Trial to Evaluate Anticoagulation Therapy in Hemodialysis Patients With Atrial Fibrillation (RENAL-AF)

RENal Hemodialysis Patients ALlocated Apixaban Versus Warfarin in Atrial Fibrillation (RENAL-AF) Randomized Clinical Trial

This is a prospective, randomized, open-label, blinded end-point evaluation trial. The patient population consists of patients on hemodialysis who have atrial fibrillation (AF) and end-stage renal disease (ESRD) .

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation; End Stage Renal Disease
• Intervention / Treatment: Drug: apixaban; Drug: warfarin

Detailed Description

This is a multicenter study in adult patients with AF and ESRD who are on hemodialysis and who have stroke risk factors making them candidates for oral anticoagulation. Patients will be randomized to apixaban versus warfarin, and will be treated for up to 15 months.

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Huntsville, Alabama, United States, 35805
      • Nephrology Consultants
  • California
    • Fresno, California, United States, 93720
      • The Medical Research Group, Inc.
    • Long Beach, California, United States, 90806
      • DaVita Clinical Trials, LLC
    • Long Beach, California, United States, 90806
      • Southland Renal Medical Group
    • Northridge, California, United States, 91324
      • Valley Renal Medical Group Research
    • Roseville, California, United States, 95661
      • Summit Nephrology Medical Group, Inc.
    • San Jose, California, United States, 95126
      • Satellite Healthcare
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Nephrology Associates
  • Florida
    • Coral Springs, Florida, United States, 33071
      • South Florida Nephrology Group PA, Research Division
    • Miami, Florida, United States, 33144
      • Nuren Medical and Research Center
    • Miami, Florida, United States, 33126
      • LG. Diagnostic, Inc. & Cosmetic Center
    • Miami, Florida, United States, 33165
      • Medical Professional Clinical Research Center
  • Idaho
    • Meridian, Idaho, United States, 83642
      • Boise Kidney and Hypertension Institute
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Crystal Lake, Illinois, United States, 60014
      • NANI Research
    • River Forest, Illinois, United States, 60305
      • NANI Research
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • NANI Research
  • Louisiana
    • Shreveport, Louisiana, United States, 71101
      • Northwest Louisiana Nephrology
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Anne Arundel Medical Center
    • Baltimore, Maryland, United States, 21224
      • The Johns Hopkins University
    • Takoma Park, Maryland, United States, 20912
      • Washington Nephrology Associates
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Plymouth, Massachusetts, United States, 02360
      • South Shore Nephrology
    • Springfield, Massachusetts, United States, 01107
      • Renal and Transplant Associates of New England
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Paragon Health Neprhology Centre
    • Port Huron, Michigan, United States, 48060
      • St. Clair Nephrology
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Brookhaven, Mississippi, United States, 39601
      • Southwest Mississippi Nephrology, PLLC
    • Gulfport, Mississippi, United States, 39501
      • Southern Clinical Research Group, LLC
    • Tupelo, Mississippi, United States, 38801
      • Nephrology & Hypertension Associates
  • Missouri
    • Saint Louis, Missouri, United States, 63136
      • Polack Renal, LLC
  • Nevada
    • Reno, Nevada, United States, 89511
      • Sierra Nevada Nephrology Consultants
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Renal Medicine Associates
  • New York
    • Poughkeepsie, New York, United States, 12601
      • Advanced Kidney Care of Hudson Valley
  • North Carolina
    • Durham, North Carolina, United States, 27704
      • Durham Nephrology Associates
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
    • Kinston, North Carolina, United States, 28504
      • Eastern Nephrology Associates, PLLC.
    • New Bern, North Carolina, United States, 28562
      • Eastern Nephrology Associates, PLLC
  • Ohio
    • Columbus, Ohio, United States, 43215
      • HNC Dialysis, Ltd.
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Northeast Clinical Research Ctr
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Health - Milton S. Hershey Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • Columbia Nephrology Associates
    • Orangeburg, South Carolina, United States, 29118
      • South Carolina Nephrology and Hypertension
    • Sumter, South Carolina, United States, 29150
      • Sumter Medical Specialists
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Regional Health Clinical Research
  • Tennessee
    • Knoxville, Tennessee, United States, 37923
      • Knoxville Kidney Center
  • Texas
    • Houston, Texas, United States, 77099
      • Southwest Houston Research, Ltd.
    • Lubbock, Texas, United States, 79416
      • Lubbock Vascular Access Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Virginia
    • Alexandria, Virginia, United States, 22304
      • Washington Nephrology Associates
    • Charlottesville, Virginia, United States, 22908
      • University of Virgina Health System
    • Newport News, Virginia, United States, 23606
      • TPMG Clinical Research
    • Roanoke, Virginia, United States, 24014
      • Valley Nephrology Associates
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington
  • West Virginia
    • Bluefield, West Virginia, United States, 24701
      • Nephrology and Hypertension Associates
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University
  • Wisconsin
    • Wausau, Wisconsin, United States, 54401
      • Aspirius Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females, age at least 18 years, or the local age of consent, whichever is greater.
• Patients with AF defined as AF on ECG at enrollment or two or more reports of AF from separate monitoring events at least 2 weeks apart (report of ECG, Holter monitor, event monitor or implantable loop recorder).
• CHA2DS2-VASc score of ≥ 2.
• End-stage renal disease treated with hemodialysis for ≥ 3 months.
• Considered by the treating physician(s) to be candidate for oral anticoagulation.
• If of childbearing potential, be willing to avoid pregnancy during the study.

