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Clinical and economic assessment: infliximab for the treatment of Crohn's disease |
Marshall J K, Blackhouse G, Goeree R, Brazier N, Irvine E J, O'Brien B J |
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Authors' objectives To review the available data supporting the efficacy, effectiveness and adverse effects of infliximab in the treatment of patients with Crohn's disease (CD).
Searching MEDLINE, EMBASE, Current Contents, HealthSTAR, TOXLINE, CINAHL and the Cochrane Library were searched from 1990 to 2001; the search terms were reported. This was supplemented with searches of pharmaceutical industry databases and contact with study authors. In addition, gastroenterology journals were handsearched through August 2001 and abstract listings from relevant scientific meetings were searched. Pharmaceutical companies involved in the production and distribution of infliximab were contacted for relevant data, websites of relevant government agencies were searched, and selected agencies were contacted. The reference lists of all potentially relevant studies were screened. The authors aimed to identify both published and unpublished data. Only studies written in English were included.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) were included in the review of clinical effectiveness. Non-randomised case series were considered if they evaluated clinical outcomes of infliximab treatment in at least 100 consecutive patients with fistulising or active CD. Adverse event data were taken from clinical trials, case series and cohort studies, as well as federal agencies and industry sources.
Specific interventions included in the reviewStudies were included if infliximab was given in one of the treatment arms. Within the included studies, infliximab was given at doses of 5, 10 or 20 mg/kg intravenously.
Participants included in the reviewStudies of adults with fistulising or treatment-resistant CD were included.
Outcomes assessed in the reviewThe studies had to report clinical end points to be included in the review. The outcomes included complete and partial closure of fistulas, changes in clinical response (defined as a drop of greater than 70 in the Crohn's Disease Activity Index, CDAI) at various stages of follow-up, duration of response, remission (CDAI <150), Inflammatory Bowel Disease Questionnaire (IBDQ) scores, corticosteroid use, withdrawals and adverse events.
How were decisions on the relevance of primary studies made?Two reviewers independently assessed the relevance of studies for inclusion.
Assessment of study quality RCTs were assessed using the Jadad scale, which evaluates the adequacy of randomisation, blinding and handling of withdrawals. Two reviewers independently assessed study validity. Any disagreements were resolved by consensus.
Data extraction Two reviewers independently extracted the data from the studies. Data on study centres (number and location), funding source, inclusion and exclusion criteria, baseline comparability of the groups, treatment regimens, validity score and outcomes were extracted.
Methods of synthesis How were the studies combined?The studies were combined in a narrative.
How were differences between studies investigated?The included studies and differences between them were described in detail in the narrative synthesis.
Results of the review Four RCTs (number of participants unclear) were included in the review of clinical effectiveness. Thirteen cohorts of at least 100 patients were identified. This was supplemented by adverse event data from 38 other sources.
The quality score for the three trials published in full ranged from 3 to 4 out of a maximum of 5. The trial published only as an abstract had a score of two, partly because few methodological details were provided.
Fistulising CD.
One placebo-controlled RCT (n=94) found infliximab to be superior to placebo for partial closure (62% versus 26%, P=0.002) and complete closure (46% versus 13%, P=0.001) of fistulas. No difference was seen between infliximab doses of 5 and 10 mg/kg. Four case series supported this finding, showing improvements in fistula closure or Perianal Disease Activity Index score in patients receiving infliximab.
Treatment-resistant CD.
One placebo-controlled RCT (n=108) was identified. Clinical response and remission were greater for infliximab than placebo at weeks 4 (response 65% versus 16%, P<0.001; remission 33% versus 4%, P=0.005) and 12 (response 41% versus 12%, P=0.008; remission 24% versus 8%, P=0.31) of follow-up.
Patients who achieved clinical response entered a placebo-controlled randomised study extension (n=73) to evaluate repeated doses of infliximab (10 mg/kg at 8-week intervals) to maintain response after week 12. More patients maintained response at 44 weeks in the infliximab group than in the placebo group, though this difference was not statistically significant (62% versus 37%, P=0.16). The difference between the groups was statistically significant for remission at week 44, and favoured infliximab (44% versus 20%, P=0.013).
One large RCT (n=335) randomised patients who responded to 5 mg/kg infliximab at week 2 to doses of infliximab (5 or 10 mg/kg) or placebo, repeated every 8 weeks. Interim results indicated that, at week 30, infliximab was superior to placebo in terms of clinical response (55% versus 27%, P=0.001), remission (42% versus 21%, P=0.01), steroid withdrawal (34% versus 11%, P=0.01), median steroid dose and median increase in IBDQ score. There was no significant difference between maintenance doses of infliximab.
Adverse events.
Across all trials, 13% of infliximab-treated patients and 4% of placebo-treated patients reported serious adverse events. There were no deaths. The reported incidences of adverse events were broadly similar to those observed in clinical trials of infliximab in rheumatoid arthritis.
Cost information A Markov model cost-utility analysis was conducted. The incremental cost-utility ratio of single-dose infliximab therapy in 2001 Canadian dollars (Can$) was estimated to be Can$181,201 per quality-adjusted life-year (QALY) from the perspective of a Canadian provincial ministry of health. This increased to Can$696,078 per QALY when maintenance therapy was added, though all estimates were sensitive to changes in drug infusion costs and rates of medical admission for drug-refractory disease.
Authors' conclusions The available literature supports the efficacy and effectiveness of infliximab for the acute treatment of fistulising CD, and for both acute and maintenance therapy of treatment-resistant CD. The short-term toxicity of infliximab seems minimal, and infusion reactions are rarely severe.
CRD commentary This review had a clear objective that was supported by relevant inclusion criteria relating to the intervention, study design and participants. The authors reported searching multiple sources (including electronic databases) to identify relevant evidence, as well as contacting authors. Two independent reviewers screened studies for inclusion and inclusion was not restricted by publication status. However, the included studies were restricted to those written in English, which increases the risk of language bias, thus relevant studies might have been missed. Two reviewers independently extracted data from the studies, including validity data derived from a well-established validity assessment scale. It should be noted that the two RCTs of infliximab maintenance therapy appear to have included only patients who had shown a clinical response to acute treatment. Nevertheless, the authors' conclusions seem appropriate given the evidence presented in the review.
Implications of the review for practice and research Practice: The authors did not state any implications for practice.
Research: The authors stated that further data on the long-term adverse effects of infliximab treatment, particularly long-term maintenance, are needed.
Bibliographic details Marshall J K, Blackhouse G, Goeree R, Brazier N, Irvine E J, O'Brien B J. Clinical and economic assessment: infliximab for the treatment of Crohn's disease. Ottawa, ON, Canada: Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Technology Overview; 8. 2002 Other publications of related interest Marshall J, Blackhouse G, Goeree R, Brazier N, Irvine E, Faulkner L, et al. Infliximab for the treatment of Crohn's disease: a systematic review and cost-utility analysis. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2002. Technology Report No.: 24.
Indexing Status Subject indexing assigned by CRD MeSH Antibodies, Monoclonal /therapeutic use; Crohn Disease /drug therapy AccessionNumber 12002008364 Date bibliographic record published 31/07/2006 Date abstract record published 31/07/2006 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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