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

Sponsor
Christopher Granger, MD (Other)
Overall Status
Completed
CT.gov ID
NCT02942407
Collaborator
Bristol-Myers Squibb (Industry)
154
Enrollment
58
Locations
2
Arms
32.3
Actual Duration (Months)
2.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief 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) .

Condition or Disease Intervention/Treatment Phase
Phase 4

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 Design

Study Type:
Interventional
Actual Enrollment :
154 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
RENal Hemodialysis Patients ALlocated Apixaban Versus Warfarin in Atrial Fibrillation (RENAL-AF) Randomized Clinical Trial
Actual Study Start Date :
Dec 1, 2016
Actual Primary Completion Date :
Jul 27, 2019
Actual Study Completion Date :
Aug 12, 2019

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Experiencing ISTH (International Society on Thrombosis and Haemostasis) Major or Clinically Relevant Non-major Bleeding [Randomization up to Month 15/Final Visit]

      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

    Secondary Outcome Measures

    1. Number of Participants Experiencing Stroke or Systemic Embolism [Randomization up to Month 15/Final Visit]

      Number of participants experiencing adjudicated stroke or systemic embolism.

    2. Number of Participants Experiencing Mortality [Randomization up to Month 15/Final Visit]

      Evaluate mortality rates for those participants randomized to warfarin and apixaban in patients with NVAF and ESRD on hemodialysis

    3. Persistence of Therapy [Randomization up to Month 15/Final Visit]

      Evaluate days between time from initiation to discontinuation of randomized therapy.

    4. Apixaban Plasma Concentration, Cmax [0-12 hours post-dose]

      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.

    5. Apixaban Plasma Concentration, Cmin [0-12 hours post-dose]

      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.

    6. Area Under the Plasma Apixaban Concentration Curve From 0 to 12 Hours After Dose (AUCO-12) [0-12 hours post-dose]

      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.

    7. Apixaban Pharmacodynamics, Chromogenic Factor Xa Assay [Baseline: Day 3, 4, or 5; Day 28]

      Evaluate the pharmacodynamics of apixaban in ESRD NVAF patients on hemodialysis

    8. Adherence to Treatment With Apixaban or With Warfarin [Month 15/Final Visit]

      Measured by self-reported days of medication compliance over the last 30 days.

    Other Outcome Measures

    1. Number of Participants Experiencing Systemic Embolism [Randomization up to Month 15/Final Visit]

      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.

    2. Number of Participants Experiencing Stroke [Randomization up to Month 15/Final Visit]

      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

    3. Number of Participants Experiencing Stroke, Systemic Embolism, Major Bleeding or All-cause Mortality [Randomization up to Month 15/Final Visit]

      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.

    4. Baseline Biomarkers [Baseline]

      Analysis of outcomes and treatment effect according to levels of cardiovascular biomarkers at baseline

