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.

Impact of direct oral anticoagulant off‐label doses on clinical outcomes of atrial fibrillation patients: A systematic review

“…SPRINT AF also assessed the prevalence of Canadian patients eligible for the reduced dose of apixaban or rivaroxaban. Accordingly, and in agreement with the mentioned studies, more patients were being prescribed with a reduced dose of the factor Xa inhibitors than those who met the reduction criteria . Choosing lower doses reflects a greater concern by the physician to avoid bleeding complications rather than thromboembolic events …”

“…Accordingly, and in agreement with the mentioned studies, more patients were being prescribed with a reduced dose of the factor Xa inhibitors than those who met the reduction criteria. 19 Choosing lower doses reflects a greater concern by the physician to avoid bleeding complications rather than thromboembolic events. 44 Real-world studies demonstrated that low doses of dabigatran and edoxaban are preferentially prescribed and their inappropriate low dosing (ILD) is greater than appropriate low dosing.…”

“…This trend towards the use of ILD may be due to the reported evidence of the effectiveness of both drugs at low doses. 25,45,46 T A B L E 1 Dose adjustments for each direct oral anticoagulant drug in accordance with European Medicines Agency and Food and Drugs Administration guidelines 16,[18][19][20][21][22][23][24][25][26][27][28][29][30][31] European Medicines Agency (EMA) The reduced dose authorization and use in special populations was based on pharmacokinetic data. c This black box warning suggests the use of another anticoagulant for patients with CrCl >95 mL/min and was based on the reported higher rates of ischaemic stroke of these patients.…”

“…However, these recommendations are not uniform worldwide, hampering the selection of the preferable posology and the identification of DOAC suboptimal use. Indeed, the approved doses and dose adjustment criteria defined by European Medicine Agency (EMA) and Food and Drugs Administration (FDA) are summarized in Table while the recommendations reported by Health Canada regulatory agency, European Society of Cardiology and Japanese guidelines, regarding DOAC dose adjustment in patients with AF, are presented in Table . Note that Japanese guidelines mention some differences in relation to EMA and FDA, particularly related to the smaller body size, different pharmacokinetic and genetic profiles of Asian populations when compared with European or American patients.…”

“…Indeed, the approved doses and dose adjustment criteria defined by European Medicine Agency (EMA) and Food and Drugs Administration (FDA) are summarized in Table 1 16,[18][19][20][21][22][23][24][25][26][27][28][29][30][31] while the recommendations reported by Health Canada regulatory agency, European Society of Cardiology and Japanese guidelines, regarding DOAC dose adjustment in patients with AF, are presented in Table 2. 7,19,[32][33][34][35][36][37][38][39][40] Note that Japanese guidelines mention some differences in relation to EMA and FDA, particularly related to the smaller body size, different pharmacokinetic and genetic profiles of Asian populations when compared with European or American patients. All these guidelines were, hence, herein taken into consideration to assess whether DOAC dose adjustment were justified or not and, therefore infer about the impact of DOAC off-label doses on clinical outcomes of patients with AF.…”