Domperidone and Risk of Serious Cardiac Events in Postpartum Women
Condition: Ventricular Tachyarrhythmia; Sudden Cardiac Death; Lactation; Breast Feeding
MeSH terms: Death, Sudden, Cardiac; Cardiovascular Diseases; Tachycardia; Tachycardia, Ventricular; Death
Study type: Observational

Summary: 
      The purpose of this study is to determine whether the use of domperidone is associated with
      an increased risk of serious cardiac events among postpartum women in the six months
      following delivery. The hypothesis is that the use of domperidone will be associated with an
      increased risk of serious cardiac events among postpartum women.

      The investigators will carry out separate population-based cohort studies using health care
      databases in five Canadian provinces. Women with live births will be eligible to enter the
      cohort. We will identify all women who start domperidone during the six months following
      delivery and match them to similar women who do not start domperidone, with all included
      women followed until the occurrence of an adverse cardiac event or for up to six months after
      delivery. The results from the separate sites will be combined to provide an overall
      assessment of the risk of serious cardiac events in users of domperidone.
    

Detailed description: 
      The overall objective of this study is to determine whether the use of domperidone is
      associated with an increased risk of serious cardiac events among postpartum women in the six
      months following delivery. More specifically, the investigators will assess whether
      domperidone is associated with the risk of ventricular tachyarrhythmia (VT) and sudden
      cardiac death (SCD).

      A distributed, common-protocol approach will be used to conduct retrospective cohort studies
      using administrative health care data from five Canadian provinces (Alberta, British
      Columbia, Manitoba, Ontario and Saskatchewan). Briefly, the Canadian databases include
      population-level data on physician billing, diagnoses and procedures from hospital discharge
      abstracts, and dispensations for prescription drugs. The Ontario data will be restricted to
      social assistance recipients.

      To assess this potential drug safety issue, the investigators will use a prevalent new-user
      cohort design as described by Suissa et al., 2017. In each jurisdiction, the investigators
      will first assemble a base cohort that includes all women aged between 15 and 55 years old
      with live births between April 1, 1997 and December 31, 2016 (or the latest available data at
      each site). Base cohort entry will be defined by the hospital discharge date after delivery.
      From this base cohort, a study cohort will be formed including all women who received a
      prescription for domperidone during the six months following delivery and matched women who
      have a physician visit at the same follow-up time and do not receive domperidone. Study
      cohort entry will be defined by the prescription date of domperidone for exposed women or the
      corresponding date of the physician visit for unexposed women. Women will be followed from
      the study cohort entry date until an event (defined below) or end of follow up (six months
      after delivery). Women will be permitted to contribute more than one observation to the study
      provided that each observation meets all the inclusion criteria.

      Exposure to domperidone will be defined as a prescription for domperidone during the six
      months following delivery. Women not exposed to domperidone will serve as the reference
      group. Analyses will be conducted using an approach analogous to an intention-to-treat.
      Unexposed women who are subsequently exposed to domperidone will be censored at the time of
      the domperidone prescription. The primary outcome will be a composite endpoint of VT or SCD.
      Secondary outcomes will be the individual endpoints of VT, SCD, and all-cause mortality;
      separate follow-up durations will be estimated for each outcome.

      Using a prevalent new-user design with time-based exposure sets, each user of domperidone
      will be matched to 10 unexposed women with a physician visit within ±30 days of the first
      domperidone dispensing of the exposed woman. Matching will be done on propensity score and
      calendar date of base cohort entry (i.e., hospital discharge from delivery hospitalization).
      Cox proportional hazards models will be used to estimate site-specific adjusted hazards
      ratios (HR) and corresponding 95% confidential intervals (CI) for each outcome of interest
      among postpartum women. Robust sandwich variance estimators will be used to account for
      potential within-subject clustering. As secondary analyses, the composite endpoint of VT or
      SCD will be stratified by domperidone dose and duration if feasible. Sensitivity analyses
      will be performed to assess the robustness of study results. Meta-analyses of the
      site-specific results will be performed using random-effects models.

      In additional analyses, the demographic and clinical characteristics (including perinatal and
      peripartum characteristics) of women prescribed domperidone in the six months postpartum with
      those of women not prescribed it during this period will be compared. Furthermore, the impact
      of Health Canada safety advisories on prescribing patterns will be assessed via interrupted
      time series analyses.
    

Intervention name(s): Domperidone
Intervention type(s): Drug
Intervention description(s): Women who received a prescription for domperidone (ATC A03FA03) during the six months following delivery.
Other intervention name(s): ATC A03FA03
Intervention MeSH terms: Domperidone
Observational model: Cohort
Time perspective: Retrospective
Sampling method: Probability Sample
Study population: 
        In each jurisdiction, the investigators will assemble a base cohort that includes all women
        aged between 15 and 55 years old with live births between April 1, 1997 and December 31,
        2016 (or the latest available data at each site). Base cohort entry will be defined by the
        hospital discharge date after delivery. From this base cohort, a study cohort will be
        formed including all women who received a prescription for domperidone during the six
        months following delivery and matched women who have a physician visit at the same
        follow-up time and do not receive domperidone. Study cohort entry will be defined by the
        prescription date of domperidone for exposed women or the corresponding date of the
        physician visit for the unexposed women.
      
Keywords: Domperidone; Postpartum; Ventricular Tachyarrhythmia; Sudden Cardiac Death