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Use of Apixaban in Patients with Nonvalvular Atrial Fibrillation and End Stage Renal Disease

Monday, February 11, 2019  
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Boluwatife Familusi, PharmD Candidate 2020, Jefferson College of Pharmacy

Preceptor: Raymond Lamore, PharmD, BCPS, Clinical Pharmacist, Penn Presbyterian Medical Center

 

Nonvalvular atrial fibrillation (NVAF) is the most common cardiac arrhythmia seen in patients with end stage renal disease (ESRD). As renal function decreases, the prevalence of NVAF has been noted to increase, with estimates ranging from 3.5% to 27% in patients on dialysis.1-3 Complications of atrial fibrillation include systemic embolism, thromboembolic stroke, death due to cardiovascular events and hemorrhage.1,4-5 Patients with advanced renal disease are at a higher risk for the development of thrombi and bleeding.4 According to Bowie et al., patients with ESRD are at a 20% increased risk of bleeding while on anticoagulation therapy.6 It is important to critically assess the risks and benefits of each anticoagulant when considering initiation for this patient population, balancing optimal pharmacokinetics with bleeding potential.

Warfarin, a vitamin K antagonist, is indicated for prophylaxis and/or treatment of thromboemboli resulting from atrial fibrillation.7 Warfarin has remained the historical anticoagulant of choice in the ESRD patient population due to its hepatic metabolism and the ability to verify therapeutic anticoagulation via INR monitoring. Additionally, reversal agents such as vitamin K, fresh frozen plasma, and/or prothrombin complex concentrates are available for the management of acute bleeding.7 Unfortunately, warfarin dosing can be dynamic, requiring extensive monitoring to optimize anticoagulation and minimize bleeding risk. Warfarin’s interaction with diet, alcohol and medications (specifically inducers and inhibitors of CYP3A4, 2C9, and 1A2) are well established.7,8 Nochaiwong et al. conducted a systematic review and meta-analysis that showed an increased risk of major bleeding in dialysis patients by approximately 35% (HR 1.35, 95% CI 1.11 to 1.64, p=0.003) and an increased risk of vascular calcification which can lead to cardiovascular complications.9 Nonetheless, familiarity with warfarin in ESRD patients promotes its use as the historically preferred anticoagulant in this population.

Apixaban (Eliquis®) is a selective, oral, direct factor Xa inhibitor.10 Apixaban when compared to warfarin is beneficial in that it is administered in fixed doses, does not require continuous anticoagulation monitoring, and has fewer interactions with food and medications because of minimal interaction with cytochrome P450 enzymes.1,9 Reversal agents are also available for apixaban, including prothrombin complex concentrates, and newly approved, andexanet alfa (Andexxa®). The recommended dosing of apixaban for NVAF is 5 mg twice daily or 2.5 mg twice daily if two of the following criteria are met: age ≥ 80, body weight ≤ 60 kg or serum creatinine ≥ 1.5 mg/dL.6,10  The ARISTOTLE study was one of the pivotal initial trials that showed that apixaban was superior to warfarin in preventing stroke or systemic embolism in AF patients, while reducing major bleeding events and all-cause mortality.12 Unfortunately, initial clinical efficacy and safety studies, including ARISTOTLE, excluded patients who had a creatinine clearance less than 25 ml/min, serum creatinine greater than 2.5mg/dl, or required dialysis.12 Apixaban, of all the direct oral anticoagulants, has the least renal clearance (~27%).6,10 The manufacturer provides dosing guidance for patients requiring intermittent hemodialysis, referencing smaller pharmacokinetic studies that demonstrated similar concentration levels as seen in the ARISTOTLE trial.10 Nonetheless, it should be noted that administering apixaban on dialysis days has shown to produce levels that are 36% and 17% higher (compared to patients with normal renal function), when checked pre- and post-dialysis, respectively. 10,13

Stanton et al., conducted a retrospective, matched cohort study that compared the safety and effectiveness of apixaban versus warfarin in patients who had a creatinine clearance less than 25 ml/min, serum creatinine greater than 2.5 mg/dl, or required peritoneal dialysis or hemodialysis.14 Seventy-three patients received warfarin, with their matched cohort receiving apixaban. The study found that there was no statistically significant difference in the occurrence of major bleeding or composite bleeding between the apixaban and warfarin groups (9.6% vs. 17.8%, p = 0.149 and 21.9% vs. 27.4%, p = 0.442).14 This led the study’s authors to conclude that apixaban could potentially be a safe option for patients with severe renal impairment. However, it is important to note, that a limited sample size likely contributed to the lack of difference between the two treatments groups, as the study required 236 patients in each treatment arm to achieve an 80% power.14

Subsequently, a single center, retrospective, cohort study conducted by Sarratt et al, analyzed the use of apixaban or warfarin in patients on chronic dialysis. A total of 160 patients were included, with 120 patients on warfarin and 40 patients receiving apixaban.15 The study’s primary outcome was to assess major and non-major bleeding events. Seven major bleeding events occurred in patients receiving warfarin and zero occurred in apixaban patients (p = 0.34). 15 Similar rates of non-major bleeding (12.5% vs. 5.8%, p = 0.17) and minor bleeding (2.5% vs. 2.5%, p = 0.74) were noted in the warfarin and apixaban groups, respectively.15 The study concluded that apixaban may be cautiously considered for use in patients on hemodialysis. Again, one should note the major limitations of this study, with disproportionate division of patient cohorts and small sample size. Both of these limitations impact the ability to distinguish differences between treatment groups, weakening the evidence presented in favor of apixaban.

