Misoprostol reduced serious NSAID-induced gastrointestinal complications in rheumatoid arthritis
ACP J Club. 1996 Mar-April;124:38. doi:10.7326/ACPJC-1996-124-2-038
Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995 Aug 15;123:241-9. [PubMed ID: 7611589]
To evaluate the effectiveness of concurrent use of misoprostol in reducing serious upper gastrointestinal (GI) complications in older patients with chronic rheumatoid arthritis who were receiving nonsteroidal anti-inflammatory drugs (NSAIDs).
Randomized, double-blind, placebo-controlled trial with 6-month follow-up.
664 clinical practices of family medicine, internal medicine, or rheumatology in the United States and Canada.
8843 patients (mean age 68 y, 71% women) who had chronic rheumatoid arthritis and were taking 1 of 10 specified NSAIDs at predefined minimum doses for 6 months. Exclusion criteria were active peptic ulcer disease within 30 days of study enrollment; taking antiulcer medication or any experimental medication; the Zollinger-Ellison syndrome, pyloric or duodenal obstruction, previous gastric resection or vagotomy, gastroesophageal reflux disease, varices, or cirrhosis; history of inflammatory bowel disease, upper GI malignancies, hepatitis, alcoholism, or bleeding diathesis; estimated life expectancy < 8 months; women of childbearing potential; or intolerance to misoprostol or any prostaglandin.
Patients were allocated to misoprostol, 200 µg (n = 4404), or placebo (n = 4439) 4 times daily.
Main Outcome Measures
Serious upper GI complications, such as perforation, gastric outlet obstruction, or bleeding, detected by clinical symptoms.
6 months of misoprostol therapy led to fewer definite upper GI complications than did placebo (P = 0.04) (Table). Within the first month of treatment, withdrawal because of diarrhea, abdominal pain, or flatulence was greater in the misoprostol group (20%) than in the placebo group (15%, P < 0.001). Patients with definite upper GI complications were older, were more likely to have a history of peptic ulcer, and were more likely to have a history of GI bleeding.
Misoprostol reduced serious nonsteroidal anti-inflammatory drug-induced upper gastrointestinal complications in older patients with chronic rheumatoid arthritis.
Source of funding: G.D. Searle & Co.
For article reprint: Dr. G.S. Geis, G.D. Searle & Company, 4901 Searle Parkway, A-1E, Skokie, IL 60077, USA. FAX 708-982-7349.
Table. Misoprostol vs placebo for reducing gastrointestinal (GI) complications in rheumatoid arthritis*
|Outcome at 6 mo||Misoprostol||Placebo||RRR (95% CI)||NNT (CI)|
|Definite upper GI complications||0.57%||0.95%||40% (2 to 63)||264 (132 to 5703)|
*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.
NSAIDs are frequently prescribed, but at a price: Symptomatic ulcers and life-threatening complications (mostly without warning) result from therapy. Misoprostol, in contrast to standard doses of histamine (type 2) receptor antagonists, significantly reduces the incidence of both gastric and duodenal ulcers in users of NSAIDs (1, 2). Until now, however, it has not been known whether this translates into fewer upper GI complications.
The trial by Silverstein and colleagues was rigorously done. Quality of life, cost-effectiveness, and Helicobacter pylori status were not considered. More patients who received misoprostol (42%) than placebo (36%) withdrew mainly because of diarrhea. Because of the side effects, it is possible that patient satisfaction was substantially poorer with misoprostol even in those persons who complied with treatment. Effects of misoprostol on NSAID-associated dyspepsia were not measured. The absolute benefit of misoprostol, although significant, was small; definite upper GI complications were reduced from just under 1% in the placebo group to 0.6% in the misoprostol group, and mortality was similar in the 2 groups. The ratio of benefit to cost for such prophylaxis is probably very modest, and patient compliance may be less in the nonstudy setting.
Although restricted to rheumatoid arthritis, the results are probably generalizable to older patients taking NSAIDs at moderate or higher doses. All current NSAIDs are toxic to the GI tract, although some may be worse than others (2). In this study, a group at higher risk was identified: Over a 6-month period, the risk for complications was 9% in those aged ≥ 75 years who had an ulcer with a bleeding history and cardiovascular disease.
The key issue is whom to treat. We consider co-prescription of misoprostol only in very high-risk patients who cannot stop taking NSAIDs.
Nicholas J. Talley, MD, PhD
Wayne H-C. Hu, MB BSUniversity of SydneySydney, New South Wales, Australia