Anticoagulation in CKD: Trials and Tribulations.

Related article, p ● Related article, p ● Compared with the general population, patients with chronic kidney disease (CKD) are more likely to experience cardiovascular comorbid conditions such as atrial fibrillation (AF).1Kim S.M. Jeong Y. Kim Y.L. et al.Association of chronic kidney disease with atrial fibrillation in the general adult population: a nationwide population-based study.J Am Heart Assoc. 2023; 12e028496Crossref Scopus (0) Google Scholar Both CKD and AF independently lead to a prothrombotic state, increasing the risk of ischemic stroke.2Zeng W.T. Sun X.T. Tang K. et al.Risk of thromboembolic events in atrial fibrillation with chronic kidney disease.Stroke. 2015; 46: 157-163Crossref PubMed Scopus (48) Google Scholar Although stroke risk can be reduced with an anticoagulant in those with AF, patients with CKD are also prone to bleeding,2Zeng W.T. Sun X.T. Tang K. et al.Risk of thromboembolic events in atrial fibrillation with chronic kidney disease.Stroke. 2015; 46: 157-163Crossref PubMed Scopus (48) Google Scholar and declining kidney function may cause accumulation of renally cleared anticoagulants. So, in balancing both thromboembolic and bleeding risks, what is the optimal treatment plan for patients with CKD and AF? Warfarin has long been the anticoagulant of choice for the prevention of stroke in patients with AF and CKD. However, there are many challenges to using warfarin. Interindividual pharmacokinetics, multiple food and drug interactions, and a narrow therapeutic window leading to difficulty maintaining INRs in a therapeutic range may increase the risk of stroke, bleeding, or death. Warfarin also increases the risk of vascular calcification and, in nondialysis CKD, is associated with anticoagulant-related nephropathy.3Ha JT, Scaria A, Andrade J, et al. Safety and effectiveness of rivaroxaban versus warfarin across GFR levels in atrial fibrillation: a population-based study in Australia and Canada. Kidney Med. Published online May 16, 2023. doi:10.1016/j.xkme.2023.100675Google Scholar In recent years, direct oral anticoagulants (DOACs), including direct inhibitors of factor Xa (apixaban, edoxaban, and rivaroxaban) or of thrombin (dabigatran), have revolutionized treatment for those with AF because of their relative ease of use compared with warfarin. Steady pharmacokinetic parameters and predictable therapeutic effects eliminate the need for continuous monitoring, and DOACs are also associated with fewer drug and food interactions.4Rogula S. Gąsecka A. Mazurek T. Navarese E.P. Szarpak Ł. Filipiak K.J. Safety and efficacy of DOACs in patients with advanced and end-stage renal disease.Int J Environ Res Public Health. 2022; 19: 1436Crossref Scopus (2) Google Scholar In addition, studies have pointed to the pleotropic effects of DOACs, including anti-inflammatory and vascular protective properties,4Rogula S. Gąsecka A. Mazurek T. Navarese E.P. Szarpak Ł. Filipiak K.J. Safety and efficacy of DOACs in patients with advanced and end-stage renal disease.Int J Environ Res Public Health. 2022; 19: 1436Crossref Scopus (2) Google Scholar which may slow the decline of kidney function in those with CKD.5Trevisan M. Hjemdahl P. Clase C.M. et al.Cardiorenal outcomes among patients with atrial fibrillation treated with oral anticoagulants.Am J Kidney Dis. 2023; 81: 307-317.e1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Although studies showing the relative effectiveness and safety of DOACs in CKD are emerging, there is still much unknown about the use of these agents in advanced CKD and end stage kidney disease. In this issue of Kidney Medicine, Ha et al3Ha JT, Scaria A, Andrade J, et al. Safety and effectiveness of rivaroxaban versus warfarin across GFR levels in atrial fibrillation: a population-based study in Australia and Canada. Kidney Med. Published online May 16, 2023. doi:10.1016/j.xkme.2023.100675Google Scholar evaluated rivaroxaban, and its comparative effectiveness and safety with warfarin across varying estimated glomerular filtration rate (eGFR) levels. By using administrative data from various jurisdictions in Canada and Australia, they included 55,568 patients (27,784 rivaroxaban-warfarin user matched pairs) who had a range of kidney function categorized as eGFR >60, 45-59, 30-44, and <30 mL/min/1.73 m2. This study suggested that rivaroxaban is at least as effective and safe as warfarin across the spectrum of kidney function. However, it is important to note that, of all the Canadians and Australians included in the study, only 2.4% of patients had an eGFR <30 mL/min/1.73 m2.3Ha JT, Scaria A, Andrade J, et al. Safety and effectiveness of rivaroxaban versus warfarin across GFR levels in atrial