Safety of off-label dose reduction of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation

Br J Clin Pharmacol. 2023 Feb;89(2):751-761. doi: 10.1111/bcp.15534. Epub 2022 Oct 3.

Abstract

Aim: To investigate the effects of off-label non-vitamin K oral anticoagulant (NOAC) dose reduction compared with on-label standard dosing in atrial fibrillation (AF) patients in routine care.

Methods: Population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink, comparing adults with non-valvular AF receiving an off-label reduced NOAC dose to patients receiving an on-label standard dose. Outcomes were ischaemic stroke, major/non-major bleeding and mortality. Inverse probability of treatment weighting and inverse probability of censoring weighting on the propensity score were applied to adjust for confounding and informative censoring.

Results: Off-label dose reduction occurred in 2466 patients (8.0%), compared with 18 108 (58.5%) on-label standard-dose users. Median age was 80 years (interquartile range [IQR] 73.0-86.0) versus 72 years (IQR 66-78), respectively. Incidence rates were higher in the off-label dose reduction group compared to the on-label standard dose group, for ischaemic stroke (0.94 vs 0.70 per 100 person years), major bleeding (1.48 vs 0.83), non-major bleeding (6.78 vs 6.16) and mortality (10.12 vs 3.72). Adjusted analyses resulted in a hazard ratio of 0.95 (95% confidence interval [CI] 0.57-1.60) for ischaemic stroke, 0.88 (95% CI 0.57-1.35) for major bleeding, 0.81 (95% CI 0.67-0.98) for non-major bleeding and 1.34 (95% CI 1.12-1.61) for mortality.

Conclusion: In this large population-based study, the hazards for ischaemic stroke and major bleeding were low, and similar in AF patients receiving an off-label reduced NOAC dose compared with on-label standard dose users, while non-major bleeding risk appeared to be lower and mortality risk higher. Caution towards prescribing an off-label reduced NOAC dose is therefore required.

Keywords: anticoagulation; atrial fibrillation; non-vitamin K antagonist oral anticoagulants; off-label dose reduction.

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Anticoagulants
  • Atrial Fibrillation* / chemically induced
  • Atrial Fibrillation* / complications
  • Atrial Fibrillation* / drug therapy
  • Brain Ischemia* / chemically induced
  • Brain Ischemia* / epidemiology
  • Brain Ischemia* / prevention & control
  • Cohort Studies
  • Drug Tapering
  • Hemorrhage / chemically induced
  • Hemorrhage / drug therapy
  • Hemorrhage / epidemiology
  • Humans
  • Ischemic Stroke* / chemically induced
  • Ischemic Stroke* / complications
  • Ischemic Stroke* / drug therapy
  • Off-Label Use
  • Stroke* / epidemiology
  • Stroke* / etiology
  • Stroke* / prevention & control

Substances

  • Anticoagulants