Apixaban in Renal Failure: Are We Approaching the End of the Warfarin Era?

A practical look at safety, pharmacokinetics, and real-world data in dialysis patients

Warfarin has historically been the main oral anticoagulant used in patients with renal insufficiency. However, it is not an ideal option, particularly in this population. Clinical trials have shown that the time in therapeutic range (TTR) is consistently below recommended levels 44% in RENAL-AF¹ and 50.7% in AXADIA-AFNET ⁸². This means that many patients remain outside the therapeutic range, increasing both thrombotic and bleeding risks. Additionally, in dialysis patients, warfarin has been associated with adverse effects such as vascular calcification and bone demineralization.³

Since the introduction of direct oral anticoagulants (DOACs), concerns have arisen regarding their use in patients with severely reduced kidney function and those on dialysis. These concerns are pharmacologically justified: dabigatran undergoes approximately 80% renal elimination, and rivaroxaban around 33–35%. This dependence on renal clearance explains the hesitation. Apixaban, in contrast, has lower renal clearance, approximately 25%, making it pharmacokinetically more attractive in this setting.³

DOACs are practical in routine clinical use, which has driven their adoption even in patients with impaired kidney function. Apixaban, given its pharmacokinetic profile, has been specifically studied in this setting. In the RENAL-AF pharmacokinetic substudy, apixaban 5 mg twice daily in dialysis patients showed plasma exposure comparable to that observed in patients with creatinine clearance (CrCl) 30–44 mL/min in the ARISTOTLE trial (median AUC₀–₁₂ 2475 vs. 2402 ng/mL×h, respectively).¹

Similarly, apixaban 2.5 mg twice daily showed comparable plasma exposure across a wide range of kidney function (CrCl 15 to 90 mL/min) in the same RENAL-AF substudy.¹ In a small prospective series of 15 dialysis patients, the 2.5 mg twice-daily regimen did not demonstrate accumulation, with approximately 75% of peak and trough measurements remaining within the 5th–95th percentile of the reference population. In about 25% of cases, levels were below this range, raising the possibility of subtherapeutic exposure in a subset of patients.⁴

While recent COBRRA trial, published in the New England Journal of Medicine, provided direct head-to-head data showing that apixaban reduces the risk of bleeding compared with rivaroxaban, they excluded patients with severe renal impairment (CrCl ❤0 mL/min). There was a 54% relative reduction in clinically relevant bleeding (3.3% vs. 7.1%; RR 0.46; 95% CI 0.33–0.65), without an increase in recurrent venous thromboembolism.⁵ Fortunately, dialysis-specific cohorts are beginning to mirror these safety signals.

Similar findings have been reported in the VTE setting in dialysis patients. In a large cohort of 11,565 dialysis patients with acute VTE, apixaban was associated with a 19% reduction in the risk of major bleeding compared with warfarin (10.3% vs. 13.7%; HR 0.81; 95% CI 0.70–0.94).⁶ This study also reported a marked increase in apixaban use in this population, from 2% in 2014 to 47% in 2018.⁶ In an ASH 2023 retrospective abstract of 302 dialysis patients with atrial fibrillation, apixaban was associated with lower overall bleeding rates (17.3% vs. 39.7% with vitamin K antagonists; adjusted OR 0.13; 95% CI 0.04–0.42; p=0.001) and lower rates of stroke or systemic embolism (1.04% vs. 7.2%/year; p<0.05).⁷ A substantial body of observational evidence points in the same direction, particularly favoring apixaban in terms of safety.

