TY - JOUR
T1 - Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation
T2 - A Multinational Population-Based Cohort Study
AU - Gilsenan, Alicia
AU - Fortuny, Joan
AU - Cainzos-Achirica, Miguel
AU - Cantero, Oscar F.
AU - Flynn, Robert W.V.
AU - Garcia-Rodriguez, Luis
AU - Harding, Abenah
AU - Kollhorst, Bianca
AU - Karlsson, Pär
AU - Linnér, Love
AU - MacDonald, Thomas M.
AU - Odsbu, Ingvild
AU - Plana, Estel
AU - Ruigómez, Ana
AU - Schink, Tania
AU - Ziemiecki, Ryan
AU - Andrews, Elizabeth B.
N1 - Funding Information:
The authors thank Antonio Gonzalez (CEIFE), who contributed to the statistical analyses of THIN data and report preparation, and Jennifer Bartsch (RTI-HS), who contributed to the statistical programming for the CPRD data. The authors are also grateful for input on the design from Patricia Tennis, Kenneth Rothman, and Eileen Ming. Helle Kieler contributed to the study as a primary investigator in Sweden. Alison McGinnis, a research nurse, toured Scottish hospitals to gather original hospital case records for the purposes of endpoint adjudication. Amy Rogers and Kerr Grieve provided assistance with event validation. Kate Lothman of RTI Health Solutions provided medical writing services, which were funded by Shire Pharmaceuticals, now part of the Takeda group of companies. This study is based in part on data from the CPRD obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the National Health Service as part of their care and support. The interpretation and conclusions contained in this study are those of the authors alone. We thank the statutory health insurance providers in Germany, AOK Bremen/Bremerhaven, DAK-Gesundheit, and Die Techniker (TK), for contributing the data for this analysis. We acknowledge the Electronic Data Research and Innovation Service (eDRIS) of ISD Scotland for providing the ISD data. We also acknowledge Quintiles IMS (now IQVIA) for providing access to THIN data.
Funding Information:
This study was performed under a research contract between RTI Health Solutions and Shire Pharmaceuticals, now part of the Takeda group of companies, and was funded by Shire. The research contract granted independent publication rights to the research team, and the content of the publications was developed independently from the study sponsor.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s40264-019-00835-0
DO - 10.1007/s40264-019-00835-0
M3 - Article
C2 - 31134512
AN - SCOPUS:85072132960
VL - 42
SP - 1179
EP - 1190
JO - Drug Safety
JF - Drug Safety
SN - 0114-5916
IS - 10
ER -