fibrillation: a population-based study in Australia and Canada. Kidney Med. Published online May 16, 2023. doi:10.1016/j.xkme.2023.100675Google Scholar Although this small sample may be representative of the population of patients with advanced CKD and AF who were deemed suitable for anticoagulation, it may also suggest a prescribing bias against DOACs in this patient group. This prescribing bias may be the result of several uncertainties surrounding the use of DOACs in advanced CKD. One of the largest knowledge gaps in DOAC therapy is how their effectiveness and safety stack up to warfarin in those with eGFR <30 mL/min/1.73 m2. Landmark randomized controlled trials have provided solid evidence on the efficacy and safety of DOACS in patients with mild to moderate CKD through subgroup analyses.6Kimachi M. Furukawa T.A. Kimachi K. Goto Y. Fukuma S. Fukuhara S. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease.Cochrane Database Syst Rev. 2017; 11: CD011373PubMed Google Scholar However, these trials largely excluded patients with advanced stages of kidney disease; so, robust randomized controlled trial data addressing the safety and efficacy of DOACs in AF and later stages of CKD is lacking. Much of the guidance available for the use of DOACs in this population comes from observational studies that have yielded mixed efficacy and safety signals.7Feldberg J, Ma J, Farrell A, Patel P, Cameron K, Battistella M. DOAC use in hemodialysis patients with atrial fibrillation: a systematic review of stroke and bleeding Outcomes NDT. 2018;1-18.Google Scholar Furthermore, optimal dosing recommendations for DOACs in patients with advanced CKD are unclear. Because all DOACs undergo a degree of kidney elimination (apixaban 27%, rivaroxaban 36%, edoxaban 50%, and dabigatran 80%), we expect drug accumulation and subsequent adverse effects (bleeding) with reduced kidney clearance.8Grandone E. Aucella F. Barcellona D. et al.Position paper on the safety/efficacy profile of direct oral anticoagulants in patients with chronic kidney disease. Consensus document from the SIN, FCSA and SISET.Blood Transfus. 2020; 18: 478-485PubMed Google Scholar Thus, dose adjustments based on kidney function would be reasonable in the advanced CKD population and would depend on estimates of kidney function. Yet, currently, there is not 1 universal measure for estimating kidney function for drug dosing, and different measurements are not numerically equivalent. Although Ha et al3Ha JT, Scaria A, Andrade J, et al. Safety and effectiveness of rivaroxaban versus warfarin across GFR levels in atrial fibrillation: a population-based study in Australia and Canada. Kidney Med. Published online May 16, 2023. doi:10.1016/j.xkme.2023.100675Google Scholar used eGFR, a value frequently reported by laboratories and often used in observational trials, creatinine clearance was used in large randomized controlled trials that informed kidney dose adjustments in product monographs. Regardless of whether we use eGFR or creatinine clearance to measure kidney function, there is generally a lack of guidance on the optimal DOAC dosing in patients with AF and eGFR <30 mL/min. Although product monographs for each DOAC list recommendations for kidney dose adjustments down to eGFR 15 mL/min, this is largely based on data from clinical pharmacology studies comparing serum drug concentrations in those with varying degrees of kidney impairment with those with normal kidney function. However, data from these studies are inconsistent. Some studies evaluating the effects of impaired kidney function on single dose of rivaroxaban suggest that it is likely to accumulate in patients with CKD and patients receiving hemodialysis, even at lesser doses.9Jain N. Reilly R.F. Clinical Pharmacology of oral anticoagulants in patients with kidney disease.Clin J Am Soc Nephrol. 2019; 14 (Published correction appears in Clin J Am Soc Nephrol. 2019;14(5):750): 278-287https://doi.org/10.2215/CJN.02630319Crossref PubMed Scopus (0) Google Scholar However, a different study of rivaroxaban in participants receiving dialysis found no significant accumulation after multiple doses.9Jain N. Reilly R.F. Clinical Pharmacology of oral anticoagulants in patients with kidney disease.Clin J Am Soc Nephrol. 2019; 14 (Published correction appears in Clin J Am Soc Nephrol. 2019;14(5):750): 278-287https://doi.org/10.2215/CJN.02630319Crossref PubMed Scopus (0) Google Scholar Further, single dose studies report modest increases in apixaban exposure in patients with advanced CKD, including those receiving dialysis, whereas another study found supratherapeutic levels in patients receiving hemodialysis and recommended dose adjustments.9Jain N. Reilly R.F. Clinical Pharmacology of oral anticoagulants in patients with kidney disease.Clin J Am Soc Nephrol. 