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Nephrology Consultants Huntsville Alabama United States 35805
    2 The Medical Research Group, Inc. Fresno California United States 93720
    3 DaVita Clinical Trials, LLC Long Beach California United States 90806
    4 Southland Renal Medical Group Long Beach California United States 90806
    5 Valley Renal Medical Group Research Northridge California United States 91324
    6 Summit Nephrology Medical Group, Inc. Roseville California United States 95661
    7 Satellite Healthcare San Jose California United States 95126
    8 Washington Nephrology Associates Washington District of Columbia United States 20010
    9 South Florida Nephrology Group PA, Research Division Coral Springs Florida United States 33071
    10 LG. Diagnostic, Inc. & Cosmetic Center Miami Florida United States 33126
    11 Nuren Medical and Research Center Miami Florida United States 33144
    12 Medical Professional Clinical Research Center Miami Florida United States 33165
    13 Boise Kidney and Hypertension Institute Meridian Idaho United States 83642
    14 Northwestern University Chicago Illinois United States 60611
    15 NANI Research Crystal Lake Illinois United States 60014
    16 NANI Research River Forest Illinois United States 60305
    17 NANI Research Fort Wayne Indiana United States 46804
    18 Northwest Louisiana Nephrology Shreveport Louisiana United States 71101
    19 Anne Arundel Medical Center Annapolis Maryland United States 21401
    20 The Johns Hopkins University Baltimore Maryland United States 21224
    21 Washington Nephrology Associates Takoma Park Maryland United States 20912
    22 Massachusetts General Hospital Boston Massachusetts United States 02114
    23 South Shore Nephrology Plymouth Massachusetts United States 02360
    24 Renal and Transplant Associates of New England Springfield Massachusetts United States 01107
    25 Paragon Health Neprhology Centre Kalamazoo Michigan United States 49007
    26 St. Clair Nephrology Port Huron Michigan United States 48060
    27 Mayo Clinic Rochester Minnesota United States 55905
    28 Southwest Mississippi Nephrology, PLLC Brookhaven Mississippi United States 39601
    29 Southern Clinical Research Group, LLC Gulfport Mississippi United States 39501
    30 Nephrology & Hypertension Associates Tupelo Mississippi United States 38801
    31 Polack Renal, LLC Saint Louis Missouri United States 63136
    32 Sierra Nevada Nephrology Consultants Reno Nevada United States 89511
    33 Renal Medicine Associates Albuquerque New Mexico United States 87109
    34 Advanced Kidney Care of Hudson Valley Poughkeepsie New York United States 12601
    35 Durham Nephrology Associates Durham North Carolina United States 27704
    36 East Carolina University Greenville North Carolina United States 27834
    37 Eastern Nephrology Associates, PLLC. Kinston North Carolina United States 28504
    38 Eastern Nephrology Associates, PLLC New Bern North Carolina United States 28562
    39 HNC Dialysis, Ltd. Columbus Ohio United States 43215
    40 Northeast Clinical Research Ctr Bethlehem Pennsylvania United States 18017
    41 Penn State Health - Milton S. Hershey Medical Center Hershey Pennsylvania United States 17033
    42 Rhode Island Hospital Providence Rhode Island United States 02903
    43 Columbia Nephrology Associates Columbia South Carolina United States 29203
    44 South Carolina Nephrology and Hypertension Orangeburg South Carolina United States 29118
    45 Sumter Medical Specialists Sumter South Carolina United States 29150
    46 Regional Health Clinical Research Rapid City South Dakota United States 57701
    47 Knoxville Kidney Center Knoxville Tennessee United States 37923
    48 Southwest Houston Research, Ltd. Houston Texas United States 77099
    49 Lubbock Vascular Access Center Lubbock Texas United States 79416
    50 University of Utah Salt Lake City Utah United States 84112
    51 Washington Nephrology Associates Alexandria Virginia United States 22304
    52 University of Virgina Health System Charlottesville Virginia United States 22908
    53 TPMG Clinical Research Newport News Virginia United States 23606
    54 Valley Nephrology Associates Roanoke Virginia United States 24014
    55 University of Washington Seattle Washington United States 98104
    56 Nephrology and Hypertension Associates Bluefield West Virginia United States 24701
    57 West Virginia University Morgantown West Virginia United States 26506
    58 Aspirius Research Institute Wausau Wisconsin United States 54401

    Sponsors and Collaborators

    • Christopher Granger, MD
    • Bristol-Myers Squibb

    Investigators

    • Principal Investigator: Christopher Granger, MD, Duke University
    • Principal Investigator: Glenn Chertow, MD, Stanford University

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Christopher Granger, MD, Professor of Medicine, Duke University
    ClinicalTrials.gov Identifier:
    NCT02942407
    Other Study ID Numbers:
    • Pro00068545
    First Posted:
    Oct 24, 2016
    Last Update Posted:
    Dec 29, 2020
    Last Verified:
    Dec 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Christopher Granger, MD, Professor of Medicine, Duke University
    Renal dialysis
    Additional relevant MeSH terms:
    Kidney Failure, Chronic
    Atrial Fibrillation
    Warfarin
    Apixaban

