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Etiology

High-dose famotidine prevented NSAID-induced ulcers in arthritis

ACP J Club. 1996 Nov-Dec;125:79. doi:10.7326/ACPJC-1996-125-3-079


Source Citation

Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med. 1996 May 30; 334:1435-9.


Abstract

Objective

To determine whether famotidine reduces the incidence of gastric and duodenal ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs) in adults with arthritis.

Design

24-week randomized, double-blind, placebo-controlled trial.

Setting

Rheumatology and orthopedic clinics of 2 U.K. hospitals.

Patients

285 patients (73% women) with rheumatoid arthritis or osteoarthritis who were ≥ 18 years of age (mean age 55 y) and were taking standard doses of NSAIDs. Exclusion criteria were ulcers confirmed by endoscopy at baseline; use of antiulcer drugs other than antacids, prednisolone ≥ 7.5 mg/d, methotrexate, or antineoplastic drugs; lactation or possibility of pregnancy; renal failure; diabetes mellitus; or clinically important abnormal laboratory test results.

Intervention

93 patients were allocated to placebo; 95 to low-dose famotidine (20 mg twice daily); and 97 to high-dose famotidine (40 mg twice daily). Co-magaldrox tablets were allowed for dyspepsia. Follow-up was 90%. Approximately 30% of each group reported abdominal pain, heartburn, or both at baseline.

Main outcome measures

The primary end point was the cumulative incidence of endoscopically proven gastric and duodenal ulcers at 24 weeks and of adverse effects. Secondary end points were presence of abdominal pain, pain scores, and antacid consumption.

Main results

The proportional-hazards model to assess prognostic factors for ulceration, Kaplan-Meier survival curves, and intention-to-treat analysis were used. The cumulative incidence in the placebo, low-dose famotidine, and high-dose famotidine groups for gastric or duodenal ulcers was 28% (95% CI 19% to 38%), 16% (CI 9% to 24%, P compared with placebo = 0.05), and 11% (CI 4% to 17%; P compared with placebo = 0.003), respectively; for gastric ulcers alone, cumulative incidence was 20% (CI 11% to 28%), 13% (CI 6% to 20%; P compared with placebo = 0.24), and 8% (CI 2% to 14%; P compared with placebo = 0.03), respectively; and 13% (CI 5% to 20%), 4% (CI 0% to 8%; P compared with placebo = 0.04), and 2% (CI 0% to 6%; P compared with placebo = 0.01), respectively, for duodenal ulcers alone. At the end of the study, fewer patients in the high-dose famotidine group had pain (17% vs 19% for low-dose famotidine and 29% for placebo; P = 0.04 for high-dose famotidine compared with placebo). When only patients with pain were considered, the groups did not differ for pain scores or antacid use. The groups did not differ for the total number of patients who had adverse events or who withdrew (14% for placebo vs 15% for low-dose famotidine and 16% for high-dose famotidine).

Conclusion

High-dose famotidine reduced the cumulative incidence of both gastric and duodenal ulcers related to NSAID use in adults with arthritis.

Source of funding: Merck Research Laboratories.

For article reprint: Dr. A.S. Taha, Department of Gastroenterology, Eastbourne General Hospital, King's Drive, Eastbourne BN21 2UD, England, UK. FAX 44-1323-414-993.


Commentary

Meta-analysis: Low-dose ibuprofen has the lowest gastrointestinal risk of any NSAID

The meta-analysis by Henry and colleagues chiefly addresses the severe upper GI complications associated with NSAIDs; such complications are by far the most common serious consequences of therapy with these drugs. The meta-analysis assigns a rank order that is probably valid for the more widely used NSAIDs, but points out that all drugs with a long enough history of use (which excludes several popular drugs introduced in the past few years) have GI consequences. The narrow CIs confirm that the rankings are probably accurate, with most NSAIDs clustered in a relatively tight intermediate grouping. The recommendation that is derived from the ranking is to first use the NSAIDs that are least often associated with upper GI problems and then, based on the patient's need and response, advance to others that have higher adverse effect ranks.

Ibuprofen is the standard NSAID but only in doses to 2400 mg/d; at higher doses, it ranks much lower. The reason for administration may differ for the various drugs; some that are perceived as more analgesic are used for milder conditions, and others that are more anti-inflammatory are given to patients with greater need and possibly greater risk for complications. Case-control and cohort studies cannot address the distinctions in patients' choices or in the utility of the drugs as perceived by physicians.

The study by Taha and colleagues presents welcome news because it discusses a way to reduce upper GI risk for patients through co-treatment with famotidine, a histamine H2-receptor antagonist. The population studied, however, differs from the epidemiologic meta-analysis of the study by Henry and colleagues, which dealt with overt clinical cases. Most previous studies have failed to find a reliable connection between endoscopically discovered problems and overt upper GI diseases in NSAID users, but most of the upper GI injuries in the study by Taha and colleagues were discovered by endoscopy. Half of the study patients harbored Helicobacter pylori—the increased risk for cancer in these patients has recently been analyzed (1), and the association between ulcers and cancer of the stomach seems to be confirmed, at least for gastric ulcers. For duodenal ulcers (for which histamine H2-blockers are the best preventive agents), this relation does not exist. This raises the possibility that successful ablation of symptoms from gastric erosion might delay discovery of a problem that is even worse than erosive GI disease. In addition, there is the risk of polypharmacy, with its potential complications and costs. In his recent commentary, Carson (2) cited a study that suggested that acetaminophen, a non-NSAID that does not cause upper GI complications, provided satisfactory treatment for osteoarthritis (3). This is true for analgesia, but to treat inflammation only NSAIDs offer the appropriate effects. The controversy about the difference in outcome is not settled. Several of Carson's conclusions are addressed in these 2 studies: The risk for GI complications remains low, the relation between NSAIDs and upper GI disease is real, and the relative toxicity of individual NSAIDs can be identified. We still need to better understand for whom, how, and why each of the NSAIDs was prescribed and whether the long-term addition of a presumed ulcer prophylaxis will result in safer, more effective, and less expensive treatment.

George E. Ehrlich, MD
University of Pennsylvania and New York UniversityPhiladelphia, Pennsylvania, USA


References

1. Hansson LE, Nyren O, Hsing AW, et al. N Engl J Med. 1996;335:242-9.

2. Carson JL.Review: Nonaspirin NSAIDs cause adverse gastrointestinal events. ACP J Club. 1992 Mar-Apr;116:60. Comment on: Gabriel SE, Jaakkimainen L, Bombardier C. Ann Intern Med. 1991;115:787-96.

3. Bradley JD, Brandt KD, Katz BP, Kalsinski LA, Ryan SI. N Engl J Med. 1991;325:87-91.