Evaluation Leflunomide Patients with Rheumatoid Arthritis · 2020. 4. 8. · Economic Evaluation of...
Transcript of Evaluation Leflunomide Patients with Rheumatoid Arthritis · 2020. 4. 8. · Economic Evaluation of...
Economic Evaluation of Leflunomide in Patients with Rheumatoid Arthritis
Andreas Maetzel
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy,
Institute of Medical Science,
University of Toronto
O Copyright by Andreas Maetzel, 200 1
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Economic Evaluation of Leflunomide in the Treatment of Rheumatoid Arthritis. Andreas Maetzel,
Doctor of Philosophy, Institute of Medical Science. University of Toronto, 200 1
Abstract
Objective: To comprehensively evaluate the pharmacoeconomic properties of leflunomide, a novel
disease-modifymg anti-rheumatic drug (DMARD) to support reimbursement decisions by Canadian
provincial decisionmakers .
Methods: The evaluation was performed using two different analytical approaches. The first was based
on economic data collected prospectively in a Nonh American trial in patients with rheumatoid arthritis
(RA) randomized to placebo, leflunomide or methotrexate, and the second was based on a 5-year
simulation model comparing two treatment strategies, one including leflunomide. The model was
supported by an independently conducted survey of US and Canadian rheumatologists and a systematic
review of treatment withdrawals among patients on DMARDs.
Results: The survey confirmed methotrexate to be the treatment of choice without any clear alternative.
Analysis of the literature confirmed that patients stay significantly longest on methotrexate. Although the
economic consequences between Ieflunomide and methotrexate were similar, the higher drug costs of
leflunomide imply an extra 5 147,437 per QALY gained compared to placebo (methotrexate: 9 lZ,t26).
Methotrexate is both less expensive than leflunomide and produces higher utilities (non-significant), but
more patients on leflunomide achieve an American College of Rheumatology 20% response status at a
cost of $66,000 per responder gained compared to methotrexate. The model also showed that adding
leflunomide as a new option within a realistic sequence of DMARDs extends the time patients may
benefit from DMARD therapy at a reasonable cost-effectiveness of $10,682 per responder gained and
cost-utility of S18,474 per QALY gained.
Conclusion: This thesis shows that leflunomide has a place in the management of patients with RA and
that it comes with a reasonable economic profile.
Acknowledgments
I would like to express my deepest gratitude to my supervisor Dr. Claire Bombardier for her
continuing support, expert guidance and patience fkom the inception to the completion of this
project. I would also like to thank the thesis committee members Dr. Allan Detsky and Dr.
Murray Krahn for providing insightful and timely input throughout this research.
I would like to express my gratitude to Dr. Peter Tugwell, Dr. Vibeke Strand, Dr. George Wells,
Louise Lafortune, Dr. Anita Wong, Helena Sustackova, Nancy Ricard and Alison Baker for their
valuable assistance in part or all the projects that constitute this thesis.
The research was conducted within the Arthritis & Autoimmunity Research Centre at the
University Health Network Research Institute, which provided necessary resources and support
to make this research possible. As well, I am indebted to the Canadian Institute of Health
Research (formerly Medical Research Council) for providing the financial means through a PhD
fellowship for the last 3 years of this research.
Finally, I am indebted to my wife Simone, who has shown tremendous patience and tolerance by
bearing with me through three thesis-based degrees, and to my parents who worked hard to
provide their children with endless opportunities.
This research was supported by an unrestricted grant to the Arthritis and Autoimmunity Research
Centre om Aventis Canada hc. The terms of the contract stipulated that the authors should
retain the right to absolute control of the methods, conclusions and means of publication of the
research.
Table of Contents
Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
I . 1 Introduction , 1
1.2 Evaluation of Disease and Response to Treatment , 1
1.3 Epidemiology of Rheumatoid Arthritis , 2
1.4 Current Clinical Practice , 3
1.5 Economic Impact of RA in Canada, 5
1.6 Efficacy of Leflunomide . 6
1.7 Objective and Overview ,8
2. How US and Canadian rheumatologists treat moderate or aggressive rheumatoid arthritis:
Asurvey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.1 Preface , 10
2.2 Introduction,lO
2.3 Materials and Methods , 12
2.4 Results,14
2.5 Discussion , 21
3. *Meta-analysis of treatment termination rates among RA patients receiving disease-
modifying anti-rheumatic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.1 Preface,24
3.2 Introduction ,24
3.3 Methods , 25
3.4 Results ,27
3.5 Discussion,34
4. A 1-year randomized controlled trial-based economic evaluation of Leflunomide and
Methotrexate in Canadian patients with rheumatoid arthritis. . . . . . . . . . . . . . . . . . . . . . 38
4.1 Preface ,38
4.2 Introduction ,38
4.3 Materials and Methods ,39
4.4 Results ,43
4.5 Discussion ,49
An estimation of the 5-year cost effectiveness of adding Leflunomide to a strategy of
conventional disease modifying antirheumatic drugs in patients with RA . . . . . . . . . . . . . 51
5.1 Preface, 51
5.2 Introduction , 5 1
5.3 Methods,52
5.4 Results , 5 9
5.5 Discussion , 62
6. Epilogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
List of Tables
Table 1.1: The American College of Rheumatology (ACR) Criteria for RA Diagnosis . . . . . . . 1
Table 1.2: Disease modifjmg anti-rheumatic drugs (DMARDs) used in the treatment of RA . . 4
Table 1.3: Efficacy of leflunomide in comparison to methotrexate and placebo in 482 patients
. . . . . with RA followed for 12 months. Results are presented on an intent-to-treat basis 7
. . . . . Table 2.1: Tabulation of results From surveys of rheurnatologists' treatment preferences 1 1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 2.2: Number of respondents by province or region 15
Table 2.3: Percentage of Canadian physicians choosing slow-acting antirheumatic agents for
patients with aggressive RA and moderate RA as depicted in the scenarios of the survey16
Table 2.4: Percentage of US physicians choosing slow-acting antirheumatic agents for patients
. . . . . with aggressive RA and moderate RA as depicted in the scenarios of the survey. 18
Table 3.1: Number of patients at risk and duration of treatment in study arms From observational
studies and randomized clinical trials reported in the literature providing information on
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . treatment withdrawals of patients. . 28
. . . . . . . . . . . . Table 3.2: Statistical comparisons of treatment withdrawal rates between drugs 33
Table 4.1: Demographic and disease characteristics of the study patients at baseline . . . . . . . . 44
. . . . . . . . . . . . . . . . . . . . . Table 4.2: Standard gamble and rating scale values for 480 patients 45
. . . . . . . . . . . . . . . Table 4.3: Number of patients incurring costs in the three cost categories. .45
Table 4.4: Health Care Resource Utilization Items Incurred by patients over the 52 week study
. . . . . . . . . . . . . . . . . . . . . period, unadjusted, and adjusted by total time of follow up . 46
Table 4.5: Descriptive Statistics of annualized total, direct, indirect, non-medical costs and
estimated yearly drug acquisition and monitoring costs by treatment group . . . . . . . . . .46
Table 4.6: Statistical Evaluation of total costs, direct costs and direct costs trimmed by the
highest 1 %. Results of statistical tests on untransformed and log-transformed costs.
.....................*............*..................................47
Table 4.7:Calculation of cost per ACR2O responder and quality-adjusted life-year (QALY)
gained. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 8
Table 5.1: Probabilities of treatment withdrawals, overall and due to toxicity, adverse events in
continuing patients and ACR2O response rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59
Table 5.2: Average. minimum and maximum costs per type and incidence weighted adverse
event . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Table 5.3: Costs of Monitoring DMARDs at baseline and during routine follow-up in a 6-month
period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Table 5.4: Expected costs, numbers of cycles patients respond to therapy, time spent on active
therapy and cost per responder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - 6 2
List of Figures
Figure 1.1: Intent-to-treat last observation carried fornard analysis of the percentage of patients
who met the American College of Rheumatology response criteria for improvement
. . . . . . . . of 20% or greater at month 1 and quarterly thereafter by treatment group. . 6
Figure 2.1: Scenarios and questions presented in both surveys. Items unique to the Canadian
......... survey are dark shaded; items unique to the US survey are light shaded. 13
Figure 2.2: Percentages of Canadian and US physicians choosing methotrexate (MTX),
parenteral gold (GST), hydroxychloroquine (HCQ), sulfasalazine (SSZ) or other
. . . . . . . . . . . . . . agents either alone or in combination (hatched parts of bargraph). 19
Figure 3.1: Survival curves representing the percentage of patients withdrawing From each agent
because of inelficacy, toxicity or other reasons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Figure 3.2: Survival curves representing the percentage of patients withdrawing from each agent
becauseofinefficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Figure 3.3: Survival curves representing the percentage of patients withdrawing from each agent
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . becausetoxicity 32
Figure 3.4: Percentage of patients withdrawing due to inefficacy, toxicity or other reasons,
separated by observational studies and randomized controlled trials. . . . . . . . . . . . . 34
Figure 5.1: Events occurring during a 6-month period as a consequence of taking a DMARD.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Figure 5.2: Sequence of DMARDs chosen for the strategies modelled in the analysis. One
strategy includes LEF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - 5 4
6 . .
