Editor's Note: Commentary based on Chan K, Edelman E, Wenger J, et al. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 2015;131:972-79.

Background

Dabigatran and rivaroxaban are two newer direct oral anticoagulants (DOACs) approved for stroke prevention in atrial fibrillation (AF). Both medications rely, in part, on renal elimination and, therefore, require dose adjustment or avoidance at lower levels of renal function. This study explored the use of dabigatran and rivaroxaban among patients on hemodialysis, for which both of these medications are not advised.

Methods

Using the prospective Fresenius Medical Care North America database of patients undergoing dialysis at more than 1,500 clinics across the U.S., 29,977 patients with AF and end-stage renal disease on dialysis were explored for use of dabigatran, rivaroxaban, and warfarin. Clinical outcomes included rates of bleeding, stroke, and arterial embolism for patients treated with each of the three medications. Poisson regression was performed to assess risk-adjusted rates of hospitalization or death from bleeding.

Results

The first use of a DOAC in a dialysis patient occurred within 45 days of U.S. Food and Drug Administration (FDA) approval for dabigatran, and 161 days for rivaroxaban. Use of both drugs has risen steadily, representing 5.9% of all dialysis patients receiving any anticoagulant. Despite decreased clearance in patients with severe renal dysfunction, 15.3% of dabigatran-treated dialysis patients received the full dose (150 mg twice-daily), while 32.1% of rivaroxaban-treated dialysis patients received the full dose (20 mg once-daily). Risk-adjusted rate ratios for hospitalization or death from bleeding were 1.48 (95% confidence interval [CI] 1.21-1.81) for dabigatran, and 1.38 (95% CI 1.03-1.83) for rivaroxaban when compared to warfarin treatment. The risk-adjusted rate ratio of hemorrhagic death was similarly elevated in dabigatran patients (1.78, 95% CI 1.18-2.68) and rivaroxaban patients (1.71, 95% CI 0.94-3.12) when compared to warfarin.

Conclusions

Dialysis patients with AF are increasingly being started on dabigatran and rivaroxaban, even when their use is contraindicated. Use of these medications is associated with increased risk- adjusted rates of bleeding complications when compared to warfarin therapy in end-stage renal disease patients with AF.

Commentary/Perspective

With the introduction of four new DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban), clinicians must change the way they approach patients requiring anticoagulation. One of the many changes includes monitoring renal function and assessing dosing appropriateness based on the level of renal function. While this was a lesser issue with warfarin, because of international normalized ratio (INR) monitoring, renal function assessment is critical for patients being prescribed any of the DOAC medications.

This article describes one of the key issues surrounding renal function and DOAC use, namely the safe use among dialysis patients. Despite dialysis patients being excluded from ALL of the major phase 3 trials of DOACs for stroke prevention in AF, Chan and colleagues describe the use of dabigatran or rivaroxaban among 5.9% of AF patients undergoing dialysis. This report is particularly noteworthy given the large sample size, high-quality data abstraction, and nation-wide representation of clinics. While the high rate of DOAC use among dialysis patients in this report is remarkable, the increased risk of bleeding is not surprising. Early reports of dabigatran use highlighted the frequency of moderate-severe renal impairment among patients experiencing bleeding events.¹ Similarly, reports of dabigatran use from a Danish national registry identified use of dabigatran among patients with moderate-to-severe renal dysfunction, many of whom were receiving the full dose (150 mg twice-daily).²

A few potential explanations exist for the use of these two DOACs among AF patients undergoing dialysis. The first is that DOACs have made prescribing oral anticoagulants much less burdensome. Without the need for frequent INR monitoring, dose adjustment, numerous drug-drug and drug-food interactions, and dramatically simplifying periprocedural management, a wider array of clinicians feel comfortable initiating DOAC therapy as compared to warfarin therapy. Additionally, the vast majority of DOAC patients are not referred to a formalized anticoagulation management service. The few anticoagulation management services that do follow DOAC patients often verify that the dosing meets FDA-prescribing recommendations at the time a patient is enrolled. The second possible explanation is the FDA's labeling of apixaban for safe use in dialysis patients. While there are no randomized data to support the use of apixaban among dialysis patients, the FDA package label for use in dialysis patients was based on a single, unpublished, single-dose pharmacokinetic study in eight patients.³ Clinicians, particularly those who do not frequently prescribe anticoagulants for AF, may not be familiar with the more subtle differences in approved indications or clinical outcomes studies for each of the DOAC medications.

The overarching question of anticoagulation for AF patients on dialysis remains a topic of important debate. While numerous studies have highlighted renal dysfunction as an important predictor of stroke risk, others have noted an increased risk of bleeding among the same patient population when treated with oral anticoagulants.^4-8 Additionally, very few studies have explored the safety of oral anticoagulation in patients undergoing hemodialysis. There are a few, small, dose-finding studies exploring the safety of DOAC use among dialysis patients.^9,10 However, these are not appropriately powered to assess for clinical outcomes. Experts are still unclear as to the best approach for stroke prevention in AF patients on chronic dialysis.^11-13

In summary, clinicians should be keenly aware of their patient's renal function when prescribing any oral anticoagulant, particularly a DOAC. Each of the four DOACs should be dose-adjusted or avoided at specific levels of renal dysfunction (CrCl > 95 mL/min for edoxaban). Although approved by the FDA, clinicians should give pause before considering use of apixaban in dialysis patients, given the paucity of clinical data supporting its use. Lastly, clinicians are well-advised to review the European Heart Rhythm Association's practical guide to the use of DOACs.¹⁴ This document makes common-sense recommendations about the frequency of renal function monitoring for DOAC-treated patients.

References

1. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012;366:864-6.
2. Larsen TB, Rasmussen LH, Skjoth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in "real-world" patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013;61:2264-73.
3. Deal EN, Pope H, Ross W. Apixaban use among patients with severe renal impairment. Ann Pharmacother 2014;48:1667.
4. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014;64:2471-82.
5. Friberg L, Benson L, Lip GY. Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study. Eur Heart J 2014;36:297-306.
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8. Jun M, James MT, Manns BJ, et al. The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study. BMJ 2015;350:h246.
9. De Vriese AS, Caluwe R, Bailleul E, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis 2015;15:00490-4.
10. Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost 2015;113:719-27.
11. Browne SD, McMaster J, Rizvi SA, Ahmed S. End-stage renal disease with atrial fibrillation: uncharted territory in the modern world of anticoagulants. Expert Opin Pharmacother 2014;15:1639-42.
12. Bansal N. The debate on warfarin use in dialysis patients with atrial fibrillation: more fuel for the fire. Am J Kidney Dis 2014;64:677-80.
13. Granger CB, Chertow GM. A pint of sweat will save a gallon of blood: a call for randomized trials of anticoagulation in end-stage renal disease. Circulation 2014;129:1190-2.
14. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094-106.

Keywords: Anticoagulants, Atrial Fibrillation, Benzimidazoles, Confidence Intervals, Embolism, Food-Drug Interactions, Hospitalization, International Normalized Ratio, Kidney Failure, Chronic, Morpholines, Pharmaceutical Preparations, Prospective Studies, Pyrazoles, Pyridines, Pyridones, Registries, Renal Dialysis, Sample Size, Stroke, Thiazoles, Thiophenes, Warfarin, beta-Alanine

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