What is the data on the use of reduced-dose apixaban in patients on hemodialysis for the indication of atrial fibrillation?

Comment by InpharmD Researcher

Overall, clinical data for the use of apixaban in patients with severe chronic kidney disease (CKD) or end-stage renal disease (ESRD) on dialysis are lacking. The 2019 updated AHA/ACC atrial fibrillation (AF) guidelines state that warfarin or apixaban may be considered in dialysis-dependent AF patients, and reports no significant safety issues with the 2.5 mg or 5 mg doses of apixaban in this population. Although data from the prescribing information and pharmacokinetic studies report hemodialysis has little impact on apixaban clearance, studies show that the apixaban 2.5 mg dose in dialysis patients has similar drug exposures to the 5 mg dose in patients with normal renal function. Despite this, results from a retrospective study revealed no difference in bleeding between patients with impaired or preserved renal function regardless of apixaban dose.

Background

According to the 2019 updated American Heart Association/ American College of Cardiology (AHA/ACC) guidelines for patients with CKD and atrial fibrillation (AF), apixaban may be considered for use in more severe CKD patients based on studies in dialysis-dependent patients. No significant safety issues were reported when apixaban 2.5 mg BID and 5 mg BID were administered to these patients and there may be lower risks of bleeding compared to warfarin which was an initial choice for dialysis patients with AF. While the guidelines state using warfarin or apixaban may be reasonable in dialysis-dependent patients with AF, further studies are needed before a recommendation can be made. In contrast, rivaroxaban (Xarelto) was associated with a higher risk of hospitalization or death from bleeding compared to warfarin in patients with end-stage renal disease (ESRD) on dialysis. [1], [2], [3]

A 2019 review article asserts the guideline's sentiments that data are still insufficient to determine the safety of apixaban or rivaroxaban. The authors believe that apixaban may be safe in ESRD patients but the data is limited to retrospective studies. Apixaban is also the least renally excreted of the DOAC. A pharmacologic study showed that rivaroxaban 10 mg may have similar drug levels as 20 mg in healthy volunteers on dialysis while another study observed 15 mg dose in dialysis patients to have similar properties to those with moderate to severe renal impairment not on dialysis. However, with the conflicting data mentioned before, rivaroxaban cannot be recommended for patients on dialysis without confirmatory studies. [4]

In a review of the use of apixaban in renal insufficiency, apixaban was associated with less major bleeding compared with warfarin across all categories of renal dysfunction, but this reduction is greater in patients with an estimated glomerular filtration rate (eGFR) of less than 50 mL/minute. It was stated that only 1.5% of patients included in trials have had a creatinine clearance (CrCl) less than 30 mL/min and those with a CrCl less than 25 mL/min or serum creatinine (SCr) greater than 2.5 mg/dL have been excluded. The use of apixaban in patients with severe renal insufficiency was concluded to be scarce. [5]

Compared to vitamin K antagonists (i.e. warfarin), apixaban is associated with a reduced risk of major bleeding in patients with end-stage renal disease (pooled odds ratio [OR] 0.42; 95% confidence interval [CI] 0.28 to 0.61). When this meta-analysis was limited to only subjects on dialysis, the risk of major bleeding was also significantly reduced (pooled OR 0.27; 95% CI 0.07 to 0.95). There was no significant difference in the risk of thromboembolic events in advanced ESRD patients on apixaban versus vitamin K antagonists (pooled OR 0.56; 95% CI 0.23 to 1.39). No dose adjustment is recommended for patients with ESRD requiring hemodialysis and apixaban is not dialyzable. [6]

A systematic review evaluating the use of direct oral anticoagulants (DOACs) in chronic kidney disease (CKD) and dialysis patients with atrial fibrillation found apixaban significantly reduces the risk of stroke or systemic embolism compared to warfarin in patients with moderate CKD. Apixaban was also associated with a significant reduction in major bleeding events compared to warfarin. In contrast, rivaroxaban showed no significant difference in major bleeding versus warfarin. In hemodialysis (HD) patients, there was no difference in stroke outcomes between apixaban, dabigatran, or rivaroxaban versus warfarin. In hemodialysis patients, rivaroxaban and dabigatran were associated with an increased major bleeding risk, whereas there was no major bleeding difference with apixaban compared to warfarin. This data is based primarily on randomized, controlled data comparing DOACs to warfarin instead of direct comparisons between the individual DOACs. [7], [8]