V l l l
List of Abbreviations
ACR
CRE'
DMARD
ESR
GNP
GST
HAQ IL-1 RA
LEF
MHAQ
MTX
NSAID
QALY
PBO
RA
RCT
RS
SG
ssz sTNFR
VAS
American College of Rheumatology
C-reactive Protein
Disease-modifying anti-rheumatic drug
Erythrocyte Sedimentation Rate
Gross National Product
Gold Sodium Aurothiomalate
Health Assessment Questionnaire
Interleukin- 1 Receptor Antagonists
Leflunomide
Modified Health Assessment Questionnaire
Methotrexate
Nonsteroidal Anti-Inflammatory Drug
Quali ty-adjusted Li fe-year
Placebo
Rheumatoid Arthritis
Randomized Controlled Trial
Rating Scale
Standard Gamble
Sulfasalazine
Soluble Tumour Necrosis Factor Receptor
Visual Analogue Scale
CHAPTER 1
1. Rheumatoid Arthritis
1.1 Introduction
Rheumatoid arthritis (RA) is a chronic disease that causes pain, stiffness, swelling and loss of
h c t i o n in the joints and inflammation in other body organs. The diagnosis of RA is made on the
basis of clinical, radiological and biological observations. The American College of
Rheumatology (ACR) has defined criteria for the diagnosis of RA (Table 1.1) which include
prolonged morning stifhess in the joints, characteristic nodules under the skin, joint erosions
apparent on X-ray tests, and blood tests of an antibody known as rheumatoid factor (1). Patients
may be suspected of having RA before all the diagnostic criteria are satisfied. Other diseases may
mimic RA as well, particularly at the onset of symptoms. The course of the disease may be
limited to a few months of discomfort, or develop into a progressive destruction of the joints
resulting in joint deformities requiring reconstructive surgery.
Table 1.1: The American College of Rhewtology (ACR) Criteria for RA Diagnosis -- - A - - - - - - - - - - - - - . - - - - - - - -
A patient is considered to have F U if at least 4 of these 7 criteria are satisfied: -- --- - - - . - - . - - -- -- -. -. - .
Morning stiffness for at least one hour and present for at least six weeks
0 Swelling of three or more joints for at least six weeks
Swelling of wrist, metacarpophalangeal or pro.uima1 interphalangeal joints for six or more weeks
Symmetric joint swelling present for at least six weeks
Hand roentgenogram changes typical of RA that must include erosions or unequivocal bony decalcification
Rheumatoid nodules
Serum rheumatoid factor by any positive method in less than 5% of n o m l subjects -.
1.2 Evaluation of Disease and Response to Treatment
There is not one single clinical measure with which to evaluate and document the
disease and its progression. Several measures taken together provide a more complete assessment
of the disease and, combined in composite measures of response, are recommended to be used
for the evaluation of new drugs. Various composite measures of response have been proposed,
the most frequently used are the criteria proposed by the ACR (2). A response, according to these
criteria, requires a predefined percentage change from baseline in both swollen and tender joint
counts, and improvement in at least three of the following five measures: 1) patient global
assessment of disease on a visual analogue scale, 2) physician global assessment of disease on a
visual analogue scale, 3) a Functional status measure, 4) patient global assessment of pain
intensity and 5) a laboratory measure of inflammation (either erythrocyte sedimentation rate
[ESR] or C-reactive protein [CRP]). The predefined percentage change may vary between 20%
(ACR 20), 50% (ACR 50) or 70% (ACR 70) improvement, with 20% showing the best
discriminatory power compared to placebo (3).
A typically used measure of fbnctional status is the Functional Disability Index of the
Stanford Health Assessment Questionnaire (HAQ) (4) and its validated shortened version, the
modified HAQ (MHAQ) (5). The MHAQ comprises questions relating to eight functional
dimensions (dressing, arising, eating, walking, hygiene, reach, grip and other activities) and the
total score is the average value which can vary between 0 (best) and 3 (worst).
Radiological measures are not part of standard response criteria, partially because
longer follow-up is needed to document changes in these measures. The Sharp and Lanen scores
are both derived fiom measuring damage of joints shown on X-ray. The Sharp score is the sum of
two sub-scores which evaluate the severity of erosions and the degree of joint space narrowing on
a scale of 0-3 for a total of 62 joints. By contrast, the Larsen score only evaluates joint erosions,
and results in a mean joint score.
1.3 Epidemiology of Rheumatoid Arthritis
It is difficult to estimate exactly how many Canadians are affected by the disease due
to the lack of an established etiologic agent and unique clinical and laboratory features that can
be used to define RA. Nevertheless, estimates based on accepted criteria indicate that in a
population of Caucasian origin approximately 1% of the population suffer fiom RA at any given
time, the incidence being lower at approximately 0.007% (6). The prevalence increases with age
in both men and women with a peak of onset in mid-working-life. The gender-ratio varies with
age, but is consistently higher in women (-70%).
RA leads to a decline in functional status as the disease progresses and can result in
premature mortality. Although patients with RA tend to die from the same type of causes as the
general population, studies suggest that patients with RA die earlier and more of cardiovascular
conditions when compared to similarly aged persons of the same gender (7).
1.4 Current Clinical Practice
Alleviating pain and preservation of function remain major therapeutic goals. This is
achieved by a combination of interventions that include rest, exercise and emotional support, and
pharmacological treatment, the choice of which is individualized and based upon such factors as
joint function, degree of disease activity, patient age, gender, occupation, family responsibilities,
and response to previous therapy. Most rheumatologists now agree that the inflammatory process
should be aggressively stopped in its beginnings, but remission-inducing therapies are not
available. Patients with RA therefore need uninterrupted therapeutic monitoring and often have
to adapt early to the specific circumstances of their disease.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually required as symptomatic
treatment to reduce joint pain and swelling, and to improve function. Analgesic effects are
prompt in onset, but reduction of inflammatory signs may take up to 1-2 weeks. There are few
significant differences in efficacy among NSAIDs, although there are more important differences
in the incidence of adverse events. Their adverse events are gastrointestinal intolerance and renal
toxicity, which sometimes lead to hospitalizations and deaths (8). The drugs traditionally
employed in the treatment of rheumatoid arthritis (&4) have rather incidentally found their way
into therapeutic usage. Common to these drugs, such as methotrexate, gold, hydroxychloroquine,
azathioprine, d-penicillarnine, sulfasalazine and others, is a slow acting therapeutic onset, the
reason for which they are sometimes called slow-acting antirheumatic drugs (Table 1.2).
However, previous classifications employed the term disease modifjmg antirheumatic drug
(DMARD) to differentiate them f?om symptomatic treatments such as NSAIDs. Hereinafter we
will refer to slow-acting antirheumatic drugs as DMARDs. Sulfasalazine was the first drug
specifically designed to treat rheumatoid arthritis but has not been shown to be more efficacious
than its competitors. Methotrexate, alone or in combination with other agents, is now
unanimously regarded as the first treatment option for patients with RA (9). With time, the
proportion of patients responding to treatment with any DMARD continuously declines, new
therapies need to be implemented or combinations of therapies are instituted to prolong the
therapeutic action.
The majority of patients with active RA are on combination therapy for the
above-mentioned reasons. They receive an NSAID and at least one DMARD, with or without
low-dose oral steroids. If disease remission is observed, regular NSAID or systemic steroid
treatment may no longer be needed. DMARDs control RA but usually do not cure the disease.
Therefore, even though remission or optimal control may be achieved, DMARDs should be
continued at maintenance dosage (10).
Hydroxychloroquine 2-4 months 200mg BID
Sulfasalazine 1-2 months Ig BID-TLD
Me tho trexa te 1-2 months 7.5- 15mg / wk
Injectable gold salts 3-6 months 25-50mg IM every 2-4 wk.
Oral gold 4-6 months 3mg DIE-BID
Azathioprine 2-3 months 50- 150mg DIE
D-penicillamine 3-6 months 250-750mg DIE
Infrequent rash, diarrhea, rare retina1 toxicity
Rash, ifiequent myelosuppression, GI intolerance
GI symptoms, stomatitis, rash, alopecia, infrequent myelosuppression. hepatotoxicity, rare but serious puimonary toxicity
Rash, stomatitis, myelosuppression, thrombocytopenia, proteinuria (monitoring prior each dose)
Same but less ftequent, more diarrhea
Myelosuppression, infrequent hepatotosicity, early flu-like illness with fever, GI symptoms
Rash, stomtitis, dysgeusia, proteinuria, myelosuppression, infrequent but serious autoimmune disease
Steroids may be used systemically or by joint injection in patients with active RA.
Oral steroids are usually given in low daily doses (prednisone 5 to 7.5mg) to patients with
inflammatory flares or as bridge therapy until DMARDs begin being efficacious. However, new
evidence indicates that low doses of prednisone could be used for longer time periods to stop
progression of the disease (1 1). Reservations will remain because the devastating consequences
of corticosteroid therapy will never be fully avoided, even with prescription of very low doses
(12;13). Furthermore, steroids (oral and parented) used in combination with other agents play a
potential role in serious toxicity, particularly liver and pulmonary toxicity. Intra-articular
injections are indicated when there is an acute local inflammation in one or several joints.
