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

Gilsenan, Alicia; Fortuny, Joan; Cainzos‐Achirica, Miguel; Cantero, Oscar Fernández; Flynn, Robert; Garcı́a-Rodrı́guez, Luis Alberto; Harding, Abenah; Kollhorst, Bianca; Karlsson, Pär; Linnér, Love; MacDonald, Thomas M.; Odsbu, Ingvild; Plana, Estel; Ruigómez, Ana; Schink, Tania; Ziemiecki, Ryan; Andrews, Elizabeth

doi:10.1007/s40264-019-00835-0

Cited by 27 publications

(36 citation statements)

References 7 publications

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“…18,22 However, a recent observational population-based cohort study showed that the pooled adjusted incidence rate ratio of major adverse cardiovascular events comparing new use of prucalopride with new use of polyethylene glycol 3350 was 0.64 (95%CI, 0.36-1.14). 23 Based on the results, the slight increase of HR by prucalopride would not induce major adverse cardiovascular events. Heart rate tachycardic outliers 0 0 0 0 Heart rate bradycardic outliers, 0 0 0 0 PR outliers, n (%) 1 As for TEAEs, no cardiovascular TEAE occurred.…”

Section: Discussionmentioning

confidence: 93%

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Hamatani

Noda

Takagaki

et al. 2020

Clinical Pharm in Drug Dev

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Minesapride (drug code: DSP-6952) is a potential gastrointestinal prokinetic agent with high selectivity for 5-hydroxytryptamine 4 (5-HT 4) receptor that acts as a partial agonist. Although 5-HT 4 receptor agonists are expected to show efficacy in patients with irritable bowel syndrome with constipation, only tegaserod is available for female patients, with limitations, in the United States. Previously, another 5-HT 4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation. Chemically, benzamide is one of the most common structures among 5-HT 4 receptor agonists. Some benzamide derivatives, such as cisapride, are responsible for QT prolongation, while some, such as mosapride, are not. Thus, we planned a thorough QT/QTc study to investigate the effects of minesapride, a newly designed benzamide derivative, on the QT/QTc. This was a randomized, placebo-controlled, 4-arm, 4-period, crossover study conducted in healthy adults, with administration of single oral doses of minesapride (40 mg and 120 mg), placebo, and moxifloxacin in the fasted state. Minesapride and placebo were administered in a double-blind fashion, while the positive control moxifloxacin was administered in an open-label fashion. Japanese subjects (48 total: 24 males and 24 females) were randomized, and 47 subjects completed all treatment periods. A review of other electrocardiographic data revealed that neither therapeutic (40 mg) nor supratherapeutic (120 mg) doses of minesapride were associated with increased risk of prolonged QT interval.

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Section: Discussionmentioning

confidence: 93%

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Hamatani

Noda

Takagaki

et al. 2020

Clinical Pharm in Drug Dev

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“…Anorectal biofeedback, nerve stimulation, and colonic surgery may be used to treat FC [9][10][11]. Although there are many methods to choose from, the side effects of these methods are notable, including diarrhea, bloating, nausea, and possible cardiovascular adverse events [12][13][14]. As a result, many people, including those who do not improve with existing medications or suffer many side effects, are interested in complementary alternative medicine.…”

Section: Introductionmentioning

confidence: 99%

The Effectiveness of Acupuncture in Management of Functional Constipation: A Systematic Review and Meta‐Analysis