A retrospective, observational study evaluated the effectiveness and safety of rivaroxaban versus apixaban in non-valvular atrial fibrillation (NVAF) patients with end-stage renal disease (ESRD) and/or receiving dialysis in routine practice using claims data from 2014 to 2017. The primary outcome was the incidence of stroke and systemic embolism while on oral anticoagulation. A total of 787 rivaroxaban and 1836 apixaban were included in this analysis, and the median age of participants was 70 years (interquartile range, 61-79). Results showed no difference in the incidence of stroke and systemic embolism between rivaroxaban and apixaban (hazard ratio [HR] 1.18; 95% confidence interval [CI] 0.45 to 2.76). There was also no difference in the primary safety endpoint of major bleeding (HR 1.00; 95% CI 0.63 to 1.58). The authors concluded that rivaroxaban and apixaban were associated with similar risks of stroke and major bleeding in NVAF patients with ESRD or on dialysis. [9]

References:

[1] January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 2019;140(2):e125-e151.
[2] Harder S. Renal profiles of anticoagulants. J Clin Pharmacol. 2012;52: 964–975.
[3] Jain N, Reilly RF. Clinical Pharmacology of Oral Anticoagulants in Patients with Kidney Disease [published correction appears in Clin J Am Soc Nephrol. 2019 May 7;14(5):750]. Clin J Am Soc Nephrol. 2019;14(2):278-287. doi:10.2215/CJN.02170218
[4] Aursulesei V, Costache II. Anticoagulation in chronic kidney disease: from guidelines to clinical practice. Clin Cardiol. 2019;42(8):774-782.
[5] Steffel J, Hindricks G. Apixaban in renal insufficiency: successful navigation between the Scylla and Charybdis. Eur Heart J. 2012;33(22):2766-8.
[6] Chokesuwattanaskul R, Thongprayoon C, Tanawuttiwat T, Kaewput W, Pachariyanon P, Cheungpasitporn W. Safety and efficacy of apixaban versus warfarin in patients with end-stage renal disease: Meta-analysis [published correction appears in Pacing Clin Electrophysiol. 2018 Jul;41(7):879]. Pacing Clin Electrophysiol. 2018;41(6):627-634. doi:10.1111/pace.13331
[7] Feldberg J, Patel P, Farrell A, et al. A systematic review of direct oral anticoagulant use in chronic kidney disease and dialysis patients with atrial fibrillation. Nephrol Dial Transplant. 2019;34(2):265-277. doi:10.1093/ndt/gfy031
[8] Belley-Cote EP, Eikelboom JW. Anticoagulation for Stroke Prevention in Patients With Atrial Fibrillation and End-Stage Renal Disease—First, Do No Harm. JAMA Netw Open. 2020;3(4):e202237. doi:10.1001/jamanetworkopen.2020.2237
[9] Miao B, Sood N, Bunz TJ, Coleman CI. Rivaroxaban versus apixaban in non-valvular atrial fibrillation patients with end-stage renal disease or receiving dialysis. Eur J Haematol. 2020;104(4):328-335. doi:10.1111/ejh.13383
Relevant Prescribing Information

ELIQUIS (apixaban):
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation:
The recommended dose is 2.5 mg twice daily in patients with at least two of the following characteristics:
•age greater than or equal to 80 years;
•body weight less than or equal to 60 kg;
•serum creatinine greater than or equal to 1.5 mg/dL

Patients with End-Stage Renal Disease on Dialysis: Clinical efficacy and safety studies with ELIQUIS did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of ELIQUIS at the usually recommended dose will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ARISTOTLE.

Pharmacokinetics: Hemodialysis in ESRD subjects
Systemic exposure to apixaban administered as a single 5 mg dose in ESRD subjects dosed immediately after the completion of a 4-hour hemodialysis session (post-dialysis) is 36% higher when compared to subjects with normal renal function. The systemic exposure to apixaban administered 2 hours prior to a 4-hour hemodialysis
session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min is 17% higher compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min. The systemic exposure of apixaban is 14% lower on dialysis when compared to not on dialysis. Protein binding was similar (92%-94%) between healthy controls and ESRD subjects during the on-dialysis and off-dialysis periods.

Warnings and Precautions: Reversal of Anticoagulant Effect
Hemodialysis does not appear to have a substantial impact on apixaban exposure. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is no experience with systemic hemostatics (desmopressin) in individuals receiving ELIQUIS, and they are not expected to be effective as a reversal agent. [10]

References:

[10] Eliquis (apixaban) [prescribing Information]. Bristol-Myers Squibb Company: Princeton, New Jersey; 2021.
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the data on the use of reduced-dose apixaban in patients on hemodialysis for the indication of atrial fibrillation?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-6 for your response.

