REVIEW - Effectiveness and cost effectiveness of Humira, Enbrel, and Remicade for RA

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Health Technol Assess. 2006 Nov;10(42):1-248.

A systematic review of the effectiveness of adalimumab, etanercept and

infliximab for the treatment of rheumatoid arthritis in adults and an

economic evaluation of their cost-effectiveness.

West Midlands Health Technology Assessment Collaboration (WMHTAC),

Department of Public Health and Epidemiology, University of Birmingham, UK.

OBJECTIVES: This report reviews the clinical effectiveness and

cost-effectiveness of adalimumab, etanercept and infliximab, agents that

inhibit tumour necrosis factor-alpha (TNF-alpha), when used in the treatment

of rheumatoid arthritis (RA) in adults.

DATA SOURCES: Electronic databases were searched up to February 2005.

REVIEW METHODS: Systematic reviews of the literature on effectiveness and

cost-effectiveness were undertaken and industry submissions to the National

Institute for Health and Clinical Excellence (NICE) were reviewed.

Meta-analyses of effectiveness data were also undertaken for each agent. The

Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was

further developed and used to produce an incremental cost-effectiveness

analysis.

RESULTS: Twenty-nine randomised controlled trials (RCTs), most of high

quality, were included. The only head-to-head comparisons were against

methotrexate. For patients with short disease duration (</=3 years) who were

naive to methotrexate, adalimumab was marginally less and etanercept was

marginally more effective than methotrexate in reducing symptoms of RA.

Etanercept was better tolerated than methotrexate. Both adalimumab and

etanercept were more effective than methotrexate in slowing radiographic

joint damage. Etanercept was also marginally more effective and better

tolerated than methotrexate in patients with longer disease durations who

had not failed methotrexate treatment. Infliximab is only licensed for use

with methotrexate. All three agents, either alone (where so licensed) or in

combination with ongoing disease-modifying antirheumatic drugs (DMARDs),

were effective in reducing the symptoms and signs of RA in patients with

established disease. At the licensed dose, the numbers needed to treat

(NNTs) (95% CI) required to produce an American College for Rheumatology

(ACR) response compared with placebo were: ACR20: adalimumab 3.6 (3.1 to

4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2 (2.7 to 4.0); ACR50:

adalimumab 4.2 (3.7 to 5.0), etanercept 3.1 (2.7 to 3.6), infliximab 5.0

(3.8 to 6.7); and ACR70: adalimumab 7.7 (5.9 to 11.1), etanercept 7.7 (6.3

to 10.0), infliximab 11.1 (7.7 to 20.0). In patients who were naive to

methotrexate, or who had not previously failed methotrexate treatment, a TNF

inhibitor combined with methotrexate was significantly more effective than

methotrexate alone. Infliximab combined with methotrexate had an increased

risk of serious infections. All ten published economic evaluations met

standard criteria for quality, but the incremental cost-effectiveness ratios

(ICERs) ranged from being within established thresholds to being very high

because of varying assumptions and parameters. All three sponsors who

submitted economic models made assumptions favourable to their product. BRAM

incorporates improvements in quality of life and mortality, but assumes no

effect of TNF inhibitors on joint replacement. For use in accordance with

current NICE guidance as the third DMARD in a sequence of DMARDs, the

base-case ICER was around pound30,000 per quality-adjusted life-year (QALY)

in early RA and pound50,000 per QALY in late RA. Sensitivity analyses showed

that the results were sensitive to the estimates of Health Assessment

Questionnaire (HAQ) progression while on TNF inhibitors and the

effectiveness of DMARDs, but not to changes in mortality ratios per unit

HAQ. TNF inhibitors are most cost-effective when used last. The ICER for

etanercept used last is pound24,000 per QALY, substantially lower than for

adalimumab ( pound30,000 per QALY) or infliximab ( pound38,000 per QALY).

First line use as monotherapy generates ICERs around pound50,000 per QALY

for adalimumab and etanercept. Using the combination of methotrexate and a

TNF inhibitor as first line treatment generates much higher ICERs, as it

precludes subsequent use of methotrexate, which is cheap. The ICERs for

sequential use are of the same order as using the TNF inhibitor alone.

CONCLUSIONS: Adalimumab, etanercept and infliximab are effective treatments

compared with placebo for RA patients who are not well controlled by

conventional DMARDs, improving control of symptoms, improving physical

function, and slowing radiographic changes in joints. The combination of a

TNF inhibitor with methotrexate was more effective than methotrexate alone

in early RA, although the clinical relevance of this additional benefit is

yet to be established, particularly in view of the well-established

effectiveness of MTX alone. An increased risk of serious infection cannot be

ruled out for the combination of methotrexate with adalimumab or infliximab.

The results of the economic evaluation based on BRAM are consistent with the

observations from the review of clinical effectiveness, including the

ranking of treatments. TNF inhibitors are most cost-effective when used as

last active therapy. In this analysis, other things being equal, etanercept

may be the TNF inhibitor of choice, although this may also depend on patient

preference as to route of administration. The next most cost-effective use

of TNF inhibitors is third line, as recommended in the 2002 NICE guidance.

Direct comparative RCTs of TNF inhibitors against each other and against

other DMARDs, and sequential use in patients who have failed a previous TNF

inhibitor, are needed. Longer term studies of the quality of life in

patients with RA and the impact of DMARDs on this are needed, as are longer

studies that directly assess effects on joint replacement, other morbidity

and mortality.

PMID: 17049139

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & dopt=Abstra\

ctPlus & list_uids=17049139

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