Trial to Evaluate Anticoagulation Therapy in Hemodialysis Patients With Atrial Fibrillation

Atrial Fibrillation Clinical Trial

— RENAL-AF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02942407
• Other study ID #: Pro00068545
• Status: Completed
• Phase: Phase 4
• Start date: December 2016
• Est. completion date: August 12, 2019

Study information

• Verified date: December 2020
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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) .

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 154
• Est. completion date: August 12, 2019
• Est. primary completion date: July 27, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• End Stage Renal Disease
• Kidney Failure, Chronic

Intervention

Drug:
• apixaban
oral anticoagulant
• warfarin
oral anticoagulant

Locations

Country	Name	City	State
United States	Renal Medicine Associates	Albuquerque	New Mexico
United States	Washington Nephrology Associates	Alexandria	Virginia
United States	Anne Arundel Medical Center	Annapolis	Maryland
United States	The Johns Hopkins University	Baltimore	Maryland
United States	Northeast Clinical Research Ctr	Bethlehem	Pennsylvania
United States	Nephrology and Hypertension Associates	Bluefield	West Virginia
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Southwest Mississippi Nephrology, PLLC	Brookhaven	Mississippi
United States	University of Virgina Health System	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Columbia Nephrology Associates	Columbia	South Carolina
United States	HNC Dialysis, Ltd.	Columbus	Ohio
United States	South Florida Nephrology Group PA, Research Division	Coral Springs	Florida
United States	NANI Research	Crystal Lake	Illinois
United States	Durham Nephrology Associates	Durham	North Carolina
United States	NANI Research	Fort Wayne	Indiana
United States	The Medical Research Group, Inc.	Fresno	California
United States	East Carolina University	Greenville	North Carolina
United States	Southern Clinical Research Group, LLC	Gulfport	Mississippi
United States	Penn State Health - Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Southwest Houston Research, Ltd.	Houston	Texas
United States	Nephrology Consultants	Huntsville	Alabama
United States	Paragon Health Neprhology Centre	Kalamazoo	Michigan
United States	Eastern Nephrology Associates, PLLC.	Kinston	North Carolina
United States	Knoxville Kidney Center	Knoxville	Tennessee
United States	DaVita Clinical Trials, LLC	Long Beach	California
United States	Southland Renal Medical Group	Long Beach	California
United States	Lubbock Vascular Access Center	Lubbock	Texas
United States	Boise Kidney and Hypertension Institute	Meridian	Idaho
United States	LG. Diagnostic, Inc. & Cosmetic Center	Miami	Florida
United States	Medical Professional Clinical Research Center	Miami	Florida
United States	Nuren Medical and Research Center	Miami	Florida
United States	West Virginia University	Morgantown	West Virginia
United States	Eastern Nephrology Associates, PLLC	New Bern	North Carolina
United States	TPMG Clinical Research	Newport News	Virginia
United States	Valley Renal Medical Group Research	Northridge	California
United States	South Carolina Nephrology and Hypertension	Orangeburg	South Carolina
United States	South Shore Nephrology	Plymouth	Massachusetts
United States	St. Clair Nephrology	Port Huron	Michigan
United States	Advanced Kidney Care of Hudson Valley	Poughkeepsie	New York
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Regional Health Clinical Research	Rapid City	South Dakota
United States	Sierra Nevada Nephrology Consultants	Reno	Nevada
United States	NANI Research	River Forest	Illinois
United States	Valley Nephrology Associates	Roanoke	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	Summit Nephrology Medical Group, Inc.	Roseville	California
United States	Polack Renal, LLC	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Satellite Healthcare	San Jose	California
United States	University of Washington	Seattle	Washington
United States	Northwest Louisiana Nephrology	Shreveport	Louisiana
United States	Renal and Transplant Associates of New England	Springfield	Massachusetts
United States	Sumter Medical Specialists	Sumter	South Carolina
United States	Washington Nephrology Associates	Takoma Park	Maryland
United States	Nephrology & Hypertension Associates	Tupelo	Mississippi
United States	Washington Nephrology Associates	Washington	District of Columbia
United States	Aspirius Research Institute	Wausau	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
Christopher Granger, MD	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

References & Publications (22)

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Herzog CA, Asinger RW, Berger AK, Charytan DM, Díez 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. — View Citation

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. — View Citation

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. — View Citation

Olesen JB, Lip GY, Kamper AL, Hommel K, Køber 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. — View Citation

Reinecke H, Brand E, Mesters R, Schäbitz WR, Fisher M, Pavenstädt 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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	Baseline Biomarkers	Analysis of outcomes and treatment effect according to levels of cardiovascular biomarkers at baseline	Baseline
Primary	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	Number of Participants Experiencing Stroke or Systemic Embolism	Number of participants experiencing adjudicated stroke or systemic embolism.	Randomization up to Month 15/Final Visit
Secondary	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
Secondary	Persistence of Therapy	Evaluate days between time from initiation to discontinuation of randomized therapy.	Randomization up to Month 15/Final Visit
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   United States Renal Data System Web Site