BACKGROUND: Given prior safety experience with other 5-HT4 agonists, an observational cohort study was conducted to evaluate the cardiovascular (CV) safety of prucalopride in support of approval of prucalopride for chronic constipation (CC) in the United States. Prevalence of these characteristics also differed from those in the UK and Sweden.
OBJECTIVES: To describe methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride and polyethylene glycol 3350 (PEG) initiators treated for CC, following a harmonized protocol; assess the performance of propensity score (PS) stratification and trimming to obtain comparable study cohorts; and report study design decisions undertaken when comparability could not be achieved.
METHODS: In this observational, population-based cohort study (EUPAS9200) conducted in 5 data sources from 3 European member states, prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Data sources included the Clinical Practice Research Datalink (CPRD), The Health Improvement Network (THIN), and the Information Services Division (ISD) of Scotland in the United Kingdom; the Swedish National Registers (SNR) in Sweden; and the German Pharmacoepidemiological Research Database (GePaRD) in Germany. Study exposures, CV risk factors, and other covariates were identified from health care utilization codes harmonized across databases. CV outcomes were identified using database-specific algorithms based on diagnosis codes. PS in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse CV events, which were the primary Post-authorisation Safety Study (PASS) endpoint.
RESULTS 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well balanced for CV risk factors and cancer. Matching on 2 additional variables (recent hospitalization, prescriber type) was needed in Sweden. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators.
CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in 4 of 5 data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany. Consequently, the pooled PASS analyses included only data from the UK and Sweden.
