Effectiveness and safety of intracranial events associated with the use of direct oral anticoagulants for atrial fibrillation: A systematic review and meta-analysis of 92 studies

Br J Clin Pharmacol. 2022 Nov;88(11):4663-4675. doi: 10.1111/bcp.15464. Epub 2022 Aug 15.

Abstract

Aims: Observational studies have investigated the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) used in nonvalvular atrial fibrillation. We performed a systematic review and meta-analysis assessing the risk of ischaemic stroke, thromboembolism (TE) and intracranial haemorrhage (ICH) associated with the use of DOACs and VKAs.

Methods: Medline and Embase were systematically searched until April 2021. Observational studies were gathered and hazard ratios (HRs) with 95% confidence intervals (CI) were extracted. Subgroup analyses based on DOAC doses, history of chronic kidney disease, stroke, exposure to VKA, age and sex were performed. A random-effects model was used.

Results: We included 92 studies and performed 107 comparisons. Apixaban was associated with lower risk of stroke (HR: 0.82, 95% CI: 0.68-0.99) compared to dabigatran. Rivaroxaban was associated with lower risk of stroke (HR: 0.90, 95% CI: 0.83-0.98) compared to VKA. Dabigatran (HR: 0.85, 95% CI: 0.80-0.91), rivaroxaban (HR: 0.83, 95% CI: 0.77-0.89) and apixaban (HR: 0.75, 95% CI: 0.65-0.86) were associated with lower risk for TE/stroke compared to VKA. Apixaban (HR: 1.32, 95% CI: 1.03-1.68) and rivaroxaban (HR: 1.58, 95% CI: 1.31-1.89) were associated with higher risk of ICH compared to dabigatran. Dabigatran (HR: 0.48, 95% CI: 0.44-0.52), apixaban (HR: 0.60, 95% CI: 0.49-0.73) and rivaroxaban (HR: 0.73, 95% CI: 0.65-0.81) were associated with lower risk of ICH compared to VKA.

Conclusion: Our study demonstrated significant differences in the risk of ischaemic stroke, TE/stroke and ICH associated with individual DOACs compared to both other DOACs and VKA.

Keywords: direct oral anticoagulants; ischaemic stroke prevention; nonvalvular atrial fibrillation; risk for intracranial haemorrhage; thromboembolism prevention; vitamin K antagonists.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Anticoagulants / adverse effects
  • Atrial Fibrillation* / complications
  • Atrial Fibrillation* / drug therapy
  • Brain Ischemia* / epidemiology
  • Brain Ischemia* / etiology
  • Brain Ischemia* / prevention & control
  • Dabigatran / adverse effects
  • Humans
  • Intracranial Hemorrhages / chemically induced
  • Intracranial Hemorrhages / complications
  • Intracranial Hemorrhages / epidemiology
  • Ischemic Stroke*
  • Pyridones / adverse effects
  • Rivaroxaban / adverse effects
  • Stroke* / epidemiology
  • Stroke* / etiology
  • Stroke* / prevention & control
  • Thromboembolism* / drug therapy
  • Vitamin K

Substances

  • Anticoagulants
  • Pyridones
  • Vitamin K
  • Rivaroxaban
  • Dabigatran