    Study Results

    Participant Flow

    Recruitment Details Participants who met protocol inclusion criteria were enrolled (randomized 1:1 apixaban and warfarin) at clinical sites across the United States.
    Pre-assignment Detail
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin as prescribed by participant's provider dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Period Title: Overall Study
    STARTED 82 72
    COMPLETED 56 48
    NOT COMPLETED 26 24

    Baseline Characteristics

    Arm/Group Title Apixaban Warfarin Total
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients) apixaban: oral anticoagulant warfarin daily dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant Total of all reporting groups
    Overall Participants 82 72 154
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    32
    39%
    25
    34.7%
    57
    37%
    >=65 years
    50
    61%
    47
    65.3%
    97
    63%
    Sex: Female, Male (Count of Participants)
    Female
    34
    41.5%
    22
    30.6%
    56
    36.4%
    Male
    48
    58.5%
    50
    69.4%
    98
    63.6%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    5
    6.1%
    3
    4.2%
    8
    5.2%
    Not Hispanic or Latino
    77
    93.9%
    67
    93.1%
    144
    93.5%
    Unknown or Not Reported
    0
    0%
    2
    2.8%
    2
    1.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    1.2%
    0
    0%
    1
    0.6%
    Asian
    3
    3.7%
    1
    1.4%
    4
    2.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    35
    42.7%
    33
    45.8%
    68
    44.2%
    White
    43
    52.4%
    36
    50%
    79
    51.3%
    More than one race
    0
    0%
    1
    1.4%
    1
    0.6%
    Unknown or Not Reported
    0
    0%
    1
    1.4%
    1
    0.6%
    Region of Enrollment (Count of Participants)
    United States
    82
    100%
    72
    100%
    154
    100%
    Weight (kilograms) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kilograms]
    87.6
    (24.1)
    93.7
    (24.9)
    90.5
    (24.6)

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Experiencing ISTH (International Society on Thrombosis and Haemostasis) Major or Clinically Relevant Non-major Bleeding
    Description 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
    Time Frame Randomization up to Month 15/Final Visit

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Population(ITT): Consists of all unique randomized participants regardless of their compliance with the study protocol. Participants are analyzed in the treatment group to which they were randomized.
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin as prescribed by participant's provider dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 82 72
    Count of Participants [Participants]
    21
    25.6%
    16
    22.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
    Comments Exploratory analysis due to failure to reach initial sample size: Non-inferiority (NI) null hypothesis: HR >= 1.4 (Non-inferiority).
    Type of Statistical Test Non-Inferiority
    Comments Due to a lower recruitment rate than anticipated in the early stage of the trial, the sample size was curtailed from 760 to 230 patients. Thus, under the initial protocol assumptions, the study is considered under-powered for the two-sided upper 95% CI on the HR to rule-out the non-inferiority margin of 1.40.
    Statistical Test of Hypothesis p-Value 0.321
    Comments
    Method Regression, Cox
    Comments Cox model was adjusted for prior warfarin status (naive vs experienced) and treatment (apixaban vs warfarin)
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.20
    Confidence Interval (2-Sided) 95%
    0.63 to 2.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments Time from randomization to first occurrence of outcome was modeled. If no event, censored at earliest of: most recent date of evaluation of outcome, month 15 target (460 days + randomization date), or end of study date (July 27, 2019).
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
    Comments
    Type of Statistical Test Superiority
    Comments Exploratory analysis due to lack of achieving initial sample size.
    Statistical Test of Hypothesis p-Value 0.583
    Comments If upper limit of 95% confidence interval < 1 this would be considered evidence of superiority.
    Method Regression, Cox
    Comments Cox model was adjusted for prior warfarin status (naive vs experienced) and treatment (apixaban vs warfarin).
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.20
    Confidence Interval (2-Sided) 95%
    0.63 to 2.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments Time from randomization to first occurrence of outcome was modeled. If no event, censored at earliest of: most recent date of evaluation of outcome, month 15 target (460 days + randomization date), or end of study date (July 27, 2019).
    2. Secondary Outcome
    Title Number of Participants Experiencing Stroke or Systemic Embolism
    Description Number of participants experiencing adjudicated stroke or systemic embolism.
    Time Frame Randomization up to Month 15/Final Visit

