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 topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

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

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  ATOMOXETINE

  METHYLPHENIDATE HYDROCHLORIDE
• Anatomical Therapeutic Chemical (ATC) code:
  (N06BA02) dexamfetamine

  dexamfetamine

  (N06BA04) methylphenidate

  methylphenidate

  (N06BA09) atomoxetine

  atomoxetine

  (N06BA12) lisdexamfetamine

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

  Myocardial infarction

  Cardiomyopathy

  Left ventricular hypertrophy

  Cerebrovascular accident

  Ventricular arrhythmia

  Psychotic symptom

  Manic symptom

  Suicidal ideation

  Suicidal behaviour

  Aggression

  Anxiety

  Agitation

  Tension

  Depressive symptom

  Tic

  Sudden cardiac death

  Hypertension

  Cardiac valve disease

  Pulmonary hypertension
• Additional medical condition(s):
  All causes of cardiovascular death

Population studied

• Short description of the study population:
  Adults newly diagnosed with ADHD, on or after the age of 18 years, in Denmark, Norway, and Sweden
• 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:
  500000

Study design details

• Study design:
  This was a retrospective observational cohort study conducted in 3 European ; countries (Denmark, Norway, and Sweden) using secondary data. A new user ; design was applied.
• 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.
• Setting:
  The study period of started from 13 June 2008 for Sweden, 06 May 2011 for ; Norway, and from 29 September 2006 for Denmark through to 31 December 2019, ; in order to allow for the minimum lookback period for confounders before the ; enrolment (12 months) and to start the study not prior to the availability of ; prescription data for MPH and at least one active comparator in the selected ; European Union (EU) market(s).; In each country, patients who were aged 18 years or more and had a diagnosis of ; ADHD were identified as eligible for inclusion into the study using the National ; Patient Register. Individual patient data were thereafter linked to the National ; Dispensed Drug Register and the Cause of Death Register.; The following selection criteria were applied for the data extraction:; Inclusion criteria for data extraction:; • A diagnosis recorded at any time in the data source of ADHD based on ; International Statistical Classification of Diseases, 10th Revision (ICD-10) codes ; F90 (Hyperkinetic disorders) or F98.8 (Other specified behavioural and emotional ; disorders with onset usually occurring in childhood and adolescence).; • Age 18 years or more at ADHD diagnosis.; • Continuous enrolment in the database for >12 months prior to date of first ; diagnosis.; • No dispensed prescription for ADHD medication in the prior 12 months before ; cohort entry (defined as the index diagnosis of ADHD).; Exclusion criteria for data extraction:; • Patients with missing age or sex.; • ADHD diagnosis prior to and including age 17 years. These patients by definition ; cannot be considered as adults newly diagnosed with ADHD in this study and are ; instead prevalent cases of the indication for treatment.; To address the research questions related to the primary and secondary endpoints ; separate cohorts were created, and cohort-specific selection criteria, nested within ; the criteria for data extraction, were applied. These cohorts were referred as the ; CV and psychiatric cohorts, respectively. ;
• 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.