The Importance of Appropriate Dosing of Nonvitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation

Jan Beyer-Westendorf,Matthew Fay,Walid Amara

doi:10.1055/s-0041-1731777

Abstract

Preventing thromboembolic events, while minimizing bleeding risks, remains challenging when managing patients with atrial fibrillation (AF). Several factors contribute to current dosing patterns of nonvitamin K antagonist oral anticoagulants (NOACs), including patient characteristics, comorbidities, and physician judgment. Application of NOAC doses inconsistent with the drug labels may cause patients to receive either subtherapeutic (increasing stroke risk) or supratherapeutic (increasing bleeding risk) anticoagulant levels. In clinical practice, under- or over-dosing of NOACs in patients with AF is not uncommon. This analysis of prospective and retrospective registry and database studies on NOAC use in patients with AF (with at least 250 patients in each treatment arm) showed that under-dosing may be associated with reduced effectiveness for stroke prevention, with similar or even increased bleeding than with the standard dose. This may reflect underlying conditions and patient factors that increase bleeding despite NOAC dose reduction. Such factors could drive the observed overuse of reduced NOAC dosages, often making the prescription of reduced-dose NOAC an intentional label deviation. In contrast, over-dosing more likely occurs accidentally; instead of providing benefits, it may be associated with worse safety outcomes than the standard dose, including increased bleeding risk and higher all-cause mortality rates. This review summarizes the main findings on NOAC doses usually prescribed to patients with AF in clinical practice.

Highlights

Patients with atrial fibrillation (AF) have a significant, nearly fivefold, increased risk of stroke compared with those without.[1]
There is limited evidence on the use of nonvitamin K antagonist oral anticoagulant (NOAC) in patients with end-stage renal disease, and NOACs should be used with caution in patients with severe renal disease when creatinine clearance (CrCl) is 15–29 mL/min
The analysis indicated that NOAC under-dosing was associated with an increased risk of thromboembolism

Summary

Introduction

Patients with atrial fibrillation (AF) have a significant, nearly fivefold, increased risk of stroke compared with those without.[1]. Dose reduction criteria were prespecified in clinical trials.[11,12,13,14,15,16] While NOACs demonstrated a favorable benefit–risk profile in the pivotal phase III randomized controlled trials (RCTs) for stroke prevention in patients with AF, which led to label recommendations for standard dosing and dose reductions, further factors warranting dose reduction may still be identified In these trials, reductions in the risk of both intracranial hemorrhage and fatal bleeding were observed, compared with warfarin.[11,12,14,15,17] real-world studies have shown that administration of anticoagulant therapy is often inconsistent with drug labeling, which may reduce the protective effect of NOACs.[18,19,20,21]. Publications were manually screened and additional publications were included according to relevance

Criteria for NOAC Dose Adjustments for Patients with Atrial Fibrillation

Erythromycin Ketoconazole

Normal dose

Criteria for dose reduction

Korea insurance claim analysis

All NOACs Apixaban Dabigatran Rivaroxaban

Open Questions Relating to NOAC Dosing

Findings

Conclusions