Better knowledge of the disease process in the recent decade has renewed the hope for
therapies that may, one day, have a more significant impact. More efficacious and safer RA
therapies are needed to reduce the burden of illness. The so-called biologics are a specific group
of recently emerged therapies. These drugs directly interfere into pathologic processes that have
been confirmed to be characteristic for RA. Drugs such as interleukin-l receptor antagonists
(IL-1 RA) (14; 1 9 , soluble Tumour Necrosis Factor receptors (sTNFR) (1 6; 17) and anti-TNFa
antibodies (1 8), are some of the agents currently under investigation and showing promising
results. These agents, however, are very expensive and, according to results presented so far,
etanercept as well as IL- l RA are only marginally superior to rnethotrexate (1 9).
1.5 Economic Impact of RA in Canada
The total economic impact of musculoskeletal conditions including arthritis and
rheumatism has been studied through analyses of Canadian national and provincial health survey
databases. An earlier 1986 estimate of the total economic impact of musculoskeletal conditions
measured the total costs of all musculoskeletal conditions to be approximately 8.2 billion
Canadian dollars in 1986 (10.8 billion in 1994 Cdn. 6) , which at the time represented 2% of GIW
and 10% of all health care expenditures (20). A more recent study of the total healthcare costs of
arthritis and rheumatism puts this figure to approximately 5.9 billion dollars (1994 Cdn.S) (21).
However, only one study provides information on the direct and indirect costs of RA collected
prospectively during the years 1983 to 1994 in a Quebec and Saskatchewan population of RA
patients (22). In this study, the total annual costs incurred by RA patients amounted to 95,953
dollars (1983 - 1989) and 56,253 (1990 - 1994). The direct costs were responsible for 64%
(53,788) and 74% ($4,656) of the total for the periods From 1983 to 1989 and 1990 to 1994
respectively. Roughly multiplying the $6,253 with the 1% of the Canadian population estimated
to be affected by RA would put the total healthcare costs of RA patients in Canada to
approximately 1.75 billion dollan (1 994 Cdn.). Therefore, RA constitutes a substantial problem
in Canada in terms of burden of illness, requiring concerted efforts to find new treatments that
lead to economic savings and to evaluate the economic benefit of existing therapies.
1.6 Efficacy of Leflunomide
Leflunornide is an antirheumatic drug whose metabolite inhibits a critical enzyme in
the synthesis of pyrimidine and impedes T-cell proliferation which plays a pivotal role in the
pathogenesis of RA. It has demonstrated an anti-inflammatory effect in both in vivo and in vitro
animal models. Following a loading dose (100 mg tablet per day for 3 days), a daily dosing of 20
mg is recommended for treatment of adult patients with RA.
The efficacy and safety of leflunomide in the treatment of RA was demonstrated in
two phase-ID, randomized and placebo-controlled clinical studies, one conducted in North
America (23) and one in Europe (24). The North American trial was conducted in 482 patients
with RA in the US and Canada. Patients in this trial were assigned to 1 of 3 treatment groups in a
3:2:3 randomization: leflunomide treatment (20mg/d), placebo or methotrexate (7.5mgwk).
Patients who were not classified as responders by week 16 or who othenvise did not tolerate
therapy up to this time were allowed to switch to alternate therapy, with methotrexate and
placebo patients being allowed to switch to leflunomide, and leflunornide patients to
methotrexate. Efficacy evaluation was performed in an intent-to treat analysis that included all
0 Leflunornide (n = 182) Placebo (n = 1 18)
A Metnotrexale (n= 180) . - - - - - .
-. -
0 3 6 9 1.2 No. of Months
Figure 1.1: Intent-to-treat last observation carried forward analysis of the percentage ofpatients who met the American CotIege of Rheumatology response criteria for improvement of 20% or greater at month 1 and quarterly thereafter by treatment group. (23)
Results of the North American study demonstrate that leflunomide is statistically
significantly superior to placebo in all efficacy measures including ACR response rate and all
individual components of the ACR response criteria (tender joint count, swollen joint count,
patient and physician global assessments, pain intensity assessment, HAQ or MHAQ, and ESR
or CRP) as well as morning stiffhess and rheumatoid factor levels (selection of results presented
in Table 1.3). The treatment effect of leflunomide was evident by 1 month, stabilizing by 3-6
months, and continuing throughout the course of treatment. A similar effect was seen for
methotrexate (Figure 1.1).
Both methotrexate and leflunomide achieved statistically equivalent ACR20 response
rates, with 35% and 41% respectively being considered successful responders, i.e. sustaining
response until study end at 52 weeks (Figure 1.1). Patients on leflunomide fared better than
methotrexate patients from a functional perspective, with statistically significant differences
favoring leflunomide in the HAQ disability index and 2 of 8 subscores of the SF-36 (Table 1.3).
Leflunomide is also statistically significantly superior to placebo in retarding disease progression
as measured by x-ray analysis of both erosions and joint space narrowing but no consistent
differences were noted between leflunomide and methotrexate on assessments of joint damage.
Table 13: Efficacy of leflunomide in comparison to methotrexate and placebo in 482 patients with RA followed for 12 months. Results are presented on an intent-to-treat basis
---- - - - - - - - -- -
Leflunornide Placebo Methotrexate - -- -- --- -
ACR response status (n=182) (n=118) (n=182) ACR success (>= 20%) 3 1% (33% - 48%) 19%(11% - 26%) 35% (29% - 42%)
ACR >= 20% improvement 52% (45% - 60%)$ 26% (18% - 34%) 46% (38% - 53%)5
ACR >= 50% improvement 34% (27% - 4 1 %)$ 8?4, (3% - 12%) 23% ( 17% - 29%)$
ACR >= 70% improvement 20% (14% - 26%)$ 3%(1%-8%) go/, (5% - 14%)$
Total Sharp Score (n=131) (n=83) (n=L38) Baseline (sd) 23.1 1 (34.0) 25.37 (3 I .3) 22.76 (39.0)
Change at endpoint (sd) 0.53 (4.5) : 7 2.16 (4.0) 0.88 (3.3) t 9 HAQ Disability Index (n= 164) (n=99) (n=168) BaseIme 1.3 1.3 1.3
Change at end point -0.45 $ * 0 -0.26
SF-36 physical component (n=157) (a=101) (n=162) Baseline 3 0 23.9 29.7
Change at endpoint 7-6 9 11 I 4.6
9 Leflunomide or methotrexate vs. placebo, p s= .001; fl Leflunomide vs. methoncxate, p = -05; $ Leflunomide vs. placebo, p r = .OO1: t Methotrexate vs. placebo , p = 0.02; 11 Leflunomide vs. methotrexate, p s= -001; * Leflunomide vs. methotrexate, p s= .O 1
The European trial was conducted in 358 patients with RA. Patients in this trial were
assigned to 1 of 3 treatment groups in a 3:2:3 randomization: leflunomide treatment (20mg/d),
placebo or sulfasalazine (2gId). Efficacy evaluation was performed at 24 weeks in an intent-to
treat analysis that included all patients who received drug and had at least one follow-up visit.
Results of the European Study are only briefly summarized here, as findings from this study will
not be fUrther utilized. ACR 20% response status was achieved by 55% of patients in the
leflunomide group (p = 0.0001 vs. placebo), 21% in the placebo group, and 56% in the
sulfasalazine group (p = 0.0001 vs. placebo). Leflunomide is thus a DMARD that is similar in
efficacy to methotrexate and sulfasalazine. Its increased drug acquisition costs require a
comprehensive assessment of its pharmacoeconomic properties to appropriately inform Canadian
decision makers about the value of this new DMARD.
1.7 Objective and Overview
?'he objective of the present thesis is to provide a comprehensive analysis of the
pharmacoeconomic characteristics of leflunomide versus potential comparators in the treatment
of RA for the purposes of reimbursement applications in Canadian jurisdictions.
This phmacoeconomic evaluation of leflunomide consists of five components. The
first component (Chapter 2) is a situational assessment, i.e. a study of the prescribing behaviour
of rheumatologists in Canada and the USA. The findings of this assessment assist in the planning
of the pharmacoeconomic evaluation by describing the type of choices physicians currently make
when treating patients with rheumatoid arthritis. The study allows to quantify the relative
importance of available S W s in the treatment of RA, when they are used, how often and in
what combinations.
The second component (Chapter 3) is a review of the clinical effectiveness of the
potential comparators of leflunomide: methotrexate, gold, hydroxychloroquine and sulfasalazine.
For economic purposes it is important to know how these drugs work in real life and also how
patients fare on these drugs over longer time periods. The review includes observational studies
and randomized clinical trials and has a special emphasis on summarizing how many patients are
able to maintain therapy over time, and their reasons for withdrawal fiom therapy. The findings
from all studies are presented as a combined "survival on therapy" curve for each comparator.
The summary withdrawal rates for specific time periods can thus be used in modelling
antirheumatic therapy over a longer time period in a simulation kamework.
The third component (Chapter 4) is a direct comparison of leflunomide to the "best"
alternative methotrexate and placebo. The data used for the direct comparison are taken from the
North-American randomized controlled trial comparing leflunomide to methotrexate and placebo
in 482 patients. Pharmacoeconomic data and outcomes relevant for pharmacoeconomic
evaluations were collected during the trial. All economic items collected as part of the trial were
costed in 1999 Canadian dollars to adapt the evaluation for a Canadian societal perspective (all
costs) and the perspective of the Ontario Health [nsurance Plan (direct medical costs). Cost-
effectiveness and cost-utility ratios are reported for leflunomide and methotrexate in comparison
to placebo and to each other.
