February 22, 2012Alimentary Pharmacology & Therapeutics271 citationsOpen Access
Systematic review: cardiovascular safety profile of 5‐HT4agonists developed forgastrointestinaldisorders
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.
Study Design
Type
Systematic Review
Structured PICO
Do selective 5-HT4 agonists have a better cardiovascular safety profile than nonselective 5-HT4 agonists in patients with gastrointestinal disorders?
P
Population
Patients receiving 5-HT4 agonists developed for gastrointestinal disorders
I
Intervention
5-HT4 agonists (cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, velusetrag, naronapride)
O
Outcome
Cardiovascular adverse events (cardiac safety and tolerability)safety
Highly selective 5-HT4 agonists appear to offer improved cardiovascular safety compared to older nonselective agents like cisapride and tegaserod.
Abstract
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UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.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.