 

Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial

Design

Prospective, randomized, open-label, blinded-outcome evaluation study (RENAL-AF trial)

N= 154

Objective

To test the hypothesis that apixaban was non-inferior to warfarin for safety with respect to major or clinically relevant nonmajor bleeding in patients with atrial fibrillation (AF) and end-stage renal disease (ESRD) on hemodialysis

Study Groups

Apixaban (n= 82)

Warfarin (n= 72)

Inclusion Criteria

Patients had to have at least one of the following: AF on an electrocardiogram at enrollment; ≥2 episodes of AF on cardiac monitoring; one episode of AF on cardiac monitoring and use of an oral anticoagulant for stroke prevention in AF; one episode of AF on cardiac monitoring and documentation of a second episode in the medical record; history of cardioversion for AF with additional documentation of a second episode in the medical record, or use of an oral anticoagulant for the purpose of stroke prevention in AF, or both

Other criteria: CHA2DS2-VASc score ≥2; have received chronic hemodialysis therapy for ≥3 months; considered by their treating physician to be a candidate for oral anticoagulation

Exclusion Criteria

Moderate or severe mitral stenosis; ongoing need for aspirin >100 mg daily; aspirin with P2Y12 antagonist therapy, oral anticoagulation for a reason other than AF; life expectancy ​<3 months; anticipated kidney transplant within the next 3 months

Methods

Eligible patients were randomized to receive either 5 mg of apixaban twice daily (2.5 mg twice daily for patients ≥80 years of age, weight ≤60 kg, or both) or dose-adjusted warfarin to maintain an international normalized ratio (INR) of 2-3. Patients were instructed to take their apixaban dose at least 2 hours before dialysis. Patients could continue receiving intravenous heparin at the start of or during hemodialysis at the discretion of their physician. Samples were collected from some patients enrolled in the apixaban group for pharmacokinetic analysis.

The trial was stopped prematurely due to enrollment challenges

Duration

January 2017 through January 2019

Intervention: up to 15 months

Outcome Measures

Primary: time to major or clinically relevant nonmajor bleeding

Secondary: stroke, mortality, and apixaban pharmacokinetics

Baseline Characteristics

  

Apixaban (n= 82)

Warfarin (n= 72)

Age, years

 69.0 (61.0 to 76.0) 68.0 (60.5 to 72.5)

Female

41.5% 30.6%

Black

 42.7%  47.2%

Weight, kg

 86.3 (69.5 to 100.5)  90.5 (72.8 to 112.2) 

CHA2DS2-VASc score

 4.0 (3.0 to 5.0) 4.0 (3.0 to 5.0)

Warfarin and nonvitamin K antagonists naive

 12.2% 5.6%

Past medical history

Myocardial infarction

Fall within the past year

Chronic hypertension

Chronic heart failure

Diabetes

Stroke

Transient ischemic attack

 

19.5%

7.3%

96.3%

52.4%

51.2%

20.7%

8.5%

 

30.6%

9.7%

93.1%

56.9%

65.3%

16.7%

4.2%

Medications*

ACE/ARB

Beta-blocker

Aspirin

Clopidogrel

Digoxin

Calcium channel blocker

Statin

Nonsteroidal anti-inflammatory drug

 

22.8%

54.4%

36.7%

2.5%

0

35.4%

51.9%

5.1% 

 

28.6%

64.3%

45.7%

1.4%

4.3%

37.1%

58.6%

10.0% 

ACE/ARB, Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker

*All medications have 5 missing values (3 from the apixaban group and 2 from the warfarin group). All medications were taken 24 hours before or on randomization

Results

Endpoint

Apixaban (n= 82)

Warfarin (n= 72)

ISTH major bleed/clinically relevant nonmajor bleed

Intracranial

Gastrointestinal

Hemodialysis access site

Other

21 926%)

1 (1%)

2 (2%)

11 (13%)

7 (9%) 

16 (22%)

1 (1%)

6 (8%)

6 (8%)

3 (4%) 

ISTH major bleed

Intracranial

Gastrointestinal

Hemodialysis access site

Other

9 (11%)

1 (1%)

4 (5%)

1 (1%)

3 (4%) 

7 (10%)

1 (1%)

5 (7%)

0

1 (1%)

ISTH clinically relevant nonmajor bleed

Intracranial

Gastrointestinal

Hemodialysis access site

Other

14 (17%)

0

0

10 (12%)

4 (5%) 

10 (14%)

0

2 (3%)

6 (8%)

2 (3%) 

Stroke

Ischemic

Hemorrhagic

2 (2%)

1 (1%)

