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Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation |
Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, Fry-Smith A |
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Authors' objectives To assess the evidence on the effectiveness, safety, cost and cost-effectiveness of zanamivir for the treatment of influenza in healthy adults and at-risk adults.
Searching MEDLINE, PubMed, EMBASE, the Science Citation Index, the Cochrane Library (Issue 1), and the Glaxo Wellcome Clinical Trials Register were searched until March 2000; a list of search terms was reported in the review paper. The search strategy was extended to further sources, including NHS EED and DARE, to look for relevant economic analyses and for data to inform the economic model. Internet searches were carried out, as were handsearches of Scrip, FDA submissions for new drug applications and conference abstracts. In addition, the reference lists of identified publications were examined for further citations, and relevant trials and data were sought from the Glaxo Wellcome submission to the National Institute for Clinical Excellence (NICE). No language or publication restrictions were applied.
Study selection Study designs of evaluations included in the reviewCompleted randomised controlled trials (RCTs) or quasi-RCTs reporting results for all or almost all the recruited patients were eligible for inclusion. The following types of trials were excluded: trials that had not finished recruiting, trials for which only interim results were available, and trials reporting results for only some of the participants.
Specific interventions included in the reviewStudies investigating zanamivir (Relenza) with placebo or another treatment for influenza as a comparator were eligible for inclusion. All of the included trials had a placebo arm.
Participants included in the reviewStudies of adults (defined as 75% of participants aged 12 years or over) with naturally occurring influenza symptoms, or who had been experimentally inoculated with influenza prior to treatment, were eligible for inclusion. Studies targeted specifically at an at-risk population were included in the at-risk population review only. Studies that excluded adult patients at risk of developing or suffering severe adverse outcomes from influenza were included in the all-adult population review only. Studies that were not specifically targeted at an at-risk population, and that included adult patients at risk of developing or suffering severe adverse outcomes from influenza, were included in both reviews.
Outcomes assessed in the reviewStudies reporting results for one or more of the following outcomes were eligible for inclusion: time to alleviation of symptoms, time to become afebrile, time to return to normal daily activities or secondary illnesses. The primary end point for all the included trials was the length of time to the alleviation of clinically-significant influenza symptoms. This was measured using patient diary records.
How were decisions on the relevance of primary studies made?Two reviewers independently applied the inclusion criteria. Any disagreements were resolved through discussion, with reference to a third party if disagreement remained. Decisions were made independently of the scrutiny of results.
Assessment of study quality The validity of the studies was assessed by examining the method of randomisation, the comparability of baseline characteristics between different arms, the concealment of allocation, blinding and withdrawals, and losses to follow-up for each patient group. A Jadad score was calculated. Two reviewers independently undertook the quality assessment. Any disagreements were resolved by discussion, with reference to a third party if disagreement remained.
Data extraction Two reviewers independently extracted the data. Any disagreements were resolved through discussion, with reference to a third party if disagreement remained. Where information was missing, further information was sought from the authors or industry. The data extracted included details relating to the following: study population; intervention, e.g. mode and time of delivery, and dose; outcomes measured; and results and summary measures for both the intention-to-treat (ITT) population and the influenza-positive population (IPP).
Methods of synthesis How were the studies combined?Where possible, all the results were analysed on an ITT basis. Where sufficient data were available and the studies were considered sufficiently clinically homogeneous, the data were pooled using a random-effects model. This was used due to the presence of statistical heterogeneity among the trials. Weighted mean differences and 95% confidence intervals (CIs) were estimated using median values.
How were differences between studies investigated?The studies were inspected for clinical heterogeneity. The chi-squared test was used to test for statistical heterogeneity.
Results of the review A total of 14 studies (n=5,484) met the inclusion criteria; 13 of these met the inclusion criteria for the all-adult review, while 7 met the inclusion criteria for the at-risk review.
The authors were unable to identify reports of three trials and no unpublished data were made available for these, therefore, data from these trials could not be used in the review. The results of the remaining 11 trials (n=5,297) were used in the review. The trials were generally of a high quality. Nine trials had a Jadad score of 5, one trial score 4 and one trial scored 2.
All-adult review (10 RCTs, n=4,772).
