre Toronto
  • Quebec
    • Montreal, Quebec, Canada, H8S 4K4
      • McGill University Health Centre
    • Montréal, Quebec, Canada, H2X 3E4
      • Centre Hospitalier de l'Université de Montréal
    • Montréal, Quebec, Canada, H4J 1C5
      • Hôpital du Sacré-Coeur de Montreal
    • Montréal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montréal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
    • Quebec City, Quebec, Canada, G1R 2J6
      • CHU de Québec - Université Laval
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4P 0W5
      • Regina General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years.
2. Receiving maintenance hemodialysis or peritoneal dialysis for > 90 days.

3. History of AF or atrial flutter as defined by:

   (i) AF or atrial flutter on a 12 lead ECG at enrollment, and not due to a reversible cause, or (ii) AF or atrial flutter documented on two separate occasions, not due to a reversible cause, at least 1 day apart prior to enrollment. AF or atrial flutter may be documented by ECG, or as an episode lasting at least 30 seconds on a rhythm strip or Holter recording, or more than 30 minutes if using pacemaker or implantable cardioverter defibrillator (ICD) recordings, or (iii) AF or atrial flutter documented on one occasion, not due to a reversible cause, prior to enrollment and being treated with an oral anticoagulant for AF or atrial flutter at enrollment. [AF or atrial flutter may be documented by ECG, or as an episode lasting at least 30 seconds on a rhythm strip or Holter recording, or more than 30 minutes if using pacemaker or implantable cardioverter defibrillator (ICD) recordings, or mentioned in the medical record], or (iv) AF or atrial flutter documented on one occasion on ECG, not due to a reversible cause, prior to enrollment and at least one more episode of AF or atrial flutter mentioned in the medical record, or (v) AF or atrial flutter documented on one occasion in a cardiologist report, not due to a reversible condition, prior to enrollment.

4. Satisfying CHADS-65 criteria: i) Age ≥65 or ii) Age <65 and one of: hypertension, diabetes mellitus, congestive heart failure, stroke/transient ischemic attack or peripheral embolism.

Exclusion Criteria:

1. Moderate or severe mitral stenosis.
2. Conditions other than non-valvular atrial fibrillation that require oral anticoagulation, such as mechanical prosthetic valve, deep venous thrombosis, or pulmonary embolism.
3. Need for aspirin at a dose > 165 mg a day, or need for aspirin in combination with P2Y12 antagonist therapy.
4. Need for an interacting drug which precludes the safe use of apixaban.
5. Life expectancy < 6 months.
6. Scheduled live-donor kidney transplant in the next 6 months.
7. A woman who is pregnant or breastfeeding or unwilling to pursue methods of contraception if < 12 months since the last menstrual period.
8. Co-enrollment in a clinical trial where the intervention is deemed to interfere with the adherence, safety or efficacy of the intervention provided herein.
9. Patient's attending physician(s) (e.g., nephrologist and/or cardiologist and/or neurologist) believes that oral anticoagulation is absolutely mandated.
10. Patient's attending physician(s) (e.g., nephrologist and/or cardiologist and/or neurologist) believes that oral anticoagulation is absolutely contraindicated.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Warfarin; Individuals randomized to this arm will be exposed to dose-adjusted daily warfarin targeting an international normalized ratio (INR) of 2.0-3.0.	Drug: Warfarin; Individuals randomized to this arm will be exposed to dose-adjusted daily warfarin targeting an international normalized ratio (INR) of 2.0-3.0.; Other Names: Coumadin
Active Comparator: Apixaban; Individuals randomized to this arm will receive apixaban 5 mg twice daily (a reduced dose of 2.5 mg twice daily will be given to selected participants).	Drug: Apixaban; Individuals randomized to this arm will receive apixaban 5 mg twice daily (a reduced dose of 2.5 mg twice daily will be given to selected participants).; Other Names: Eliquis
Active Comparator: No oral anticoagulation; Individuals in this arm will be exposed to a treatment strategy in which no oral anticoagulation is prescribed.	Other: No oral anticoagulation; No oral anticoagulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Recruitment of the target population within 2 years	2 years from start of trial
At least 80% of randomized participants remain in the trial and on the allocated study treatment at the end of the 26-week study period.	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients randomized to warfarin achieving a Time in the Therapeutic Range (TTR) >65%.		26 weeks
>95% of randomized patients adhere to the enrollment criteria with respect to atrial fibrillation or atrial flutter	Through adjudication of ECGs or other cardiac diagnostics	End of trial
Major bleeding	As defined by the International Society of Thrombosis and Haemostasis (ISTH)	26 weeks
Clinically relevant non-major bleeding	As defined by the International Society of Thrombosis and Haemostasis (ISTH)	26 weeks
Stroke and systemic embolism		26 weeks
All cause mortality		26 weeks
Non-fatal myocardial infarction		26 weeks
Vascular events not related to dialysis access		26 weeks
Events of special interest related to dialysis access, the dialysis procedure or the oral anticoagulants	Thrombosis of fistula or graft; fistula or graft abandonment; thrombosis of dialysis catheter; red blood cell transfusions; calciphylaxis	26 weeks

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: Canadian Institutes of Health Research (CIHR); The George Institute for Global Health (Sydney, Australia)
• Investigators: Principal Investigator: Ziv Harel, Unity Health Toronto; Principal Investigator: Ron Wald, Unity Health Toronto

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2019
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: June 12, 2019
• First Submitted That Met QC Criteria: June 12, 2019
• First Posted (Actual): June 17, 2019

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 19, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Disease Attributes; Renal Insufficiency; Arrhythmias, Cardiac; Renal Insufficiency, Chronic; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Atrial Fibrillation; Kidney Failure, Chronic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban; Warfarin
• Other Study ID Numbers: SAFE-D-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No