1 (1%)

2 (3%)

2 (3%)

0 

Death

Cardiovascular

Noncardiovascular

Undetermined

Major bleeding-related death*

21 (26%)

9 (11%)

5 (6%)

7 (9%)

1 (1%)

13 (18%)

4 (6%)

8 (11%)

1 (1%)

2 (3%) 

ISTH, International Society for Thrombosis and Haemostasis 

*Major bleed occurred within 30 days of death

Pharmacokinetic samples were collected from 43 (68%) patients receiving the 5 mg twice-daily dose and 20 (32%) patients receiving the 2.5 mg twice-daily dose. The median steady-state 12-hour area under the curve (AUC0-12) was 2475 ng/mL×h (1342 to 3285) and 1269 ng/mL×h (615 to 1946) for patients who received the 5 mg and 2.5 mg twice-daily doses, respectively. 

The AUC0-12 for the 5 mg dose in the RENAL-AF trial did not differ from the AUC0-12 for patients with creatinine clearance (CrCl) < 60 mL/min from the ARISTOTLE trial but was significantly higher than patients with normal renal function (CrCl ≥90 mL/min; median 1374 ng/mL×h) from the ARISTOTLE trial. For the 2.5 mg dose, the AUC0-12 in the RENAL-AF trial did not differ from the AUC0-12 for patients with eCrCl ≥15 and ​<90 mL/min from the ARISTOTLE trial.

Study Author Conclusions

There was inadequate power to draw any conclusion regarding rates of major or clinically relevant nonmajor bleeding comparing apixaban and warfarin in patients with AF and end-stage kidney disease on hemodialysis. Clinically relevant bleeding events were ≈10-fold more frequent than stroke or systemic embolism among this population on anticoagulation, highlighting the need for future randomized studies evaluating the risks versus benefits of anticoagulation among patients with AF and end-stage kidney disease on hemodialysis. 

InpharmD Researcher Critique

The study is limited by its open-label design and the lack of power to ascertain the statistical significance of the results due to its early termination. There was no direct comparison of patients who received the 5 mg dose and the 2.5 mg dose of apixaban hence, inferences cannot be made on whether there are differences in efficacy and safety between both doses in this population.



References:

Pokorney SD, Chertow GM, Al-Khalidi HR, et al. Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial. Circulation. 2022;146(23):1735-1745. doi:10.1161/CIRCULATIONAHA.121.054990

 

Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis

Design

Open-label, parallel-group, single-dose trial

N=16

Objective

To investigate the effect of ESRD on apixaban pharmacokinetics and pharmacodynamics and to assess the ability of hemodialysis to remove apixaban from the systemic circulation

Study Groups

Healthy (n=8)

ESRD (n=8)

Inclusion Criteria

18 to 65 years old, either normal renal function or ESRD on hemodialysis

Exclusion Criteria

Deviation from normal in physical exam for healthy subjects, lab/clinical abnormalities beyond that which is consistent in ESRD subjects, uncontrolled conditions (e.g. hypertension, diabetes, etc) within 6 months of study, coagulation disorder

Methods

The subjects were divided into 2 groups. The healthy subjects received apixaban 5 mg on day 1 and were discharged on day 4 after evaluations.

The ESRD subjects were admitted for 15 days and received dialysis thrice a week. They received apixaban 5 mg on day 1, followed 2 hours later by a 4-hour hemodialysis session. Seven days later, they received another apixaban 5 mg immediately after a 4-hour hemodialysis session. The ESRD subjects were discharged on day 8 of period 2 after evaluations.

Duration

 For the healthy subjects, the intervention lasted 4 days while it lasted 15 days in the ESRD subjects.

Outcome Measures

Primary outcome: the pharmacokinetics of a single oral dose of apixaban in subjects with end-stage renal disease (ESRD) maintained on chronic stable hemodialysis compared with subjects with normal renal function. 

Baseline Characteristics

  

Healthy (n=8)

ESRD (n=8)

Age, years

 47 ± 7.7 46.9 ± 7.9

Male

 6 (75%) 6 (75%)

White

 6 (75%) 1 (12.5%)

Black/African American

 1 (12.5%) 7 (87.5%)

BMI, kg/m2

 29.7 ± 3.9 29.7 ± 7.4

Results

  

Healthy (n=8)

ESRD, first dose  (n=8)

ESRD, second dose (n=8)

T½, hours

 20 ± 14.45 12.5 ± 3.14 12.7 ± 3.40
AUC, ng*h/mL 1265 ± 30%

1474 ± 44%

 1717 ± 24%

Cmax, ng/mL

126 ± 29%

98.9 ± 29%

 114 ± 31%

Adverse Events

Headache (two patients with ESRD)

Study Author Conclusions

The pharmacokinetic and pharmacodynamic results of this study suggest that apixaban can be used without dose modification in patients with ESRD maintained on hemodialysis. This conclusion is based on the modest increase in apixaban exposure off hemodialysis and the limited removal of apixaban during hemodialysis observed in the ESRD subjects in this study.

