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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.

Nonsteroidal anti-inflammatory drug (NSAID)associated injury to the gastrointestinal tract is now a well-established fact. Indeed, studies have shown a prevalence of peptic ulcer in 20 –25% of patients taking these agents. The incidence of gastrointestinal bleeding, perforation, or obstruction in these patients is 1–3%, indicating that approximately one out of every 10 NSAID-associated peptic ulcers becomes complicated (ie, development of hemorrhage, perforation, or obstruction). These complications occur most often in well-defined, high-risk patients, primarily those who are elderly, those who have a history of gastrointestinal disease, and those who are receiving high-dose or multiple-drug regimens. The evaluation of any mucosal-protective agent is extremely difficult. For example, what end-point should be measured to determine efficacy: hemorrhages and erosions in healthy volunteers, peptic ulcers in volunteers or patients, or complication rates in patients taking NSAIDs? It is now generally agreed by most investigators that hemorrhages seen in short-term healthy volunteer studies are of little use. In a study from our laboratory evaluating the ability of the H2-receptor antagonist cimetidine to prevent naproxen-induced gastric injury, it was shown that the antagonist prevented hemorrhages but had no effect on the occurrence of erosions or peptic ulcers. This finding suggests that hemorrhages are acid dependent and are unrelated to more important lesions. Erosions, on the other hand, are probably more significant lesions in short-term healthy volunteer studies, and trials evaluating the prevention of these lesions by various agents are often predictive of findings in arthritic patients during long-term studies. Erosions may therefore be useful as a positive screening mechanism for new prophylactic agents. Healthy volunteer studies have shown that sucralfate is generally ineffective in preventing erosions and ulcers, that H2-receptor antagonists prevent erosions and ulcers in the duodenum but not in the stomach, and that misoprostol prevents both gastric and duodenal erosions and ulcers. –7 Longer-term studies in arthritic patients using ulcer as the end point have demonstrated essentially the same findings. –13 The use of ulcer as an end-point in these longer-term patient studies is justified by the fact that the major complications of NSAID use are those associated with peptic ulcer disease; erosions are found in a high percentage of patients taking NSAIDs chronically, but they are not associated with complications. Studies evaluating sucralfate have shown that it is essentially ineffective in preventing any type of NSAID-associated peptic ulcer disease. Two large, multicenter studies evaluating the H2-receptor antagonist ranitidine, 150 mg twice daily, in the prevention of NSAID-associated peptic ulcer have shown that this agent is significantly better than placebo in the prevention of duodenal ulcer, whereas it has no effect on the prevention of gastric ulcer. However, a recent study has shown that the H2-receptor antagonist famotidine, in addition to preventing duodenal ulcer, significantly reduces the incidence of gastric ulcer when given at high dose in patients receiving chronic NSAID therapy, when compared with placebo. Finally, numerous studies in arthritic patients have shown that misoprostol prevents both gastric and duodenal ulcers in patients taking NSAIDs, –12 although the side-effects caused by misoprostol sometimes prevent its use.

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

A single-blind, randomized endoscopic tolerance study was conducted to compare daily doses of flurbiprofen (Ansaid, Upjohn) at 100, 150, and 200 mg per day with 2,600 mg of aspirin per day. Ten normal volunteers were enrolled in each of the flurbiprofen groups, and five were enrolled in the aspirin group. Analysis of the mean gastric mucosal injury scores obtained on day eight revealed statistically significant lower mean scores (p = 0,05) in the 100-mg and 150-mg flurbiprofen treatment groups when compared with the 200mg flurbiprofen group and the aspirin group. No significant differences were found between any of the treatment groups in duodenal mucosal injury scores. Mean scores for gastric mucosal Injury in the three groups receiving flurbiprofen showed a definite dose relationship. The aspirin-treated subjects had significantly decreased uric acid levels (p = 0.006) and a significantly higher incidence of tinnitus (p = 0.04) compared with the flurbiprofen treatment groups. There was a poor correlation between subjective symptomatology and endoscopic pathologic findings.

The effects of fenbufen (1,000 mg a day), indomethacin (150 mg a day), naproxen (750 mg a day), and placebo on gastric mucosa were determined by endoscopy and recorded photographically. One hundred normal subjects, randomly divided into equal, paralleltreatment groups, were given the drugs in divided daily doses for seven consecutive days. The results revealed that the effects of fenbufen on gastric mucosa were significantly (p ≤0.05) less than those of either naproxen or indomethacin and not statistically different from those observed with placebo.

The effects of fenbufen (1,000 mg a day), indomethacin (150 mg a day), naproxen (750 mg a day), and placebo on gastric mucosa were determined by endoscopy and recorded photographically. One hundred normal subjects, randomly divided into equal, parallel-treatment groups, were given the drugs in divided daily doses for seven consecutive days. The results revealed that the effects of fenbufen on gastric mucosa were significantly (p less than or equal to 0.05) less than those of either naproxen or indomethacin and not statistically different from those observed with placebo.

The toxic effects of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) were endoscopically evaluated in several studies conducted between 1975 and 1983 and involving 843 normal volunteers. Anti-inflammatory doses of acetylsalicylic acid (2,400 and 3,900 mg/day) consistently produced significantly more mucosal injury than did any of the newer NSAIDs. Buffering did not reduce the degree of damage. Little or no mucosal injury was seen with placebo, "pro drugs," enteric-coated aspirin, or 1,200 mg/day of ibuprofen (Motrin, Upjohn). However, varying degrees of generally dose-dependent mucosal injury were evident with larger doses of ibuprofen, naproxen, tolmetin sodium, and indomethacin. The amount of mucosal damage after 2,400 mg/day of ibuprofen did not increase when 4,800 mg daily was administered. Duodenal injury corresponded to gastric injury, but it was generally less severe. Short-term studies of one to three days indicated that ibuprofen produced little or no injury when given at a dose of 2,400 mg for one day or 1,600 mg/day for three days. No relation was noted between subjective symptoms and endoscopic findings.