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)

Methods

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, and coagulation disorder.

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

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

Male

White

Black/African American

BMI, kg/m²

Results

Healthy (n=8)

ESRD, first dose  (n=8)

ESRD, second dose (n=8)

T½, hours

1474 ± 44%

C_max, ng/mL

126 ± 29%

98.9 ± 29%

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.

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=30467

Objective

To evaluate the appropriateness of the initial prescribed daily dose of non-vitamin K antagonist oral anticoagulants (NOACs) 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 NOAC 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 NOAC initiation. 

Methods

The calculated daily dose of the index NOAC based on the product instructions (quantity, pack size, number of tablets and posology) for the first recorded NOAC 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 NOAC 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 NOAC dose according to renal function status. 

Baseline Characteristics

Apixaban, standard dose (n=7061)

Apixaban, reduced dose (n=3773)

Age, <60

Female

eGFR, mL/min

>50

30-50

<30

Results

Recommended Daily Dose of Index NOAC

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 NOAC 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 NOAC 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. 

 A 70-year-old, 167-kg man (height, 147 cm) was initially presented to the hospital emergency department with sudden onset of shortness of breath and chest pain and was diagnosed with nonvalvular atrial fibrillation. His medical history included diastolic heart failure, type 2 diabetes mellitus, stage III kidney disease (baseline SCr, 1.5 mg/dL), coronary heart disease, hypertension, and obesity.  The patient was started on apixaban 5mg twice daily and was discharged with serum creatinine of 1.7mg/dL. 

Approximately two weeks later, the patient presented to the hospital with increased shortness of breath and serum creatinin at 3.1 mg/dL.  Apixaban was discontinued on the day of admission due to acute kidney injury.  

Intermittent hemodialysis was also initiated on hospital day 2 and continued throughout the course of active treatment due to fluid overload and acute kidney injury. The patient remained on a continuous heparin infusion for atrial fibrillation for the remainder of his hospitalization without complications or bleeding events. 

Novel Oral Anticoagulant and Kidney Injury: Apixaban-Related Acute Interstitial Nephritis

Case Report (N=1) 

 A 76-year-old, female was admitted for acute kidney injury.  The patient had a medical history of stage 4 chronic kidney disease (CKD)(baseline creatinine of 247.52 µmol/L), hypertension, pulmonary hypertension, type 2 diabetes mellitus and paroxysmal atrial fibrillation and was taking nifedipine, amiodarone, glipizide, hydralazine, metoprolol, atorvastatin, aspirin, apixaban, and sildenafil. 

The patient was diagnosed with acute interstitial nephritis (AIN) based on these laboratory values: creatinine of 1281.80 µmol/L, blood urea nitrogen of 72.83 mmol/L, bicarbonate 17 mmol/L and an anion gap of 26.  A renal ultrasound showed diffuse echogenicity in both kidneys but no obstructive uropathy. 

The patient was switched to warfarin from apixaban because apixaban was suspected to be the likely culprit since it was the most recently introduced medication.  Her serum creatinine improved significantly from 1281.80 µmol/L to 804.44 µmol/L within 1 week of withdrawal of apixaban and continued to improve after discharge from the hospital and was noted to be 433.04 µmol/L after 16 days of withdrawing apixaban. No renal replacement therapy was required.

Acute Kidney Injury Aggravated by Treatment Initiation with Apixaban: Another Twist of Anticoagulant-Related Nephropathy

Case report (N=1)

A 82-year-old Caucasian female with history of hypertension, chronic obstructive pulmonary disease (COPD), coronary artery disease, congestive heart failure, and CKD stage III with baseline serum creatinine between 1.5 and 2.0 mg/dl   presented with symptoms of COPD exacerbation and AKI with a serum creatinine of 1.7 mg/dL. Her serum creati-nine plateaued at a 3.26 mg/dL by March 13, 2017  She developed new-onset atrial fibrillation, for which treatment with apixaban (Eliquis) 2.5mg BID was initiated on March 15, 2017.  

After starting apixaban, serum creatinine significantly increased (from 3.2 to 8.5 mg/dL) within a few days, and the patient became oligoanuric. A kidney biopsy was performed on April 3, 2017 after apixaban was stopped; however, she did receive subcutaneous heparin and the patient remains dialysis dependent as of August 2017.

We suggest that kidney function should be closely monitored in all CKD patients after initiation of anticoagulation therapy.

 A 70-year-old Caucasian, male with no known kidney disease (baseline creatinine of 0.84 mg/dL) and medical history of hyperlipidemia, hypertension and atrial fibrillation initially presented with a 2-month history of fatigue, shortness of breath and intermittent gross hematuria. Laboratory values showed a creatinine of 2.5mg/dL, blood urea nitrogen 24mg/dL, bicarbonate 25mg/dl and anion gap of 5.  The patient was diagnosed with acute kidney injury. 

Due to his gross hematuria, the patient’s apixaban was held in which the serum creatinine stabilized at 2.51 mg/dL. 

In the outpatient setting, his creatinine continued to rise with a creatinine maximum of 3.83 mg/dL, and he was readmitted to the hospital. Apixaban was presumed to be the cause of his AIN since the only time his creatinine stabilised was prior to the kidney biopsy when apixaban was held. His apixaban was discontinued and was started on a VKA with a prednisone taper of 2 months.

With discontinuation of the apixaban, the patient’s serum creatinine in 1 day improved to 3.07 mg/dL. His creatinine continued to improve, after completion of the steroids with the apixaban discontinued, to 1.3 mg/dL, and his haematuria improved to microscopic hematuria over a 4-month period.