Atrial Fibrillation, End Stage Renal Disease
Conditions
Keywords
Renal dialysis
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) .
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.
Interventions
DRUGapixaban
oral anticoagulant
DRUGwarfarin
oral anticoagulant
Sponsors
Bristol-Myers Squibb
Christopher Granger, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Persistence of Therapy | Randomization up to Month 15/Final Visit | Evaluate days between time from initiation to discontinuation of randomized therapy. |
| 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. |
| 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. |
| 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 |
| 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. |
| Number of Participants Experiencing Stroke or Systemic Embolism | Randomization up to Month 15/Final Visit | Number of participants experiencing adjudicated stroke or systemic embolism. |
| 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 |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Baseline Biomarkers | Baseline | Analysis of outcomes and treatment effect according to levels of cardiovascular biomarkers at baseline |
| 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: 1. 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. 2. Renal embolism will be diagnosed when sudden flank pain or a change in renal laboratory findings occurred. 3. 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. |
| 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 |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Apixaban apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients)
apixaban: oral anticoagulant | 82 |
| Warfarin warfarin daily dose adjusted to target International Normalized Ratio (INR) of 2-3
warfarin: oral anticoagulant | 72 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 16 | 13 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Withdrawal by Subject | 7 | 9 |
Baseline characteristics
| Characteristic | Apixaban | Warfarin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 50 Participants | 47 Participants | 97 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 25 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants | 67 Participants | 144 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 35 Participants | 33 Participants | 68 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 43 Participants | 36 Participants | 79 Participants |
| Region of Enrollment United States | 82 Participants | 72 Participants | 154 Participants |
| Sex: Female, Male Female | 34 Participants | 22 Participants | 56 Participants |
| Sex: Female, Male Male | 48 Participants | 50 Participants | 98 Participants |
| Weight | 87.6 kilograms STANDARD_DEVIATION 24.1 | 93.7 kilograms STANDARD_DEVIATION 24.9 | 90.5 kilograms STANDARD_DEVIATION 24.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 21 / 82 | 13 / 72 |
| other Total, other adverse events | 4 / 79 | 2 / 68 |
| serious Total, serious adverse events | 13 / 79 | 8 / 68 |
Outcome results
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
Time frame: Randomization up to Month 15/Final Visit
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants Experiencing ISTH (International Society on Thrombosis and Haemostasis) Major or Clinically Relevant Non-major Bleeding | 21 Participants |
| Warfarin | Number of Participants Experiencing ISTH (International Society on Thrombosis and Haemostasis) Major or Clinically Relevant Non-major Bleeding | 16 Participants |
Comparison: Exploratory analysis due to failure to reach initial sample size: Non-inferiority (NI) null hypothesis: HR \>= 1.4 (Non-inferiority).p-value: 0.32195% CI: [0.63, 2.3]Regression, Cox
p-value: 0.58395% CI: [0.63, 2.3]Regression, Cox
Secondary
Adherence to Treatment With Apixaban or With Warfarin
Measured by self-reported days of medication compliance over the last 30 days.
Time frame: Month 15/Final Visit
Population: Participants who reported medication compliance at month 15.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Apixaban | Adherence to Treatment With Apixaban or With Warfarin | 5 days or fewer | 1 Participants |
| Apixaban | Adherence to Treatment With Apixaban or With Warfarin | 6 to 23 days | 4 Participants |
| Apixaban | Adherence to Treatment With Apixaban or With Warfarin | 24 days or more | 23 Participants |
| Warfarin | Adherence to Treatment With Apixaban or With Warfarin | 24 days or more | 15 Participants |
| Warfarin | Adherence to Treatment With Apixaban or With Warfarin | 5 days or fewer | 1 Participants |
| Warfarin | Adherence to Treatment With Apixaban or With Warfarin | 6 to 23 days | 2 Participants |
Secondary
Apixaban Pharmacodynamics, Chromogenic Factor Xa Assay
Evaluate the pharmacodynamics of apixaban in ESRD NVAF patients on hemodialysis
Time frame: Baseline: Day 3, 4, or 5; Day 28
Population: Data not collected.
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.
Time frame: 0-12 hours post-dose
Population: Participants in the Apixaban group who had a plasma sample collected. This outcome measure is not relevant to the Warfarin group.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Apixaban Plasma Concentration, Cmax | 59.7 ng/mL | Geometric Coefficient of Variation 34.3 |
| Warfarin | Apixaban Plasma Concentration, Cmax | 97.9 ng/mL | Geometric Coefficient of Variation 37.9 |
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.
Time frame: 0-12 hours post-dose
Population: Participants in the Apixaban group who had a plasma sample collected. This outcome measure is not relevant to the Warfarin group.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Apixaban Plasma Concentration, Cmin | 28.2 ng/mL | Geometric Coefficient of Variation 62.1 |
| Warfarin | Apixaban Plasma Concentration, Cmin | 49.7 ng/mL | Geometric Coefficient of Variation 57.1 |
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.
Time frame: 0-12 hours post-dose
Population: Participants in the Apixaban group who had a plasma sample collected. This outcome measure is not relevant to the Warfarin group.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Area Under the Plasma Apixaban Concentration Curve From 0 to 12 Hours After Dose (AUCO-12) | 507 ng*h/mL | Geometric Coefficient of Variation 40.4 |
| Warfarin | Area Under the Plasma Apixaban Concentration Curve From 0 to 12 Hours After Dose (AUCO-12) | 868 ng*h/mL | Geometric Coefficient of Variation 44 |
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
Time frame: Randomization up to Month 15/Final Visit
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants Experiencing Mortality | 21 Participants |
| Warfarin | Number of Participants Experiencing Mortality | 13 Participants |
Comparison: 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).95% CI: [0.74, 2.93]
Secondary
Number of Participants Experiencing Stroke or Systemic Embolism
Number of participants experiencing adjudicated stroke or systemic embolism.
Time frame: Randomization up to Month 15/Final Visit
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants Experiencing Stroke or Systemic Embolism | 2 Participants |
| Warfarin | Number of Participants Experiencing Stroke or Systemic Embolism | 2 Participants |
Secondary
Persistence of Therapy
Evaluate days between time from initiation to discontinuation of randomized therapy.
Time frame: Randomization up to Month 15/Final Visit
Population: Consists of all unique participants who took at least one dose of the randomized study drug. Participants were analyzed as randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Persistence of Therapy | 304.4 Days | Standard Deviation 140 |
| Warfarin | Persistence of Therapy | 279.6 Days | Standard Deviation 138.2 |
Other Pre-specified
Baseline Biomarkers
Analysis of outcomes and treatment effect according to levels of cardiovascular biomarkers at baseline
Time frame: Baseline
Other Pre-specified
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
Time frame: Randomization up to Month 15/Final Visit
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants Experiencing Stroke | 2 Participants |
| Warfarin | Number of Participants Experiencing Stroke | 2 Participants |
Other Pre-specified
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.
Time frame: Randomization up to Month 15/Final Visit
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants Experiencing Stroke, Systemic Embolism, Major Bleeding or All-cause Mortality | 27 Participants |
| Warfarin | Number of Participants Experiencing Stroke, Systemic Embolism, Major Bleeding or All-cause Mortality | 29 Participants |
Comparison: 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).95% CI: [0.67, 2.17]
Other Pre-specified
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: 1. 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. 2. Renal embolism will be diagnosed when sudden flank pain or a change in renal laboratory findings occurred. 3. 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants Experiencing Systemic Embolism | 0 Participants |
| Warfarin | Number of Participants Experiencing Systemic Embolism | 0 Participants |