DARWIN EU® - Clozapine and the incidence of agranulocytosis over time

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Disease epidemiology

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

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Medicinal product name, other:
  Clozapine
• Anatomical Therapeutic Chemical (ATC) code:
  (N05AH02) clozapine

  clozapine
• Medical condition to be studied:
  Agranulocytosis

Population studied

• Short description of the study population:
  The study population will include all new users of clozapine registered in the respective data sources between 1st of January 2010 and 31st of December 2024 (or latest date available). ; “New use” refers to a first prescription of clozapine within the study period with no clozapine prescription in the medical history. ; Eligibility Criteria: ; At least 1 year of data visibility before starting clozapine treatment.; Additional eligibility criteria:; To ensure sufficient follow-up, only individuals who initiated clozapine treatment at least one year before the end of the available data in the respective data source will be included.;
• Age groups:
  • In utero
  • Paediatric Population (< 18 years)

    • Neonate

      • Preterm newborn infants (0 – 27 days)
      • Term newborn infants (0 – 27 days)
    • Infants and toddlers (28 days – 23 months)
    • Children (2 to < 12 years)
    • Adolescents (12 to < 18 years)
  • 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)

Study design details

• Study design:
  A cohort study will be conducted using routinely collected health data from 5 data sources. The study will comprise three consecutive parts:; • Population-level cohort study (Objective 1, Population-level descriptive epidemiology of agranulocytosis and neutropenia in new users of clozapine).; • Cohort
• Main study objective:
  1. To estimate the incidence rates of agranulocytosis and neutropenia in consecutive weekly and monthly intervals following the initiation of clozapine treatment, overall and stratified by age and sex. ; 2. To characterise the timing of agranulocytosis and neutropenia events during clozapine treatment using Kaplan-Meier curves, overall and stratified by age and sex.; 3. To characterise individuals initiating clozapine treatment in terms of demographics and pre-specified conditions related to the indication for clozapine use.; 4. To determine the treatment duration for clozapine use. ;
• Outcomes:
  A combined outcome of neutropenia and agranulocytosis (broad definition) following the initiation of clozapine treatment. Cohort diagnostics showed that coding limitations and inconsistent SNOMED mappings prevented reliable distinction between neutropenia and agranulocytosis. To reduce misclassification and ensure consistency, the outcome was defined as a composite of both conditions. To ensure that only incident cases were captured, individuals with a prior history of agranulocytosis or neutropenia were excluded.
• Data analysis plan:
  Population-level descriptive epidemiology: Incidence rates of newly diagnosed agranulocytosis and neutropenia were estimated following clozapine treatment initiation (objective 1). These rates are expressed as the number of individuals with the newly diagnosed outcome of interest following clozapine initiation per 1,000 person-years of individuals fulfilling inclusion criteria. Incidence rates were calculated for consecutive weekly (0-7 days, 8-14 days, 15-21 days etc.) and monthly intervals (0-30 days, 31-60 days, 61-90 days etc.) since the initiation of clozapine treatment (index date), with a maximum follow-up period of 24 months for reporting both weekly and monthly estimates. The statistical analysis was performed based on OMOP-CDM mapped data using the IncidencePrevalence” R package. The results are reported overall and stratified by age and sex. ; Patient-level characterisation: The timing of agranulocytosis and neutropenia events during clozapine treatment was characterised using Kaplan-Meier curves (objective 2). This analysis was conducted using the “CohortSurvival” R package based on OMOP-CDM mapped data. The results were stratified by age and sex. ; Patient-level utilisation of clozapine: Characterisation including age and sex was assessed at the date of new ; (incident) prescription of clozapine (index date) (objective 3). The frequency of pre-specified conditions related to clozapine initiation was assessed at any time prior to 1 day before index date, 365 days prior to 1 day before index date and at the index date (objective 3). Duration of treatment was calculated and summarised providing the minimum, quartiles and maximum, where available (objective 4). Statistical analyses were conducted using the “CohortCharacteristics” and “DrugUtilisation” R packages based on OMOP-CDM mapped data. ; Sensitivity analysis: [truncated]
• Summary results:
  Discussion ; This multi-database cohort study provides evidence on incidence and timing of agranulocytosis and neutropenia following clozapine treatment initiation across different European countries. The findings reaffirm that these adverse events are rare and typically occur early in treatment, consistent with prior evidence. This underscores the importance of close monitoring during the initial treatment period, aligning with existing clinical guidance. ; However, several methodological limitations should be considered when interpreting these findings. Specifically, it was not feasible to reliably differentiate between agranulocytosis and neutropenia, nor to assess the severity of individual events. Furthermore, challenges in accurately capturing treatment duration of clozapine may have affected estimates of both event timing and frequency, although overall incidence rates remained low. ; Despite these limitations, the consistently low incidence of events observed beyond the early months following clozapine initiation raises important questions about the necessity of prolonged intensive haematological monitoring. This highlights a potential opportunity to revisit and refine existing monitoring guidelines to balance safety with improved treatment accessibility and patient adherence.