Am J Gastroenterol. 2023 Mar 16. doi: 10.14309/ajg.0000000000002249. Online ahead of print.
ABSTRACT
Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT4) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first 5-HT4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT4 agonist approved in the USA in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram (ECG) parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia's formula following placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In 2 24-month observational studies among 2,468 patients, changes in ECG parameters over time were minor, except at occasional timepoints when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64 [95% CI: 0.36-1.14]). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.
PMID:36927957 | DOI:10.14309/ajg.0000000000002249