Clinical Pharmacology of Oral Anticoagulants in Patients with Kidney Disease

Abstract

Oral anticoagulants are commonly used drugs in patients with CKD and patients with ESKD to treat atrial fibrillation to reduce stroke and systemic embolism. Some of these drugs are used to treat or prevent deep venous thrombosis and pulmonary embolism in patients with CKD who undergo knee and hip replacement surgeries. Warfarin is the only anticoagulant that is approved for use by the Food and Drug Administration in individuals with mechanical heart valves. Each oral anticoagulant affects the coagulation profile in the laboratory uniquely. Warfarin and apixaban are the only anticoagulants that are Food and Drug Administration approved for use in patients with CKD and patients with ESKD. However, other oral anticoagulants are commonly used off label in this patient population. Given the acquired risk of bleeding from uremia, these drugs are known to cause increased bleeding events, hospitalization, and overall morbidity. Each anticoagulant has unique pharmacologic properties of which nephrologists need to be aware to optimally manage patients. In addition, nephrologists are increasingly asked to aid in the management of adverse bleeding events related to oral anticoagulant use in patients with CKD and patients with ESKD. This article summarizes the clinical pharmacology of these drugs and identifies knowledge gaps in the literature related to their use.

Keywords: Anticoagulants; Apixaban; Atrial Fibrillation; Chronic; Dabigatran; Edoroxaban; End-stage Kidney Disease; Heart Valves; Humans; Kidney Failure; Nephrologists; Off-label Use; Oral Anticoagulants; Pharmaceutical Preparations; Pulmonary Embolism; Pyrazoles; Pyridones; Renal Insufficiency; Rivaroxaban; Stroke; United States Food and Drug Administration; Venous Thrombosis; Warfarin; chronic kidney disease; hospitalization; uremia.

Figure 1.

Carboxylation of vitamin K–dependent proteins requires the reduced form of vitamin K, γ-glutamyl carboxylase enzyme, molecular oxygen, and carbon dioxide. Because body stores of vitamin K are low, the oxidized (inactive) form of vitamin K is recycled to the reduced (active) form by vitamin K epoxide reductase, which is inhibited by warfarin. Inhibition results in reduced hepatic synthesis of these clotting factors and reduction in their activities by 40%–50%.

Figure 2.

Oral anticoagulants act at different sites in the coagulation cascade for their anticoagulant effects.