A recent meta-analysis of patients on dialysis, including eight studies (two randomized controlled trials and six retrospective studies), totaling 22,405 patients, showed that apixaban was associated with a statistically significant reduction in major bleeding (RR 0.61; 95% CI 0.48–0.77), gastrointestinal bleeding (RR 0.74; 95% CI 0.64–0.85), and intracranial hemorrhage (RR 0.64; 95% CI 0.49–0.84) compared with vitamin K antagonists.³ However, this reduction in bleeding was largely driven by observational studies; the two randomized trials showed no significant difference in major bleeding (RR 0.87; 95% CI 0.41–1.82).³ This highlights the lack of adequately powered randomized trials, as RENAL-AF¹ and AXADIA-AFNET ⁸² did not achieve sufficient statistical power. But taken together, pharmacokinetic rationale, observational data, and limited randomized evidence consistently point toward a more favorable safety profile of apixaban compared with vitamin K antagonists in this population.

In venous thromboembolism (VTE) among dialysis patients, the optimal dose is not well defined. The standard regimen (10 mg twice daily for 7 days followed by 5 mg twice daily) lacks robust supporting evidence in this population. Most available data are observational and heterogeneous. In the literature, there is a tendency to use 5 mg twice daily; however, in clinical practice, the 2.5 mg twice-daily dose is also frequently used.⁶ ⁸

Similarly, in atrial fibrillation, there is no clear consensus on dosing. Some studies used 2.5 mg twice daily,² ⁷ while others used 5 mg twice daily with dose reduction based on age, body weight, and serum creatinine.¹ Given the advanced kidney disease in this population, there is a tendency toward using 2.5 mg twice daily.⁸ ⁹

Although high-quality evidence supporting apixaban in end-stage kidney disease remains limited, its main comparator, vitamin K antagonists, is well known for its limitations. As a result, apixaban has been gaining ground in this setting. In my opinion, it is becoming the first-line treatment option for this population.

References

1. 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.
2. Reinecke H, Engelbertz C, Bauersachs R, et al. A randomized controlled trial comparing apixaban with the vitamin K antagonist phenprocoumon in patients on chronic hemodialysis: the AXADIA-AFNET 8 study. Circulation. 2023;147(4):296–309. doi:10.1161/CIRCULATIONAHA.122.062779.
3. Zhang Y, Wang J, Shen N, Jiang J, Xie Y. Safety and efficacy of apixaban versus vitamin K antagonists in patients undergoing dialysis: a systematic review and meta-analysis. Renal Failure. 2024;46(1):2349114. doi:10.1080/0886022X.2024.2349114.
4. Tseng CI, Roddick AJ, Bottomley MJ, Shapiro S, Udayaraj U. Safety and pharmacokinetic profile of apixaban in end-stage renal disease: a real-world analysis. eJHaem. 2022. doi:10.1002/jha2.606.
5. Castellucci LA, Chen VM, Kovacs MJ, et al. Bleeding risk with apixaban vs rivaroxaban in acute venous thromboembolism. New England Journal of Medicine. 2026. doi:10.1056/NEJMoa2510703.
6. Ellenbogen MI, Ardeshirrouhanifard S, Segal JB, Streiff MB, Deitelzweig SB, Brotman DJ. Safety and effectiveness of apixaban versus warfarin for acute venous thromboembolism in patients with end-stage kidney disease: a national cohort study. Journal of Hospital Medicine. 2022. doi:10.1002/jhm.12926.
7. Muzio S, Artaza G, Benitez Hidalgo O, et al. Apixaban vs vitamin K antagonist as anticoagulant therapy in patients with end-stage kidney disease on hemodialysis and with atrial fibrillation. Blood. 2023;142(Suppl 1). doi:10.1182/blood-2023–190604. (ASH 2023 abstract.)
8. Gillis S, Phelan E, Pitman J, et al. Scoping review of apixaban and rivaroxaban dosing for atrial fibrillation and venous thromboembolism in advanced chronic kidney disease. International Journal of Clinical Pharmacy. 2026. doi:10.1007/s11096–026–02096–1.
9. Oliveira HM, Barros LP, Vaz de Campos MCA, et al. Anticoagulation strategies for atrial fibrillation in CKD stage G5 and dialysis patients: an updated scoping review. Reviews in Cardiovascular Medicine. 2025;26(3):26736. doi:10.31083/RCM26736.