Wang

Zheng

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Objective. The purpose of this study was to assess the effectiveness and safety of acupuncture for functional constipation (FC). Methods. A rigorous literature search was performed in English (PubMed, Web of Science, the Cochrane Library, and EMBASE) and Chinese (China National Knowledge Infrastructure (CNKI), Chinese Biological Medical (CBM), Wanfang database, and China Science and Technology Journal (VIP)) electronic databases from their inception to October 2019. Included randomized controlled trials (RCTs) compared acupuncture therapy with sham acupuncture or pharmacological therapies. The outcome measures were evaluated, including the primary outcome of complete spontaneous bowel movement (CSBM) and secondary outcomes of Bristol Stool Form Scale (BSFS), constipation symptoms scores (CSS), responder rate, the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire, and safety evaluation. Meta-analysis was performed by using RevMan5.3. Results. The merged data of 28 RCTs with 3525 participants indicated that acupuncture may be efficient for FC by increasing CSBMs (p<0.00001; MD = 0.84 [95% CI, 0.65 to 1.03]; I2 = 0%) and improving constipation symptoms (p=0.03; SMD = −0.4 [95% CI, −0.78 to −0.03]; I2 = 74%), stool formation (p<0.00001; MD = 0.24 [95% CI, 0.15 to 0.34]; I2 = 0%), quality of life (p<0.00001; N = 1, MD = −0.33 [95% CI, −0.45 to −0.21]), and responder rates (p=0.02; RR = 2.16; [95% CI, 1.1 to 4.24]; I2 = 69%) compared with the effects of sham treatment. No increased risk of adverse events was observed (p=0.44; RR = 1.18; [95% CI, 0.77 to 1.81]; I2 = 0%). With regard to medication comparisons, the pooled data indicated that acupuncture was more effective in increasing CSBMs (p=0.004; MD = 0.53 [95% CI, 0.17 to 0.88]; I2 = 88%) and improving patients’ quality of life (p<0.00001; SMD = −0.73 [95% CI, −1.02 to −0.44]; I2 = 64%), with high heterogeneity. However, there were no significant differences in responder rate (p=0.12; RR = 1.31; [95% CI, 0.94 to 1.82]; I2 = 53%), BSFS (p=0.5; MD = 0.17 [95% CI, −0.33 to 0.68]; I2 = 93%), or CSS (p=0.05; SMD = −0.62 [95% CI, −1.23 to −0.01]; I2 = 89%). Regarding safety evaluation, acupuncture was safer than medications (p<0.0001; RR = 0.3; [95% CI, 0.18 to 0.52]; I2 = 30%). Conclusions. Current evidence suggests that acupuncture is an efficient and safe treatment for FC. Acupuncture increased stool frequency, improved stool formation, alleviated constipation symptoms, and improved quality of life. However, the evidence quality was relatively low and the relationship between acupuncture and drugs is not clear. More high-quality trials are recommended in the future. PROSPERO registration number: CRD42019143347.

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“…In the context of a multinational, multi-database study using a common protocol to evaluate the occurrence of major adverse cardiovascular events (MACE) among initiators of prucalopride and initiators of polyethylene glycol (PEG), the aim of this manuscript is to show the performance of propensity score (PS) stratification and trimming to obtain comparable study cohorts; and to report study design decisions undertaken when balance could not be achieved. The findings in terms of MACE of the prucalopride safety study are reported elsewhere [5].…”

Section: Introductionmentioning

confidence: 87%

“…Finally, the deciles of the PS were derived, and balance of the potential confounding factors between cohorts was checked. Stratification on the deciles of the PS was used to obtain adjusted estimates for the main study [5]. For each data source, the following characteristics of all variables of interest were described for each cohort after trimming: for categorical variables, the frequency (i.e.…”

Section: Methodsmentioning

confidence: 99%

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

Fortuny¹,

Gilsenan

Cainzos‐Achirica

et al. 2019

Drug Saf

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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.

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

Cited by 27 publications

References 7 publications

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

The Effectiveness of Acupuncture in Management of Functional Constipation: A Systematic Review and Meta‐Analysis

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

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

Cited by 27 publications

References 7 publications

Thorough QT/QTc Study Shows That a Novel 5‐HT4 Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Thorough QT/QTc Study Shows That a Novel 5‐HT4 Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

The Effectiveness of Acupuncture in Management of Functional Constipation: A Systematic Review and Meta‐Analysis

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

Contact Info

Product

Resources

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Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation

Thorough QT/QTc Study Shows That a Novel 5‐HT₄ Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation