Managing Anticoagulation in a Patient With Nonvalvular AFib on Hemodialysis
A 66-year-old male with end-stage renal failure is referred to the cardiovascular clinic for management of newly diagnosed paroxysmal atrial fibrillation (AF). A day prior to presentation he underwent hemodialysis and complained of palpitations. A 12-lead electrocardiogram (ECG) demonstrated AF at a rate of 100 beats per minute. After a few minutes, and without any intervention, the palpitations stopped and a second ECG demonstrated normal sinus rhythm. In retrospect, the patient reported that he had been experiencing intermittent palpitations during the last three months.
He has medical history of hypertension, hyperlipidemia, diabetes, and end-stage renal disease (on hemodialysis three times per week). In 2010 he experienced a deep vein thrombosis of the right lower extremity after a total knee replacement surgery. He was treated with warfarin for three months. During this time he had frequent bruising without trauma. His outpatient medications included lisinopril 5 mg daily, rosuvastatin 10 mg daily, aspirin 81 mg daily, insulin glargine 20 units at night, insulin aspart 7 units before meals, salbutamol inhaler as needed, and inhaled tiotropium 18 mcg daily. He does not have reported allergies.
On arrival to the cardiovascular clinic, he is asymptomatic. He is afebrile and has an irregular heart rate of 90 beats per minute, blood pressure of 140/75 mm Hg, respiratory rate of 14 breaths per minute, oxygen saturation of 95% on room air, and body weight of 180 pounds (81 kilograms). Physical exam is only remarkable for an irregular irregular rhythm. An ECG shows AF with a ventricular rate of 90 beats per minute. A transthoracic echocardiogram shows an ejection fraction of 55% with a moderately enlarged left atrium but no significant valvular abnormalities. The patient is reluctant to try warfarin again.
Which of the following medical interventions is the most appropriate to reduce the risk of stroke and systemic embolism in this patient?
The correct answer is: A) Apixaban 5 mg twice daily
Patients with chronic kidney disease (CKD) and atrial fibrillation (AF) represent a population with unique characteristics. Several studies have reported CKD as an independent risk factor for stroke and systemic embolic events (SEE).1-5 Likewise, retrospective studies 6-9 show that patients with end-stage renal disease (ESRD) have an elevated risk of gastrointestinal and cerebrovascular hemorrhage. Not surprisingly, renal dysfunction is a predictor of bleeding events in the HAS-BLED and ATRIA bleeding scores. Furthermore, the use of dialysis adds complexity to the management of patients with AF and CKD since the risk of thromboembolism and bleeding may increase.10-13 Additionally, the use of dialysis may alter the pharmacokinetics of some drugs, including anticoagulants.
Although there is clear evidence that the benefit of warfarin outweighs its risk in the general and non-dialysis dependent CKD patients with AF, there is limited and conflicting evidence on patients with CKD undergoing hemodialysis. A 2003 analysis of the United States Renal Data System Dialysis Morbidity and Mortality Study Wave II 14 showed that the use of warfarin was associated with reduced mortality in patients hospitalized for AF. However, other studies reported that the use of warfarin in patients undergoing hemodialysis is associated with increased risk of stroke 15,10 and intracranial bleeding 16 compared to non-dialysis individuals. A recent population-based retrospective cohort study 17 reported that warfarin is not useful to reduce stroke and significantly increases the risk of bleeding in individuals diagnosed with AF and undergoing dialysis. Furthermore, INR variability is higher in patients maintained on hemodialysis and warfarin compared to non-dialysis patients on warfarin.18 Therefore, patients treated with warfarin and maintained on dialysis should undergo close and frequent INR monitoring.
The efficacy and safety of the new oral anticoagulants (NOACs) have been assessed in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy),19 ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation),20 ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) 21 and ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) 22 trials. Furthermore, apixaban was compared with aspirin to prevent strokes and SEE in patients unsuitable to receive a vitamin K antagonist (VKA) in the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) trial.23 Individuals with creatinine clearance (CrCl) <30 mL/min were excluded from the RE-LY, ROCKET-AF, and ENGAGE AF-TIMI 48 trial, while the ARISTOTLE and AVERROES trial excluded patients with CrCl <25 mL/min or serum creatinine >2.5 mg. Within each trial, NOACs were at least non-inferior to VKAs within the overall population. The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have approved dabigatran, rivaroxaban, and apixaban for use in patients with nonvalvular AF, while edoxaban is currently being evaluated by these agencies.
