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Direct-Acting Oral Anticoagulants (DOACs) use in Patients with Chronic Kidney Disease

16 Sep 2018 11:06 PM | Anonymous

Direct-Acting Oral Anticoagulants (DOACs) use in Patients with Chronic Kidney Disease

Authors:  Kaily Kurzweil, Pharm.D. Candidate UMKC School of Pharmacy and Andrew Smith, Pharm.D., FCCP, BCPS, UMKC School of Pharmacy

Background
Since the approval of the first direct-acting oral anticoagulant (DOAC), dabigatran in 2010, the management of oral anticoagulation in patients has significantly changed.  In the years following its approval, four more agents were approved as well: rivaroxaban, apixaban, edoxaban, and betrixaban.1-5  The introduction of these drugs into practice provides an alternative to warfarin, which has historically been the only option for oral anticoagulation in patients.  Where warfarin requires monitoring every 2-4 weeks and frequent regimen modifications, the DOACs do not have any monitoring requirements and rarely require dose adjustments.1-5  The DOACs also have notably less interactions with diet and other medications or supplements.  These qualities make the DOACs a more patient and provider-friendly option to those requiring anticoagulation.

The populations that predominantly benefit from the DOACs are patients at risk for a venous thromboembolism (VTE) and those diagnosed with nonvalvular atrial fibrillation (AF) for the prevention of stroke and systemic embolism.1-5  Patients that concurrently have a diagnosis of chronic kidney disease (CKD) or end stage renal disease (ESRD) are a high-risk population that has largely been excluded from the potential benefits of the DOACs due to limited data regarding use in patients with poor renal function.   It has been established that patients with CKD have increased likelihood of developing AF, believed to be due to poor kidney function.  Patients who develop AF with CKD are five times more likely to suffer from a stroke which often leads to mortality in these patients.6 

In an effort to assess the use of DOACs in patients with impaired renal function, many post-marketing studies and analyses have been completed.  This article examines new evidence supporting dosing strategies for renal insufficiency in rivaroxaban and apixaban, as pharmacokinetically these agents are more reasonable for use in kidney impairment due to decreased renal clearance in comparison to the other agents in the class.1-4  Due to the newness of betrixaban to the market, there is not enough comparative data to include it in this assessment.5 

Clinical Trial Review

The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial was the study that established rivaroxaban’s efficacy in patients with atrial fibrillation.  Rivaroxaban was shown to be non-inferior to dose-adjusted warfarin in terms of prevention of stroke and systemic embolism.   Major and non-major clinically relevant bleeding rates were similar in both arms, rivaroxaban did show less frequent cases of intracranial hemorrhage, critical bleeding, and fatal bleeding.7  The ROCKET-AF trial did show that the rivaroxaban group had more gastrointestinal bleeding, but post-market studies have not confirmed this.8  The initial safety and efficacy of rivaroxaban was only assessed and approved in patients with a creatinine clearance (CrCl) of 30 ml/min or greater, including a dose reduction to 15mg daily for patients with CrCl between 30-49 ml/min.7  After post-market sub-studies of patients with renal impairment the 15mg daily dose was approved for patients with a CrCl of 15 ml/min or greater.8  In a sub-analysis of patients with a CrCl < 50 ml/min both groups had comparable rates of stroke or systemic embolism as well as major and non-major clinically relevant bleeding.  However, fatal bleeding was less frequent in the rivaroxaban group.7 

A small study looked further into the pharmacokinetics (PK) and pharmacodynamics (PD) in patients on hemodialysis without residual kidney function.  This study looked to assess potential accumulation, levels of anti-Xa activity, and the timing of the dose in relation to dialysis treatments.  The study found that rivaroxaban 10mg resulted in similar exposure to that of a healthy patient taking rivaroxaban 20mg and that rivaroxaban was not eliminated via dialysis.9  This study was set up as a phase I or phase II trial and studies of similar size and design have been completed since, showing that dialysis does not affect the PK and PD properties of rivaroxaban.10  These results are encouraging but larger, randomized studies still need to be performed to more conclusively study the safety and efficacy of rivaroxaban in CKD and ESRD.

