Effect of cisapride on QT interval in patients with end-stage renal disease

Abstract

C isapride (Propulsid, Janssen Pharmaceutica, Titusville, New Jersey) is an orally administered prokinetic agent used in the treatment of dyspepsia, diabetic gastroparesis, and gastroesophageal reflux disease. Cisapride increases gastrointestinal tract motility by enhancing the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus.1 Although the drug is useful and generally well tolerated, numerous cases of QT interval prolongation, torsades de pointes, and sudden death have been reported.2–4 Cisapride-induced rhythm disturbances are most likely caused by blockade of the rapid component of the potassium rectifier current via high-affinity blockade of the human cardiac potassium channel HERG.5–7 This leads to delayed repolarization, early afterdepolarization, and potentially torsades de pointes. Clinically, cisapride-induced rhythm disturbances can be explained by pharmacokinetic and/or pharmacodynamic mechanisms. Pharmacokinetic mechanisms have been attributed to situations that result in an increase in cisapride blood concentrations secondary to inhibition of cytochrome p450 3A4 (CYP3A4) metabolism (the CYP isoenzyme primarily responsible for cisapride metabolism) by concomitant drugs3,8 (e.g., clarithromycin), disease-related alterations in drug removal (e.g., hepatic dysfunction), or higher than recommended cisapride doses.9 In fact, it has been suggested that the degree of QT interval prolongation is directly related to the cisapride serum concentration.8 Pharmacodynamic mechanisms include factors leading to additional blockade of cardiac potassium currents (concomitant drugs, diseases, electrolyte disturbances, and so forth)4,10 In May 1998, Janssen Pharmaceutica introduced labeling changes for cisapride. New contraindications to the drug were added, which included patients with renal failure. Cisapride’s manufacturer has reported that patients with renal failure were “predisposed to arrhythmias with cisapride.”11 More recently, Janssen Pharmaceutica announced that it had voluntarily stopped marketing cisapride in the United States effective July14, 2000.12 Patients who have no success with other therapies and who meet carefully defined eligibility criteria will be eligible to receive cisapride in the manufacturer’s “investigational limited-access program.”13 Two published case reports describe the occurrence of torsades de pointes in patients with end-stage renal disease (ESRD) receiving cisapride and clarithromycin2 (a well-known inhibitor of CYP3A4). It is apparent that patients with ESRD receiving drugs known to inhibit cisapride metabolism are at risk for the development of QT interval prolongation and subsequent cardiac arrhythmias. No publication to date has documented the proarrhythmic action of cisapride in patients with ESRD, in the absence of interacting drugs. The purpose of this study was to examine the degree of cisapride-induced corrected QT interval (QTc) prolongation and QT dispersion in patients with ESRD in a typical clinical setting. • • • Nine subjects with ESRD receiving dialysis treatment at the Indiana University Medical Center Outpatient Dialysis Unit were included in this study. Subjects were included in the study if their physician wanted to discontinue cisapride therapy, and they were aged .18 years of age, were receiving thrice weekly maintenance on hemodialysis, and were currently taking oral cisapride chronically. Subjects were excluded if they had serum electrolyte disturbances that may have induced QT interval changes (e.g., persistent hypokalemia, hyperkalemia, hypomagnesemia, hypocalcemia before hemodialysis sessions), or were taking medications, which, when used alone or in combination with cisapride, increase the risk of QT interval prolongation. The protocol was approved by the Indiana University-Purdue University-Indianapolis Institutional Review Board and each subject gave written informed consent before enrollment in the study. Subjects’ medical charts were reviewed and data collected for age, sex, concomitant diseases, details of cisapride therapy (indication, dose, duration of therapy), concomitant drug therapy, and serum electrolyte concentrations. Cardiac rhythm, ventricular rate, and QT intervals were determined from 12-lead electrocardiograms recorded at 50 mm/s immediately before the regularly scheduled hemodialysis session. Electrocardiograms were obtained during cisapride therapy and after cisapride had been discontinued for at least 2 weeks. The terminal elimination half-life of cisapride in a published study of patients with ESRD was 9.6 6 3.3 hours (range 5.1 to 14.1).14 Consequently, the 2-week time period allowed nearly complete elimination of cisapride from the systemic circulation. All electrocardiograms were evaluated by 2 cardiologists blinded to the treatment phase. Heart rate was determined as the average of the RR intervals obtained From the Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, Indianapolis; and the Divisions of Nephrology and Cardiology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana. Dr. Sowinski’s address is: Purdue University, Department of Pharmacy Practice, D711 Myers Building, WHS, 1001 W. 10th Street, Indianapolis, Indiana 46202–2879. E-mail: ksowinsk@iupui.edu. Manuscript received January 24, 2000; revised manuscript received and accepted May 1, 2000.