The fourth component (Chapter 5) is an indirect evaluation of leflunomide within a
simulation framework and is modelled in a decision analysis tree with two treatment arms. One
arm consists of a sequence of DMARDs that includes leflunomide whereas the other arm
incorporates a sequence of DMARDs without leflunornide. The sequence of DMARDs
represents findings fiom the survey of rheumatologists (Chapter 2). Withdrawal rates and the
percentages of patients switching to new therapy are derived fiom the clinical review of the
effectiveness of DMARDs (Chapter 3). Costs for the management of adverse events are provided
by the results of a detailed adverse event questionnaire answered by five rheurnatologists.
Efficacy data are derived from meta-analyses of the literature. Extensive sensitivity analyses was
conducted over possible ranges for all variables used in the model. Results are reported as cost
per additional ACWO responder gained and per quality-adjusted life-year (QALY) gained.
CHAPTER 2
How US and Canadian rheumatologists treat moderate or aggressive
rheumatoid arthritis: A survey
2.1 Preface
The survey described in this chapter was published in 1998 (9). The purpose of this
survey was to identify, which primary DMARDs rheurnatologists would choose in the treatment
of patients with mild, moderate and severe RA and what the alternative would be in case of
efficacy failure. It was planned to use the findings to support the order of treatments in the
strategies for the model-based economic comparison of leflunomide.
2.2 Introduction
Current guidelines recommend treating most patients with active rheumatoid arthritis
(RA) aggressively and early, possibly before joint destruction begins (25;26). As a result,
slow-acting antirheumatic drugs once reserved for the later stages of disease are now being
prescribed in the early years. However, although many patients benefit from the use of these
often toxic agents, others do not. The selection of therapeutic strategies has therefore become a
challenge, particularly as patients with milder manifestations of RA generally require a different
approach to that taken in individuals with aggressive disease.
Hydroxychloroquine, gold sodium aurothiomalate (gold), methotrexate, and
sulfasalazine are the most frequently used slow-acting antirheumatic agents. Preferences between
them have shifted slowly over recent years, with s w e y s showing an increasing trend towards
methotrexate administration effectively replacing gold as the treatment of first choice. As
recently as 1985, gold was the initial drug of choice for patients with RA recruited in
rheumatology practices in Alberta (27). Methotrexate was seldom prescribed, either as the drug
of first choice or as consecutive treatment. By 1992, a survey mailed to Canadian physicians
revealed that gold and methotrexate were equally preferable in moderate RA, but that
methotrexate was preferable to gold in aggressive RA (Table 2.1) (28). An identical survey in
Australia showed that 44% of physicians favoured sulfasalazine for the treatment of moderate
RA, and 6 1% preferred methotrexate for severely aggressive disease (29).
Table 2.1: Tabulation of results tiom surveys of rheumatologists' treatment preferences
Canada - 1985 (27) Canada 1992 (28) Australia 1992 (29)
- Iritial Rx. Mod. RA Aggr. RA Mod. RA Aggr-RA
Methotrexate 0.0% 35.1% 44.5% 29.0% 6 1 .O%
I.M. Gold 39.6% 36.4% 3 1.6% 15.0% 2 1 .O%
Sulfasalazine 14.6% 5.8% 2.6% 44.0% 5 .O%
Aurano fin 25 -0% 0.0% 0.0% 1 .O% 1 .O%
Others 2 .O% 6.4% 5.2% t -0% 1 .O%
Rx. : Prescription; Mod.: moderate; Aggr.: aggressive
Many physicians in Canada or the US may consider methotrexate to be the treatment
of choice for both moderate and aggressive disease, although individual factors may affect the
strength of preference (30). Several observational studies support the superiority of methotrexate,
reporting that approximately 36% of patients continue drug treatment over a period of five years
(3 1-34). Unfortunately, however, all presently available antirheumatic agents, including
methotrexate, start to fail from day 1 and will eventually need to be discontinued, whether due to
immediate toxicity in the early phases or to lack of efficacy or some other reason later on. That
fact, and the paucity of alternatives, has led to considerable attention being paid to the
investigation of novel combination treatments and the development of new slow-acting
antirheumatic drugs.
Many of the latter are now under investigation in phase II and III trials and will
require economic assessment for formulary approval. Current guidelines for the economic
evaluation of health care interventions require new approaches to be compared to current
practice. In order to appropriately position a new agent it is therefore necessary to ascertain
existing treatment preferences among rheumatologists. The present paper reports two separate
s w e y s in which the views of Canadian and US rheumatologists, respectively, were elicited on
the treatment of moderate RA, aggressive RA, and aggressive RA that fails to improve in
response to high doses of methotrexate. As well as being necessary for the purposes of economic
evaluation, the infomation gathered may also be of interest to clinicians and policy makers.
2.3 Materials and Methods
The Canadian survey was initiated in September 1996. The Canadian Rheumatology
Association supplied the names of all 295 members; 32 who were not living in Canada or who
were known not to practice adult rheumatology were excluded, leaving 263 to whom the survey
was sent by fax (n=191) or mail (n=72).
The US survey was initiated in November 1996, at which time 3594 physicians were
registered with the American College of Rheumatology (ACR) and indicated that patient care
was part of their daily routine. A 10% random sample, weighted by region, was obtained from
the ACR mailing list. It consisted of 351 physicians: 102 from the Southeastern region, 1 16 From
the Central region, 58 From the Northern region, and 75 From the Western region. Thirty-one
physicians identified as paediatric rheumatologists or out of practice, or who had moved to an
unknown location, were excluded, giving a total of 320 who were sweyed either by fau (n=268)
or by mail (n=52) during April and May 1 997.
In both studies, the questionnaire consisted of a one-page document featuring an introductory
statement, three case scenarios and some questions (Figure 2.1).
SCLVARIO 1: [Iist second line agent(s) you would prescribe, either alone or in combination] Aggressive RA, ? 38 y 1st choice: DMARD-naive 26 activeIy inflamed joints 6 erosions 2nd choice:
ESR & RF markedly elevated
SCENARIO t : [list second line agent(s) you would prescribe, either alone or in combination] Moderately progressive RA, ? 32 y 1st Choice: DMARD-naive, NSALDs not helpful 6 act~vely inflamed joints -- - a - - .. - - - -- - - - -- -
no erosions 2nd Choice:
ESR & RF moderately elevated
-- - -- - . - . - - -. - --
What percentage of your population of RA patients similar to the ? Scenario 1 Scenario t
SCESARIO 0 3: Patient from scenario 1 1st Choice: initially bcner on MTX 25 rnglwcck now loss of efficacy - - - - - - - - - -- -- - - -- - - . . - --
a 22 actively inflamed joints 2nd Choice:
7 erosions
What percentage of your RA patients are in managed care?
What percentage have their drug prescriptions restricted by formularies?
What percentage require a refernl from their primary care physician to see you?
Was your choice of agents in this survey influenced by formulary restrictions?
LLLi "/. LLL1"/0 L U I 1% CI yes 0 no
Figure 2.1: Scenarios and questions presented in both surveys. Items unique to the Canadian survey are dark shaded; items unique to the US survey are light shaded.
The fint scenario described a patient with aggressive RA, 26 actively inflamed joints
and three erosions. The patient in the second scenario had moderately progressive RA, six
actively inflamed joints and no erosions. Finally, the third example described the same patient as
in scenario 1, but with an increase in inflamed joints and erosions despite treatment with
methotrexate 25 mg. Respondents were asked for their fint and second choice of second-line
agent in each case. They were invited to be f?ee in their therapeutic choices and to consider both
single and combination therapy. Respondents were also asked about the percentages of their
patients with moderate and aggressive RA who were receiving systemic corticosteroids.
The Canadian survey differed slightly from the US one in that it omitted a specific
invitation to consider combinatior? therapy in the three patient scenarios. Instead, Canadian
rheurnatologists were asked to indicate which therapy they would use if they had been asked to
combine agents, rather than to select a single second-iine treatment. In addition, three questions
addressed exclusively to US rheumatologists inquired about the proportions of patients who were
in managed care, who had their drug prescriptions restricted by formularies, and who had
required referral from a primary care physician. Finally, US physicians were asked whether their
choice of agents as reported in the survey was influenced by formulary restrictions.
Repeat faxes or mailings of both surveys were sent twice, with Cweek intervals. The
sample size was selected in order to obtain at least 200 usable responses From each country and
to permit estimation of percentages with a maximum error of 7%. Responses to all questions in
the survey were analysed using descriptive statistics, statistical tests were not performed as there
was no plan to test specific hypotheses.
2.4 Results
Choices of therapies
The Canadian survey was returned by 23 1 physicians (response rate, 87.8%), 17 who indicated
they were not practising adult rheumatology were excluded, leaving a total of214 eligible
respondents. Of 230 US physicians who returned the survey (response rate, 7 1.7%), 16 indicated
they were not practising adult rheumatology, again leaving 2 14 eligible respondents. The
majority of Canadians worked in Ontario or Quebec and most responding US rheurnatologists
had practices in the Central or southeastern regions (Table 2.2).