Apixaban currently is FDA approved for use in hemodialysis patients despite limited safety data.3  Initially, apixaban was not recommended in patients with a CrCl less than 25 ml/min as the safety and efficacy of apixaban was not studied in this population.  A sub-group analysis of the ARISTOTLE trial focused on the impact renal function had on outcomes and it was noted that apixaban significantly decreased stroke and systemic embolism as well as major bleeds regardless of renal function.11  These trends have led to further studies looking at apixaban use in comparison to warfarin in patients with renal function that would be classified as more severe than mild or moderate impairment. 

A large retrospective cohort study that compared over 600 patients with advanced CKD receiving apixaban or warfarin was recently published.  All of the patients included in outcome measurements had stage 4 or stage 5 CKD and patients including those concurrently on hemodialysis.  The primary outcome analyzed major bleeding at 3 months after enrollment.  At 3 months there was no difference in the number of patients with a major bleed in the apixaban and warfarin groups (8.3% vs. 9.9%; p= 0.48).  The secondary outcome of major bleeds at  3-6 months showed a continued trend towards improvement with apixaban, but did not achieve statistical significance (apixaban 1.4% vs warfarin 4%; p= 0.07).  Apixaban did show an improvement in major bleeding after 6-12 months (apixaban 1.5% vs. warfarin 8.4%; p<0.001) No differences in stroke or thromboembolism was seen between groups.  Based on this study, one could conclude that apixaban may be an acceptable alternative to warfarin long-term in patients with late stage kidney disease.12  It must be considered that retrospective cohort studies are not capable of providing conclusive results, therefore randomized trials should be evaluated before using this data to revise current recommended standard of care.

Currently, large trials are in the recruiting phase looking at anticoagulation strategies in patients with AF and CKD.  The RENAL-AF trial (NCT02942407) is measuring time to first major bleeding/non-major clinically relevant bleeding event in a comparison of apixaban versus warfarin in patients on hemodialysis with ESRD as well as AF.13  The XARENO trial (NCT02663076) is looking at patients with both AF and CKD who are treated with VKA or rivaroxaban as their anticoagulation agent.  Primary outcomes will look at bleeding and thrombotic events, all-cause mortality, change in eGFR, major cardiovascular events, and net-clinical benefit.14  Results for these trials will likely not become available until later in 2019 but will hopefully bring some clarity to managing AF patient who have concomitant kidney dysfunction. 

Conclusion

In summary, current guidelines still do not offer much support for the use of DOACs in patients with both AF and severe renal dysfunction.  Strong and conclusive evidence supporting the use of DOACs in this patient population is still lacking, but there is encouraging research becoming increasingly available to help guide clinicians in making decisions regarding anticoagulation in this patient population.  The evidence is beginning to suggest a benefit in the use of rivaroxaban or apixaban in patients with more advanced kidney disease and as more information becomes available we may see the treatment guideline governing bodies implement changes in current practice to how we manage anticoagulation in AF patients with CKD or ESRD.   

References:

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  3. Eliquis®[package insert]. Princeton, NK: Bristol-Myers Squibb Company; 2012.
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  8. Sanmartin-Fernandex M, Marzal-Martin D. Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Clinical Practice: Focus on Rivaroxaban in Stroke Prevention in Patients With Atrial Fibrillation. Clinical and Applied Thrombosis/Hemostasis 2017; 23(7): 711-724. DOI:10.1177/1076029616668404.
  9. De Vriese AS, Caluwe R, Bailleul E, et al. Dose-Finding Study of Rivaroxaban in Hemodialysis Patients. American Journal of Kidney Disease 2015; 66(1): 91-98.
  10. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis. American Journal of Nephrology 2016; 43:229-236. DOI:10.1159/000445328.
  11. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. European Heart Journal 2012; 33: 2821-2830. DOI:10.1093/eurhearth/ehs274.
  12. Schafer JH, Casey AL, Dupre KA, Staubes BA. Safety and Efficacy of Apixaban Versus Warfarin in Patients With Advanced Chronic Kidney Disease. Annals of Pharmacotherapy 2018; DOI:10.1177/1060028018781853.
  13. ClinicalTrials.gov. Trial to Evaluate Anticoagulation Therapy in Hemodialysis Patients With Atrial Fibrillation (RENAL-AF). Available at: https://clinicaltrials.gov/ct2/show/NCT02942407.  Accessed July 4, 2018.
  14. ClinicalTrials.gov. Factor XA - Inhibition in RENal Patients With Non-valvular Atrial Fibrillation (XARENO). Available at https://clinicaltrials.gov/ct2/show/study/NCT02663076. Accessed July 4, 2018.

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