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The cost-utility analysis of the BeSt trialIs a camel in fact a horse with abnormalities in the distribution of dorsal fat Comment on the article by van den Hout et al.

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Letters
Table 2. Association between hydroxychloroquine and
diminished glomerular filtration rate or end-stage renal
disease among systemic lupus erythematosus patients
with renal involvement from the LUMINA cohort*
Model
Odds ratio
95% CI
P
Crude
Adjusted†
0.65
0.72
0.36–1.19
0.36–1.44
0.1617
0.3574
* LUMINA ⫽ LUpus in MInorities, NAture versus nurture; 95%
CI ⫽ 95% confidence interval.
† Adjusted for age, sex, ethnicity, arthritis, malar rash, photosensitivity, serositis, Systemic Lupus Activity Measure-Revised (without
renal manifestations), World Health Organization class IV glomerulonephritis, HLA–DRB1*1503, low-density lipoprotein cholesterol, and azathioprine and glucocorticoid dose.
reduction (71%; 95% confidence interval [95% CI] 32– 87)
in the risk of renal damage occurrence among those receiving HCQ as compared with those not receiving HCQ. Since
this is a time-to-event analysis, what the data indicate are
that patients with lupus nephritis who are receiving HCQ
experience a prolonged time to the occurrence of renal
damage (anywhere from 32– 87% as per the 95% CI) in
comparison with those who do not take HCQ. So, it is not
that they will not develop renal damage, but it is that the
time to this occurrence will be delayed as compared with
those who do not take HCQ, which is still very important
from the clinical point of view (the maintenance of HCQ
treatment even when serious disease manifestations occur).
In short, the time-dependent analyses support the protective effect of HCQ in retarding the development of renal
damage in lupus patients with renal involvement.
Graciela S. Alarcón, MD, MPH
Guillermo Pons-Estel, MD
Gerald McGwin, Jr., PhD
Maria I. Danila, MD, MSc
Jie Zang, MPH
Holly M. Bastian, MD, MSPH
University of Alabama at Birmingham
Luis M.Vilá, MD
University of Puerto Rico Medical Sciences Campus
San Juan, Puerto Rico
1. Alarcon GS, McGwin G Jr, Bertoli AM, Fessler BJ, Calvo-Alen
J, Bastian HM, et al. Effect of hydroxychloroquine in the survival of patients with systemic lupus erythematosus: data from
LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum
Dis 2007;66:1168 –72.
2. Seshadri R, Feldman BM, Ilowite N, Cawkwell G, Pachman
LM. The role of aggressive corticosteroid therapy in patients
with juvenile dermatomyositis: a propensity score analysis.
Arthritis Rheum 2008;59:989 –95.
3. Landewe RB. The benefits of early treatment in rheumatoid
arthritis: confounding by indication, and the issue of timing
[editorial]. Arthritis Rheum 2003;48:1–5.
4. Schmoor C, Caputo A, Schumacher M. Evidence from nonrandomized studies: a case study on the estimation of causal
effects. Am J Epidemiol 2008;167:1120 –9.
5. Sturmer T, Joshi M, Glynn RJ, Avorn J, Rothman KJ, Schneeweiss S. A review of the application of propensity score methods yielded increasing use, advantages in specific settings, but
not substantially different estimates compared with conventional multivariable methods. J Clin Epidemiol 2006;59:437–
47.
DOI 10.1002/art.24821
The cost-utility analysis of the BeSt trial: is
a camel in fact a horse with abnormalities
in the distribution of dorsal fat? Comment
on the article by van den Hout et al
To the Editors:
I read with great interest the results of the cost-utility
analysis of the BeSt (Behandelstrategieën voor Reumatoide
Artritis) trial by van den Hout et al and the accompanying
editorial by Bansback and Marra published recently in
Arthritis Care & Research (1,2). It is an excellent state-ofthe-art study brimming with interesting data. My only
concern is with the interpretation.
A casual reader might assume from the abstract and
conclusion, and also from the editorial, that the case on the
cost utility of biologic therapies as first-line therapy is far
from closed, since scientists do not agree on the proper
methodology (e.g., for attributing productivity costs). Not
understanding the finesses of health economics, the reader
cannot be blamed for concluding that it may be good value
for the money to start patients with early rheumatoid arthritis on infliximab and high-dose methotrexate as firstline treatment. After all, in one of the analyses, this strategy (as given to group 4 of the trial) was calculated to cost
a mean of €22,000 per quality-adjusted life year (QALY)
compared with the costs and utility of an oral pulse of
prednisolone plus methotrexate and sulfasalazine (the COBRA [Combinatietherapie Bij Reumatoı̈de Artritis] strategy
as given in group 3 of the trial).
So is that the “BeSt” conclusion? That remains to be
seen.
To start, the differences in QALYs between the groups
are quite small, and most prominent in the first year of
study. For example, for the British EuroQol Index (with a
scale where 0 ⫽ dead and 1 ⫽ perfect health) the QALY at
1 year was 0.58 in the worst group versus 0.68 in the best
group. In the second year the range was 0.68 – 0.73 and the
differences were no longer statistically significant.
The simplest cost-utility analysis ignores societal costs
and focuses on direct health care costs, i.e., drug and other
medical expenditures. In this analysis, the incremental
upfront cost per QALY of infliximab was €190,000. The
authors say, with some understatement, that these are
“costs that are generally considered too high.”