2019; 14 (Published correction appears in Clin J Am Soc Nephrol. 2019;14(5):750): 278-287https://doi.org/10.2215/CJN.02630319Crossref PubMed Scopus (0) Google Scholar Similarly, varying dosing regimens have been suggested to offset the increased dabigatran and edoxaban exposure observed in patients with severe kidney impairment.9Jain N. Reilly R.F. Clinical Pharmacology of oral anticoagulants in patients with kidney disease.Clin J Am Soc Nephrol. 2019; 14 (Published correction appears in Clin J Am Soc Nephrol. 2019;14(5):750): 278-287https://doi.org/10.2215/CJN.02630319Crossref PubMed Scopus (0) Google Scholar, 10Liesenfeld K.H. Clemens A. Kreuzer J. Brueckmann M. Schulze F. Dabigatran treatment simulation in patients undergoing maintenance haemodialysis.Thromb Haemost. 2016; 115: 562-569Crossref PubMed Google Scholar, 11Salazar D.E. Mendell J. Kastrissios H. et al.Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation.Thromb Haemost. 2012; 107: 925-936Crossref PubMed Scopus (123) Google Scholar The dosing of DOACs is further complicated by interpatient variability, which has been observed in patients with variable stages of kidney disease.12Chen A. Stecker E. Warden B.A. Direct oral anticoagulant use: a practical guide to common clinical challenges.J Am Heart Assoc. 2020; 9e017559Crossref Scopus (180) Google Scholar This may be owing to factors such as body size and composition, gastrointestinal physiology, additional comorbid conditions, pharmacogenetic factors, and drug interactions.12Chen A. Stecker E. Warden B.A. Direct oral anticoagulant use: a practical guide to common clinical challenges.J Am Heart Assoc. 2020; 9e017559Crossref Scopus (180) Google Scholar,13Gulilat M. Keller D. Linton B. et al.Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care.J Thromb Thrombolysis. 2020; 49: 294-303Crossref PubMed Scopus (28) Google Scholar Thus, generalizing the benefits of DOACS reliably and safely across the spectrum of kidney function becomes difficult because the extent of pharmacokinetic and subsequent pharmacodynamic alterations in various stages of kidney impairment is uncertain. Faced with this clinical conundrum, clinicians may turn to evidence-based guidelines to offer insight on best practices. However, the American Guidelines American Heart Association/American College of Cardiology/Heart Rhythm Society,14January C.T. Wann L.S. 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.J Am Coll Cardiol. 2019; 74 (Published correction appears in J Am Coll Cardiol. 2019;74(4):599): 104-132https://doi.org/10.1016/j.jacc.2019.06.034Crossref PubMed Scopus (3) Google Scholar the European Society of Cardiology,15Hindricks G. Potpara T. Dagres N. et al.2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.Eur Heart J. 2021; 42 (Published correction appears in Eur Heart J. 2021;42(40):4194): 373-498https://doi.org/10.1093/eurheartj/ehab648Crossref PubMed Scopus (105) Google Scholar the Kidney Disease Improving Global Outcomes,16Turakhia M.P. Blankestijn P.J. Carrero J.J. et al.Chronic kidney disease and arrhythmias: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Eur Heart J. 2018; 39: 2314-2325Crossref PubMed Scopus (143) Google Scholar and the Canadian Cardiovascular Society17Andrade J.G. Aguilar M. Atzema C. et al.The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.Can J Cardiol. 2020; 36: 1847-1948Abstract Full Text Full Text PDF PubMed Google Scholar are not aligned with one another when it comes to the recommended anticoagulant in those with eGFR <30 mL/min/1.73 m2. For example, the 2019 American guidelines on AF provide a class IIb recommendation for the use of either apixaban or warfarin in patients with AF and end stage kidney disease or receiving hemodialysis.14January C.T. Wann L.S. 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.J Am Coll Cardiol. 2019; 74 (Published correction appears in J Am Coll Cardiol. 2019;74(4):599): 104-132https://doi.org/10.1016/j.jacc.2019.06.034Crossref PubMed Scopus (3) Google Scholar Conversely, the European and Canadian guidelines caution DOAC use in patients with eGFR between 15-30 mL/min/1.73 m2 and contraindicate use in eGFR <15 mL/min/1.73 m2 and those undergoing dialysis.15Hindricks G. Potpara T. Dagres N. et al.2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.Eur Heart J. 2021; 42 (Published correction appears in Eur Heart J. 2021;42(40):4194): 373-498https://doi.org/10.1093/eurheartj/ehab648Crossref PubMed Scopus (105) Google Scholar,17Andrade J.G. Aguilar M. Atzema C. et al.The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society comprehensive guidelines for the management of atrial fibrillation.Can J Cardiol. 