Nonvitamin K antagonist oral anticoagulant use in patients with renal impairment

Abstract

The nonvitamin K antagonist oral anticoagulants (NOACs), also referred to as direct oral anticoagulants (DOACs), dabigatran, apixaban, edoxaban, and rivaroxaban, have emerged as effective alternatives to vitamin K antagonists (VKAs) across several indications, including the prevention of stroke and systemic embolism (SSE) in patients with atrial fibrillation (AF) and the treatment of venous thromboembolism (VTE). Their use in patients with renal impairment is of particular importance, given the prevalence of renal dysfunction in the indicated populations and the impact of renal function on the metabolism of the NOACs. This publication reviews the pharmacokinetic/pharmacodynamic properties of the NOACs and clinical trial results for patients with renal impairment within the AF and VTE indications. Pharmacokinetic/pharmacodynamic data show the NOACs are dependent on renal clearance to varying extents. Relative to VKAs, the efficacy and safety of the NOACs is preserved in patients with moderate renal impairment. The dosing recommendations for patients with renal impairment differ depending on the NOAC, whereby some of the NOACs require dose reductions based solely on renal function, while others require consideration of additional criteria. However, despite these specific dosing recommendations, emerging real-world evidence suggests patients are not being dosed appropriately, indicating a possible knowledge gap. Adherence to recommended dosing algorithms has implications on the optimal efficacy and safety of the NOACs. To this end, renal function should be assessed in patients on a NOAC, as worsening of renal function may warrant change in the dose of a NOAC or change in oral anticoagulant.

Keywords: NOAC; anticoagulation; nonvalvular atrial fibrillation; nonvitamin K antagonist oral anticoagulant; renal impairment; venous thromboembolism.

Figure 1.

Area under the curve (AUC) accumulation with declining renal function. Plasma concentrations for the nonvitamin K antagonist oral anticoagulant, reported as AUC, for patients with renal impairment as compared with patients with normal renal function (⩾80 ml/min).^– AUC, area under the curve; CrCl, creatinine clearance.

Figure 2.

Health Canada dosing algorithm for dabigatran according to renal function. BID, twice daily; CrCl, creatinine clearance.

Figure 3.

Health Canada dosing algorithm for apixaban according to renal function. ^*In patients with estimated creatinine clearance (eCrCl) 15–24 ml/min, no dosing recommendation can be made, as clinical data are very limited.

Figure 4.

Health Canada dosing algorithm for edoxaban according to renal function. ^*Except amiodarone and verapamil. CrCl, creatinine clearance; OD, once daily; P-gp, P-glycoprotein.

Figure 5.

Health Canada dosing algorithm for rivaroxaban according to renal function. CrCl, creatinine clearance; OD, once daily.

Figure 6.

Health Canada dosing regimens for the treatment of venous thromboembolic events and prevention of deep vein thrombosis and pulmonary embolism. Depicted are the Health Canada approved dosing regimens for (A) dabigatran, (B) apixaban, (C) edoxaban and (D) rivaroxaban.^{– *}Dabigatran 110 mg twice a day (BID) should be considered for patients ⩾ 80 years, or those at higher risk of bleeding (⩾75 years with ⩾1 risk factor for bleeding). ^$Edoxaban 30 mg once a day (OD) is recommended for moderate renal impairment (creatinine clearance 30–50 ml/min), weight ⩽ 60 kg, or concomitant use of P-glycoprotein inhibitors (except amiodarone and verapamil).

Figure 7.

Breakdown of CHADS₂ scores in nonvitamin K antagonist oral anticoagulant pivotal trials and renal subanalyses. The breakdown of patients according to CHADS₂ score in ARISTOTLE, RE-LY, ENGAGE AF and ROCKET AF are depicted according to (a) overall trial population^– and (b) patients with moderate renal impairment (30–49 ml/min).^{– *}Mean CHADS₂ score not reported for dabigatran according to renal function. AF, atrial fibrillation; CHADS₂, score for estimating risk of stroke.

Figure 8.

Stroke and systemic embolism in atrial fibrillation patients by renal function. Risk of stroke and systemic embolism for the nonvitamin K antagonist oral anticoagulant (dabigatran, apixaban,^, edoxaban, and rivaroxaban) versus warfarin according to renal function subgroups and overall trial populations. Data are reported for the intention-to-treat populations. Mean CHADS₂ scores are reported for the respective nonvitamin K antagonist oral anticoagulant arm from the phase III pivotal trials. AF, atrial fibrillation; CHADS₂, score for estimating risk of stroke; NOAC, nonvitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist.

Figure 9.

Major bleeding in atrial fibrillation patients by renal function. Risk of major bleeding for the nonvitamin K antagonist oral anticoagulants (dabigatran, apixaban, edoxaban and rivaroxaban) versus warfarin according to renal function subgroups and overall trial populations. Data are reported for the safety populations on treatment, except for dabigatran which only reported data for the randomized set. Mean CHADS₂ scores are reported for the respective nonvitamin K antagonist oral anticoagulant arm from the phase III pivotal trials. AF, atrial fibrillation; CHADS₂, score for estimating risk of stroke; NOAC, nonvitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist.

Figure 10.

Major bleeding in atrial fibrillation patients according to renal function for nonvitamin K antagonist oral anticoagulant and warfarin arms of the phase III trials. Major bleeding event rates (%/year) according to renal function subgroups from the phase III pivotal trials for (a) dabigatran, (b) apixaban, (c) edoxaban and (d) rivaroxaban.^–, Mean CHADS₂ scores are reported for the respective arm from the phase III pivotal trials. AF, atrial fibrillation; CHADS₂, score for estimating risk of stroke; CrCl, creatinine clearance; VKA, vitamin K antagonist.

Figure 11.

Venous thromboembolic event recurrence or death related to venous thromboembolic event by renal function. Efficacy outcomes of recurrent venous thromboembolic event or death related to venous thromboembolic event for dabigatran, apixaban, edoxaban and rivaroxaban versus warfarin by renal function subgroups as reported by Geldhof et al. Data are reported as risk ratios for nonvitamin K antagonist oral anticoagulant versus warfarin. Comp, comparator arm; CrCl, creatinine clearance; DVT, deep vein thrombosis; NOAC, nonvitamin K antagonist oral anticoagulant; PE, pulmonary embolism.

Figure 12.

Major bleeding in venous thromboembolic event patients by renal function. Major bleeding data for dabigatran, apixaban and rivaroxaban according to renal function subgroups as reported by Geldhof et al. Data are reported as risk ratios of nonvitamin K antagonist oral anticoagulant versus warfarin. The definition of major bleeding was similar in all included trials and conformed to the International Society on Thrombosis and Haemostasis guidelines. Major bleeding data for edoxaban by renal function was not available at the time of publication. Comp, comparator arm; CNOAC, nonvitamin K antagonist oral anticoagulant; CrCl, creatinine clearance; DVT, deep vein thrombosis; PE, pulmonary embolism.