Information from pharmacokinetic studies can guide clinicians to make appropriate therapeutic decisions. As 35% of plasma dabigatran is bound to proteins, it can substantially be removed from plasma by hemodialysis. After four hours of dialysis, 68% of the pre-dialysis concentration of plasma dabigatran is removed and anticoagulation activity declines with decreasing plasma concentrations of dabigatran.24 The U.S. FDA does not provide a recommended dose of dabigatran for patients with CrCl <15 mL/min or on dialysis, and the EMA emphasizes that dialysis substantially reduces the anticoagulant effect of dabigatran. In the case of edoxaban, 55% of the drug in plasma is known to be bound to proteins, however a recent pharmacokinetic study showed that hemodialysis has minimal effects on the clearance of edoxaban and dose adjustment might not be necessary.25
Since 87% and 90% of plasma apixaban and rivaroxaban, respectively, are bound to proteins,26 they are not expected to be substantially dialyzable. Therefore, apixaban and rivaroxaban could represent reasonable alternatives for patients with AF maintained on dialysis. Although the EMA and U.S. FDA do not recommend the use of rivaroxaban in patients with CrCl <15 mL/min and highlights that rivaroxaban is unlikely to be dialyzable, they do not provide a specific statement regarding the use of rivaroxaban in patients on hemodialysis. For apixaban, the U.S. FDA released a supplemental approval letter on January 30, 2014, that changed the full prescribing information and added a new subsection ("8.6 End-Stage Renal Disease Patients Maintained with Hemodialysis") that reads 27:
"Patients with ESRD with or without hemodialysis were not studied in clinical efficacy and safety studies with ELIQUIS [apixaban]; therefore, the dosing recommendation is based on pharmacokinetic and pharmacodynamics (anti-Factor Xa activity) data in subjects with ESRD maintained on dialysis. The recommended dose for ESRD patients maintained with hemodialysis is 5 mg orally twice daily. For ESRD patients maintained with hemodialysis with one of the following patient characteristics, age ≥80 years or body weight ≤60 kg, reduce dose to 2.5 mg twice daily."
Aspirin should only be considered in patients with a CHADS2 score or CHA2DS2-VASc score of 0-1. In individuals with scores ≥2, oral anticoagulation is strongly recommended. Additionally, studies have suggested that in patients with a CHADS2 score of 1, warfarin could be more effective than aspirin to prevent ischemic strokes without increasing the risk of bleeding.28-30 The guidelines of the European Society of Cardiology for the management of AF 31 do not recommend the use of aspirin in patients with a CHA2DS2-VASc score of 1 (a CHADS2 score of 0) and instead suggest the consideration of oral anticoagulation. Likewise, the 2014 guidelines of the American Heart Association, American College of Cardiology, and Heart Rhythm Society 32 only support aspirin as a potential treatment in patients with a CHA2DS2-VASc score of 1 (IIb). The AVERROES trial 23 found that in patients unsuitable to receive warfarin, apixaban was far superior to aspirin to prevent strokes and SEE without increasing the risk of bleeding.
- Collins AJ, Foley RN, Chavers B, et al. United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States. Am J Kidney Dis 2012;59 (1 Suppl 1):A7, e1-420.
- Tsukamoto Y, Takahashi W, Takizawa S, Kawada S, Takagi S. Chronic kidney disease in patients with ischemic stroke. J Stroke Cerebrovasc Dis 2012; 21(7):547-550.
- Ninomiya T, Kiyohara Y, Kubo M, et al. Chronic kidney disease and cardiovascular disease in a general Japanese population: the Hisayama Study. Kidney Int 2005;68 (1):228-236.
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- Nakayama M, Metoki H, Terawaki H, et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population--the Ohasama study. Nephrol Dial Transplant 2007;22 (7):1910-1915.
- Wasse H, Gillen DL, Ball AM, Kestenbaum BR, Seliger SL, Sherrard D, Stehman-Breen CO. Risk factors for upper gastrointestinal bleeding among end-stage renal disease patients. Kidney Int 2003;64(4):1455-1461.
- Shimizu Y, Maeda K, Imano H, Ohira T, Kitamura A, Kiyama M, Okada T, Ishikawa Y, Shimamoto T, Yamagishi K, Tanigawa T, Iso H (2011) Chronic kidney disease and drinking status in relation to risks of stroke and its subtypes: the Circulatory Risk in Communities Study (CIRCS). Stroke 2011; 42 (9):2531-2537.
- Molshatzki N, Orion D, Tsabari R, Schwammenthal Y, Merzeliak O, Toashi M, Tanne D. Chronic kidney disease in patients with acute intracerebral hemorrhage: association with large hematoma volume and poor outcome. Cerebrovasc Dis 2011;31 (3):271-277.
- Rhoney DH, Parker D, Jr., Millis SR, Whittaker P. Kidney dysfunction at the time of intracerebral hemorrhage is associated with increased in-hospital mortality: a retrospective observational cohort study. Neurol Res 2012;34 (5):518-521.
- Wizemann V, Tong L, Satayathum S, Disney A, Akiba T, Fissell RB, Kerr PG, Young EW, Robinson BM. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010;77 (12):1098-1106.
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