BACKGROUND: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union (EU) for the treatment of chronic constipation, thus providing opportunity to include real-world observational data on cardiovascular safety to support approval of prucalopride in the United States.
OBJECTIVES: To estimate the pooled adjusted incidence rate ratio (IRR) for major adverse cardiovascular events (MACE, defined as hospitalization for non-fatal acute myocardial infarction orstroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) treated for chronic constipation, following a common protocol.
METHODS: The pooled analyses from this observational, population-based cohort study (EUPAS9200) included data from the Clinical Practice Research Datalink (CPRD), The Health Improvement Network (THIN), and the Information Services Division (ISD) of Scotland in the United Kingdom, and the Swedish National Registers (SNR) in Sweden. Up to 5 PEG initiators were selected for each prucalopride initiator, matched by age, sex, and year of first prucalopride or PEG prescription or dispensing. Standardized incidence rates (SIRs) and IRRs of MACE were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, cancer, and unmeasured confounding.
RESULTS: The pooled analyses included 5,715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled SIR per 1,000 person-years (95% confidence interval) of MACE was 6.57 (3.90-10.39) for patients initiating prucalopride and 10.24 (6.97-14.13) for PEG. The pooled adjusted IRR for MACE was 0.64 (0.36-1.14), and results were consistent for individual MACE components. Sensitivity analyses yielded results consistent to the main analysis, with IRRs for first episode of use only, extension to 30 days of risk, and past use of 0.69 (0.34-1.42), 0.65 (0.38-1.09), and 0.65 (0.45-0.92), respectively. Inclusion of out-of-hospital cardiovascular deaths in the MACE definition yielded an IRR of 0.43 (0.25-0.73) and inclusion of probable cases yielded an IRR of 0.75 (0.27-2.05). Adjustment for hypothetical additional confounding factors under various assumptions did not change the direction of the associations observed in the main analyses.
CONCLUSIONS: Results suggest no increased risk of MACE above the prespecified safety threshold of 3.00 in patients with chronic constipation using prucalopride as compared with PEG.