The previous studies mentioned, served as critical first steps in assessing the use of apixaban in the ESRD population. However, the major limitations of these studies hindered change in clinical practice. Siontis and colleagues address these limitations with a larger, retrospective, matched cohort study. They specifically evaluated  survival free of stroke or systemic embolism, bleeding (intracranial, gastrointestinal, and/or major), as well as mortality.16 A total of 25,523 patients were enrolled, with 1,034 receiving apixaban standard dose and 1,317 receiving a reduced dose (2.5 mg every 12 hours). Each patient receiving apixaban was matched to three patients receiving warfarin, based on prognostic score.16 Results showed no difference between the apixaban and warfarin cohorts in terms of stroke or systemic embolism (HR 0.88, 95% CI 0.69-1.12, p =0.29).16 Apixaban demonstrated lower risk for major bleeding (HR 0.72; 95% CI 0.59-0.87; p <0.001).16 They also assessed for dosing impact, comparing standard and reduced dose. Their evaluation showed that standard dose apixaban resulted in a significant decrease in risk of stroke or systemic embolism and death when compared to reduced dose apixaban (HR 0.61; 95% CI 0.37-0.98; p = 0.05 for stroke or systemic embolism; HR 0.64; 95% CI 0.45-0.92; p =0.01 for death).16 The authors concluded that apixaban, for the prevention or treatment of stroke in patients with NVAF, may lower the risk for major bleeding compared to warfarin, and that standard dose performed better in reducing the risk of thromboembolism and death.16 Although these outcomes are notable, it is important to recognize the retrospective nature of the study and the possible impact reduced dose apixaban may have on the reduced bleeding risk for the entire apixaban cohort.

In conclusion, apixaban and warfarin remain appropriate anticoagulant therapies in patients with NVAF. However, controversy remains as to whether or not apixaban can be effectively and safely used in patients with ESRD. The studies reviewed have all provided additional efficacy, safety, and dosing insight. Some may consider this data adequate to support apixaban utilization in this population. Given the noted limitations of these studies, and identified risks with this population, it would be most prudent to critically assess all supporting literature through your hospital’s Pharmacy and Therapeutics Committee to take a unified stance on the approved inpatient prescribing practices.    

 

 

 

 

 

 

References

  1. Mccullough PA, Ball T, Cox KM, Assar MD. Use of Oral Anticoagulation in the Management of Atrial Fibrillation in Patients with ESRD: Pro. Clin J Am Soc Nephrol. 2016;11(11):2079-2084.
  2.  Tsagalis G, Bakirtzi N, Manios E, et al. Atrial fibrillation in chronic hemodialysis patients: prevalence, types, predictors, and treatment practices in Greece. Artif Organs. 2011;35(10):916-922.
  3. Alonso A, Lopez FL, Matsushita K, et al. Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2011;123(25):2946-2953.
  4. Lau YC, Proietti M, Guiducci E, Blann AD, Lip GYH. Atrial Fibrillation and Thromboembolism in Patients With Chronic Kidney Disease. J Am Coll Cardiol. 2016;68(13):1452-1464.
  5. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation. 2009;119(10):1363-1369.
  6. Bowie M, Valencia V, Perez-alvarez I, Tran MH. Safety analysis of apixaban versus warfarin in patients with advanced kidney disease. J Thromb Thrombolysis. 2018;46(2):246-252.
  7. Coumadin (warfarin) [package insert]. Princeton NJ: Bristol Myers Squibb; 2015
  8. Da silva RM. Novel oral anticoagulants in non-valvular atrial fibrillation. Cardiovasc Hematol Agents Med Chem. 2014;12(1):3-8.
  9. Nochaiwong S, Ruengorn C, Awiphan R, et al. Efficacy and safety of warfarin in dialysis patients with atrial fibrillation: a systematic review and meta-analysis. Open Heart. 2016;3:e000441:1-14
  10. Eliquis (apixaban) [package insert]. Princeton NJ: Bristol-Myers Squibb; 2015
  11. 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
  12. Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 2010;159:331-339 [Erratum, Am Heart J 2010;159:1162.]
  13. Wang X, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016 May;56(5):628-636.
  14. Stanton BE, Barasch NS, Tellor KB. Comparison of the Safety and Effectiveness of Apixaban versus Warfarin in Patients with Severe Renal Impairment. Pharmacotherapy. 2017;37(4):412-419.
  15. Sarratt SC, Nesbit R, Moye R. Safety Outcomes of Apixaban Compared With Warfarin in Patients With End-Stage Renal Disease. Annals of Pharmacotherapy. 2017;51(6):445-450.
  16. Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated with Apixaban Use in End-Stage Kidney Disease Patients with Atrial Fibrillation in the United States. Circulation. 2018;138:1519-1529.    

 


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