A systematic review of the effectiveness of adalimumab

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Effectiveness
adalimumab plus methotrexate in patients naïve to
both treatments. The study therefore allowed two
comparisons: adalimumab versus methotrexate
(comparison 1), and combination of adalimumab
plus methotrexate versus methotrexate
(comparison 3). No statistical adjustment was
made for the multiple comparisons within a trial.
Although subgroup analyses according to disease
duration (mean disease duration ≤ 3 years versus
>3 years) were planned, on reviewing the data it
was felt that they were insufficient to support this,
as disease duration relates closely to patients’ prior
exposure to DMARD therapies, which was strongly
associated with the type of trials that had been
carried out. For example, trials that compared
TNF inhibitors with placebo tended to recruit
predominately RA patients with long disease
duration and with prior exposure to multiple
DMARDs, whereas trials that included genuine
head-to-head comparison between TNF inhibitors
and conventional DMARDs were predominantly
carried out in patients with early RA.
Handling of data and presentation of results
For continuous outcomes, results are presented as
a weighted mean difference (WMD). For binary
outcomes, results are presented as relative risk
(RR). Risk differences (RD) were also used to
calculate numbers needed to treat (NNT).
For outcomes with continuous data, the decision
about whether to use the change from baseline or
the final result depended on whether data were
available for a sufficient number of studies. Where
possible, the standard deviation (SD) was taken
directly from the reported results, or derived from
the standard error of the mean (SEM) or confidence
intervals (CIs). When only the baseline SD was
available, it was used as the SD for the final results
as well. 100 SDs for mean change from baseline, if
not available, were imputed using baseline SD and
final SD assuming an intercorrelation coefficient of
0.5. 101 When only the median and interquartile
ranges (IQRs) were reported, the median was used
as the mean, and the difference between the first
and third quartiles was considered equivalent to
1.35 SD. 101 Where the SD could not be estimated
from trial data using the above methods, an
imputed SD was calculated from the baseline SD of
other trials with the same intervention.
Many outcomes were meta-analysed; for brevity,
only the summary results are presented. Forest plots
of the primary analyses for the six key outcomes
(ACR20, ACR50, ACR70, HAQ, SAEs and
malignancies) are shown. A fixed effects model was
used unless trials demonstrated statistical
heterogeneity (test for heterogeneity p < 0.10), in
which case a random effects model was also used. In
such cases the most conservative result is presented.
Results for effectiveness review
Number and type of studies included
In total, 29 RCTs are included in this systematic
review: nine on adalimumab, 11 on etanercept
and nine on infliximab. One further trial (BeSt) is
also described here.
The process of study selection is summarised in
Figure 1. Thirty-six citations met inclusion criteria
(kappa for two independent reviewers was 0.70, 95%
CI 0.66 to 0.75): ten papers or conference abstracts
describing further results from two trials [Early
Rheumatoid Arthritis (ERA) and Anti-TNF Trial in
Rheumatoid Arthritis with Concomitant Therapy
(ATTRACT)] included in the previous technology
assessment report (TAR), 1 and 26 papers or
conference abstracts describing results from 15
RCTs not included in the previous review. For more
details of excluded studies see Appendix 3.
Seven new RCTs were identified through
manufacturers’ submissions and abstracts (not yet
indexed in electronic databases) from conferences.
Five met the inclusion criteria. Trial reports were
obtained from the manufacturers for four of the
trials [PREMIER, 102 Codreanu, 103 Baumgartner, 104
and Safety Trial for Rheumatoid Arthritis with
Remicade Therapy (START) 105 ] which are included
in the systematic review. The study by
Schattenkirchner and colleagues 106 (adalimumab
DE004) could not be included because attempts to
obtain the trial report from the manufacturer were
unsuccessful. Two trials, Add Enbrel or Replace
Methotrexate (ADORE) 107 and BeSt 108 did not meet
the inclusion criteria as they had TNF inhibitors in
all arms, thereby preventing appropriate
comparisons between TNF inhibitors and other
active comparators or placebo. However, although
BeSt, which was a trial of DMARD sequences in RA,
could not be included in meta-analyses, this study is
described in detail in the section ‘Infliximab’ (p.
46), because it reports data that may inform the
appropriate use of these agents.
The results of the PREMIER, 109 Trial of
Etanercept and Methotrexate with Radiographic
Patient Outcomes (TEMPO; 2-year data), 110
START 111 and the BeSt 108 trials were published in
full after the initial completion of this review, but
before the publication of this report. In addition, a