Editorials

Misoprostol in patients taking non-steroidal anti-inflammatory drugs

The past decade has seen considerable improvements in attempts to prevent the gastrointestinal complications of non-steroidal anti-inflammatory drugs. Increased awareness of the problems that these compounds cause and more careful prescribing have had an appreciable effect, although better access to diagnostic facilities and the availability of drugs both to treat and to prevent gastroduodenal ulceration have also contributed. However, progress in preventing the relatively rare but potentially life threatening complications such as perforation and gastrointestinal haemorrhage has until recently been disappointing.

The availability of misoprostol, a synthetic analogue of prostaglandin, has provided some cause for optimism. Endoscopic studies show that misoprostol reduces the frequency of asymptomatic gastric and duodenal ulceration induced by non-steroidal anti-inflammatory drugs, while ranitidine reduces only the frequency of duodenal ulcers but is better tolerated.^{1 2} The extent of benefit from proton pump inhibitors such as omeprazole is being evaluated. A more pressing and important question is whether prophylactic use of such drugs can reduce the frequency of the severe gastrointestinal complications of non-steroidal anti-inflammatory drugs.

This issue has been addressed in a well conducted double blind placebo controlled trial of patients taking non-steroidal anti-inflammatory drugs.³ Silverstein et al randomised 8843 patients with rheumatoid arthritis to receive either misoprostol 200 µg four times daily or placebo for six months. Patients with previous peptic ulceration were included but only if the ulcer had been inactive in the prior month. All gastrointestinal events were evaluated by an independent panel consisting of a rheumatologist, a gastroenterologist, and an epidemiologist, all of whom were unaware of the randomisation. The panel was required to reach consensus on whether the event was related to non-steroidal anti-inflammatory drugs and to assign the complication to one of 11 predefined categories, the first six of which were classified as serious and included perforation, gastric outlet obstruction, and bleeding.

The mean age of the patients studied was 68, but the range was from 52 to over 75. Twenty eight per cent of the patients taking misoprostol withdrew because of side effects, compared with 20% taking placebo. An intention to treat analysis showed no reduction in mortality in patients taking misoprostol, but the number of deaths due to proved gastrointestinal events was small. Sixty seven serious complications arose, of which 42 were in patients taking placebo. Risk factors identified for serious complications included age over 75, a history of peptic ulcer or gastrointestinal bleeding, and cardiovascular disease. Gastrointestinal bleeding occurred in 56 patients and was no less common in those taking misoprostol. Misoprostol, however, led to fewer cases of perforation (placebo 7, misoprostol 1) and gastric outlet obstruction (placebo 3, misoprostol 0). Of the eight cases of perforation, three were in the duodenum and four above the pylorus, while the site of one was unspecified. The authors concluded that misoprostol led to an overall 40% reduction in serious gastrointestinal complications from non-steroidal anti-inflammatory drugs.

How should we interpret these results to make them applicable in clinical practice? In a previous issue of this journal Cook and Sackett made a persuasive case for using "the number needed to treat" when presenting data, since it is a meaningful measure for clinical decision making.⁴ It can be calculated from these data as the inverse of the absolute risk reduction: 741 patients would need to be treated to prevent one perforation, 1480 to prevent one gastric outlet obstruction, and 493 to prevent either. The numbers may be smaller in high risk patients. Although this study was in patients with rheumatoid arthritis, its results can be generalised to include all older patients requiring a non-steroidal anti-inflammatory drug, regardless of the diagnosis.

Should we then be prescribing prophylactic misoprostol to all patients over 65 who are taking non-steroidal anti-inflammatory drugs? Given the quite large number of patients who would need to be treated to prevent one serious side effect, and the suggestion from another study that taking regular prophylactic misoprostol may worsen the quality of life for some patients,⁵ such a policy seems difficult to justify except in those at highest risk. Nor could it be entirely justified on grounds of cost.⁶

In patients at highest risk a more cautious approach to using non-steroidal anti-inflammatory drugs seems prudent. If such drugs are absolutely necessary, those whose main effect is on inducible cyclo-oxygenase may be the best choice. Another option may be to use essential fatty acids as pharmacological agents, since they have been shown to modify synthesis of cytokines if given in high enough doses.⁷ Clinical trials of both strategies are, however, necessary.

In conclusion, prophylaxis with misoprostol should be considered in any patient over 75 requiring a non-steroidal anti-inflammatory drug who has a history of peptic ulcer or gastrointestinal bleeding, or cardiovascular disease. During the first six months of use misoprostol reduces the risk of gastrointestinal perforation but not of bleeding. Compliance may be poor because of the high incidence of side effects.

Senior house officer in rheumatology Consultant rheumatologist Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow G4 0SF

N Maiden, R Madhok 

1. Graham YD, White HR, More LW, Schubert TT, Katz R, Jaszewski R, et al. Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs. Ann Intern Med 1993;119:257-62. [Abstract/Free Full Text]
2. Ehsanullah RS, Page MC, Tildesley G, Wood JR. Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine. BMJ 1988;297:1017-21.
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