Sa2022 Does Prucalopride Have a Pro-Arrhythmic Potential? Lessons From Randomized Clinical Trials in Chronic Constipation

Abstract

Background: Available therapies for chronic constipation (CC) have limited efficacy. Gastrointestinal prokinetics represent an attractive option, but both cisapride and tegaserod, the two agents with proved efficacy in CC, have been withdrawn because of cardiac adverse events. Prucalopride is the first selective, high-affinity 5-HT4 agonist, without any significant activity towards other (5-HT and non 5-HT) receptors or channels (e.g. hERG) at the therapeutic doses. In vitro binding studies have shown that its affinity towards the hERG is more than 250 times lower than that displayed against 5-HT4-receptors. Aim: To evaluate the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH) for prucalopride, at the recommended dose (2 mg daily), in randomized clinical trials (RCTs), carried out in patients with CC. Effective and safe treatments are characterized as having low NNBs (2-6) and relatively high NNHs. Methods: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials as well as abstracts from the major American, European and Asian meetings were searched up to November 2012. Large (≥ 250 patients) randomized controlled trials (RCTs) in adult patients with CC, treated with prucalopride, were included. NNT and NNH with 95% CI were calculated from the pooled risk difference, obtained using a random effect model in order to provide a more conservative estimate. The outcomes assessed (at 12 weeks) were the number of patients with an average increase of ≥3 SCBM, the number of patients with an average increase of ≥1 SCBM or SBMs as well as increase of QT corrected according to Bazett's Formula (QTcB) > 500 ms in patients that had a baseline QTcB < 450 ms Results are summarized in Table 1. Conclusions: The NNH for QTcB prolongation largely exceeds the NNT for each of the efficacy end-points analyzed. These results confirm experimental data suggesting that, at clinically relevant concentrations, prucalopride is unlikely to block hERG channels. Therefore, at the recommended therapeutic doses, the pro-arrhythmic potential of this highly selective 5-HT4 agonist is minimal, if any. Table 1