Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Omeprazole maintained remission from ulcers better than misoprostol

ACP J Club. 1998 Jul-Aug;129:8. doi:10.7326/ACPJC-1998-129-1-008


Source Citation

Hawkey CJ, Karrasch JA, Szczepañski L, et al., for the Omeprazole versus Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) Study Group. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med. 1998 Mar 12;338:727-34.


Abstract

Question

Are omeprazole and misoprostol comparable for healing and maintaining remission in patients with gastroduodenal ulcers and erosions associated with long-term nonsteroidal anti-inflammatory drug (NSAID) use?

Design

Randomized, double-blind trial.

Setting

93 centers in 14 countries.

Patients

935 patients aged 18 to 85 years (mean age 58 y, 63% women) who required continuous treatment with at least a minimal dose of oral or rectal NSAIDs; had ulcers ≥ 3 mm in diameter in the stomach, duodenum, or both; or had > 10 gastric or duodenal erosions. Exclusion criteria were concurrent major reflux esophagitis, clinically important upper gastrointestinal hemorrhage, or disorders that could modify absorption of study drugs. Glucocorticoids or prednisolone was allowed.

Intervention

In the treatment phase, 308 patients were allocated to omeprazole, 20 mg/d; 315 to omeprazole, 40 mg/d; and 298 to misoprostol, 200 µg 4 times/d for 4 weeks. This was extended to 8 weeks if healing did not occur. In the maintenance phase, the 725 patients who were considered healed were allocated to omeprazole, 20 mg/d (n = 274); misoprostol, 200 µg twice/d (n = 296); or placebo (n = 155). Maintenance was done for 6 months.

Main outcome measures

Predefined treatment success at 8 weeks and maintenance of remission at 6 months.

Main results

Efficacy analysis included 921 patients in the treatment phase and 725 in the maintenance phase. Treatment success rates at 8 weeks were similar in all groups (76% and 75% in the low- and high-dose omeprazole groups, respectively, and 71% in the misoprostol group). Maintenance of remission was higher in the omeprazole group (P = 0.001), and both groups had a higher rate of staying in remission than the placebo group (P < 0.001 for both). More patients in the misoprostol group reported adverse effects during the treatment phase (59% vs 48% for low-dose and 46% for high-dose omeprazole { P ≤ 0.007 for both compared with misoprostol}*).

Conclusions

In patients who used long-term NSAIDs, omeprazole (20 or 40 mg daily) was as effective as misoprostol (800 µg daily) at healing ulcers and was better at maintaining remission than misoprostol (400 µg daily). Misoprostol caused more adverse events during treatment.

Source of funding: Astra Hässle.

For correspondence: Dr. C.J. Hawkey, Nottingham Gastrointestinal Trials Service, Division of Gastroenterology, University Hospital, Nottingham NG7 2UH, England, UK. FAX 44-115-951-3666.

*Numbers calculated from data in article.


Table. Omeprazole (OM) and misoprostol vs placebo for maintaining remission in nonsteroidal anti-inflammatory drug-induced ulcers†

Comparison Rates RBI (95% CI) NT (CI)
OM vs misoprostol 61% vs 48% 27% (9 to 48) 8 (5 to 21)
OM vs placebo 61% vs 27% 126% (72 to 199) 3 (2 to 4)
Misoprostol vs placebo 48% vs 27% 78% (35 to 137) 5 (3 to 9)

†Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.


Commentary

Omeprazole healed ulcers and maintained remission better than ranitidine

Despite many studies over the past 3 decades that repeatedly highlighted the gastroduodenal side effects of NSAIDs and their serious complications (hemorrhage, perforation, and death), no evidence exists to suggest a decrease in their use or side effects. In the absence of a breakthrough in the treatment of arthritic diseases, NSAIDs are likely to stay in common use well into the next century. Management of NSAID-related ulcers and erosions remains a clinical challenge and should include prevention (prophylaxis), healing, and maintenance of remission.

Misoprostol and ranitidine have dominated this field over the past 10 years. Their use has been the subject of debate among researchers and clinicians alike. Misoprostol is inexpensive and prevents gastric and duodenal ulcers and their complications, but its use can be limited by the abortifacent activity in young women. It is contraindicated in the absence of contraception in these women and by the development of transient abdominal discomfort and diarrhea, which occurs in up to 30% of persons in most clinical studies. Ranitidine is better tolerated but at normal doses only prevents duodenal ulcers—NSAID ulcers are more likely to affect the stomach.

While the debate on ulcer prophylaxis continues, a more pressing clinical question is how to heal an ulcer that has already developed. The place of misoprostol and ranitidine in healing NSAID-induced peptic ulcers is not well established, and healing can be slowed by continued NSAID intake. New approaches are needed, and therefore the studies by Hawkey and Yeomans and their colleagues are important. Patients in these international multicenter studies were carefully selected through use of similar and well-defined inclusion and exclusion criteria. The minimum ulcer size of 3 mm, which might not satisfy some clinicians, is similar to that in almost all the studies of misoprostol. Despite their similarities, the 2 studies had some interesting demographic variations. Patients recruited by Yeomans and colleagues were more likely to be women, to have rheumatoid arthritis, to be infected with Helicobacter pylori, and to have a history of peptic ulceration.

Misoprostol used in the doses tested, 400 or 800 µg/d, has acid inhibitory effects. However, these effects do not explain its therapeutic effects, which are probably caused by the prostaglandin-mediated mucosal protective activity (known as cytoprotection). A key finding in both studies was that omeprazole, 20 mg/d, is as effective as 40 mg/d in healing NSAID ulcers. This suggests a ceiling beyond which no more acid is available to inhibit; therefore, doses of omeprazole > 20 mg/d offer no extra healing in long-term users of NSAIDs. This has cost-saving implications. It also explains the findings of Yeomans and colleagues of the superiority of omeprazole over the weaker acid inhibitor ranitidine in both healing ulcers and maintaining remission.

One should not assume, however, that acid explains the whole story in the multifactorial pathophysiology of NSAID-related gastroduodenal disease, particularly given the different patterns of activity of the two drugs, against erosions and ulcers. Omeprazole may be superior to misoprostol in maintaining remission only if the dose of misoprostol is divided to the maintenance level licensed at 400 µg/d. Omeprazole was better tolerated than misoprostol, but both studies showed a high rate of adverse events. However, adverse events are not necessarily the same as drug side effects, and it might not be possible to prove a causal relation, particularly in patients with chronic diseases. These important findings widen our choice of therapies used to heal NSAID-related ulcers and maintain their remission. They establish the role of omeprazole, 20 mg/d, and leave the door open for the use of other agents, particularly misoprostol.

Ali S. Taha, MD, PhD
Crosshouse HospitalKilmarnock, Scotland, UK