Table 2.2: Number of respondents by province or region * - Canada USA
Province Frequency Percent Region Frequency Percent - - - - - -- - - --
Ontario 96 44.9 Southeastern 5 8 27. I
Quebec 48 22.4 Central 7 8 36.4
British Columbia 22 10.3 Northern 35 16.4 Alberta 19 8.9 Western 43 20.1
Manitoba 7 3.3 - Saskatchewan 6 2.8
New Brunswick 6 2.8 Nova Scotia 5 2.3
Newfoundland 4 1.9 - Total: 213 99.5* 2 14 100.0 - - -. - - - - - -. - - - - - - - -. - - -. - . - . - - - - - . - - - -- . - - . - . - - . . - . - - -
* 1 Canadian respondent answered anonymously
Several major findings emerged From the Canadian survey (Table 2.3, following page):
Scenario 1 : Methotrexate was the drug of first choice of 68.7% of Canadian rheumatologists for
the treatment of patients with aggressive RA. Intramuscular gold was the first choice of 14.5%
and the second choice of 50%.
Scenario 1: More than 90% chose a single agent for the treatment of moderate RA: 47.2% opted
for hydroxychloroquine, 22.0% for methotrexate, 1 1.2% for gold, and 7.9% for sulfasalazine.
Sulfasalazine was the second choice of 27.6% of respondents.
Scenario 3: Over 50% of Canadian rheumatologists would continue their therapy with a single
agent, predominantly gold (34.6%). The preferred combination was methotrexate plus
hydroxychloroquine (40% of all combinations chosen).
TabIe 23: Percentage of Canadian physicians choosing slow-acting antirheumatic agents for patients with
aggressive RA and moderate RA as depicted in the scenarios of the survey. ---- --
Single Agents: Methotrexate I.M. Gold S ul fasalazine Hydroxychloroquine Azathioprine D-Penicillarnine
Cyc lo spo~e Chloroquine Autano fin Methotrexate I.M.
Combination: Methotrexate & Hydroxychloroquine Methotrexate & I.M. Gold Methotrexate & SuIfasalazine Methoaexate & Cyclosporine Methotrexate 8r Chloroquine Methotrexate & Azathioprine Methotrexate & D-Penicillarnine Hydroxychloroquine & I.M. Gold Hydroxychloroquine & Sulfasalazine Hydroxychloroquine & Azathioprine I.M. Gold & Sulfasafazine I.M. Gold & Azathioprine I.M. Gold & Chloroquine Methotrexate I.M. & Sulfasatazine
Methotrexate I.M. & Chloroquine Triple Therapy:
Methotrexate/Hydro;uyc~oroquineA.M. Gold Metho~exate/Hydroxychloroquine/Sulfasalazine
Methotrexate/Hydroxychloroquine/Azathioprine
Methotrexate I.M./HydroxychloroquineA.M. Gold 1.M. ~o~d/Hydroxych~oroquine/Azathiop~e
Aggressive RA Moderate RA 1st 2nd 1st 2nd
Choice Choice Choice Choice
--
No answer provided: 0.0
MTX ineff. 1st 2nd
Choic Choic
. --
- numbers may not add to 100% due to rounding)
The responses of the US physicians were somewhat different (Table 2.4 - following
page):
Scenario 1 : 78.5% of physicians reported that methotrexate was their drug of first choice for the
treatment of patients with aggressive RA as depicted. Intramuscular gold predominated as a
second choice (24.8%), followed by sulfasalazine (1 4.O%), azathioprine (1 2.6%) and
hydroxychloroquine (8.4%).
Scenario 2: 90% of respondents reported preferring single agents for the treatment of moderate
RA as depicted. Hydroxychloroquine (39.3%) and methotrexate (38.8%) were equally widely
used. Sulfasalazine was given as a second choice by 25.7%.
Scenario 3: Only 37% of US rheumatologists chose single therapy for patients with aggressive
RA failing methotrexate, and no clearly preferred agent emerged. Although the majority of
respondents indicated that they would use combination (38.3%) or triple (23.8%) therapy, most
combinations included methotrexate plus either sulfasalazine or hydroxychloroquine. The same
agents also dominated triple therapy, with 2 1.5% of respondents nominating methotrexate plus
hydroxychloroquine and sulfasalazine.
Table 2.4: Percentage of US physicians choosing slow-acting antirheumatic agents for patients with aggressive
RA and moderate RA as depicted in the scenarios of the survey.*. --
Aggressive RA Moderate RA MTX ineff. 1 s t 2nd 1 s t 2nd 1st 2nd
Choice Choice Choice Choice Choice Choice Single Agents:
Methotrexate 1.M. Gold Sul fasalazine Hydroxychloroquine Aza thioprine D-Penicillamine Cyclosporine Aurano fin Minocyctine Cyclophosphamide
Combination: Methotrexate & Hydroxychloroquine Methotrexate & I M . Gold Methotrexate & Sulfasalazine Methotrexate & Cyclosporine Methotrexate & Auranofin Methotrexate & Aza th iop~e Methotrexate & Minocycline Methotrexate & Cyclophosphamide Hydroxychloroquine & I.M. Gold HydroxychIoroquine & Sulfasalazine Hydroxychloroquine & Azathioprine Hydroxychloroquine & Minocycline 1.M. Gold & Azathioprine Azathloprine & Sulfasalazine Cyclosporine & D-Penicillamine
Triple Therapy: Methotrexiitem ydroxyc h1oroquineA.M. Gold Methotrexate/HydroxychloroquineiSulfasalazine Methotrexate/Hydroxychloroquine/Azathioprine Methotrexate /HydroxychIoroquine~inocycIine Methotrexate/Hydroxychloroquine/CycIosporine Methonexate/l.M. GoId/Azathioprine Meth0trexateA.M. GoId/Sulfasalrtzine
No answer provided: * numbers may not add to 100% due to rounding
Looking only at the first
choices of single or combination
therapy (Figure 2.2 ) both Canadian
and US rheumatoIogists reported
relying primarily on methotrexate
when treating patients with
aggressive RA and
hydroxychloroquine or methotrexate
in patients with moderate RA.
Canadian rheumatologists also
favoured gold in aggressive or
moderate RA, thereby slightly
reducing the strength of their
preference for methotrexate. In
particular, Canadians said they liked
to prescribe gold to patients who fail
adequate doses of methotrexate,
whereas no leader emerged from the
choices of US rheumatologists. Most
combinations chosen by either group
of rheumatoIogists included
methotrexate plus
hydroxychloroquine with or without
sulfasalazine; 2 1.5% of US
rheumatologists preferred a triple
combination of all three, compared
to only 3.3% of the Canadian
sample.
MTX GST HCQ SSZ Chhcn 5 ( m GST HCQ 552 Olhcn
C3n3& US
10006 Scenario 2 - Moderate RA
MTX GST HCQ SSZ Wrn 5tTS GST HCQ SSZ Othm Cam& US
Scenario 3 - Aggressive RA failing 25mg MTX
W R G!X HCQ SSZ Ochcn M I 3 GSf HCQ SSZ Men Canada US
Figure 2.2: Percentages of Canadian and US physicians choosing methotrexate (MTX), parented gold (GST), hydroxychloroquine (HCQ), sulfasalazine (SSZ) or other agents either done or in combination (hatched parts of bargraph).
US rheumatologists indicated that, on average, 66.7% of patients with RA similar to that
described in scenario 1 would receive steroids (SD: 30.5%; median: 75%; inter-quartile range:
50% - 90%; missing: 11). In comparison, the Canadian figure was 44.5% (SD: 32.2%; median:
40%; inter-quartile range: 1575%; missing: 13). For patients with moderate RA similar to
scenario 2, US rheumatologists estimated that 38.9% would receive systemic steroids (SD:
29.1 %; median: 30%; inter-quartile range: 1 O-SO%; missing: 13), compared to 16.1 % in the
Canadian survey (SD: 20.3%; median: 10%; inter-quartile range: 045%; missing: 16).
Answers to the additional questions in the US survey showed that, on average, 36.9% of
patients were estimated to be in managed care (SD: 30.4%; median: 30%; interquartile range:
1040%; missing: 16), 35.1% were estimated to have formulary restrictions (SD: 33.2%; median:
25%; interquartile range: 10-60%; missing: 19) and 43.8% were estimated to require referral for
rheumatologic care (SD: 33.1 %; median: 40%; interquartile range: 1 WO%; missing: 17).
2.5 Discussion
The results of the present surveys confirm methotrexate as the primary choice in the
treatment of aggressive RA. Most Canadian and US rheumatologists preferred it, although some
Canadians also favoured gold. Most preferred combinations were also based on methotrexate,
usually plus hydroxychloroquine with or without sulfasalazine. The triple combination of
rnethotrexate, hydroxychloroquine and sulfasalazine was primarily favoured by US
rheumatologists treating patients who fail methotrexate 25 mg. Both sets of findings also
demonstrate that there is no clear single agent alternative to methotrexate: respondents were
divided between competing single agents or tended to use methotrexate-containing combination
therapy.
Comparison of the Canadian results to reports in the literature indicates that methotrexate
is increasingly preferred by rheumatologists for the treatment of moderate or aggressive RA.
However, when compared to the findings of the survey by Collins and associates (28), these
results suggest little change in the preference among Canadian rheumatologists to reserve
combination therapy for later in the treatment process, even in patients with aggressive RA.
Historical comparisons were not possible with the US information because of a lack of published
surveys of the prescription choices of American rheurnatologists.