A more complex analysis is one that uses the societal
perspective. Bansback and Marra note in their editorial
that this perspective may be the most appropriate to
choose since it includes costs of productivity losses that
may be recouped by society due to effective therapy. However, it involves tough choices on how paid and unpaid
labor are valued. In this study, the choice between the
so-called friction cost method and the human capital
method led to huge differences in the conclusions on the
cost-utility, i.e., €22,000 or €130,000 per QALY, with even
Letters
larger confidence intervals, which raised questions about
the analysis itself. In other studies, such differences could
be blamed on an unreasonably long horizon for extrapolation that favors the human capital method, but here the
horizon was properly limited to the study duration of 2
years. Given that both the differences in measured utilities
as well as productivity between the groups (especially
groups 3 and 4) were relatively small, the only reason for
these results that I can think of is in the baseline differences in productivity. At baseline, contract hours ranged
between 14.1 in groups 1–3 to 16.7 in group 4. Differences
were not significant due to highly skewed distributions.
Contract hours decreased in all groups except group 3.
Hours absent from work decreased in all groups, but if
“loss” is related to contract hours then the baseline differences are important. Because worked hours are multiplied
with wages to obtain the productivity “benefit,” small
imbalances can then strongly influence the results. I find
no mention that a correction for these imbalances was
made in the analyses.
Another concern is that the editorialists assume there
were no deaths in the first 2 years, but in my recollection
there were. If so, how were these accounted for? Finally,
9% missing data in utility scores and 16% in cost diaries
increase the uncertainty of the results, despite the use of
state-of-the-art imputation techniques.
Looking beyond the study, probably the most costeffective strategy is to start with the COBRA regimen of
group 3, but switch to infliximab on nonresponse at 6
months. Thinking of the camel, and staying within the
bounds and the uncertainties in the study outlined above,
I suggest a more proper conclusion would read, “Initial
combination therapy with methotrexate, sulfasalazine,
and an oral pulse of prednisolone (COBRA regimen) appears to be the dominant cost-effective strategy as initial
therapy in early active rheumatoid arthritis. Under extreme assumptions, starting combination therapy with infliximab might become cost effective at €22,000/QALY
compared with the COBRA regimen.”
Dr. Boers is the inventor of the COBRA regimen and a part-time
employee at VU University Medical Center, which participated in
the BeSt trial.
Maarten Boers, MSc, MD, PhD
VU University Medical Center
Amsterdam, The Netherlands
1. Van den Hout WB, Goekoop-Ruiterman YP, Allaart CF, de
Vries-Bouwstra JK, Hazes JM, Kerstens PJ, et al. Cost-utility
analysis of treatment strategies in patients with recent-onset
rheumatoid arthritis. Arthritis Rheum 2009;61:291–9.
2. Bansback N, Marra CA. Now that we know what’s BeSt, what is
good value for the money? [editorial]. Arthritis Rheum 2009;
61:289 –90.
DOI 10.1002/art.24820
Reply
To the Editors:
We thank our colleague, Dr. Boers, for his careful discussion of critical methodologic aspects of the economic
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evaluation of the BeSt study. We would like to respond to
the concerns that he raises.
First, we agree that the QALY differences in our study
were small, although statistically significant, and that tight
disease control achieved similar long-term improvements
in patients in all 4 adaptive treatment strategies. We think
that other studies with fixed medication schedules or with
optimistic mathematical models have tended to overestimate the impact of biologic therapies. Nevertheless, even
the relatively small QALY gain that was obtained in our
study by starting directly with infliximab would already
justify the difference in medical costs if productivity is
valued according to the human capital method, an established approach rather than an extreme assumption to
calculate the economic consequences of illness.
Second, Boers suggests that the only reason for our observed (significant) differences in productivity costs must
be the (nonsignificant) difference in initial labor participation, and he suggests that our statistical analyses should
have corrected for these differences. Boers disregards the
fact that cost-of-illness studies have invariably shown that
rheumatoid arthritis (RA) has a large impact on productivity, and that therefore the observed differences in early
effectiveness in our study are very likely to lead to differences in productivity. It is true that initial labor participation in groups 1 and 2 was relatively low (40% and 33%,
respectively). This may have worsened the outcome in
groups 1 and 2, which is why we explicitly reported and
discussed the difference in initial labor participation.
However, initial labor participation was very similar in
groups 3 and 4 (both 46%). All cost-utility ratios quoted by
Boers compare groups 3 and 4, so these cannot have been
influenced by the initial level of labor participation. Moreover, with hindsight, random baseline differences should
not be used to highlight or to remove statistical differences.
Third, Boers raises a concern about the number of
deaths. Mortality in the 4 different study groups was not
statistically significantly different (0, 1, 0, and 2 patients,
respectively). This mortality was incorporated by using
zero utility values, but QALY losses were not extrapolated
beyond the 2-year study period. Patterns of infliximab use
had not yet stabilized after 2 years, so extrapolating study
results to a longer horizon could be inaccurate. Moreover,
a proper long-term model would also have to incorporate
reduced RA mortality due to effective treatment. Compared with many other economic evaluations, an important strength of our study is the use of primary data only,
without modeling. Likewise, we do not speculate on strategies that were not included in the trial.
Camels and horses are both very useful animals. The
economic and statistical analyses of the BeSt study were
performed according to current state-of-the-art and most
objections raised by Boers were already presented and
discussed in our paper. His response confirms our conclusion that the crucial factor in the economic evaluation of
biologic therapies is whether and how productivity is valued. The human capital method counts every hour lost as
costs, whereas the friction cost method only takes into
account the losses until an absent employee has been
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