InpharmD Researcher Critique

The study shows that hemodialysis had little impact on the clearance of apixaban and thus the medication does not need to be dose-adjusted. It is important to acknowledge that the hemodialysis sessions were done heparin-free to avoid any drug interactions.

 

References:

Wang X, Tirucherai G, Marbury TC (etal). Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-36.

 

Safety outcomes of apixaban in patients with nonvalvular atrial fibrillation and severe renal impairment

Design

Retrospective, single-center, cohort study

N=340

Objective

To determine clinical safety of apixaban 5 mg BID for patients with nonvalvular atrial fibrillation (NVAF) and severe renal impairment compared to patients with preserved renal function

Study Groups

Preserved renal function (n=287)

Impaired renal function (n=53)

Inclusion Criteria

 Aged ≥18 years, documentation of receiving apixaban 2.5-5 mg BID for atrial fibrillation (regardless of dose appropriateness based on age, weight, and SCr) for at least 48 hours before admission

Exclusion Criteria

Admitted with a documented bleed attributed to trauma, or to other anticoagulant, antiplatelet therapy, or nonsteroidal anti-inflammatory (NSAID) therapy; dual antiplatelet therapy use with apixaban; history of a hypercoagulable state; apixaban used for indications other than NVAF; if an apixaban dosage change was required during admission

Methods

This was a retrospective study of a single center in Tennesee. Patients taking apixaban 2.5-5 mg BID for nonvalvular atrial fibrillation were divided into patients with impaired renal function (CrCl <25 mL/min and/or SCr >2.5 mg/dL [including hemodialysis]) or preserved renal function (CrCl ≥25 mL/min and SCr ≤2.5 mg/dL).

A major bleeding event was defined as an acute overt bleed plus: hemoglobin decrease of ≥2 g/dL, transfusion of ≥2 Units of packed red blood cells or fresh frozen plasma, bleed in one or more critical sites, or fatal bleed.

Duration

May 2013 to November 2017

Outcome Measures

Primary: major bleeding events in patients with impaired renal function compared to patients with preserved renal function

Secondary: incidence of clinically relevant non-major bleed or minor bleed in both dosage groups

Baseline Characteristics

  

Preserved renal function (n=287)

Impaired renal function (n=53)

 P-value

Age, years

 73.71 ± 9.99 74.23 ± 11.24 0.736

Female

51.6% 64.2% 0.092

Length of stay, days (IQR)

 4 (2-7) 6 (3-11) 0.0029

Chronic kidney disease

Dialysis

29.2%

0

81.1%

35.9%

N/A

N/A

CHA2DS2VASc score

5 ± 1.65

5 ± 1.55

 0.257

HAS-BLED score

Low (0-2)

Medium (3-4)

High (5-9)

 

60.1%

35.6%

3.5%

 

37.7%

56.6%

5.7%

 

0.0017

0.0038

0.448

Apixaban dose

2.5 mg

5 mg

 

20.9%

79.1%

 

52.8%

47.2%

 N/A

SCr, mg/dL (IQR)

 1.08 (0.85-1.36) 3.19 (2.48-4.70) N/A
CrCl (adjusted BW), mL/min (IQR) 56.4 (42.4-72.5) 18.9 (12.2-22.9)

N/A
IQR=interquartile range

Results

 

Preserved renal function (n=287)

Impaired renal function (n=53)

P-value
  2.5 mg (n=227) 5 mg (n=60) 2.5 mg (n=28) 5 mg (n=25)  

Major bleeding

 4.41% 5.33% 3.57%* 8% Not significant

Minor bleeding

 11.45% 10% 0.71% 16% Not significant

*All patients who presented with bleeding were taking aspirin or an NSAID except for the one patient with impaired renal function taking apixaban 2.5 mg BID.

Two of the minor bleeding events in the preserved group occurred in patients with documentation of receiving a concomitant CYP3A4 inhibitor. Two patients in the apixaban 2.5 mg impaired group who experienced a minor bleeding event were undergoing hemodialysis.

None of the patients on an apixaban regimen higher than approved labeling (n=13) experienced a bleeding event. Of those patients treated with an apixaban regimen lower than approved dosage (n=48), 5 (8.83%) experienced a major bleed and 5 (10.4%) experienced a minor bleed.

