Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a systematic review and meta-analysis

Abstract

ObjectiveThere has been limited systematic evaluation of outcomes and drivers of inappropriate non-vitamin K antagonist oral anticoagulants (NOACs) dosing among patients with atrial fibrillation (AF). This review identified and systematically evaluated literature on clinical and economic outcomes of inappropriate NOAC dosing and associated patient characteristics.MethodsMEDLINE, Embase, Cochrane Library, International Pharmaceutical Abstracts, Econlit, PubMed and NHS EEDs databases were searched for English language observational studies from all geographies published between 2008 and 2020, examining outcomes of, or factors associated with, inappropriate NOAC dosing in adult patients with AF.ResultsOne hundred and six studies were included in the analysis. Meta-analysis showed that compared with recommended NOAC dosing, off-label underdosing was associated with a null effect on stroke outcomes (ischaemic stroke and stroke/transient ischaemic attack (TIA), stroke/systemic embolism (SE) and stroke/SE/TIA). Meta-analysis of 15 studies examining clinical outcomes of inappropriate NOAC dosing found a null effect of underdosing on bleeding outcomes (major bleeding HR=1.04, 95% CI 0.90 to 1.19; p=0.625) but an increased risk of all-cause mortality (HR=1.28, 95% CI 1.10 to 1.49; p=0.006). Overdosing was associated with an increased risk of major bleeding (HR=1.41, 95% CI 1.07 to 1.85; p=0.013). No studies were found examining economic outcomes of inappropriate NOAC dosing. Narrative synthesis of 12 studies examining drivers of inappropriate NOAC dosing found that increased age, history of minor bleeds, hypertension, congestive heart failure and low creatine clearance (CrCl) were associated with an increased risk of underdosing. There was insufficient evidence to assess drivers of overdosing.ConclusionsOur analysis suggests that off-label underdosing of NOACs does not reduce bleeding outcomes. Patients prescribed off-label NOAC doses are at an increased risk of all-cause mortality. These data underscore the importance of prescriber adherence to NOAC dosing guidelines to achieve optimal clinical outcomes for patients with AF.PROSPERO registration numberCRD42020219844.

Clinical consequences of off-label reduced dosing of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis

“…In a recent meta-analysis, Caso et al compared OLRD to on-label dosing (ie, both on-label reduced and on-label non-reduced). This showed that OLRD increased the risk of all-cause mortality (HR 1.28 (95% CI 1.10 to 1.49)) with a null effect on major bleeding (HR 1.04 (95% CI 0.90 to 1.19)) 18…”

“…Several systematic reviews have evaluated the clinical consequences of such OLRD 14 16–18. However, the included studies in these reviews are highly heterogeneous, suffer from confounding and/or compare patients with OLRD to all patients receiving an on-label dose (ie, both on-label reduced and on-label non-reduced).…”

Appropriateness of rivaroxaban and apixaban dosing in hospitalized patients with a newly diagnosed nonvalvular atrial fibrillation at a single tertiary hospital

“…The issue of underdosing of NOACs is global, and it might be explained by the fact that prescribers believe this might decrease the risk of bleeding without paying attention to the risk of ischemic stroke and all-cause mortality due to underdosing. [10,17,18] A single-center retrospective cohort study conducted in a teaching hospital in the Netherlands to evaluate the appropriateness of NOACs dosing in 3231 hospitalized patients with NVAF found that patients who were prescribed dabigatran, rivaroxaban, or apixaban received the reduced dose inappropriately in 5.4% compared to 4.5% who received overdose. [9] Additionally, another single-center retrospective cohort study in Japan included 316 patients to investigate NOACs appropriateness in NVAF patients revealed that patients who were prescribed dabigatran, rivaroxaban, apixaban, or edoxaban received the reduced dose inappropriately in 19.3% compared to only 2.5% received overdose.…”

“…A recent meta-analysis found that an overdose of NOACs can increase the risk of major bleeding, while an underdose can increase the risk of allcause mortality with no effect on ischemic stroke. [10] Rivaroxaban, is factor Xa inhibitor, has been approved to decrease the risk of stroke and systemic embolism in NVAF at a dose of 20 mg orally once daily in patients with a creatinine clearance (CrCl) >50 mL/min, and a dose of 15 mg orally once daily in patients with a CrCl ≤ 50 mL/min. The package insert of rivaroxaban recommends avoiding concomitant administration of known combined p-glycoprotein (P-gp) and strong CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir.…”

“…A recent meta-analysis found that an overdose of NOACs can increase the risk of major bleeding, while an underdose can increase the risk of all-cause mortality with no effect on ischemic stroke. [10]…”