Review: 5-aminosalicylic acid is more effective than placebo but not sulfasalazine for ulcerative colitis
ACP J Club. 1993 July-Aug;119:12. doi:10.7326/ACPJC-1993-119-1-012
Sutherland LR, May GR, Shaffer EA. Sulfasalazine revisited: a meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis. Ann Intern Med. 1993 Apr 1; 118:540-9.
To evaluate the effectiveness of the new 5-aminosalicylic acid (5-ASA) delivery systems compared with sulfasalazine or placebo in patients with ulcerative colitis using meta-analysis.
Citations were retrieved from MEDLINE and BIOS from January 1981 to May 1992. Key words included ulcerative colitis and aminosalicylates. Bibliographies of original and review articles, proceedings from symposia, and textbooks were also searched.
Randomized controlled trials were included if they compared oral 5-ASA with sulfasalazine or placebo for a minimum of 4 weeks for acute therapy and 6 months for maintenance therapy in patients with mild-to-moderate ulcerative colitis. Of 59 trials identified, 27 met the inclusion criteria: 16 for active treatment and 11 for remission maintenance.
For reports of acute therapy, the number of patients in remission were recorded. For studies of maintenance therapy, the number of patients remaining in remission were recorded. Data were abstracted in duplicate; the methodologic quality of the primary studies was assessed. Using an intention-to-treat analysis, pooled odds ratios (ORs) were calculated by using a random-effects model.
Studies were separated into 3 groups: 5-ASA compared with placebo for acute therapy, 5-ASA compared with sulfasalazine for acute therapy, and 5-ASA compared with sulfasalazine for maintenance therapy. 8 trials, involving 1007 patients, examined oral 5-ASA compared with placebo; the pooled OR for complete remission was 2.0 (95% CI 1.5 to 2.7) favoring oral 5-ASA. A dose-dependent trend was apparent when results were grouped according to 5-ASA dose (dose < 2 g/d [OR 1.5, CI 0.89 to 2.6]; dose 2 to 2.9 g/d [OR 1.9, CI 1.3 to 2.8]; dose ≥ 3 g/d [OR 2.7, CI 1.8 to 3.9]). 8 trials, involving 553 acute patients, examined 5-ASA compared with sulfasalazine; the pooled OR for complete remission was 1.2 (CI 0.83 to 1.6). No dose-response relation was evident. 11 studies, involving 1153 patients, examined 5-ASA with sulfasalazine for maintenance therapy; the pooled OR was 0.85 (CI 0.64 to 1.2). No dose-response relation was evident, and the adverse reaction rates did not differ.
The newer 5-aminosalicylic acid preparations in a dose of at least 2 g/d are more effective than placebo in the treatment of mild-to-moderate ulcerative colitis. These newer 5-aminosalicylic agents are found to be no more effective than sulfasalazine.
Source of funding: In part, Calgary Gastroenterology Research and Education Foundation.
For article reprint: Dr. L. Sutherland, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. FAX 403-270-7307.
The review by Sutherland and colleagues does little to change the views of the relative merits of sulfasalazine and newer 5-ASA preparations in the treatment of ulcerative colitis. This is, however, a reflection of the weaknesses of the trials themselves rather than any problems with the meta-analysis.
The average response to sulfasalazine in the acute trials was 45%, and during the maintenance trials, 65%. To show a 10% improvement in these rates with new 5-ASA preparations would require trials with approximately 1000 participants each. In the face of uncertainty about relative efficacy, this review enables us to speculate further about the appropriate clinical use of the newer agents. In the acute studies, a relation existed between 5-ASA dosage and response. If the new drugs enable the administration of higher dosages of 5-ASA, this may translate into a clinical advantage. Fewer adverse reactions occurred with the new 5-ASA drugs than with sulfasalazine, and the price difference between them is less important during acute treatment than when being used for maintenance of remission. These considerations may favor use of the newer preparations in the management of acute mild-to-moderate ulcerative colitis. In maintenance treatment, however, the best course of action is unclear. Smaller doses of 5-ASA are used in this situation; the newer agents were no more efficacious and no better tolerated than sulfasalazine in these studies. The relatively high price of the new 5-ASA drugs becomes the cost of avoiding the uncommon but severe toxicity of sulfasalazine. Because the event rates are so low, questions of appropriate use cannot be addressed in clinical trials and no doubt will be the subject of decision and cost-effectiveness analyses. In the meantime, it seems reasonable to restrict maintenance treatment with the new drugs to patients who cannot take sulfasalazine.
David A. Henry, MB
The University of NewcastleWaratah, Australia