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

Alicia Gilsenan (), Joan Fortuny, Miguel Cainzos-Achirica, Oscar F. Cantero, Robert W. V. Flynn, Luis Garcia-Rodriguez, Abenah Harding, Bianca Kollhorst, Pär Karlsson, Love Linnér, Thomas M. MacDonald, Ingvild Odsbu, Estel Plana, Ana Ruigómez, Tania Schink, Ryan Ziemiecki and Elizabeth B. Andrews
Additional contact information
Alicia Gilsenan: RTI Health Solutions
Joan Fortuny: RTI Health Solutions
Miguel Cainzos-Achirica: RTI Health Solutions
Oscar F. Cantero: Centro Español de Investigación Farmacoepidemiológica
Robert W. V. Flynn: University of Dundee
Luis Garcia-Rodriguez: Centro Español de Investigación Farmacoepidemiológica
Abenah Harding: RTI Health Solutions
Bianca Kollhorst: Leibniz Institute for Prevention Research and Epidemiology-BIPS
Pär Karlsson: Karolinska Institutet
Love Linnér: Karolinska Institutet
Thomas M. MacDonald: University of Dundee
Ingvild Odsbu: Karolinska Institutet
Estel Plana: RTI Health Solutions
Ana Ruigómez: Centro Español de Investigación Farmacoepidemiológica
Tania Schink: Leibniz Institute for Prevention Research and Epidemiology-BIPS
Ryan Ziemiecki: RTI Health Solutions
Elizabeth B. Andrews: RTI Health Solutions

Drug Safety, 2019, vol. 42, issue 10, No 7, 1179-1190

Abstract: Abstract Introduction The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. Methods This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. Results The pooled analyses included 5715 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 standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90–10.39) for patients initiating prucalopride and 10.24 (6.97–14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36–1.14). Results remained consistent in various sensitivity analyses. Conclusions The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

Date: 2019
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DOI: 10.1007/s40264-019-00835-0

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