Study Design and Cohort Comparability in a Study of Major Cardiovascular Events in New Users of Prucalopride Versus Polyethylene Glycol 3350

Abstract

IntroductionGiven prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride.ObjectivesOur objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol.MethodsPrucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (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 cardiovascular events.ResultsIn total, 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 cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden.ConclusionsMatching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.Electronic supplementary materialThe online version of this article (10.1007/s40264-019-00836-z) contains supplementary material, which is available to authorized users.

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study

“…This was an observational population-based cohort study of patients initiating prucalopride or PEG from five data sources across Germany, Sweden, and the UK (including England, Wales, Scotland, and Northern Ireland) following a common protocol (EUPAS9200) [9]. Data from Germany were excluded from the pooled analyses because the patient population was markedly different compared with the other countries in terms of comorbidities, likely owing to differences in prescribing and reimbursement practices for laxatives in Germany as compared with the other countries, as well as specifically between prucalopride and PEG within Germany [8].…”

“…In Germany, the German Pharmacoepidemiological Research Database, a claims database of four statutory healthcare insurance providers, was used. Based on the results of an interim analysis assessing the characteristics of the study cohorts [8], the final pooled analysis presented in this article combined the three databases from the UK and the SNR; data from Germany were not included because of marked differences between prucalopride and PEG initiators, as well as differences in both cohorts compared with the data sources in the UK and Sweden. Patients and practices that overlapped in the UK data sources were retained in only one data source (see Electronic Supplementary Material 1 of Fortuny et al [8] for more details on each data source).…”

“…Details regarding the inclusion and exclusion criteria are presented elsewhere by Fortuny et al [8]. The prucalopride cohort consisted of adult patients who had a dispensing (for claims data sources and the Prescribed Drug Register in Sweden) or prescription (as recorded in electronic medical record data sources) for prucalopride within the study period with at least 12 months of data coverage in the data source before this first dispensing or prescription, no evidence in the data source of prior use of prucalopride, and no evidence of short use of PEG (i.e., < 5 days) within 12 months before this first prucalopride prescription/dispensing.…”

“…Crude and adjusted incidence rates of each outcome of interest were calculated for the prucalopride and PEG cohorts by categories of each covariate of interest, and corresponding crude and standardized IRRs and IRDs were estimated. Adjusted IRRs and IRDs were calculated using standardization by the deciles of the propensity score (PS), derived as explained in Fortuny et al [8]. Pooled analyses of aggregate data were conducted by the coordinating center (RTI Health Solutions) and involved standardization of the source-specific PS deciles and data source as stratification variables.…”

“…Secondary objectives were to estimate the incidence rates for MACE and its individual components in the prucalopride and PEG cohorts, and to estimate their adjusted IRRs comparing prucalopride and PEG. This article focuses on the results of the primary and secondary study outcomes; the study design, general methods, and a detailed description of the study cohorts are presented in Fortuny et al [8].…”