Adverse Events

N/A

Study Author Conclusions

There were no observed differences in bleeding between groups with preserved or impaired renal function, regardless of apixaban dose. Because patients with severe renal impairment were excluded from original trials, this study contributes clinical safety outcomes to the limited data for use of apixaban in this patient population.

InpharmD Researcher Critique

The expected ratio of preserved to impaired renal function was 4:1; so this study is at risk of a type II error, particularly when comparing the 2.5 mg dose (whose ratio is 8:1). Other limitations stem from the single-center, retrospective design. Documentation of bleeding events and relationship to apixaban was not always clear, therefore subject to information bias.

The significant difference in baseline HAS-BLED score between groups is to expected since renal impairment is a criterion.



References:

Jones MJ, Eudaley ST, Moye RA, Hodge TA, Nesbit RM, Franks AS. Safety outcomes of apixaban in patients with nonvalvular atrial fibrillation and severe renal impairment. J Thromb Thrombolysis. 2020;50(2):330-336. doi:10.1007/s11239-019-02028-z

 

Apixaban pharmacokinetics at steady state in hemodialysis patients

Design

Single-center, investigator-driven, open-label, crossover study

N=7

Objective

To determine apixaban pharmacokinetics at steady state in stable patients on hemodialysis at the doses of 2.5 mg twice daily and 5 mg twice daily

Study Groups

Apixaban 2.5 mg twice daily (n=7)

Apixaban 5 mg twice daily (n=5)

Inclusion Criteria

18–79 years of age with ESRD on stable hemodialysis treatment (three weekly sessions of 4 hours each) for at least 6 months, no significant residual kidney function, and nonvalvular atrial fibrillation

Exclusion Criteria

Active bleeding, high bleeding risk (hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, elderly, drugs or alcohol [HAS BLED] score >3), active malignancy, psychiatric disorders, drug or alcohol abuse, decompensated heart failure, pregnancy or lactation, acute myocardial infarction/cerebrovascular accident/head trauma in the last 3 months, previous history of venous thromboembolic disease in the last 6 months

Methods

Apixaban 2.5 mg BID was given before hemodialysis for 8 days. After a washout on days 10-14, apixaban 5 mg BID was given for days 15 to 22.

Duration

22 days 

Outcome Measures

Primary outcome: AUC 0–24 (the AUC across one dosing interval AUC 0–12 was initially calculated and then doubled to estimate AUC 0–24)

Secondary outcomes: Cmax, Cmin, time to peak apixaban concentration, t1/2, and accumulation index. 

Baseline Characteristics

  

All patients (N=7)

      

Age, years

 62 ± 15      

Male

 5 (71%)      

Race

White

Asian

Afro-Caribbean

 

5 (71%)

1 (14%)

1 (14%)

      

Results

 

Apixaban 2.5 mg (n=7)

P-value

Apixaban 5 mg (n-5)

P-value

AUC increase, fold

 2-5.4      

AUC 0 to 24 hours increase, ng*h/mL

2,054

0.001

6045

 0.03

Trough levels increase, ng/mL

132

 0.001

218

 0.03

Adverse Events

Common Adverse Events: minor bleeding in 1 patient with 5 mg dose

Study Author Conclusions

Apixaban 2.5 mg twice daily in patients on hemodialysis resulted in drug exposure comparable with that of the standard dose (5 mg twice daily) in patients with preserved renal function and might be a reasonable alternative to warfarin for stroke prevention in patients on dialysis. Apixaban 5 mg twice daily led to supratherapeutic levels in patients on hemodialysis and should be avoided.

InpharmD Researcher Critique

This study provided evidence of apixaban 2.5 mg twice daily dosing with similar drug exposure in hemodialysis patients compared to poor renal function. Limitations of this study include a small sample size and use of factor Xa-based assay to estimate apixaban plasma concentration instead of directly measuring with mass spectrometry. 

 

References:

Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients. J Am Soc Nephrol. 2017;28(7):2241-2248.

