Key result
Highly selective 5-HT(4) agonists showed no cardiovascular safety concerns, whereas nonselective agents cisapride and tegaserod were associated with cardiovascular adverse events.
Why the study?
Do selective 5-HT4 agonists have a better cardiovascular safety profile than nonselective 5-HT4 agonists in patients with gastrointestinal disorders?
Systematic Review
Do selective 5-HT4 agonists have a better cardiovascular safety profile than nonselective 5-HT4 agonists in patients with gastrointestinal disorders?
Highly selective 5-HT4 agonists appear to offer improved cardiovascular safety compared to older nonselective agents like cisapride and tegaserod.
Answers are grounded in this paper and cite their sources.
Supports preferring highly selective 5-HT4 agonists in GI disorders; extends Level 1 evidence distinguishing their cardiovascular safety from nonselective agents.
BACKGROUND: The nonselective 5-HT(4) receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). AIM: To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT(4) agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. METHODS: Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. RESULTS: Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT(4) agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT(4) agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT(1) receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT(4) agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT(4) agonists with no hERG or 5-HT(1) affinity (renzapride, clebopride, mosapride). CONCLUSIONS: 5-HT(4) agonists for GI disorders differ in chemical structure and selectivity for 5-HT(4) receptors. Selectivity for 5-HT(4) over non-5-HT(4) receptors may influence the agent's safety and overall risk-benefit profile. Based on available evidence, highly selective 5-HT(4) agonists may offer improved safety to treat patients with impaired GI motility.
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Tack et al. (2012) conducted a systematic review in Gastrointestinal disorders. 5-HT(4) agonists was evaluated on Cardiovascular adverse events. Highly selective 5-HT(4) agonists showed no cardiovascular safety concerns, whereas nonselective agents cisapride and tegaserod were associated with cardiovascular adverse events.
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