A post-authorisation safety study (PASS) to evaluate the long-term cardiovascular and psychiatric safety profile of methylphenidate (MPH) in adult patients with attention deficit/hyperactivity disorder (ADHD) in European Countries (PASS on methylphenidate in adults)

Study type

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

Non-interventional study

• Non-interventional study design:
  Cohort

  Other
• Non-interventional study design, other:
  Retrospective cohort study (new user design)

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  100000097719

  dexamfetamine

  100000097721

  methylphenidate

  100000097726

  atomoxetine

  100000125051

  lisdexamfetamine
• Medical condition to be studied:
  Attention deficit hyperactivity disorder

Population studied

• 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:
  500000

Study design details

• Main study objective:
  To compare the incidence rate of first-time cardiovascular events (composite) in adults newly diagnosed with ADHD between cumulative person-time newly exposed to MPH versus cumulative person-time newly exposed to MPH versus cumulative person-time newly treated with non-MPH ADHD medication.
• Outcomes:
  First-time cardiovascular events (composite of hospitalization for myocardial infarction, cardiomyopathy, left-ventricular hypertrophy, hospitalization for stroke, ventricular arrhythmia, sudden cardiac death or all other causes of cardiovascular death of interest), First-time psychiatric events of interest (composite of psychotic or manic symptoms, suicidal ideation or behaviour, aggressive and hostile behaviour, anxiety or agitation or tension, depressive symptoms, motor or verbal tics)
• Data analysis plan:
  • Descriptive analysis for each cohort post data-extraction, • Cohort-specific descriptive statistics summarizing demographic, health and clinical patient characteristics will be presented. • Crude incidence (presented as both proportions and rates) for the relevant outcomes reported during person-time treated with MPH, treated with Non-MPH, or time untreated will be calculated for 1-year, 2-year, 3-year, 4-year and 5-year intervals cumulatively, stratified by potential confounders • Time to event, high and low risk periods will be summarized. • Univariate analyses will be used to inform on potential confounders and risk factors. • Cardiovascular and psychiatric risk scores will be determined via regression • Time-varying analysis of cardiovascular and psychiatric hazard rates will be performed using time-varying Cox regression models by country and pooled estimate calculated using random effects meta-analysis.