Are There Viable Alternatives to Warfarin in a Patient With Renal Disease on Hemodialysis?

Authors:
Eric A. Dietrich, PharmD, BCPS, and Kyle Davis, PharmD, BCPS

Citation:
Dietrich EA, Davis K. Are there viable alternatives to warfarin in a patient with renal disease on hemodialysis? Consultant. 2017;57(6):365-366.

Acute venous thromboembolism (VTE), consisting of deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a commonly encountered clinical scenario. Patients with acute VTE events can be effectively treated with various oral anticoagulants (warfarin, apixaban, dabigatran, edoxaban, or rivaroxaban) that have demonstrated efficacy and relative safety. Usually, the factors influencing the choice of agent are relatively easy to navigate: cost, patient preferences, physician experience and preferences, potential drug-drug interactions, and in the case of warfarin, a patient’s willingness or ability to frequently present to the clinic for international normalized ratio (INR) monitoring. However, certain infrequently encountered clinical conditions that are outside of the clinical trial parameters for these agents can create a more difficult decision.

A relatively common scenario of these infrequently encountered clinical conditions is a patient who requires anticoagulation for an acute VTE and who is receiving chronic hemodialysis (HD). Historically, warfarin has been a mainstay of treatment in patients on HD, given that warfarin requires no dose adjustments for changes in renal function. But the nonwarfarin oral anticoagulants are being considered more frequently for these patients—specifically apixaban, since it has the lowest degree of renal elimination relative to the other agents. Given the narrow therapeutic index for anticoagulants, much stands to be lost from either subtherapeutic or supratherapeutic drug levels, and little information is available to guide drug dosing in these complex patients.

While its pharmacokinetics suggest that apixaban is adequate for use in patients on HD, is there clear evidence showing that the agent is both safe and effective in this role?

Patient Case

JB is a 63-year-old man with a past medical history of hypertension, coronary artery disease, dyslipidemia, and end-stage renal disease (ESRD). He requires HD every Monday, Wednesday, and Friday. One month ago, JB was admitted to the hospital for an acute popliteal-vein thrombosis in his right leg. While in the hospital, he had been treated with an unfractionated heparin infusion and then transitioned to warfarin therapy. He presents today for a postdischarge follow-up visit.

JB does not report any bleeding, and he states that his leg is feeling much better since his hospitalization. His current medications are as follows: warfarin, 5 mg daily (his INR today is 2.1); atorvastatin, 80 mg daily; amlodipine, 5 mg daily; lisinopril, 20 mg daily; and metoprolol succinate, 100 mg daily. All of his laboratory test results are within normal limits except for an elevated serum creatinine level of 2.8 mg/dL.

He asks whether any other treatment options are available for his blood clot, because he does not like going in for laboratory blood draws. He states that he would prefer an alternative agent, but only if it is just as safe and effective as warfarin. Does an alternative exist that meets these criteria?

The Evidence

The efficacy and safety of the oral factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) for the treatment of VTE in patients with ESRD requiring HD has not been established. Patients with ESRD were excluded in both of the landmark trials evaluating apixaban (AMPLIFY¹) and rivaroxaban (EINSTEIN²) for the management of VTE. Therefore, following their Food and Drug Administration approval, the use of both agents was not recommended in patients with ESRD.

However, not long after the agents came on the market, 2 pharmacokinetic studies attempted to establish the safety of these agents in patients with ESRD. The first, by Wang and colleagues,³ evaluated the effects of a single 5-mg dose of apixaban on patients with ESRD on HD (n = 8) and compared the results with the effect on healthy volunteers (n = 8). The researchers found that patients with ESRD had a 36% greater apixaban exposure compared with healthy volunteers. The median half-life of apixaban was roughly 12 to 14 hours in the patients with ESRD, which is similar to the 15-hour median half-life observed in healthy patients. Following HD, apixaban exposure was reduced by 14%, a reduction that the authors deemed to be minimal. Finally, no patients experienced any adverse effects following the single dose. The authors concluded that apixaban could be used without dose modification for the treatment of VTE in patients with ESRD on HD. As a result, the package insert for apixaban does not recommend dose adjustments in this patient population.⁴

