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The risk of serious cardiac arrhythmias among cisapride users in the United Kingdom and Canada1,

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Abstract

Purpose: Serious, although rare, ventricular arrhythmias and deaths have been reported in patients taking cisapride monohydrate. Without quantification of the risk involved, it is impossible to develop rational therapeutic guidelines.

Subjects and Methods: Arrhythmic events (sudden deaths and other events compatible with serious ventricular arrhythmias) were sought among 36,743 patients prescribed cisapride in the United Kingdom and Saskatchewan, Canada. Prescriptions and cases were identified from computerized medical claims data and physicians’ office records. We compared rates of events between periods of recent cisapride use and nonrecent use, using cohort analysis. Potential confounding factors, including concomitant treatment with agents that inhibit CYP3A4 metabolism or that prolong the QT interval, were assessed in a nested case-control study.

Results: In the cohort analysis, the incidence of the arrhythmic events was 1.6 times greater (95% confidence interval [CI]: 0.9 to 2.9) in periods of recent use. With adjustment for clinical history, use of CYP3A4 inhibitors, and use of drugs that prolong the QT interval, the odds ratio for cisapride and cardiac outcomes was 1.0 (95% CI: 0.3 to 3.7). There was no identifiable increase in risk when cisapride was dispensed at about the same time as QT-prolonging drugs or CYP3A4 inhibitors. QT- prolonging agents were associated with a 2.5-fold increase in the risk of arrhythmic events (95% CI: 1.1 to 5.8).

Conclusions: Serious rhythm disorders were not associated with cisapride use, although the upper confidence bounds do not rule out an increase in risk.

Section snippets

United Kingdom

A commercial vendor (Value Added Medical Products) provides hardware and software to general practitioners throughout the UK for computerizing patient record-keeping and office functions. To obtain this system at a reduced cost, many physicians agreed to record information in a standardized manner and to provide the information for research purposes. The resulting data, the General Practice Research Database, is now held by Britain’s Office of National Statistics, which permits analyses of

Results

During the study period, there were 18,571 eligible cisapride users in the UK and 18,172 in Saskatchewan. The study sample in the UK was somewhat younger than in Saskatchewan. In the UK, the median age at first cisapride use was 55 years; in Saskatchewan, the median age was 60 years. The most frequently used comparison drugs were ranitidine, omeprazole, cimetidine, and metoclopramide (Table 1).

Discussion

The cohort and case-control analyses from both the UK and Canada are consistent with an absence of any cisapride-induced increase in rates of arrhythmic events, at least under the conditions of cisapride usage that were prevalent in the first half of this decade. However, the upper confidence bounds for the relative risk of arrythmic events associated with cisapride use do not rule out a threefold to fourfold increase in risk. Thus, our results cannot rule out an increase in risk of that

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    Citation Excerpt :

    Finally, well-designed mechanistic studies are often the best way to identify drugs associated with LQTS. For instance, in the case of cisapride, Walker et al.44 reviewed the use of cisapride in 36,743 patients and could not find any link between cisapride use and LQTS; the odds ratio for cisapride use and cardiac outcomes was 1 (95% CI 0.3–3.7). However, at the same time, mechanistic in vitro (patch clamp) studies, ex vivo studies (explanted hearts), in vivo animal models, and case reports in patients were all pointing toward the conclusion that cisapride use is associated with an increased risk of drug-induced LQTS and death in certain patients.15

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The research was supported by Janssen Pharmaceutica Research Foundation, Titusville, NJ, under a contract that guaranteed the authors unrestricted right of publication. Janssen is the manufacturer of cisapride. One of the authors, Chuen L. Yee, works for the R.W. Johnson Pharmaceutical Research Institute, which (like Janssen) is owned by Johnson & Johnson. Dr. Walker has served as a consultant to Janssen on issues of drug safety. None of the authors has a financial interest that relates to the outcome of this study.

1

This study is based in part on data provided by the Saskatchewan Department of Health. The interpretation and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Department of Health.

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