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Population (ITT): Consists of all unique randomized participants regardless of their compliance with the study protocol. Participants are analyzed in the treatment group to which they were randomized.
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin as prescribed by participant's provider dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 82 72
    Count of Participants [Participants]
    2
    2.4%
    2
    2.8%
    3. Secondary Outcome
    Title Number of Participants Experiencing Mortality
    Description Evaluate mortality rates for those participants randomized to warfarin and apixaban in patients with NVAF and ESRD on hemodialysis
    Time Frame Randomization up to Month 15/Final Visit

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Population(ITT): Consists of all unique randomized participants regardless of their compliance with the study protocol. Participants are analyzed in the treatment group to which they were randomized..
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin as prescribed by participant's provider dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 82 72
    Count of Participants [Participants]
    21
    25.6%
    13
    18.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
    Comments Hazard ratios (apixaban vs warfarin) and 95% confidence intervals obtained using Cox model adjusted for prior warfarin status (naive vs experienced) and treatment. Time from randomization to first occurrence of the composite outcome/censoring date modeled. Those that did not experience the outcome are censored at the earliest of the following: 1) most recent date of evaluation of all of the components, 2) month 15 target (460 days + randomization date), and end of study date (July 27, 2019).
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.47
    Confidence Interval (2-Sided) 95%
    0.74 to 2.93
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Persistence of Therapy
    Description Evaluate days between time from initiation to discontinuation of randomized therapy.
    Time Frame Randomization up to Month 15/Final Visit

    Outcome Measure Data

    Analysis Population Description
    Consists of all unique participants who took at least one dose of the randomized study drug. Participants were analyzed as randomized.
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin as prescribed by participant's provider dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 77 68
    Mean (Standard Deviation) [Days]
    304.4
    (140.0)
    279.6
    (138.2)
    5. Secondary Outcome
    Title Apixaban Plasma Concentration, Cmax
    Description 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.
    Time Frame 0-12 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Participants in the Apixaban group who had a plasma sample collected. This outcome measure is not relevant to the Warfarin group.
    Arm/Group Title Apixaban 2.5 mg Apixaban 5 mg
    Arm/Group Description Plasma apixaban concentration, Cmax for apixaban 2.5 mg Plasma apixaban concentration, Cmax for apixaban 5mg
    Measure Participants 20 41
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    59.7
    (34.3)
    97.9
    (37.9)
    6. Secondary Outcome
    Title Apixaban Plasma Concentration, Cmin
    Description 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.
    Time Frame 0-12 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Participants in the Apixaban group who had a plasma sample collected. This outcome measure is not relevant to the Warfarin group.
    Arm/Group Title Apixaban 2.5 mg Apixaban 5mg
    Arm/Group Description Plasma apixaban concentration, Cmin from apixaban 2.5 mg Plasma apixaban concentration, Cmin from apixaban 5 mg
    Measure Participants 20 41
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    28.2
    (62.1)
    49.7
    (57.1)
    7. Secondary Outcome
    Title Area Under the Plasma Apixaban Concentration Curve From 0 to 12 Hours After Dose (AUCO-12)
    Description 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.
    Time Frame 0-12 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Participants in the Apixaban group who had a plasma sample collected. This outcome measure is not relevant to the Warfarin group.
    Arm/Group Title Apixaban 2.5 mg Apixaban 5mg
    Arm/Group Description Plasma apixaban concentration curve from 0 to 12 hours after dose for apixaban 2.5 mg Plasma apixaban concentration curve from 0 to 12 hours after dose for apixaban 5 mg
    Measure Participants 20 41
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    507
    (40.4)
    868
    (44)
    8. Secondary Outcome
    Title Apixaban Pharmacodynamics, Chromogenic Factor Xa Assay
    Description Evaluate the pharmacodynamics of apixaban in ESRD NVAF patients on hemodialysis
    Time Frame Baseline: Day 3, 4, or 5; Day 28

