Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation

A Multinational Population-Based Cohort Study

Alicia Gilsenan (Lead / Corresponding author), 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, Elizabeth B Andrews

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1179-1190
Number of pages12
JournalDrug Safety
Volume42
Issue number10
Early online date27 May 2019
DOIs
Publication statusE-pub ahead of print - 27 May 2019

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prucalopride
Constipation
Cohort Studies
Safety
Incidence
Population
Serotonin 5-HT4 Receptor Agonists
Confidence Intervals
Drug Approval
Propensity Score
Information Storage and Retrieval
European Union
Sweden
Germany
Hospitalization

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Gilsenan, A., Fortuny, J., Cainzos-Achirica, M., Cantero, O. F., Flynn, R. W. V., Garcia-Rodriguez, L., ... Andrews, E. B. (2019). Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study. Drug Safety, 42(10), 1179-1190. https://doi.org/10.1007/s40264-019-00835-0
Gilsenan, Alicia ; Fortuny, Joan ; Cainzos-Achirica, Miguel ; Cantero, Oscar F ; Flynn, Robert W V ; Garcia-Rodriguez, Luis ; Harding, Abenah ; Kollhorst, Bianca ; Karlsson, Pär ; Linnér, Love ; MacDonald, Thomas M ; Odsbu, Ingvild ; Plana, Estel ; Ruigómez, Ana ; Schink, Tania ; Ziemiecki, Ryan ; Andrews, Elizabeth B. / Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation : A Multinational Population-Based Cohort Study. In: Drug Safety. 2019 ; Vol. 42, No. 10. pp. 1179-1190.
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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.",
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Gilsenan, A, Fortuny, J, Cainzos-Achirica, M, Cantero, OF, Flynn, RWV, Garcia-Rodriguez, L, Harding, A, Kollhorst, B, Karlsson, P, Linnér, L, MacDonald, TM, Odsbu, I, Plana, E, Ruigómez, A, Schink, T, Ziemiecki, R & Andrews, EB 2019, 'Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study', Drug Safety, vol. 42, no. 10, pp. 1179-1190. https://doi.org/10.1007/s40264-019-00835-0

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation : A Multinational Population-Based Cohort Study. / Gilsenan, Alicia (Lead / Corresponding author); Fortuny, Joan; Cainzos-Achirica, Miguel; Cantero, Oscar F; Flynn, Robert W V; Garcia-Rodriguez, Luis; Harding, Abenah; Kollhorst, Bianca; Karlsson, Pär; Linnér, Love; MacDonald, Thomas M; Odsbu, Ingvild; Plana, Estel; Ruigómez, Ana; Schink, Tania; Ziemiecki, Ryan; Andrews, Elizabeth B.

In: Drug Safety, Vol. 42, No. 10, 10.2019, p. 1179-1190.

Research output: Contribution to journalArticle

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

PY - 2019/5/27

Y1 - 2019/5/27

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.

U2 - 10.1007/s40264-019-00835-0

DO - 10.1007/s40264-019-00835-0

M3 - Article

VL - 42

SP - 1179

EP - 1190

JO - Drug Safety

JF - Drug Safety

SN - 0114-5916

IS - 10

ER -