Elsevier

Kidney International

Volume 97, Issue 4, April 2020, Pages 664-675
Kidney International

Review
Role of direct oral anticoagulants in patients with kidney disease

https://doi.org/10.1016/j.kint.2019.11.027Get rights and content

The anticoagulation field is experiencing a renaissance that began with regulatory approval of the direct thrombin inhibitor dabigatran, a direct oral anticoagulant (DOAC), in 2010. The DOAC medication class has rapidly evolved to include the additional approval of 4 direct factor Xa inhibitors. Commensurately, DOAC use has increased and collectively account for the majority of new anticoagulant prescriptions. Despite exclusion of patients with moderate-to-severe kidney disease from most pivotal DOAC trials, DOACs are increasingly used in this setting. An advantage of DOACs is similar or improved antithrombotic efficacy with less bleeding risk when compared with traditional agents. Several post hoc analyses, retrospective studies, claims data studies, and meta-analyses suggest that these benefits extend to patients with kidney disease. However, the lack of randomized controlled trial data in specific kidney disease settings, with their unique pathophysiology, should be a call to action for the kidney community to systematically study these agents, especially because early data suggest that DOACs may pose less risk of anticoagulant-related nephropathy than do vitamin K antagonists. Most DOACs are renally cleared and are significantly protein bound in circulation; thus, the pharmacokinetics of these drugs are influenced by reduced renal function and proteinuria. DOACs are susceptible to altered metabolism by P-glycoprotein inhibitors and inducers, including drugs commonly used for the management of kidney disease comorbidities. We summarize the currently available literature on DOAC use in kidney disease and illustrate knowledge gaps that represent important opportunities for prospective investigation.

Section snippets

Anticoagulation Pharmacology

Heparins are indirect anticoagulants that potentiate the enzymatic activity of antithrombin (Figure 1).26 This activity is dependent on the interaction of a specific heparin pentasaccharide sequence with antithrombin. Whereas standard (unfractionated) heparin effectively inhibits both thrombin and factor Xa, low-molecular-weight heparins (LMWHs; e.g., enoxaparin and dalteparin) are less potent thrombin antagonists, exerting their effects predominantly via factor Xa inhibition. The synthetically

Anticoagulation Scenarios in Kidney Disease

Kidney disease has been identified as a risk factor for both VTE and AF, 2 common indications for anticoagulation.1, 2, 3,17, 18, 19, 20, 21, 22, 23, 24 Although patients with CKD were excluded from the pivotal phase 3 DOAC trials, data on their use, efficacy, and side effects in various kidney diseases and levels of renal function are emerging from postmarketing studies. Below, we describe common causes of kidney disease and particular scenarios that might warrant anticoagulation (Table 2).45

Anticoagulant-related nephropathy

Anticoagulant-related nephropathy was first described in patients on warfarin with acute kidney injury (AKI).117 Clinical findings included hematuria and AKI in patients with supratherapeutic INR (>3) without other known AKI causes. Kidney biopsies demonstrated dysmorphic RBCs in Bowman’s space, RBC casts in dilated distal tubules, and tubular hemosiderin deposition. Hypothesized injury mechanisms are nephron obstruction by RBC casts or tubular oxidative stress from RBC-derived iron.118

Conclusions

DOACs are increasingly used in various kidney disease settings, despite the lack of controlled trial data. The field would benefit from carefully designed trials that consider renal function, intravascular volume, plasma protein drug binding, and interactions with commonly used medications in each type of kidney disease where anticoagulation is frequently indicated. Although the early forms of data described in this review suggest that DOACs hold promise for improved efficacy and safety in the

Disclosure

MNR is a site primary investigator in clinical trials for Retrophin, Advicenne, Reata, and Genentech and has received research funding from Goldfinch Bio, Novartis, National Institute of Diabetes and Digestive and Kidney Diseases, and Department of Defense unrelated to direct oral anticoagulants. VKD has received consultant fees from Novartis and Retrophin and honoraria from RTI International and UpToDate unrelated to direct oral anticoagulants. VKD is, or has been, a site primary investigator

Acknowledgments

We are indebted to Lisa Feurer for her graphical design expertise (Figure 1).

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (award numbers K08DK103982 and R03DK118315 to BAK and award numbers U54DK083912 and P01DK058335 to VKD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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