Because physicians were asked to indicate two therapeutic choices for patients with either
moderate or aggressive RA, additional conclusions became evident - not least that there is an
obvious scarcity of treatment options. US rheumatologists reported using methotrexate to treat
patients with aggressive disease. Canadians said they would prescribe either rnethotrexate or
gold. However, there is no agreement about alternatives to methotrexate. In patients with
aggressive RA who fail methotrexate, agents such as cyclosporine and azathioprine were
favoured by only a few respondents, indicating that expectations of their therapeutic potential are
limited. For most Canadian and US rheurnatologists, the next step after methotrexate appears to
be to add an additional drug such as hydroxychloroquine or sulfasalazine. The strong preference
for triple therapy among US rheumatologists (2 1.5%) was probably influenced by the
encouraging results published by O'Dell and associates (35).
The study also showed wide variation between rheumatologists in their estimates of how
many of their patients with aggressive or moderate RA would receive steroids. Compared to US
rheurnatologists, Canadian rheumatolo$sts estimated that fewer of their patients with aggressive
or moderate RA would receive steroids, but these differences were smaller than the variations
between individual rheumatologists.
The questions in the present study, unlike those generally used in surveys, were designed
to elicit open answers that needed to be spelled out instead of being checked off fiom a list. This
reduced the likelihood of bias due to respondents being cued towards particular answers, and
increased the probability that the type of treatment selected would reflect that chosen in a real-life
situation. It is well known that answers of physicians to written case simulations do not fully
coincide with the reasoning and actions they adopt in real life (36;37). The few studies using
written case scenarios in patients with rheumatoid arthritis (38;39) and osteoarthritis (40),
although not evaluating therapeutic strategies, have demonstrated acceptable agreement. The
validity of the US survey is supported by data fiom an inception cohort of 750 US RA patients
with disease of less than 1 year. Wolfe et al. (41) showed that alone or in combination
methotrexate represented 47% of the prescriptions (46.2% in the US survey for patients with
moderate RA), hydroxychloroquine 56% (48.6% in the US survey) and sulfasalazine 10%
( 1 1.2% in the US survey).
Our surveys achieved response rates that were high - 87.8% response rate in a census of
Canadian rheurnatologists and 71.7% in a scientific random sample of US rheumatologists - and
compare favourably with the 44% response rate obtained by Prashker and Meenan on a random
sample of 300 board-certified US rheumatologists (42), and the 29% response rate achieved by
Moreland et al. in a survey of 4032 US rheurnatologists (43) . An equally high response rate of
68% was achieved by O'Dell and associates in a survey of a random sample i.f 200 US
rheumatologists (44). A recent literature review revealed that only 20% of 68 published mail
surveys using physicians as respondents achieved response rates exceeding 70% (45).
Both surveys were conducted within the 9-month period between September 1996 and
June 1997. The Canadian study differed slightly in structure kom the US one. Canadian
physicians were asked to indicate the type of second-line agents they would prescribe to the
patients in the three scenarios, but no reference was made to the prescription of combination
therapy. Nevertheless, 6% to 30% reported that they would administer combination therapy,
depending on the scenario. These percentages are similar to those derived from Canadian
physicians' responses to a previous survey (28). Only at the end of the questionnaire were
rheumatologists specifically asked about combination therapy. Many referred to their answers to
scenario I , for which they had already chosen combination treatment. In the US s w e y , the
combination question was eliminated as redundant. Nonetheless, rheumatologists were
specifically asked to record their treatment choices, whether single agent or combination therapy.
In conclusion, the responses of Canadian and US rheumatologists to the present survey
illustrate the paucity of treatment options for patients with RA and confirm that there is no clear
preference of choice between the alternatives to rnethotrexate. New agents are therefore needed
to increase the therapeutic options for aggressive disease. There is also a need for more
information about patient preferences.
CHAPTER 3
Meta-analysis of treatment termination rates among RA patients receiving disease-
modifying anti-rheumatic drugs
3.1 Preface
The meta-analysis presented in this chapter was conducted to summarize experience from
observational studies of the potential comparators for leflunomide. The study was published in
2000 (46). Observational studies report on the effectiveness of DMARDs under routine care
conditions, thus providing more realistic estimates of withdrawal rates than those reported in
randomized controlled trials. These withdrawal rates are essential to build a realistic decision
analysis model for the comparison of DMARDs.
3.2 Introduction
Given the chronic nature of rheumatoid arthritis (RA), it is important to obtain long-term
evidence of the success of therapy with disease modifjmg anti-rheumatic drugs (DMARDs). This
may be provided by the findings of observational studies or randomized controlled trials (RCTs).
Compared with observational studies, RCTs generate more detailed and standardized data
concerning therapeutic response (47), but are generally conducted over time periods that rarely
exceed one year. The therapeutic potential of the study drugs must therefore often be extrapolated
beyond the period of investigation. Furthemore, patient populations in RCTs are highly selected,
and monitoring is intense. Some investigators have argued that observational studies, which
typically document treatment failure as the proportion of patients who withdraw from therapy
due to lack of efficacy, treatment toxicity, or reasons unrelated to therapy, provide more realistic
estimates of how patients respond to therapy (48-53).
Observational studies of drug therapy often use survival analysis to assess treatment
withdrawal rates. For outcomes such as time to treatment failure, the product limit method is a
fundamental part of this approach, allowing for the estimation of withdrawal rates even when
patients enter a study at different times and are therefore observed for varying periods (54).
However, because estimates of s w i v d become unstable at follow-up periods reached by only a
few patients, such analyses are usually stopped when too few subjects remain on treatment for
reasonable inferences to be drawn. It is therefore advantageous to combine data from several
observational studies in order to increase sample size, particularly at the tail end of the s w i v a l
curve.
A number of observational studies of DMARD therapy in RA have now been published,
creating an important opportunity to summarize their findings in combination with those of
RCTs. Agents considered in the present meta-analysis are parenteral gold (GST),
hydroxychloroquine (HCQ), methotrexate (MTX), and sulfasalazine (SSZ). The primary
objective is to determine overall treatment withdrawal rates, and to look at how they break down
according to lack of efficacy and toxicity. A secondary objective is to compare treatment
withdrawal rates fiom observational studies with those fiom RCTs.
3.3 Methods
Selection of references
The Medline database fiom 1966 to August 1997 was searched by combining the
keyword 'rheumatoid arthritis' with textwords and keywords for GST, SSZ, MTX, and HCQ,
including common synonyms. Letters, editorials and comments were excluded, as were articles
written in languages other than English, French, German or Spanish. The resulting references
were reduced to a set of' 1387 by excluding all those that did not address efficacy or toxicity. A
further 1035 references derived fkom a broader search conducted by the RA subgroup of the
Cochrane Musculoskeletal Review Group were added, to give a total of 2422. The Cochrane set
of references was retrieved from the Excerpta Medica and Medline electronic databases, using
keywords and textwords for 1) randomized clinical trial, 2) clinical trial, 3) comparative study, 4)
evaluation study, 5) follow-up study, 6 ) prospective study, combined with all references indexed
under 7) arthritis, rheumatoid.
Screening and assessment of references
Based on information in titles and abstracts, the 2422 references resulting from both
searches were classified according to the four agents of interest and the design of the study.
Eligible designs were RCTs, and observational studies including case series, case control and
cohorts, and case reports. Paper copies were obtained of all clearly relevant papers, plus those
with uninformative titles and/or abstracts. A total of 445 investigations were found that provided
original information. These were then assessed by two authors according to the following
criteria: (1) Does the study document the experience of patients from the day therapy was
initiated? (2) Does the study provide data for one of the four therapies of interest? (3) Does the
study provide information on treatment withdrawal rates? (4) Do all included patients have a
documented diagnosis of RA? Investigations meeting all four criteria were retained as the set of
studies providing withdrawal information. Of those, only those studies disclosing the actual
number of patients withdrawing fiom the study drug were used for the meta-analysis. Authors of
four large excluded studies were approached with a request to provide additional information but
were either unable to provide the data or declined to collaborate.
All observational studies were further appraised according to the following criteria:
(1) Was reporting of termination rates a primary or secondary objective?
(2) Was outcome ascertainment prospective or retrospective?
(3) Was clinical response specifically defined?
(4) With regard to follow-up, were:
a) all patients followed over a fixed interval independent of treatment status
(no censoring); or were
b) patients followed over intervals varying from a few months to several
years depending on study entry and treatment termination (with
censoring)?
( 5 ) Were lifetable or Kaplan Meier swiva l analysis techniques applied?
(6) Did the study provide information about the numbers ofpatients at risk, censored
and terminating treatment at each interval?
Data extraction
Numbers of patients reported to have withdrawn from treatment with each DMARD were
abstracted independently by two of the authors, whose findings were checked for agreement and
corrected where necessary. The dataset was then constructed. Take for example the treatment arm
of a study of 6 months' duration in which five of 20 patients had withdrawn fiom treatment by 6
months. Those five patients were coded as one observation and classified as treatment failures at
the midpoint of the interval (month 3), whereas the 15 patients who continued treatment were
coded as a second observation and classified as censored at study end (month 6). Each
observation was weighted by the number of patients, such that the first counted as contributing
five patients, and the second 15. Observations from a few studies conducted over long time
periods without providing detailed interval information were modified by apportioning
withdrawals to 6-month intervals assuming a constant failure rate.
