ReviewRole of direct oral anticoagulants in patients with kidney disease
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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Cited by (33)
Left atrial appendage occlusion should be offered only to select atrial fibrillation patients
2022, Heart Rhythm O2Citation Excerpt :Warfarin is the most studied oral anticoagulant in these groups of patients; however, it can be associated with calcific arteriolopathy (calciphylaxis), a potentially life-threatening condition.48 Most of the DOACs undergo some degree of renal clearance, thus making their pharmacokinetics unpredictable in patients with CKD and ESRD.49,50 Unfortunately, the landmark trials evaluating percutaneous LAAO have limited participation of patients with advanced kidney disease, and no subgroup analyses have been performed on such patients.15,16
Anticoagulants and Antiplatelet Drugs
2022, Comprehensive PharmacologyAnticoagulation in patients with kidney failure on dialysis: factor XI as a therapeutic target
2021, Kidney InternationalCitation Excerpt :We are aware of a study aspiring to evaluate the overall benefits and risks of vitamin K antagonists in patients with atrial fibrillation and kidney failure undergoing dialysis (ClinicalTrials.gov identifier: NCT02886962); to date (April 2021), recruitment of participants into this study has started.58 The lack of evidence of the effectiveness of oral anticoagulation in this particularly high-risk population highlights an unmet need for more studies of anticoagulants that can be used effectively and safely in people with CKD.59 FXI inhibition is a potential therapeutic avenue currently under investigation that may be particularly attractive in populations at high background bleeding risk, such as those with kidney failure on dialysis.
A case-control study indicates that coagulation imbalance is associated with arteriosclerosis and markers of endothelial dysfunction in kidney failure
2021, Kidney InternationalCitation Excerpt :Patients with ESKD are exposed to the delicate balance between a risk of thrombosis and a risk of bleeding. Anticoagulant drugs can trigger adverse bleeding events, thus complicating treatment selection in kidney disease patients55 who are particularly susceptible to arterial stiffening and endothelial dysfunction, 2 independent predictors of mortality. Evaluating the hypercoagulable status using classic tests (prothrombin fragments 1+2 and D-dimer) alone masks a paradoxical decrease in ETP in the presence of platelets.