 

Appropriateness of Initial Dose of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation in the UK

Design

Population-based cross-sectional study

N=30,467

Objective

To evaluate the appropriateness of the initial prescribed daily dose of direct oral anticoagulants (DOACs) according to label in patients with non-valvular atrial fibrillation (NVAF) in the UK

Study Groups

Apixaban (n=10834); Standard dose (n=7061), Reduced dose (n=3773)

Dabigatran (n=4381); Standard dose (n=2018), Reduced dose (n=2363)

Rivaroxaban (n=15252); Standard dose (n=12091), Reduced dose (n=3081)

Inclusion Criteria

Patients aged ≥18 years with a first recorded prescription (index date) for apixaban, dabigatran or rivaroxaban between 01 January 2011 and 31 December 2016. Patients were required to have been registered with a GP for at least 1 year before their first DOAC prescription and to have at least 1 year prescription history. We subsequently identified patients with NVAF as those with a record of AF any time before the index date or in the 2 weeks after, and with no record of heart valve replacement or mitral stenosis during this time. 

Exclusion Criteria

Patients with a record of deep vein thrombosis, pulmonary embolism or hip/knee replacement surgery in the 3 months before the index date because these could all have been alternative reasons for DOAC initiation. 

Methods

The calculated daily dose of the index DOAC based on the product instructions (quantity, pack size, number of tablets and posology) for the first recorded DOAC prescription and extracted information on patients’ age, renal function and weight at the time of the index date, using the most recently recorded values. Patients’ renal function was ascertained using the closest valid serum creatinine value to the index date (within the year before) to calculate an estimated glomerular filtration rate (eGFR) expressed as mL/min/1.73 m2 applying the Chronic Kidney Disease Epidemiology Collaboration equation, but omitting ethnicity because this is not routinely recorded in UK primary care. 

Duration

January 2011 and December 2016

Outcome Measures

Percentage of patients prescribed a DOAC dose according to the European Union (EU) labels (appropriately dosed), and not according to the EU labels (inappropriately dosed—including both underdosed and overdosed patients); percentage of patients prescribed an initial DOAC dose according to renal function status. 

Baseline Characteristics

  

Apixaban, standard dose (n=7061)

Apixaban, reduced dose (n=3773)

 Dabigatran, standard dose (n=2018) Dabigatran, reduced dose (n=2363) Rivaroxaban, standard dose (n=12091) Rivaroxaban, reduced dose (n=3081)

Age, <60

 11.8% 1.7% 18.8% 3.1% 10.2% 2.1%

Female

 39.5% 60.6% 31.6% 51.6% 41.8% 58.2%

eGFR, mL/min

>50

30-50

<30

 

75.4%

9.8%

0.4%

 

52.2%

29.8%

6.8%

 

80.5%

5.5%

0.2%

 

69.1%

19.6%

0.7%

 

79.0%

7.4%

0.4%

 

35.9%

47.9%

7.2%

Results

Recommended Daily Dose of Index DOAC

 Standard dose

Reduced Dose

Contraindicated

Total (overall)

Apixaban

Recommended

Too low

Too high

 

74.5%

25.5%

0

 

91%

0

9.0%

2.4%

N/A

N/A

N/A

 

74.9%

21.6%

1.1%

Dabigatran

Recommended

Too low

Too high

 

78.7%

21.3%

0

 

78.4%

0

21.6%

5.3%

N/A

N/A

N/A

 

74.4%

8.7%

11.6%

Rivaroxaban

Recommended

Too low

Too high

 

88.5%

11.0%

0.4%

 

63.9%

0

36.1%

0.5%

N/A

N/A

N/A

 

84.2%

9.1%

6.6%

Among patients starting DOAC therapy on a standard daily dose, the prescription was appropriate for the vast majority of those in the apixaban cohort (97.0%) and rivaroxaban cohort (92.3%), but for fewer patients in the dabigatran cohort (69.8%)

In all three cohorts, there was a trend towards dose reduction with increasing renal impairment. Among patients with severe renal impairment (eGFR <30 mL/min /1.73 m2), most were prescribed a reduced daily dose: apixaban (91.1%, ≤5 mg), dabigatran (80.0%, ≤200 mg) and rivaroxaban (83.0%, 15 mg). 

Adverse Events

Not disclosed

Study Author Conclusions

The majority of patients starting DOAC therapy in UK primary care were prescribed a daily dose in line with the approved EU drug label.

InpharmD Researcher Critique

This study was descriptive with dosing information obtained from medical records in the primary care setting. No subsequent dosing information after the first dose prescribed was evaluated in this study.  In addition, the dosing recommendations were based on the EU-approved drug label which may differ slightly from clinical practice in the US. 