    Outcome Measure Data

    Analysis Population Description
    Data not collected.
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients) apixaban: oral anticoagulant warfarin daily dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 0 0
    9. Secondary Outcome
    Title Adherence to Treatment With Apixaban or With Warfarin
    Description Measured by self-reported days of medication compliance over the last 30 days.
    Time Frame Month 15/Final Visit

    Outcome Measure Data

    Analysis Population Description
    Participants who reported medication compliance at month 15.
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients) apixaban: oral anticoagulant warfarin daily dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 28 18
    5 days or fewer
    1
    1.2%
    1
    1.4%
    6 to 23 days
    4
    4.9%
    2
    2.8%
    24 days or more
    23
    28%
    15
    20.8%
    10. Other Pre-specified Outcome
    Title Number of Participants Experiencing Systemic Embolism
    Description 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.
    Time Frame Randomization up to Month 15/Final Visit

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin as prescribed by participant's provider dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 82 72
    Count of Participants [Participants]
    0
    0%
    0
    0%
    11. Other Pre-specified Outcome
    Title Number of Participants Experiencing Stroke
    Description 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
    Time Frame Randomization up to Month 15/Final Visit

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin as prescribed by participant's provider dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 82 72
    Count of Participants [Participants]
    2
    2.4%
    2
    2.8%
    12. Other Pre-specified Outcome
    Title Number of Participants Experiencing Stroke, Systemic Embolism, Major Bleeding or All-cause Mortality
    Description 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.
    Time Frame Randomization up to Month 15/Final Visit

