Novel Oral Anticoagulants in Chronic Kidney Disease: Ready for Prime Time?

Justin Ashley; Manish M. Sood

Disclosures

Curr Opin Nephrol Hypertens. 2018;27(3):201-208. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: Patients with chronic kidney disease (CKD) are at increased risk of atrial fibrillation, stroke, and bleeding posing unique clinical challenges. Novel oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban have become recognized as alternative therapy to Vitamin K Antagonists (VKA) regarding the prevention of venous thromboembolism (VTE) and reduce the risk of stroke in atrial fibrillation. However, the understanding of NOACs in CKD is still underdeveloped. This review summarizes recent literature on the efficacy and safety of NOACs in patients with CKD.

Recent findings: Studies focusing on patients with moderate kidney disease were drawn from post hoc analyses from three major NOAC trials, meta-analyses, and postmarketing surveillance studies. Cumulatively, these studies continue to demonstrate NOACs as equivalent if not superior therapies to VKAs in regards to both efficacy and safety. These studies are limited by small sample sizes as well as a lack of direct comparison between NOACs.

Summary: The role of NOACs in managing VTE and atrial fibrillation is increasing. Current research suggests that NOACs are at least as efficacious and well tolerated as VKAs. More research is required to elucidate which NOAC is preferable in the clinical setting.

Introduction

Chronic kidney disease (CKD) and cardiovascular morbidity and mortality are intricately linked[1–4] posing unique challenges in the clinical setting.[5] Atrial fibrillation is the most common arrhythmia in the CKD and dialysis populations and affects 15–20% of patients.[1,4,6,7] Declining estimated glomerular filtration rate (eGFR) and proteinuria are independently associated with the risk of developing atrial fibrillation.[8–10]

The combination of atrial fibrillation and CKD can lead to a four-fold to five-fold higher risk of stroke.[2–4,6,7,9,11] CKD is also highly associated with venous thromboembolism (VTE) including deep vein thrombosis (DVT), and pulmonary embolism.[12–14] The reported relative risk for VTE was higher in patients with CKD, increasing with CKD severity, compared with patients with normal kidney function [mild CKD – relative risk (RR) 1.28, 95% CI 1.02–1.59; CKD stage 3/4 – RR 2.09, 95% CI 1.47–2.96].[15]

Vitamin K antagonists (VKA) such as warfarin are the mainstay for stroke prevention in atrial fibrillation and VTE.[5] However, multiple drug and dietary interactions with warfarin compounded by vitamin K deficiency in the CKD population[16] limits the time in therapeutic range (TTR). This significantly affects warfarin's safety and efficacy.[17,18] There is little evidence of the effectiveness of VKAs in stroke reduction in patients with advanced CKD or on dialysis. In fact, there may be an increased bleeding risk.[19–21]

Nonvitamin K oral anticoagulants (novel oral anticoagulants; NOAC) are a group of anticoagulants that directly antagonize either factor II or Xa in the coagulation cascade.[22] Dabigatran, a direct thrombin inhibitor, inhibits the protease enzyme that is responsible for the conversion of fibrinogen to fibrin – the final step in the coagulation cascade.[22,23] Rivaroxaban, apixaban, and edoxaban work by inhibiting factor Xa, the rate-limiting step in the coagulation cascade.[23]

Multiple randomized controlled trials[24–27] and real-world studies[28–32] have identified NOACs as safer (i.e. lower risk of bleeding and all-cause mortality) and more efficacious (i.e. lower risk of ischemic stroke and embolic events) medications in the general population whenever compared with warfarin.[24,25,27] A recent meta-analysis found that major bleeding was reduced by 19% in patients with atrial fibrillation on NOACs compared with warfarin.[23,33] With a shorter half-life and less dietary and medication interactions, NOACs have a more predictable pharmacological profile than VKAs.[5] This reduces the need for frequent blood testing and improves patient adherence.

NOACs still have clinical challenges. Unlike warfarin, NOACs do not have a standardized test to monitor drug levels.[23] Secondly, all NOACs are renally excreted to various degrees (Table 1). Accordingly, as patient's eGFR decline the effects of NOACs become less predictable 34 consequently increasing bleeding risk. To address this, NOACs often have standard and reduced dosing to reflect patients with normal and reduced eGFRs[5,35–45] (Table 1).

Nonetheless, our understanding of the efficacy and safety of NOACs in CKD and end-stage kidney disease (ESKD) is still underdeveloped. The major trials that evaluated NOACs excluded patients with a creatinine clearance (CrCl) less than 25–30 ml/min and on dialysis; patients that are at the highest risk of atrial fibrillation, stroke, and VTE.[2,13,14,22] Secondly, little data is available regarding, which anticoagulant is most appropriate for patients with CKD and ESKD. This review explores recent work on NOACs in patients with CKD.

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