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Thus, the design of the study by Bombardier et al. (Nov. 23 issue)3 surprised us. Assuming a lower risk of adverse gastrointestinal events in the rofecoxib group than in the naproxen group,4 we could understand the absence of prophylaxis in the rofecoxib group. However, in the naproxen group, in which about half the patients were over the age of 60 (mean [±SD] age, 58±10 years), 56.2 percent were receiving glucocorticoids, and 7.8 percent had a history of clinical gastrointestinal events, the lack of prophylaxis does not seem ethical. Indeed, H2–receptor antagonists were used in just 8.3 percent of the patients in this group, and at low doses. Prophylaxis for patients in the naproxen group — as recommended — would not have lessened the potential value of the study results.
Marcial Delgado Fernández, M.D.
José Luis Zambrana García, M.D.
Felipe Díez García, M.D.
Hospital de Poniente
El Ejido, Almería, Spain
References
Samardeep Gupta, M.D.
University of Michigan
Ann Arbor, MI 48109
References
To the Editor: Delgado Fernández et al. suggest that the lack of prophylaxis in some of the patients in our trial does not seem ethical. The ethical aspects of including patients with risk factors, such as a history of gastrointestinal events, without the use of a proton-pump inhibitor or misoprostol were carefully considered by the steering committee during the development of the protocol. We clearly and strongly indicated in the protocol that no patient who needed to receive protective gastrointestinal therapy because of a history of gastrointestinal events should be enrolled in the study. Furthermore, in no patient could these drugs be discontinued for the purpose of enrollment in the study. Patients who were enrolled in the study were not believed by their treating physicians to require use of these agents and would not have received prophylactic therapy even if they had not participated in the trial. Patients in the study were, however, allowed to take low-dose H2-receptor antagonists. The mean time between the prior gastrointestinal event and enrollment in the study was 12 years, indicating that the history was remote in most of the patients.
Misoprostol has been shown to reduce the incidence of clinically important gastrointestinal events in patients taking NSAIDs,1 and proton-pump inhibitors have been shown to reduce the incidence of gastroduodenal ulcers on endoscopy.2 The use of these agents could potentially have confounded our results and would not have allowed us to address our primary hypothesis: that the highly selective cyclooxygenase-2 inhibitor rofecoxib would cause fewer clinical upper gastrointestinal events than a nonselective NSAID. An even larger outcome study would be required to evaluate properly the incidence of gastrointestinal events with a cyclooxygenase inhibitor as compared with a nonselective NSAID plus a protective agent.
Gupta asks us to elaborate on the adverse renal events reported in our article. The events described were related to decreases in renal function — primarily increases in creatinine (in 1.0 percent of the rofecoxib group and 0.7 percent of the naproxen group). Most were transient increases that resolved with therapy. Only 0.2 percent of the patients in each group withdrew from the study because of decreased renal function.
Claire Bombardier, M.D.
University of Toronto
Toronto, ON M5G 1N8, Canada
Loren Laine, M.D.
University of Southern California School of Medicine
Los Angeles, CA 90033
Alise Reicin, M.D.
Merck
Rahway, NJ 07065
References
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