A systematic search of the English language literature using MEDLINE, EMBASE, Current Contents and the Cochrane database from 1966 to April 2002, as well as a manual search of references from retrieved articles, were performed.
STUDY SELECTION: Prospective, randomized, controlled clinical trials evaluating
amantadine and
rimantadine for prophylaxis of naturally occurring
influenza A illness were considered. The control arm used either a placebo or an
antiviral agent.
DATA EXTRACTION: Each trial was assessed by two authors to determine the adequacy of randomization and description of withdrawals. Efficacy data were extracted according to a predefined protocol. Discrepancies in data extraction among the investigators were solved by consensus. Nine prophylaxis studies of
amantadine and
rimantadine met the criteria for this systematic review.
DATA SYNTHESIS: Seven
amantadine versus placebo trials (n=1797), three
rimantadine versus placebo trials (n=688) and two
amantadine versus
rimantadine studies (n=455) were included for the meta-analysis on the prevention of
influenza A illness. The summary of results for the relative odds of illness indicated a 64% reduction in the
amantadine group compared with placebo (OR 0.36, 95% CI 0.23 to 0.55, P< or =0.001), a 75% reduction in illness for the
rimantadine group compared with placebo (OR 0.25, 95% CI 0.07 to 0.97, P=0.05) and no significant differences in the odds of illness for the
amantadine versus
rimantadine groups (OR 1.15, 95% CI 0.57 to 2.32, P=0.32). The summary of results examining adverse events showed significantly higher odds of central nervous system adverse reactions and premature withdrawal from the clinical trials in the
amantadine-treated group than in the placebo-treated group. Compared with the placebo-treated group, the
rimantadine-treated group did not have a significantly higher rate of withdrawal or central nervous system events. However, there was a significant increase in the odds of gastrointestinal adverse events for those treated with
rimantadine compared with those treated with placebo (OR 3.34, 95% CI 1.17 to 9.55, P=0.03). In the comparative trials of
amantadine to
rimantadine,
rimantadine was associated with an 82% reduction in the odds of central nervous system events (OR 0.18, 95% CI 0.03 to 1.00, P=0.05) and a 60% reduction in the odds of discontinuing treatment (OR 0.40, 95% CI 0.20 to 0.79, P=0.009).
CONCLUSION: This meta-analysis demonstrates that
amantadine and
rimantadine are superior to placebo in the prevention of
influenza A illness. Both
antiviral agents have an increased number of adverse events compared with placebo; however, the use of
amantadine is associated with significantly higher numbers of central nervous system events and treatment withdrawals compared with
rimantadine. Thus,
rimantadine should be the preferred agent in this class for the prevention of influenza A virus
infection and should be made available in Canada.