Exclusion Criteria:

• Not considered by the treating physician(s) to be candidates for oral anticoagulation (for example, hemoglobin < 8.5g/dL, history of intracranial hemorrhage, active bleeding, recent gastrointestinal bleed or retroperitoneal bleed, severe hepatic impairment, or anaphylactic reaction to apixaban)
• Moderate or severe mitral stenosis
• Conditions other than AF that require anticoagulation such as mechanical prosthetic valve, deep venous thrombosis, or pulmonary embolism
• Need for aspirin at a dose > 81 mg a day or need for P2Y12 antagonist therapy (for example clopidogrel, prasugrel, or ticagrelor)
• Life expectancy < 3 months
• Anticipated kidney transplant within the next 3 months
• Prisoners or others who are involuntarily incarcerated or detained
• Pregnant, breastfeeding, or considering pregnancy.
• Participation in a clinical trial of an experimental treatment within the past 30 days

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: apixaban; apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients)	Drug: apixaban; oral anticoagulant; Other Names: Eliquis
Experimental: warfarin; warfarin daily dose adjusted to target International Normalized Ration(INR) of 2-3	Drug: warfarin; oral anticoagulant; Other Names: Coumadin; Jantoven

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing ISTH (International Society on Thrombosis and Haemostasis) Major or Clinically Relevant Non-major Bleeding	Assess the safety of apixaban versus warfarin regarding ISTH major bleeding or clinically relevant non-major bleeding events in patients with NVAF (nonvalvular atrial fibrillation) and ESRD (end-stage renal disease) on hemodialysis. Major bleeding event is defined as:Acute clinically overt bleeding (including access site related bleeding) accompanied by 1 or more of the following: Decrease in Hgb of 2g/dL or more with overt bleeding; Transfusion of 2 or more units of packed RBCs in the setting of an overt bleeding event; Bleeding within a critical site. Hemorrhagic stroke (primary or infarction with hemorrhagic conversion) were classified as major bleeds. Non-major bleeding event is defined as: Acute or sub-acute clinically overt bleeding (including access site related bleeding) that does not meet criteria for major bleeding & results in Hospital admission for bleeding, physician guided medical or surgical treatment for bleeding, or change in antithrombotic therapy	Randomization up to Month 15/Final Visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Stroke or Systemic Embolism	Number of participants experiencing adjudicated stroke or systemic embolism.	Randomization up to Month 15/Final Visit
Number of Participants Experiencing Mortality	Evaluate mortality rates for those participants randomized to warfarin and apixaban in patients with NVAF and ESRD on hemodialysis	Randomization up to Month 15/Final Visit
Persistence of Therapy	Evaluate days between time from initiation to discontinuation of randomized therapy.	Randomization up to Month 15/Final Visit
Apixaban Plasma Concentration, Cmax	Evaluate the pharmacokinetics of apixaban in ESRD NVAF patients on hemodialysis. The measurement was done from 0-12 hours after the dose was given on Day 1.	0-12 hours post-dose
Apixaban Plasma Concentration, Cmin	Evaluate the pharmacokinetics of apixaban in ESRD NVAF patients on hemodialysis. The measurement was done from 0-12 hours after the dose was given on Day 1.	0-12 hours post-dose
Area Under the Plasma Apixaban Concentration Curve From 0 to 12 Hours After Dose (AUCO-12)	Evaluate the pharmacokinetics of apixaban in ESRD NVAF patients on hemodialysis. The measurement was done from 0 to 12 hours after dose was given on Day 1.	0-12 hours post-dose
Apixaban Pharmacodynamics, Chromogenic Factor Xa Assay	Evaluate the pharmacodynamics of apixaban in ESRD NVAF patients on hemodialysis	Baseline: Day 3, 4, or 5; Day 28
Adherence to Treatment With Apixaban or With Warfarin	Measured by self-reported days of medication compliance over the last 30 days.	Month 15/Final Visit

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Systemic Embolism	Adjudicated diagnosis of systemic arterial embolism (Non-pulmonary, non-cranial events) will require a positive clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), which is supported by evidence of embolism/thrombosis from surgical specimens, autopsy, angiography, vascular imaging, or other objective testing. Clinical presentation would include: Abrupt development of pain, absent pulses, pallor, and/or paresis in an extremity (at least an entire digit) without previous severe claudication or findings of severe peripheral vascular disease.; Renal embolism will be diagnosed when sudden flank pain or a change in renal laboratory findings occurred.; Abdominal vascular/visceral embolism was considered definite if acute abdominal symptoms or referred symptoms developed along with a change in abdominal examination or appropriate laboratory values.	Randomization up to Month 15/Final Visit
Number of Participants Experiencing Stroke	Adjudcated stroke defined as a new, non-traumatic episode of focal or global neurological dysfunction of sudden onset caused by central nervous system (CNS) vascular injury as a result of hemorrhage or infarction and not due to a readily identifiable non-vascular cause (i.e. brain tumor). CNS includes brain, spinal cord and retina. The required duration of the deficit is ≥ 24 hours.; Events with neurologic deficit lasting for < 24 hours and an imaging modality showing evidence of an acute stroke will be counted as stroke as well.; A retinal ischemic event (embolism, infarction) will be considered a stroke	Randomization up to Month 15/Final Visit
Number of Participants Experiencing Stroke, Systemic Embolism, Major Bleeding or All-cause Mortality	Evaluate those experiencing stroke, systemic embolism, ISTH major bleeding, or all-cause mortality for those randomized to warfarin and apixaban in patients with NVAF and ESRD on hemodialysis Definitions of stroke and systemic embolism are provided under the measurement description of the secondary outcomes for each individual event. Definition of major bleed is provided in outcome measurement description of the primary outcome measure.	Randomization up to Month 15/Final Visit
Baseline Biomarkers	Analysis of outcomes and treatment effect according to levels of cardiovascular biomarkers at baseline	Baseline

Collaborators and Investigators

• Sponsor: Christopher Granger, MD
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Christopher Granger, MD, Duke University

