Exploring mediation through major bleeding between direct oral anticoagulants and cardiovascular events (MB mediation in CV RWE)

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)

  Method development or testing
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine:
  APIXABAN

  DABIGATRAN ETEXILATE

  RIVAROXABAN
• Name of medicine, other:
  Warfarin
• Study drug International non-proprietary name (INN) or common name:
  APIXABAN

  DABIGATRAN

  DABIGATRAN ETEXILATE

  EDOXABAN

  RIVAROXABAN
• Anatomical Therapeutic Chemical (ATC) code:
  (B01AE07) dabigatran etexilate

  dabigatran etexilate

  (B01AF01) rivaroxaban

  rivaroxaban

  (B01AF02) apixaban

  apixaban

  (B01AF03) edoxaban

  edoxaban
• Medical condition to be studied:
  Atrial fibrillation

  Ischaemic stroke

  Myocardial infarction
• Additional medical condition(s):
  Extracranial major bleeding

Population studied

• Short description of the study population:
  The study will include patients who meet criteria for inclusion in the target cohorts (1. rivaroxaban intiators or 2. direct oral anticoagulants intitiators) and comparator cohort (warfarin intiators). Both target and comparator cohorts are defined as first exposure to drug of interest (index date), requiring 365 days of prior observation. Patients are required to have ≥1 condition occurrence record of non-valvular atrial fibrillation observed between 365 days before until and including the index date. Full details of the target, comparator, mediator, and outcome definitions are reported in protocol sections 16.
• 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:
  2974000

Study design details

• Study design:
  Causal mediation cohort study. New-user comparative cohort design, comparing a target to a comparator cohort for risk of outcome in time-to-event data. A single mediator – extracranial major bleeding - is included in the Cox proportional hazards model.
• Main study objective:
  The study will quantify the following estimands: ; - Main effect: The effect of the target on the outcome, relative to the comparator.; - Direct effect: The effect of the target on the outcome, relative to the comparator, not mediated by the mediator.; - Indirect effect: The effect of the target on the outcome, relative to the comparator, mediated by the mediator. The indirect effect is estimated using the difference method, subtracting the (log) direct effect from the (log) main effect. Estimating the indirect effect is the primary study objective.;
• Setting:
  The data will be drawn from five large secondary use observational databases from the United States (four administrative claims, one electronic health record). These data sources met data element requirements per empirical evaluation. The study period is 01-11-2010 to 31-12-2022, the time during which exposure index dates can occur. A patient’s baseline data will be extracted, where available, up to the index date of the target and comparator cohorts, respectively. The exposure date is defined as the date of treatment initiation provided ≥365 days of prior database observation time. Full target and comparator cohort definitions are available in protocol sections 16.
• Comparators:
  Warfarin initiators with non-valvular atrial fibrillation.
• Outcomes:
  Cardiovascular events ischaemic stroke and acute myocardial infarction. Mediator condition extracranial major bleeding. Definitions are provided in protocol section 16.
• Data analysis plan:
  For each target-comparator-outcome triplet, two Cox modes will be fitted, one with the mediator and one without. From these two models, the following estimands will be reported, each on the hazard ratio scale, including their 95% confidence intervals.; - Main effect: The effect of the target on the outcome, relative to the comparator.; - Direct effect: The effect of the target on the outcome, relative to the comparator, not mediated by the mediator.; - Indirect effect: The effect of the target on the outcome, relative to the comparator, mediated by the mediator. The indirect effect is estimated using the difference method, subtracting the (log) direct effect from the (log) main effect.