Health Technology Assessment 2004; Vol 8: number 18
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W Clark,1 P Jobanputra,2 P Barton3 and A Burls4*
1 Medicines Evaluation Unit, Department of Medicines Management, Keele University, UK
2 Department of Rheumatology, University Hospital Birmingham NHS Trust, Selly Oak Hospital, UK
3 Health Economics Facility, Health Services Management Centre, University of Birmingham, UK
4 West Midlands Health Technology Assessment Collaboration, Department of Public Health and Epidemiology, University of Birmingham, UK
* Corresponding author
This report reviews the evidence of the clinical and cost-effectiveness of anakinra, an interleukin-1 receptor antagonist (IL-1Ra), for the treatment of rheumatoid arthritis (RA) in adults. Anakinra is licensed in Europe for use in combination with methotrexate, for patients with an inadequate response to methotrexate alone. Anakinra acts in the same way as naturally occurring IL-1Ra, transiently binding to the IL-1 receptor, augmenting the natural regulation of the proinflammatory effects of IL-1.
RA is a chronic illness characterised by inflammation of the synovial tissues in joints, which can lead to joint destruction. Key aims of treatment include:
RA affects around 0.51% of the population, with approximately 421,330 patients affected in England and Wales. Prevalence increases with age, so that prevalence at the age of 65 is six times that at 25 years. Peak age of onset is in the sixth decade and RA is more common in women than in men, by a ratio of 2.5:1.
Corticosteroids, non-steroidal anti-inflammatory drugs and analgesics are used to control symptoms, but early use of disease-modifying antirheumatic drugs (DMARDs) is key, with the aim of slowing disease progression. There are approximately eight DMARDs currently in common use in the UK. Variable effectiveness or loss of effectiveness over time and toxicity hamper their use, with low continuation rates seen over time. New DMARDs are therefore of great importance. Several new agents have appeared in recent years, including the tumour necrosis factor (TNF) inhibitors, infliximab and etanercept.
Five randomised controlled trials (RCTs) of anakinra in adult patients with RA, involving a total of 2905 patients, of whom 2146 received anakinra, were identified. All compared anakinra with placebo and all but one presented outcome data at 24 weeks. In three trials anakinra was administered in combination with methotrexate/other DMARDs and in two as monotherapy. Only two trials evaluated the licensed dose of 100mg daily. All five trials were identified as high quality.
The results of the clinical trials are consistent with clinical benefit (compared with placebo) as measured by American College of Rheumatology (ACR) composite response rate at 6 months. Variation in response rate was seen across the trials, which is likely to be a reflection of the size of the trials and the wide range of doses evaluated. Consistent benefit was seen at the higher dose evaluated [number needed to treat (NNT) to achieve an ACR20 response of 7, 95% confidence interval (CI) 5 to 11, at licensed dose]. Benefit was evident both with monotherapy and when used in combination with methotrexate.
Data on the efficacy end-points evaluated in a large pragmatic safety study (0757) have not been made available. This is of concern. Given the nature and scale of this study such data have the potential to alter the overall findings of this review. In the absence of data the reviewers made an educated guess about the result of trial 0757. Assuming that this trial failed to reach conventional levels of statistical significance with a p-value of treatment difference in the order of p < 0.1 to < 0.2, an estimate of effectiveness was derived for trial 0757. The derived estimate has been combined with the data from the earlier trials, using a random effects model, to give a best estimate about anakinras effectiveness for ACR20 response: relative risk 1.43 (95% CI 1.16 to 1.76), risk difference 0.11 (95% CI 0.04 to 0.18), NNT 9 (95% CI 6 to 25).
Anakinra can be considered modestly effective in the treatment of RA based on ACR response. Reduction in Health Assessment Questionnaire scores, a measure of disability, was small. Robust data on radiologically assessed joint damage are not currently available. No conclusion can therefore be made on the effect of treatment on disease progression.
Direct comparisons with other biological modifiers are not available. Adjusted indirect comparison suggests that anakinra may be significantly less effective at relieving the clinical signs and symptoms of RA, as measured by the ACR response criteria, than TNF inhibitors all used in combination with methotrexate. Such indirect results should be interpreted with caution, but can be useful in guiding clinical practice in the absence of direct comparisons between agents.
Anakinra treatment was associated with a high incidence of injection-site reactions. Serious adverse events were infrequent, but longer term follow-up is required.
The Birmingham Rheumatoid Arthritis Model (BRAM) was used to compare DMARD sequences of drugs, chosen to reflect current clinical practice, with and without the addition of anakinra at different points in the DMARD sequence. The BRAM gives a base-case estimate of the incremental cost-effectiveness ratio (ICER) of anakinra of £106,000 to £604,000/QALY. This model uses data from public domain trial results only. These recruited a highly selective patient population and may well give a more favourable estimate of cost-effectiveness than would be achieved in an average clinic population.
In the sensitivity analyses substantial variations were made in key parameters and ICERs were shown to be responsive. However, ICERs did not drop below £50,000/QALY in any univariate sensitivity analysis.
The BRAM produces an ICER for anakinra substantially higher than those for infliximab and etanercept. However, patients may respond to anakinra when they have not responded to other TNF inhibitors, as these agents have a different mechanism of action. Thus, anakinra may produce a clinically significant and important improvement in some patients that they could not otherwise have achieved.
Clark W, Jobanputra P, Barton P, Burls A. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis. Health Technol Assess 2004;8(18).
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