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat Population(ITT): Consists of all unique randomized participants regardless of their compliance with the study protocol. Participants are analyzed in the treatment group to which they were randomized.
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin as prescribed by participant's provider dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    Measure Participants 82 72
    Count of Participants [Participants]
    27
    32.9%
    29
    40.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Apixaban, Warfarin
    Comments Hazard ratios (apixaban vs warfarin) and 95% confidence intervals obtained using Cox model adjusted for prior warfarin status (naive vs experienced) and treatment. Time from randomization to first occurrence of the composite outcome/censoring date modeled. Those that did not experience the outcome are censored at the earliest of the following: 1) most recent date of evaluation of all of the components, 2) month 15 target (460 days + randomization date), and end of stud date (July 27, 2019).
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.20
    Confidence Interval (2-Sided) 95%
    0.67 to 2.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    13. Other Pre-specified Outcome
    Title Baseline Biomarkers
    Description Analysis of outcomes and treatment effect according to levels of cardiovascular biomarkers at baseline
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame Informed Consent date through 30 days after permanent drug discontinuation.
    Adverse Event Reporting Description For the apixaban group, 79 of the 82 participants randomized were assessed for adverse events. For the warfarin group, 68 of the 72 participants randomized were assessed for adverse events. The participants that were not assessed for adverse events either died on the same day as randomization (n=1) or withdrew consent for additional follow-up on Day 1 and, therefore, were not assessed for AEs. (n=6).
    Arm/Group Title Apixaban Warfarin
    Arm/Group Description apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients; >= 80 years old or dry body weight/hemodialysis target body weight <= 60 kg) apixaban: oral anticoagulant warfarin daily dose adjusted to target International Normalized Ratio (INR) of 2-3 warfarin: oral anticoagulant
    All Cause Mortality
    Apixaban Warfarin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 21/82 (25.6%) 13/72 (18.1%)
    Serious Adverse Events
    Apixaban Warfarin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 13/79 (16.5%) 8/68 (11.8%)
    Blood and lymphatic system disorders
    Anaemia 0/79 (0%) 0 2/68 (2.9%) 2
    Cardiac disorders
    Angina Pectoris 1/79 (1.3%) 1 0/68 (0%) 0
    Atrioventricular dissociation 1/79 (1.3%) 1 0/68 (0%) 0
    Bradyarrhythmia 1/79 (1.3%) 1 0/68 (0%) 0
    Bradycardia 1/79 (1.3%) 1 0/68 (0%) 0
    Cardiac tamponade 1/79 (1.3%) 1 0/68 (0%) 0
    Gastrointestinal disorders
    Diarrhoea 1/79 (1.3%) 1 0/68 (0%) 0
    Gastritis 1/79 (1.3%) 1 0/68 (0%) 0
    General disorders
    Asthenia 0/79 (0%) 0 1/68 (1.5%) 1
    Non-cardiac chest pain 0/79 (0%) 0 1/68 (1.5%) 1
    Infections and infestations
    Cellulitis 1/79 (1.3%) 1 0/68 (0%) 0
    Gangrene 1/79 (1.3%) 1 0/68 (0%) 0
    Osteomyelitis 1/79 (1.3%) 1 0/68 (0%) 0
    Injury, poisoning and procedural complications
    Foot fracture 0/79 (0%) 0 1/68 (1.5%) 1
    Hip fracture 1/79 (1.3%) 1 0/68 (0%) 0
    Tibia fracture 0/79 (0%) 0 1/68 (1.5%) 1
    Vena cava injury 1/79 (1.3%) 1 0/68 (0%) 0
    Metabolism and nutrition disorders
    Failure to thrive 0/79 (0%) 0 1/68 (1.5%) 1
    Hyperkalaemia 1/79 (1.3%) 1 0/68 (0%) 0
    Hypoglycaemia 1/79 (1.3%) 1 0/68 (0%) 0
    Metabolic disorder 1/79 (1.3%) 1 0/68 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/79 (0%) 0 1/68 (1.5%) 1
    Myositis 1/79 (1.3%) 1 0/68 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 0/79 (0%) 0 1/68 (1.5%) 1
    Nervous system disorders
    Generalized Anxiety Disorder 1/79 (1.3%) 1 0/68 (0%) 0
    Syncope 0/79 (0%) 0 1/68 (1.5%) 1
    Renal and urinary disorders
    Bladder spasm 1/79 (1.3%) 1 0/68 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/79 (0%) 0 1/68 (1.5%) 1
    Chronic obstructive pulmonary disease 0/79 (0%) 0 1/68 (1.5%) 1
    Hypoxia 0/79 (0%) 0 1/68 (1.5%) 1
    Pulmonary Mass 0/79 (0%) 0 1/68 (1.5%) 1
    Pulmonary embolism 0/79 (0%) 0 1/68 (1.5%) 1
    Respiratory failure 1/79 (1.3%) 1 0/68 (0%) 0
    Sleep apnoea syndrome 0/79 (0%) 0 1/68 (1.5%) 1
    Tracheal stenosis 1/79 (1.3%) 1 0/68 (0%) 0
    Vascular disorders
    Hypotension 0/79 (0%) 0 1/68 (1.5%) 1
    Peripheral arterial occlusive disease 1/79 (1.3%) 1 0/68 (0%) 0
    Peripheral arterly occlusion 1/79 (1.3%) 1 0/68 (0%) 0
    Other (Not Including Serious) Adverse Events
    Apixaban Warfarin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/79 (5.1%) 2/68 (2.9%)
    Blood and lymphatic system disorders
    Anaemia 0/79 (0%) 0 1/68 (1.5%) 1
    General disorders
    Catheter site haemorrhage 1/79 (1.3%) 1 0/68 (0%) 0
    Investigations
    International normalised ratio abnormal 0/79 (0%) 0 1/68 (1.5%) 5
    Musculoskeletal and connective tissue disorders
    Musculoskeletal stiffness 1/79 (1.3%) 1 0/68 (0%) 0
    Myalgia 1/79 (1.3%) 1 0/68 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer 1/79 (1.3%) 1 0/68 (0%) 0

    Limitations/Caveats

    PK data are not final and are undergoing further modeling and analyses that will be reported in a separate manuscript.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Christopher Granger, MD
    Organization Duke Universitey
    Phone 919-668-8900
    Email christopher.granger@duke.edu
    Responsible Party:
    Christopher Granger, MD, Professor of Medicine, Duke University
    ClinicalTrials.gov Identifier:
    NCT02942407
    Other Study ID Numbers:
    • Pro00068545
    First Posted:
    Oct 24, 2016
    Last Update Posted:
    Dec 29, 2020
    Last Verified:
    Dec 1, 2020