title: Meta-analysis of randomized controlled trials as a method of estimating rare complications of non-steroidal anti-inflammatory drug therapy.
abstract: The design of randomized controlled trials to assess the efficacy of pharmacological measures for the prevention of the gastrointestinal side-effects of anti-inflammatory drugs requires an accurate estimate of excess risk under controlled conditions. Photocopies of 952 randomized controlled trial publications were obtained after scanning titles and abstracts of a MEDLINE computer search, 427 were excluded for obvious reasons, and 525 were again photocopied after obliterating source and results. Selection criteria were: the presence of a non-anti-inflammatory drug control group; at least 4 days of therapy; at least 3 days without anti-inflammatory drugs before randomization; no complicating background drugs; mention of side-effects; and a clear differentiation of gastrointestinal complications. Observer error, with two independent readings, for inclusion suitability in the study was 19% for Methods and 9% for Results. For the 44 aspirin trials, the mean therapy duration was 357 days; the unweighted rate difference between therapy and control groups ( +/- 1 S.E.M.) for ulcer was 0.006 +/- 0.003, for gross haemorrhage 0.006 +/- 0.002 and for unspecified gastric symptoms 0.03 +/- 0.01. In 123 non-aspirin non-steroidal anti-inflammatory drug (NA-NSAID) trials, the mean duration was 67 days; the unweighted rate difference for ulcer was 0.0005 +/- 0.0003, for gross haemorrhage 0.007 +/- 0.004 and for unspecified gastric symptoms 0.02 +/- 0.005. Risk differences were also pooled using the DerSimonian and Laird method, which weights studies inversely according to variance. Using this method, only the unspecified gastric symptoms for non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) and the haemorrhage for aspirin were found to be statistically significant. Longer studies have higher risk differences. Randomized control trials to determine prophylactic efficacy against haemorrhage (that is, to demonstrate a reduction of ulcer rate in the therapy group to the rate of controls) would require 190 patients in each group for NA-NSAIDs in studies of 2-6 months; 950 subjects would be needed to detect a 50% reduction. Randomized control trials to determine a reduction in ulcer rate to that of controls in patients on aspirin for more than 6 months would require 700 subjects in each group; 3346 subjects would be needed to detect a 50% reduction. Such studies are feasible.
authors.affiliation: Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts 02115.
authors.forename: T C
authors.initials: TC
authors.lastname: Chalmers
authors.forename: J
authors.initials: J
authors.lastname: Berrier
authors.forename: P
authors.initials: P
authors.lastname: Hewitt
authors.forename: J
authors.initials: J
authors.lastname: Berlin
authors.forename: D
authors.initials: D
authors.lastname: Reitman
authors.forename: R
authors.initials: R
authors.lastname: Nagalingam
authors.forename: H
authors.initials: H
authors.lastname: Sacks
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D015201:Meta-Analysis as Topic; D016032:Randomized Controlled Trials as Topic
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal