Effectiveness and safety of non-vitamin K anticoagulants (NOACs) versus warfarin in frail patients with nonvalvular atrial fibrillation (AF): a nationwide cohort study

Study type

• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

  Effectiveness study (incl. comparative)

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (B01AA03) warfarin

  warfarin

  (B01AE07) dabigatran etexilate

  dabigatran etexilate

  (B01AF01) rivaroxaban

  rivaroxaban

  (B01AF02) apixaban

  apixaban
• Medical condition to be studied:
  Atrial fibrillation
• Additional medical condition(s):
  All frail patients with an inpatient or outpatient primary or secondary discharge diagnosis of non-valvular atrial fibrillation. Frail patients will be identified using the Hospital Frailty Risk Score (HFRS). HFRS, a score utilizing ICD-codes, was developed to identify patients at low (HFRS <,5), intermediate (HFRS 5-15) and high risk (HFRS >15) of frailty.

Population studied

• Age groups:
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)
• Estimated number of subjects:
  30000

Study design details

• Main study objective:
  (1) To present population characteristics and rates of effectiveness and safety outcomes among frail patients with non-valvular atrial fibrillation in Denmark according to OAC treatment regimen (no OAC, warfarin, or NOAC). (2) To investigate the comparative effectiveness and safety of NOACs versus warfarin in a Danish nationwide cohort of frail patients with non-valvular atrial fibrillation.
• Outcomes:
  The primary effectiveness outcome is a diagnosis of stroke or systemic embolism. The primary safety outcome is major bleeding recorded as intracranial, gastro-intestinal, and major bleeding in various anatomical positions and reported in total as ‘any bleeding’. All-cause death was also included as an outcome.
• Data analysis plan:
  Substudy 1: Patient baseline characteristics will be described for the overall study population and according to age (≥80 or <80). Cumulative incidence functions will be used to visualize how risk of outcomes evolve over time since AF diagnosis according to OAC regimen and age group using the Aalen–Johansen estimator assuming death as competing risk. The absolute risk of each study outcome according to OAC regimen and age group will be calculated at 1 year after AF diagnosis. Substudy 2: Patient baseline characteristics will be described for the study population according to baseline treatment group. To compare the risk of each endpoint among NOAC users with warfarin users reference), pooled logistic regression models will be used to estimate treatment effects by means of hazard ratios for the effectiveness and safety outcomes (both an ITT and PP approach). To allow an unbiased comparison of the treatment groups, we plan to use inverse probability of treatment weighting (IPTW).