Comparative safety and effectiveness of warfarin, dabigatran, and rivaroxaban among Japanese patients with non-valvular atrial fibrillation (NVAF) and concomitant coronary artery disease (CAD) (1160.0308)

Study type

• Study topic:
  Other
• Study topic, other:
  Disease/Epidemiology study
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)

  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Population studied

• Short description of the study population:
  The study population involved patients with at least one diagnosis of non-valvular atrial fibrillation (NVAF) and concomitant coronary artery disease (CAD) aged 18 years or older identified from the Japan Medical Data Vision Co. Ltd. (MDV) database during the study period of April 1st, 2011 to December 31st, 2020.; Inclusion Criteria:; 1. ≥18 years of age; 2. Has at least one year of look-back period prior to the index date (defined as the first date of prescription for dabigatran, rivaroxaban, or warfarin during the study period); 3. New users of warfarin, dabigatran, and rivaroxaban, defined as patients without historic use of any oral anticoagulants during the look-back period; 4. Has at least 1 diagnosis of NVAF during the look-back period prior to or on the index date; 5. Has at least 1 diagnosis of CAD during the look-back period prior to or on the index date; ; Exclusion Criteria: ; 1. Diagnosed with end-stage renal disease, or undergo hemodialysis, or experience pregnancy during the study period; 2. Initiate warfarin, dabigatran, rivaroxaban due to valvular AF, AF associated with mechanical valve malfunction or mechanical complication of heart valve prosthesis, or rheumatic AF; 3. Underwent joint replacement procedures or diagnosed with venous thromboembolism during the look-back period prior to or on the index date; 4. Prescribed with more than 1 OAC on the index date
• Age groups:
  • Adults (18 to < 46 years)
  • Adults (46 to < 65 years)
  • Adults (65 to < 75 years)
  • Adults (75 to < 85 years)
  • Adults (85 years and over)
• Estimated number of subjects:
  1000

Study design details

• Main study objective:
   Respective rate of fatal or non-fatal major bleeding (defined as any transfusion and/or any hospitalization with associated bleeding) in all three patient groups
• Outcomes:
   Respective rate of fatal or non-fatal major bleeding (defined as any transfusion and/or any hospitalization with associated bleeding) in all three patient groups,  Respective rate of composite outcomes of stroke/systemic embolism (SE)/myocardial infarction (MI)/all-cause mortality (inpatient)/major bleeding (MI)/gastrointestinal (GI) bleeding/ intracranial hemorrhage (ICH) in all three patient groups (the rate indicates the net clinical benefit, calculated as the net rate of all above safety and effectiveness outcomes)
• Data analysis plan:
  Comparative analysis for primary and secondary outcomes will be conducted between groups. The comparative analysis will follow a two-step approach. The first step will compare the event rates and baseline characteristics of NOAC (Dabigatran, Rivaroxaban) - and warfarin-treated groups. To minimize potential confounding bias, the baseline characteristics of the two NOAC groups will be adjusted against that of the warfarin group using Stabilized Inverse Probability of Treatment Weighting (s-IPTW). Based on estimated HRs from the first step, the second step will determine the required sample size for comparisons between dabigatran- and rivaroxaban-treated groups. If the database can fulfil the sample size requirement, analysis will move forward for comparative analysis between the two NOAC groups. A Cox proportional hazard regression model with the time since NOAC drug index date as the underlying timescale will be used to compute adjusted hazard ratios (aHRs) with 95% CIs.