 

References:

García Rodríguez LA, Martín-Pérez M, Vora P, et al. Appropriateness of initial dose of non-vitamin K antagonist oral anticoagulants in patients with non-valvular atrial fibrillation in the UK [published correction appears in BMJ Open. 2019 Oct 8;9(10):e031341corr1]. BMJ Open. 2019;9(9):e031341. Published 2019 Sep 20. doi:10.1136/bmjopen-2019-031341

 

Effect of Renal Impairment on the Pharmacokinetics, Pharmacodynamics, and Safety of Apixaban

Design

Prospective, multicenter, open-label, parallel-group, single-dose study

N=32

Objective

To evaluate apixaban pharmacokinetics, pharmacodynamics, safety, and tolerability in healthy subjects and in subjects with mild, moderate, or severe renal impairment as measured by 24-hour creatinine clearance

Study Groups

Normal renal function (n=8)

Mild renal impairment (n=10)

Moderate renal impairment (n=7)

Severe renal impairment (n=7)

Inclusion Criteria

 Aged 18-90 years old

Exclusion Criteria

Women of childbearing potential or who were pregnant or breast-feeding; patients who had significant medical illness; bleeding or coagulation disorders; history of significant drug allergies; or prior exposure to apixaban

Subjects with normal renal function were excluded if they had a clinically significant deviation from normal on physical examination or from assessment of vital signs, electrocardiogram (ECG), or clinical laboratory findings.

Subjects with renal impairment were excluded if they had clinical or laboratory abnormalities beyond those consistent with their degree of renal dysfunction.

Methods

Participants were recruited based on their renal function (using the Cockcroft-Gault equation): 

  • normal renal function (CLcr >80 mL/min);
  • mild renal impairment (CLcr >50 to 80 mL/min);
  • moderate renal impairment (CLcr ≥30 to ≤50 mL/min);
  • and severe renal impairment (CLcr <30 mL/min and not on dialysis).

After fasting for 10 hours, patients received a single oral dose of apixaban 10 mg and an IV dose of iohexol (7.5 mL of a 300-mg/mL solution or 12.5 mL of a 180-mg/mL solution). The patients' renal function was measured using four methods: 24-hour CLcr, iohexol clearance, the Cockcroft-Gault equation, and the modification of diet in renal disease (MDRD) equation.

Duration

Participants were followed up to 96 hours post-dose

Outcome Measures

 Pharmacokinetic parameters

Baseline Characteristics

  

Normal renal function (n=8)

Mild impairment (n=10)

Moderate impairment (n=7)

 Severe impairment (n=7)

Age, years

 59 ± 2 61 ± 13 68 ± 11 65 ± 7

Female

63% 60% 14% 29%

White

 100% 6% 71% 71%

BMI, kg/m2

 29.0 ± 3.8 29.4 ± 4.4 26.6 ± 3.7 29.6 ± 7.5

Renal function, mL/min

24-h CLcr

Cockcroft-Gault

MDRD

Iohexol clearance

 

106.7 ± 14.3

98.9 ± 11.2

80.7 ± 5.6

112.5 ± 17.6

 

58.8 ± 8.1

53.7 ± 9.8

49.3 ± 12.8

50.2 ± 10.4

 

38.0 ± 6.4

41.1 ± 11.0

44.7 ± 19.3

42.5 ± 22.7

 

24.5 ± 4.1

23.7 ± 5.0

19.2 ± 6.7

19.1 ± 4.5

Results

  

Normal renal function (n=8)

Mild impairment (n=10)

Moderate impairment (n=7)

Severe impairment (n=7)

Cmax, ng/mL

 224 229 288 210

Tmax, hours

 2.8 4.0 4.0 4.0

T1/2, hours

 15.1 ± 7.6 14.6 ± 7.3 17.6 ± 6.0 17.3 ± 7.4

AUC, ng*h/mL

 2528 3288 4479 3221

CL/F, mL/min

CLrenal, mL/min

65.9

6.83

50.7

3.81

37.2

1.94

51.7

1.94

A regression analysis showed that decreasing renal function resulted in modestly increased apixaban exposure, but it did not affect Cmax or the direct relationship between apixaban plasma concentration and anti-factor Xa activity or INR.

Adverse Events

The frequency of adverse events in subjects with various degrees of renal impairment ranged from 29% to 42% and was higher than that in subjects with normal renal function (13%).

The most frequently occurring event was mild to moderate dyspepsia (20% in the mild renal impairment group); all other adverse events were reported once. All adverse events resolved prior to study completion.

Study Author Conclusions

Apixaban was well tolerated in this study. These results suggest that dose adjustment of apixaban is not required on the basis of renal function alone.

InpharmD Researcher Critique

This was only a single-dose study in a small sample size. Longer-term studies are needed to confirm the safety of apixaban in patients with renal impairment.



References:

Chang M, Yu Z, Shenker A, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2016;56(5):637-645. doi:10.1002/jcph.633