In a similar fashion, Dias and colleagues⁵ evaluated the effects of a single 15-mg dose of rivaroxaban on patients with ESRD receiving HD (n = 8) compared with control patients with normal renal function (n = 8). The researchers found that patients with ESRD on HD experienced a 56% increase in rivaroxaban exposure compared with healthy control patients. Additionally, similarly to apixaban, HD did not play a significant role in the elimination of rivaroxaban. When compared with the pharmacokinetics of patients with chronic kidney disease not undergoing HD, the parameters assessed in the patients on HD did not significantly differ. As a result, this information was added to the package insert,⁶ which suggests that 15 mg of rivaroxaban may be a safe therapy for patients with ESRD.

To date, only one retrospective cohort study, by Stanton and colleagues,⁷ has evaluated clinical outcomes in patients with severe renal impairment or ESRD receiving warfarin (n = 73) or apixaban (n = 73); roughly 60% of patients in the apixaban cohort received the 2.5-mg twice-daily dosing regimen. The primary outcome of major bleeding was nonsignificantly higher in patients receiving warfarin (9.6% vs 17.8%, P = .149), and no difference was seen in the rate of stroke or VTE. When evaluating HD patients exclusively, no difference was observed in the rate of major bleeding.

Clinical Application

Despite the limited evidence available about oral factor Xa inhibitors in patients on HD for ESRD, important conclusions still can be reached. While the studies by Wang and colleagues and Dias and colleagues offer comforting information about the safety of apixaban and rivaroxaban, respectively, in patients with ESRD, the fact that these are single-dose studies cannot be overlooked; patients with acute VTE would be expected to take their medication daily for 3 to 6 months, and it is unclear whether the drug levels observed from single doses would remain with continued administration. Additionally, these studies were conducted in healthy volunteers, so efficacy could not be assessed (the single-dose design also limited efficacy assessment).

The study by Stanton and colleagues is limited in that it is a retrospective cohort study with a small sample size, but the advantage was that patients were receiving continued dosing of the medications so that safety and efficacy could be evaluated in more of a real-world manner. The fact that the rates of stroke and major bleeding were not significantly different between the warfarin group and the apixaban group suggests that apixaban, 2.5 mg twice daily, may represent a reasonable alternative to warfarin for patients on HD. Given that this study investigated clinical outcomes, it should carry more weight than the single-dose studies conducted in healthy volunteers. However, these data are still extremely limited by the small sample size, making it important to consider the relative merits of this study carefully.

Overall, the data are extremely limited in support of a role for nonwarfarin oral anticoagulants in patients with ESRD receiving HD. However, based on the available evidence, it appears that apixaban, 2.5 mg daily, is the most evidence-based option, with data (albeit limited) supporting safety and efficacy in this population. Warfarin would still be the preferred agent owing to its longer history of use, but in cases in which warfarin cannot be used, apixaban represents the most reasonable alternative.

A patient’s preference simply to avoid the monitoring associated with warfarin therapy may not be a significant enough factor to outweigh the difference in safety and efficacy and the experience of warfarin use compared with apixaban in this setting. Additionally, patients with well-controlled INRs can come to the clinic for INR checks at monthly intervals or have their INR measured at HD sessions as part of other required laboratory blood draws, thereby minimizing some of the monitoring burden.

Even though monitoring directly related to apixaban is not available, if JB were to be switched to apixaban from warfarin, he would still need to be monitored closely for signs and symptoms of bleeding or thrombosis, given the uncertainty related to using apixaban in a patient with ESRD on HD. So a switch to apixaban may not result in a large reduction in the frequency of necessary monitoring compared with warfarin.

Outcome of the Case

The potential alternatives to warfarin, including apixaban and rivaroxaban, were discussed at length with JB. He was informed of the clinical efficacy of both alternative agents and of the limited available data about their use in patients with ESRD receiving HD. After evaluating the risks and benefits of these alternatives, JB decided to continue therapy with warfarin, since he had no difficulty achieving a therapeutic INR and did not report any hemorrhagic adverse events with its use.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.

REFERENCES:

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