A systematic review of the effectiveness of adalimumab

inhibitors, although the incremental benefits were
significantly smaller (with the exception of joint
damage) than those observed in comparisons
between TNF inhibitors and placebo.
Combination of infliximab and methotrexate in
this context was associated with increased risk of
serious infection, and a similar, non-significant
trend (which may be due to insufficient statistical
power) was observed for adalimumab. No trials
have compared a combination of methotrexate
with a conventional DMARD to the combination
of methotrexate with a TNF inhibitor.
Overall effectiveness and safety
At the licensed dose the NNTs (95% CI) required
to produce an improvement in ACR20 response in
comparison with placebo are: adalimumab 3.6 (3.1
to 4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2
(2.7 to 4.0). While these are favourable NNTs for
medical interventions, they also emphasise the
importance of direct comparisons between
DMARDs in estimating the ICER of new
treatments for RA.
The NNT figures appear to be slightly in favour of
etanercept. Indirect comparisons of agents should
be interpreted with caution, however, given the
potential differences in patient populations, study
design and method of analysis across trials. This is
particularly the case when using NNTs with a
metric like the ACR response. Not only do ACR
responses have a ceiling effect, but the absolute
health gain obtained from achieving a positive
ACR response is a function of the baseline health
status of patients. Truly fair and unbiased
comparisons can only be made through direct
comparisons of TNF inhibitors in trials and these
are urgently needed.
An important clinical difference between the
included trials is whether patients recruited were
concurrently receiving newly initiated
methotrexate in both intervention and control
arms. The relative risks of achieving ACR
response (TNF inhibitor plus methotrexate
versus methotrexate alone) were, perversely,
larger in trials in which patients were no longer
responding to methotrexate than in trials
where patients had not previously received
methotrexate or had not failed to respond
previously. For example, pooled RRs for ACR70
for methotrexate plus TNF inhibitor versus
methotrexate alone range from 3.16 (infliximab)
to 9.44 (etanercept) in trials of methotrexate
partial or non-responders; these are reduced to a
range from 1.57 (infliximab) to 2.53 (etanercept)
in trials of methotrexate-naïve patients or
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Health Technology Assessment 2006; Vol. 10: No. 42
responders. This is largely due to the fact that the
response rates in the methotrexate arm were much
higher in the latter trials. When interpreting these
results, it is important to take into account the
absolute risk differences between treatment
groups, which are reflected in NNTs.
Methodology
In this systematic review, results were pooled from
the end of trials irrespective of the duration of
follow-up. This was done to maximise the number
of studies and to increase the statistical power of
meta-analyses. The authors acknowledge that it
may, on occasion, be preferable to pool results
with similar duration of follow-up when there is
evidence that the effect size of the treatment varies
over time. Nevertheless, statistical heterogeneity in
the end-of-trial results between studies was not
found for the majority of analyses that were
carried out. Where heterogeneity was observed,
the differences in the duration of follow-up do not
usually explain the heterogeneity, except for the
single case of Keystone 129 in the analysis of
etanercept versus placebo. This 8-week study is the
only trial included in the meta-analyses with a
duration of less than 12 weeks. Its short duration
might explain the smaller RR observed for
ACR50 and ACR70 compared with other
etanercept trials.
As the duration of trial increases, the influence of
imputation methods used to deal with missing
data (e.g. last observation carried forward or
assuming that all withdrawals were nonresponders)
becomes greater. This is because
losses to follow-up and withdrawals increase as
study length increases. The impact is difficult
to assess, however, as results obtained using
different analytical methods are rarely reported
together.
The differential withdrawal and follow-up between
treatment groups, particularly in placebocontrolled
trials, makes the assessment of adverse
events difficult. The quality of reporting adverse
events in published papers needs to be improved
but, commonly, cause and effect relationships are
difficult to determine. 35 Skin carcinomas, for
example, were omitted from the reporting of
malignancy in several trials. Trials lack power to
identify potentially important toxicities, and
although postmarketing surveillance through
databases such as the BSRBR can be useful in
detecting rarer adverse events, such large-scale
studies are resource intensive, depend on the
goodwill of many specialists and raise important
concerns about data quality and ownership.
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