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Time Trends in the Coprescribing of Cisapride and Contraindicated Drugs in Umbria, Italy
To the Editor: Concern has been raised about the cardiovascular safety of cisapride following postmarketing reports of QT-interval prolongation and serious ventricular arrhythmias.1 As a consequence, the labeling of cisapride has been revised and there have been efforts to inform health care professionals about this.2-3 Despite these risk management efforts, Janssen Pharmaceutica Inc decided to stop marketing cisapride in the United States in July 2000.4 In Europe, the United Kingdom and Germany suspended licensing for the drug while its risks and benefits are being reevaluated by the European Agency for the Evaluation of Medicinal Products. The degree of prescribers' adherence to the warnings and contraindications raised by health authorities remains critical in the evaluation of the overall safety of the drug.5
We carried out a cohort study, in the Italian region of Umbria, to evaluate the frequency of overlapping prescription of cisapride and contraindicated drugs and to evaluate the impact of regulatory action.
Methods
All Italian citizens are enrolled in the National Health Service (NHS), which provides health care free of charge. We obtained data from the NHS archive of drug prescriptions, which contains all outpatient prescriptions filled within the NHS, and from the archive of NHS enrollees, which contains demographic data about the 831 000 residents of Umbria.
The study cohort includes all patients who received at least 1 prescription for cisapride between February 1, 1996, and November 30, 1999. For each cohort member, prescriptions of drugs potentially able to prolong the QT interval or to inhibit cytochrome P-3A4 were analyzed. These included antimycotic drugs, macrolides, antiarrhytmics and  -blocking agents, antipsychotics, antidepressants, antihistamines, and antimalarial drugs. Troleandomycin, maprotiline, and proteinase inhibitors were not considered because they were either not provided by the NHS or were dispensed only in hospital settings.
Exposure to a "cycle" of a study drug was defined as the interval from the date of dispensing through the expected duration of therapy, estimated from the quantity dispensed expressed in defined daily doses. For each cohort member, any partly coincident cycle of contraindicated drugs with a cisapride cycle ("overlapping" event) was counted.
Results
In the 4-year study period, 227 879 cisapride cycles were prescribed to 77 146 patients and a total of 10 211 overlapping events (4.5%) were identified in 7.6% of the cohort. More than 50% of these individuals received a prescription of cisapride and contraindicated drugs on the same day. The annual prevalence of use of cisapride and the proportion of overlapping prescription are reported in Table 1. The drugs most frequently associated with cisapride were macrolides, antiarrhythmics, and -blocking agents.
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Table. Annual Prevalence of Cisapride Use in the Umbria Region and Overlapping Prescriptions of Contraindicated Drugs*
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Comment
During the study period, increasing knowledge about drugs that can cause QT-interval prolongation in association with cisapride led to changes in the cisapride Summary of Product Characteristics and the patient information leaflet. In 1998 the Italian health authorities published a "Dear Doctor" letter, which focused on the risk of serious ventricular arrhythmias after concomitant use of the drugs that we analyzed in this study. Nevertheless, neither the prevalence of use of cisapride nor the proportion of overlapping prescriptions substantially changed during this time.
Warnings to physicians did not prove effective in changing prescribing habits and reducing the number of patients potentially exposed to risk of arrhythmias.5 In Italy, health authorities have now restricted cisapride use to hospital settings and for the specific indications of gastroesophageal reflux disease in children and gastroparesis in adults. Our results suggest that such careful monitoring of cisapride is appropriate.
AUTHOR INFORMATION
Funding/Support: This work was supported by grants from the Umbria region.
Roberto Raschetti, MSc;
Marina Maggini, DBiol;
Roberto Da Cas, MSc
Department of Epidemiology and Biostatistics
Istituto Superiore di Sanità
Rome, Italy
Patrizia Popoli, MD
Department of Pharmacology
Istituto Superiore di Sanità
Rome
Angela Rossi, MD
Assessorato Regionale alla Sanità, Umbria Region
Perugia, Italy
1. Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia. N Engl J Med. 1996;35:290-291.
2. Medicines Control Agency Committee on Safety of Medicines. Cisapride (prepulsid): risk of arrhythmias. Curr Probl Pharmacovigilance. 1998;24:11.
3. Ministero della Sanità. Cisapride e rischi di aritmie cardiache. Boll Inform Farm. 1998:31.
4. Henney JE. Withdrawal of troglitazide and cisapride. JAMA. 2000;283:2228.
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5. Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride: impact of Food and Drug Administration regulatory action. JAMA. 2000;284:3036-3039.
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Letters Section Editors: Stephen J. Lurie, MD, PhD, Senior Editor; Jody W. Zylke, MD, Contributing Editor.
JAMA. 2001;285:1840-1841.
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