Inhaled zanamivir, 10 mg twice daily for 5 days (licensed dose), was found to reduce the duration of symptoms of influenza (5 RCTs) by one day (95% CI: 0.4, 1.7), from about 6 to 5 days in the ITT population. In addition, it reduced the time to return to normal activities (5 RCTs) by 0.5 days (95% CI: -0.4, 1.5), from about 7 to 6.5 days (not statistically significant). In the IPP, the treatment effect was marginally larger, but this was not significantly different from that in the ITT population. The pooled analyses of all zanamivir treatment arms combined compared with placebo showed similar results for both of these outcomes (statistically significant for time to return to normal activities). The pooled analysis for the outcome of time to become afebrile (4 RCTs) showed a non statistically-significant reduction of 0.4 days (95% CI: -0.07, 0.95) in the duration of fever, which usually lasted for 2 to 2.5 days, using 10 mg zanamivir. The pooled analysis for all zanamivir treatment arms combined showed similar results and the ITT population effect became statistically significant.
At-risk review (7 RCTs, n=4,244).
Inhaled zanamivir, 10 mg twice daily for 5 days, was found to reduce the duration of symptoms of influenza (5 RCTs) by 1.16 days (95% CI: 0.13, 2.19), from about 8 to 7 days, in the ITT population and by 1.67 days (95% CI: -0.02, 3.37) in the IPP. The data did not have the power to demonstrate any differences in hospitalisation or the death rates for either group. The drug had a similar adverse event profile to the placebo group.
Cost information Data on the cost and cost-effectiveness were reported.
Authors' conclusions The evidence base for at-risk adults has greatly increased since this product was first reviewed by NICE. The data available suggest that it may prove useful when used judiciously in at-risk patients. It will be important to monitor its use and incorporate new trial evidence as it becomes available to confirm this.
CRD commentary The review question was clearly stated and appropriate pre-determined inclusion and exclusion criteria were applied to identified studies. The literature search was comprehensive, with attempts to identify non-English language and unpublished studies. The validity of the included studies was assessed systematically and the studies were appropriately pooled in a quantitative synthesis. Relevant study details were tabulated clearly and full details relating to the review process (i.e. how decisions on the relevance of primary studies were made, how judgements of validity were made and how the data were extracted) were reported. The authors' conclusions follow on from the results.
Implications of the review for practice and research Practice: The authors state that zanamivir is an effective treatment for influenza in at-risk adults. Individuals with influenza can expect to gain about a 1-day reduction in illness if they take zanamivir within 48 hours of the onset of influenza symptoms. Patients should know that there will be no benefit if taken later than that, and that no medication is without some risk.
Research: The authors state that there is a need for pragmatic research or evaluation in a realistic primary care setting to assess the true benefits, harms and costs in the real world situation. This should take into account such variables as the prevalence of influenza among those with influenza-like illness, the number of people with influenza visiting their general practitioner when they would otherwise not have done so, referral rates, time after onset of symptoms when patients present, off-indication prescribing, use of other medications, complications, hospitalisations and death rates.
A meta-analysis of individual patient data from existing evidence, to allow a proper survival analysis and true comparison of the IPP and influenza-negative population using hazard ratios, might provide better evidence about the treatment effect, size and precision.
Amantadine and zanamivir have different mechanisms of action. It could be that their effect is additive. An RCT of combined therapy in at-risk adults might be warranted. Oseltamivir or other neuraminidase inhibitors will almost certainly come onto the market in the near future, and there needs to be a systematic review of their effectiveness and cost-effectiveness. It will be important for trials to directly compare the effectiveness of these drugs.
It is important that new emerging new evidence is systematically reviewed in the context of existing information.
Funding NHS R&D Health Technology Assessment (HTA) Programme, project number 99/13/01.
Bibliographic details Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, Fry-Smith A. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation. Health Technology Assessment 2002; 6(9): 1-87 Indexing Status Subject indexing assigned by NLM MeSH Adult; Antiviral Agents /adverse effects /economics /therapeutic use; Cost-Benefit Analysis; Great Britain; Guanidines; Orthomyxoviridae Infections /drug therapy; Pyrans; Randomized Controlled Trials as Topic; Sialic Acids /adverse effects /economics /therapeutic use; Treatment Outcome AccessionNumber 12002008442 Date bibliographic record published 30/09/2003 Date abstract record published 30/09/2003 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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