Analvsis
Survival analysis and statistical comparisons were then performed. Actuarial survival
curves stratified by DMARD were plotted for all studies entered into the database using four
different definitions of failure: I) withdrawal due to lack of efficacy, toxicity or other reason; 2)
withdrawal due to lack of efftcacy or toxicity; 3) withdrawal due to lack of efficacy; and 4)
withdrawal due to toxicity. For the purposes of analyses 2, 3 and 4, withdrawals not defined as
treatment failure were coded as treatment continuations up to the midpoint of the interval.
Statistical comparisons were undertaken in two steps: first, the cumulative survival
probabilities for treatment with each of the four DMARDs were compared pairwise using log-
rank and Wilcoxon statistics; second, withdrawal rates for each agent were compared using Cox's
proportional hazards model (proc PHREG in SAS) with adjustment for study type and year of
publication. As many treatment failures occurred at the same timepo int, the exact algorithm for
tied events was used. HCQ treatment was excluded From the comparisons due to the limited
amount of data available and because it is generally prescribed in mild RA, although survival
c w e s are presented. Three statistical comparisons were performed within each of the four
groups: 1) MTX vs GST; 2) MTX vs SSZ; and 3) SSZ vs GST. Further subgroup analyses
compared the effect of study type on treatment withdrawal rates for MTX, SSZ and GST
separately. A time limit of 24 months was set and the same statistical approaches used.
3.4 Results
Of the initial 445 studies, 1 59 satisfied all four screening criteria; 7 1 were RCTs and 88
observational studies. Reasons for the 286 exclusions were as follows: 132 (46.2%) did not
evaluate an inception cohort, 220 (76.9%) did not provide information on treatment withdrawal,
32 (1 1.2%) studied diagnoses other than RA, and 45 (1 5.7%) evaluated drugs other than MTX,
GST, HCQ or SSZ (some studies were excluded for more than one reason). Included in the
present meta-analysis were 1 10 of the 159 studies which provided detailed withdrawal
information.
Further assessment of the observational studies for methodological characteristics showed
that provision of information on treatment termination rates was a primary objective in 42 (48%),
and outcome ascertainment was prospective in 62 (70%); treatment success or failure was
defined by explicit criteria in 2 1 (24%). Follow-up over a fixed interval independent of treatment
status was documented in 38 (43%), and of the remaining 50 observational studies that reported a
variable follow-up, 26 presented the data using Kaplan Meier survival analysis techniques. Raw
numbers of patients at risk, censored, and terminating treatment at within-study intervals were
reported in only 13, four and seven papers, respectively.
The 1 10 studies included in the meta-analysis contributed 142 arms, the majority of them
reporting results with GST or MTX administration. Only three observational study arms provided
withdrawal information for HCQ (Table 3.1). The maximum observation time on HCQ treatment
was only 24 months, whereas data for GST, MTX and SSZ were reported for as long as 72
months.
Table 3.1: Number of patients at risk and duration of treatment in study arms From observational studies and
randomized clinical trials reported in the literature providing information - . -- - - - on - treatment withdrawals of patients. - -- -
Gold Hydrorychloroquine Methotrexate Sulfasalazine
Length OBS RCT OBS RCT OBS RCT OBS RCT (months) N Pat. N Pat. N Pat. N Pat. N Pat. N Pat. N Pat. N Pat. -- PA a - - - - -- - - - - - . - - - .
[O* 61 3 647 14 387 2 5 6 9 4 194 2 523 14 404 2 181 9 469
(6, 121 9 366 I8 689 - 8 327 7 191 1 1 616 2 103 5 163
(12,243 5 349 2 149 1 2 3 1 18 3 198 2 88 2 180 - (24,361 2 127 - - 3 171 1 185 (36,481 1 49 - - 2 174 - (48,601 2 392 - - 2 247 - 1 222 1 100
(60,721 - 1 78 - Total: 22 1930 34 1225 3 592 13 539 20 1582 28 1293 7 686 15 732
RCT = randomized controlled trial, OBS = Observational Study, N = Number of treatment arms, Pat. = Number of
patients in treatment arms
Sunrivalsn-therapy curves including all types of withdrawals indicate that 36%, 23% and
22% of the patients continued MTX, GST and SSZ, respectively, for 60 months (Figure 3.1) with
median swiva l times of 4 1 months, 24 months and 18 months respectively. The combined
29
number of patients at risk at baseline for each of the three drugs was 2875 (MTX), 3155 (GST)
and 14 1 8 (SSZ). When considering only withdrawals for lack of efficacy or toxicity (excluding
administrative reasons or relocation), the percentage of patients estimated to continue MTX as
compared with GST or SSZ increased to 5 1%, indicating that a considerable proportion failed to
continue MTX for reasons other than lack of efficacy or toxicity (data now shown as figure).
Data on withdrawals for lack of efficacy only (Figure 3.2) indicate that 75%, 73% and
53% of patients receiving MTX, GST and SSZ, respectively, would continue therapy for 60
months. For this subgroup analysis, the combined number of patients at risk at baseline for each
of the three drugs was 201 3 (MTX), 2233 (GST) and 1392 (SSZ). Analysis of withdrawals due to
toxicity (treating all other withdrawals as non-informative) revealed that 65%, 36% and 48% of
the patients continued MTX, GST and SSZ, respectively, for 60 months (Figure 3.3).
Percentage of Patients remaining on treatment Withdrawals are for inefficacy, toxicity or other reasons
Months Adiusted Sam~Ie Size GST 3128 2186 977 623 404 33 1 252 23 5 181 172 HCQ 1131 640 129 29 1 1 MTX 2813 2084 1029 749 578 393 254 214 159 151 SSZ 1399 870 392 316 217 186 140 I40 1 1 1 1 1 1
- -- - - - - . - - - - - -- - - - - - -- - - -- - - - - - - - - - - - - - - - - - --
Figure 3.1: Survival curves representing the percentage of patients withdrawing From each agent because of inefficacy, toxicity or other reasons. Six-month interval data were generated from studies providing withdrawal information for intervals larger than 12 months. The data are from observational studies and randomized controlled trials.
Percentage of Patients remaining on treatment Withdrawals are for inefficacy
\------ I ----__-_-_ L \ 80% 1 ).,. \ . - _ _ _ _ _ _ . . _ _ _ _ _ _ _ - - - . - - . _ _ _ _ MTX
' \---.- \, -
! \ \. ', \.
'. GST
, I \ HCQ k
'- - . 60% - '..-.. ssz
0% . 42 48 54 60
Months Adiusted Sample Size GST 2055 1512 857 509 338 244 HCQ 495 330 96 12 4 AMTX 1903 1426 805 561 462 288 SSZ 1261 812 399 316 224 1 SO
- -- -- -- - A A -- - -- - - - --- - - - - PA - - - - - - -- -
Figure 3.2: Survival curves representing the percentage of patients withdrawing from each agent because of inefficacy. Six-month interval data were generated from studies providing withdrawal information for intervals larger than 12 months. The data are from observational studies and randomized controlled trials.
Percentage of Patients remaining on treatment Withdrawals are for toxicity
Adiusted Sample Size GST 2171 1638 860 53 1 338 255 193 171 133 120 HCQ 504 33 1 99 10 4 MTX 1930 1462 807 563 465 29 2 19 1 149 128 122
-- SSZ 1326 811 399 3 14 224 181 149 139 t 15 108
- --- A - - - -- - - - - -
Figure 3.3: Survival curves representing the percentage of patients withdrawing from each agent because toxicity. Six-month interval data were generated from studies providing withdrawal information for intervals larger than 12 months. The data are from observational studies and randomized controlled trials.
Combined data from all published studies indicate that, after adjusting for study type and
year of publication, patients treated with SSZ are up to 1.9 times more likely to fail therapy than
patients treated with MTX (Table 3.2). Patients treated with GST are up to 2.3 times more likely
to fail therapy compared to patients treated with MTX, however when looking at failures for lack
of efficacy only, it turns out that patients treated with GST are significantly less likely to
discontinue therapy compared to patients on MTX. This finding is significant only after adjusting
for type of study and year of publication. Overall, more patients withdrew from SSZ than GST
and, compared to GST, twice as many patients withdrew from SSZ due to lack of efficacy.
However, less patients withdrew from SSZ due to toxicity.
Table 3.2: Statistical comparisons of treatment withdrawal rates between drugs by
means of the Log-Rank, Wilcoxon, and Cox's proportional hazards regression. -
- - . . . . - - - - - - - .
All reasons Log-Rank Wilcoxon
Cox's Proportional Hazard
Toxicityflnefficacy Log-Rank Wilcoxon
Cox's Proportions[ Hazard
inefficacy Log- Rank Wilcoxon
Cox's Proportional Hazard
Toxicity Log-Rank
Wilcoxon Cox's Proportional Hazard
GST vs. hITX
P .- .- - -
< .0001 c .0001
< .0001 1.40
< .0001 < -000 I < .000f 1.68
0.36
0.02
0.0077 0.73
< .ooo 1
< ,000 1
< .0001 2.28
SSZvs. MTX SSZ vs. GST
HR = h a r d ratio (see text for explanation)
The comparison of withdrawal rates between observational studies and RCTs involving
MTX, GST and SSZ revealed no statistically significant differences for up to 24 months (Figure
3.4).
GST
Obs. Studies ~ Obs. Studies . - . . ._ - _.