2020; 36: 1847-1948Abstract Full Text Full Text PDF PubMed Google Scholar This is not surprising, given the lack of robust randomized controlled trial data, and the conflicting observational and pharmacokinetic data in this population. So, the question still exists, can we effectively use DOACs in patients with AF who have eGFR <30 mL/min/1.73 m2. Certainly, concerns about accumulation of renally cleared DOACs and safety implications of increased risk of bleeding remain a top priority. Nevertheless, understanding the efficacy implications of kidney dose adjustments is an equally important piece of this puzzle, especially in with eGFR <15 mL/min/1.73 m2 and those dependent on dialysis. In a study comparing effectiveness and safety of apixaban versus warfarin among dialysis patients, there was no difference overall in rates of stroke or embolism.18Siontis K.C. Zhang X. Eckard A. et al.Outcomes associated with Apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States.Circulation. 2018; 138 (Published correction appears in Circulation. 2018;138(15):e425): 1519-1529Crossref PubMed Scopus (263) Google Scholar Yet, the 5 mg apixaban group showed significantly lesser rates of stroke compared with warfarin versus the group that received 2.5 mg apixaban. Such findings highlight the need for outcome-based studies evaluating the most effective dose of each DOAC in patients with advanced CKD, receiving dialysis. As the quest for the optimal anticoagulation strategy for those with AF and advanced CKD continues, it is important to emphasize the practical aspects of the different agents. Although warfarin presents the challenge of maintaining in-target INRs, there is comfort in measuring INR to determine a patient’s coagulation state. Importantly, the availability of a cost effective reversal agent such as vitamin K is reassuring given the risk of bleeding. DOACs on the other hand have much steadier and predictable pharmacokinetics and less risk of major bleeding compared with warfarin in the general population, yet only dabigatran has a direct-acting reversal agent.19van Es N. De Caterina R. Weitz J.I. Reversal agents for current and forthcoming direct oral anticoagulants.Eur Heart J. 2023; 44: 1795-1806Crossref PubMed Scopus (1) Google Scholar Reversal of rivaroxaban and apixaban involves using inactive human factor Xa to combat the direct inhibitory effects of these DOACs on endogenous factor Xa.31 These agents are very costly, and there is no guidance on their post reversal effects on hypercoagulation. In addition, DOACs are not completely free of drug interactions. P-gp inhibitors like ketoconazole and inducers like rifampin may increase or decrease levels of DOACs, respectively, and CYP3A4 inducers like valproic acid may reduce levels of apixaban and rivaroxaban.20Ferri N. Colombo E. Tenconi M. Baldessin L. Corsini A. Drug-drug interactions of direct oral anticoagulants (DOACs): from pharmacological to clinical practice.Pharmaceutics. 2022; 14: 1120Crossref Scopus (11) Google Scholar Considering the existing evidence on anticoagulant use in those with advanced CKD, it is clear that 1 agent is not the magic potion above all others. Still, Ha et al3Ha JT, Scaria A, Andrade J, et al. Safety and effectiveness of rivaroxaban versus warfarin across GFR levels in atrial fibrillation: a population-based study in Australia and Canada. Kidney Med. Published online May 16, 2023. doi:10.1016/j.xkme.2023.100675Google Scholar were able to add to a limited body of real-world evidence showing effectiveness and safety of rivaroxaban in those with eGFR <30 mL/min/1.73 m2. More robust studies are needed to demystify the role of DOACs across the spectrum of kidney function. Whether 1 anticoagulant is a greater poison to those with advanced CKD, including those dependent on dialysis, is a tantalizing question that remains to be answered. Mai Mohsen, BSc Phm, MScPhm, Tracy Zhang, BSc Phm, MSc Phm, Marisa Battistella, HBSc, BScPhm, Pharm D None. Dr Battistella has received speaking honoraria from Pfizer Canada (manufacturer of apixaban) in 2020. The remaining authors declare that they have no relevant financial interests. Received May 25, 2023 in response to an invitation from the journal. Accepted May 26, 2023 after editorial review by the Editor-in-Chief. ▪▪▪ Safety and Effectiveness of Rivaroxaban Versus Warfarin Across GFR Levels in Atrial Fibrillation: A Population-Based Study in Australia and CanadaKidney MedicineVol. 5Issue 7PreviewThe benefit–risk profile of rivaroxaban versus warfarin for atrial fibrillation (AF) in patients with chronic kidney disease is uncertain. We compared rivaroxaban with warfarin across the range of kidney function in adults with AF. Full-Text PDF Open Access