Publications and helpful links

General Publications

• Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27.
• Granger CB, Chertow GM. A pint of sweat will save a gallon of blood: a call for randomized trials of anticoagulation in end-stage renal disease. Circulation. 2014 Mar 18;129(11):1190-2. doi: 10.1161/CIRCULATIONAHA.113.007549. Epub 2014 Jan 22. No abstract available.
• Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, Granger CB, Hanna M, Held C, Husted S, Hylek EM, Jansky P, Lopes RD, Ruzyllo W, Thomas L, Wallentin L. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014 Jul 21;35(28):1864-72. doi: 10.1093/eurheartj/ehu046. Epub 2014 Feb 20.
• Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, Eckardt KU, Kasiske BL, McCullough PA, Passman RS, DeLoach SS, Pun PH, Ritz E. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011 Sep;80(6):572-86. doi: 10.1038/ki.2011.223. Epub 2011 Jul 13.
• Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007 Jun 19;146(12):857-67. doi: 10.7326/0003-4819-146-12-200706190-00007.
• Nigwekar SU, Bhan I, Turchin A, Skentzos SC, Hajhosseiny R, Steele D, Nazarian RM, Wenger J, Parikh S, Karumanchi A, Thadhani R. Statin use and calcific uremic arteriolopathy: a matched case-control study. Am J Nephrol. 2013;37(4):325-32. doi: 10.1159/000348806. Epub 2013 Mar 21.
• Shah M, Avgil Tsadok M, Jackevicius CA, Essebag V, Eisenberg MJ, Rahme E, Humphries KH, Tu JV, Behlouli H, Guo H, Pilote L. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation. 2014 Mar 18;129(11):1196-203. doi: 10.1161/CIRCULATIONAHA.113.004777. Epub 2014 Jan 22.
• Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011 Mar 3;364(9):806-17. doi: 10.1056/NEJMoa1007432. Epub 2011 Feb 10.
• Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med. 1990 Dec;9(12):1447-54. doi: 10.1002/sim.4780091208.
• Wizemann V, Tong L, Satayathum S, Disney A, Akiba T, Fissell RB, Kerr PG, Young EW, Robinson BM. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int. 2010 Jun;77(12):1098-106. doi: 10.1038/ki.2009.477. Epub 2010 Jan 6.
• Olesen JB, Lip GY, Kamper AL, Hommel K, Kober L, Lane DA, Lindhardsen J, Gislason GH, Torp-Pedersen C. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012 Aug 16;367(7):625-35. doi: 10.1056/NEJMoa1105594. Erratum In: N Engl J Med. 2012 Dec 6;367(23):2262.
• Yang F, Chou D, Schweitzer P, Hanon S. Warfarin in haemodialysis patients with atrial fibrillation: what benefit? Europace. 2010 Dec;12(12):1666-72. doi: 10.1093/europace/euq387. Epub 2010 Nov 2.
• Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol. 2009 Oct;20(10):2223-33. doi: 10.1681/ASN.2009030319. Epub 2009 Aug 27.
• Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation. 2015 Mar 17;131(11):972-9. doi: 10.1161/CIRCULATIONAHA.114.014113. Epub 2015 Jan 16.
• Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol. 2011 Nov;6(11):2599-604. doi: 10.2215/CJN.02400311. Epub 2011 Sep 8.
• Reinecke H, Brand E, Mesters R, Schabitz WR, Fisher M, Pavenstadt H, Breithardt G. Dilemmas in the management of atrial fibrillation in chronic kidney disease. J Am Soc Nephrol. 2009 Apr;20(4):705-11. doi: 10.1681/ASN.2007111207. Epub 2008 Dec 17.
• Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol. 2011 Nov;6(11):2662-8. doi: 10.2215/CJN.04550511. Epub 2011 Sep 29.
• Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, Keltai M, Lanas F, Lopes RD, Lopez-Sendon J, Granger CB, Wallentin L. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012 Nov;33(22):2821-30. doi: 10.1093/eurheartj/ehs274. Epub 2012 Aug 29. Erratum In: Eur Heart J. 2020 Jun 7;41(22):2069.
• Elliott MJ, Zimmerman D, Holden RM. Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates. Am J Kidney Dis. 2007 Sep;50(3):433-40. doi: 10.1053/j.ajkd.2007.06.017.
• Wu JR, DeWalt DA, Baker DW, Schillinger D, Ruo B, Bibbins-Domingo K, Macabasco-O'Connell A, Holmes GM, Broucksou KA, Erman B, Hawk V, Cene CW, Jones CD, Pignone M. A single-item self-report medication adherence question predicts hospitalisation and death in patients with heart failure. J Clin Nurs. 2014 Sep;23(17-18):2554-64. doi: 10.1111/jocn.12471. Epub 2013 Dec 20.
• Gonzalez JS, Schneider HE, Wexler DJ, Psaros C, Delahanty LM, Cagliero E, Safren SA. Validity of medication adherence self-reports in adults with type 2 diabetes. Diabetes Care. 2013 Apr;36(4):831-7. doi: 10.2337/dc12-0410. Epub 2012 Nov 30.
• Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011 Oct;32(19):2387-94. doi: 10.1093/eurheartj/ehr342. Epub 2011 Aug 28.

Helpful Links

• United States Renal Data System Web Site

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): July 27, 2019
• Study Completion (Actual): August 12, 2019

Study Registration Dates

• First Submitted: April 14, 2016
• First Submitted That Met QC Criteria: October 20, 2016
• First Posted (Estimate): October 24, 2016

Study Record Updates

• Last Update Posted (Actual): December 29, 2020
• Last Update Submitted That Met QC Criteria: December 2, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Renal dialysis
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Arrhythmias, Cardiac; Renal Insufficiency, Chronic; 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: Pro00068545

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO