Using the Case-Crossover Design to Assess Short-Term Risks of Bleeding and Arterial Thromboembolism After Switching Between Oral Anticoagulants in a Population-Based Cohort of Patients With Atrial Fibrillation

Am J Epidemiol. 2020 Dec 1;189(12):1467-1477. doi: 10.1093/aje/kwaa133.


Using nationwide Danish registries, we conducted a population-based case-crossover study evaluating the association between switching from a vitamin K antagonist (VKA) to a direct oral anticoagulant (DOAC), and vice versa, and 30-day risks of bleeding and arterial thromboembolism in patients with atrial fibrillation (AF). The case-crossover population was identified among oral anticoagulant users during 2011-2018 (n = 123,217) as patients with AF with 1) a case-defining outcome and 2) an anticoagulant switch during the 180 days preceding the outcome. Odds ratios were estimated using conditional logistic regression by comparing the occurrence of switching during the 30-day window immediately preceding the outcome to that in reference windows in the same individual 60-180 days before the outcome. The case-crossover populations for switching from VKA to DOAC and DOAC to VKA comprised 1,382 and 287 case patients, respectively. Switching from VKA to DOAC, but not from DOAC to VKA, was associated with an increased short-term risk of bleeding (odds ratio = 1.42; 95% confidence intervals: 1.13, 1.79, and 1.06; and 0.64, 1.75, respectively) and ischemic stroke (odds ratio = 1.74; 95% confidence intervals: 1.21, 2.51, and 0.92; and 0.46, 1.83, respectively). Our findings suggest that switching from VKA to DOAC is an intermittent risk factor of bleeding and ischemic stroke in patients with AF.

Keywords: anticoagulants; atrial fibrillation; confounding; pharmacoepidemiology; thromboembolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anticoagulants / adverse effects*
  • Atrial Fibrillation / complications*
  • Cohort Studies
  • Cross-Over Studies
  • Drug Substitution / adverse effects*
  • Female
  • Hemorrhage / chemically induced*
  • Humans
  • Male
  • Thromboembolism / etiology
  • Thromboembolism / prevention & control*
  • Vitamin K / antagonists & inhibitors


  • Anticoagulants
  • Vitamin K