RCTs RCTs - Figure 3.4: Percentage of patients withdrawing due to inefficacy, toxicity or other reasons, separated by observational studies and randomized controlled trials. The comparison was limited to 24 months duration and showed no statistically significant difference in withdrawal rates between observational studies and randomized controlled trials for all three agents.
3.5 Discussion
The present study summarises rates of treatment withdrawal in published observational
studies and RCTs of MTX, GST, SSZ and HCQ. Analysis of the combined data shows that
patients stayed longest on single DMARD therapy with MTX. However, nearly two thirds of all
subjects started another therapy within 5 yean because of lack of efficacy, treatment-associated
adverse events, or other factors. When withdrawals due to lack of efficacy alone were considered,
there were more patients withdrawing £kom MTX than GST, and it was noted that a large
proportion of patients who withdrew from MTX did so for reasons other than inefficacy or
toxicity.
This is not the first investigation to make a formal attempt to review withdrawals from
treatment with selected DMARDs (48;55;56), but it is the first to combine data from
observational studies and RCTs, and to specifically compare rates of withdrawal due to lack of
efficacy, toxicity and other reasons. Wolfe noted in a review that estimates of 5-year treatment
withdrawal vary considerably, with those for MTX ranging kom 30% to 75% (57). Wolfe
combined the 5-year estimates of MTX therapy, weighting them according to the sample size of
patients at risk at baseline; however, this may not be appropriate as the precision of the survival
estimates is determined by the number of patients at risk not only at baseline but throughout the
study period. Felson et al. compared withdrawal rates between DMARDs but restricted their
review to RCTs (56). Furthermore, they compared overall withdrawal rates and those due to
toxicity, but did not calculate combined survival curves.
Some investigations that were not included in the present meta-analysis - because they
did not disclose the actual number of patients withdrawing - documented higher rates of MTX
maintenance at the 5-year interval. For example, Wolfe et al. estimated that -45% of subjects
remained on MTX at 5 years (3 l), and Pincus et al. put the figure at -65% beyond 5 years (32).
Inclusion of these data would have slightly increased the combined percentage of patients
continuing MTX for up to 5 years. In fact, the year of publication independently contributed to
survival differences for MTX and SSZ. Withdrawal rates on MTX and SSZ have therefore
declined in recent years. Year of publication was insignificant for HCQ and GST, documenting
no change in survival on therapy For these drugs over the years. This is confirmed by the
similarity of the present 5-year treatment survival estimate of 23% to those by Wolfe et al. (3 1)
and Pincus et al. (32) who noted, respectively, that 20% and 28% of patients continued GST
therapy for up to 5 years.
Even though the combined rates of survival on therapy here are obtained from several
studies, only two treatment arms each for GST (58;59) and SSZ (59;60), and three for MTX (6 1 -
63), contributed information for up to 60 months. However, survival-on-therapy curves for the
combined studies reveal a consistent pattern within the first two years and most are parallel,
suggesting that additional studies of the same agents would be unlikely to make a considerable
difference. More detailed information concerning the disease status and demographic
characteristics of patient populations would probably facilitate analysis of subgroups exhibiting
different rates of survival on therapy, but that level of detail could not, unfortunately, be
achieved. Thus, this meta-analysis can offer only a rough guide to physicians who want to know
how long a particular patient is likely to continue treatment with an individual DMARD.
A M e r limitation of the present study is the lack of adjustment for meaninghl
covariables in the statistical comparisons. Although information was sought on common
variables such as joint count, rheumatoid factor status, disease duration, and the number of prior
DMARDs, it had too seldom been collected by investigators to allow for a more detailed
analysis. Earlier studies might have included patients with more severe disease, leading to lower
treatment survival rates - particular with GST.
Examination of the underlying reasons for treatment withdrawal in the present meta-
analysis indicated that, after adjustment for year of publication, patients on GST were
significantly less likely to withdraw from therapy due to lack of efficacy than MTX patients.
These data do not reveal how many patients achieved remission or significant clinical
improvement during treatment with these two agents, but they do encourage us to take a closer
look. GST is one of the least favoured DMARDs (9), despite efficacy comparable to MTX
having been demonstrated by RCTs (64;65), on large databases (66;67), and in the meta-analysis
by Felson et al. (56) The present results suggest that toxicity is the main reason for GST being
out of favour. It is likely that most of the problems relate to the cutaneous rash that, it has been
speculated, occurs more often in patients slated for remission (55). However, GST-associated
adverse events can be managed in such a way as to avoid discontinuation of therapy (68) or
promote initiation of a second course (68-70). Furthermore, withdrawal rates reported in the
literature may obscure the true efficacy of GST, as it has been observed that patients who
withdraw from GST are more likely to experience a sustained improvement compared to patients
withdrawing fkom MTX (71). This finding may be a direct consequence of using implicit
judgment to classify patients as toxicity or inefficacy withdrawals. h this meta-analysis we had
to rely on the original author's classification of withdrawals which is often performed without
clear guidance by specific criteria, which in turn leaves the possibility for classification biases
that may artificially favour one drug over others.
It is encouraging that, contrary to current opinion, there is no apparent difference in
withdrawal rates between observational studies and RCTs. Theoretically, withdrawal rates in
RCTs could be either higher (due to protocol-mandated withdrawals or patients fearing that they
are taking placebo) or lower (because subjects participating in RCTs receive more care and
attention than is usual in a real world setting). However, although the present results show that
equal trust can be placed in reported withdrawal rates, whether they originate from RCTs or
observational studies, the relevant comparison was possible for only up to 24 months of follow-
UP*
The product limit calculation of treatment survival probabilities is a routine method
employed in the reporting of treatment success of various DMARDs. However, it is possible that
the method is often applied to data which violate some basic assumptions for its use (72). For
example, survival estimates in many older studies may be biased downwards, as these patients
generally received their first DMARD late in the disease course, but also because survival on a
specific treatment may improve as rheumatologists gain experience with it (72). This better
survival for patients will not be given its due respect when all patients are grouped together for
the purpose of the survival analysis. The results presented here will only repeat the same
potential biases that may afflict the underlying studies, unless these biases cancel each other out.
The decision to withdraw therapy is oflen implicitly made in observational studies. Those
that adopt explicit definitions of clinical response and follow common methodological reporting
standards will enhance the short-term results provided by RCTs and supply valuable information
on the long-term performance of antirheumatic therapies to physicians, patients and researchers.
CHAPTER 4
A 1-year randomized controlled triabbased economic evaluation of Leflunomide
and Methotrexate in Canadian patients with rheumatoid arthritis.
4.1 Preface
This chapter reports the economic comparison of leflunomide and methotrexate based on
data that were prospectively collected alongside the North-American phase ID randomized
controlled trial comparing leflunomide to methotrexate and placebo during a 52-week period.
4.2 introduction
The last decade has seen an intense debate about appropriate treatment strategies in the
management of patients with rheumatoid arthritis (RA). A consensus seems to have emerged that
patients with moderate or aggressive RA should be treated early and aggressively, with some
experts arguing for combination of disease modifying anti-rheumatic drugs @MARDs) as initial
therapy. However, these recommendations were made in the absence of potent therapeutic
alternatives, thus necessitating a recurrence to combination of presently available, but less potent
drugs such as sulfasalazine or hydroxychloroquine. Fortunately, in the last few years several new
medications were approved for the treatment of patients with RA. In 1998, leflunomide was the
first disease modi fylng drug approved in over a decade by the US Food and Drug Administration
(FDA). Soluble TNFa receptor and monoclonal anti-TNFa antibodies followed. These drugs add
new and powefil options to the management of RA. Compared to available therapies which may
cost as low as USS300 per year, these new agents cost between USS3,500 and USS 13,000 per
year. Thus, their therapeutic potential needs to be measured not only by their ability to slow or
halt disease progression, but also by their share in decreasing the healthcare costs incurred by
patients with RA. Reimbursement approval for these new agents will likely depend on their
demonstrated cost-effectiveness.
RA is a costly disease due to its chronic nature and sometimes severe progression that can
require hospitalization and intense medical and surgical treatment. Published estimates of the
yearly costs of RA were recently summarized by Cooper, who estimated that RA patients incur
yearly costs of US$8,416 per patient in 1996 dollan. This estimate was shared to equal parts by
direct medical and nonmedical costs and indirect costs, such as losses in productivity. The
authors documented wide variation around the cost-estimates translating into standard deviations
of nearly 53,000. Only one cost of illness study was conducted in Canada, so far. In this study the
annual costs incurred by RA patients were calculated to average CADS6,253 (1994 dollars) in
the period extending from 1990 to 1994 (22). Direct costs were responsible for 74% ($4,656) of
the total costs and prescription drugs for - 20% of the direct costs. Extrapolating these costs to
the 0.5% to 1% of the Canadian population estimated to be affected by RA leads to an estimate
of the total healthcare costs of RA patients in Canada between 0.9 and 1.75 billion dollan (1994
Cdn.).
There are few published economic evaluations of DMARDs (73-75) and only one
collected data prospectively alongside a clinical trial (75). Traditionally, economic evaluations
are made by combining information From various sources into a modelling Framework, however
most current ongoing trials incorporate economic outcomes such as healthcare and productivity
costs into their protocols. The present study reports the results of an economic comparison of
leflunornide, methotrexate and placebo based on economic outcomes measured prospectively
alongside a North American phase EI trial comparing leflunomide to methotrexate and placebo in
482 patients with RA followed for one year (76). Costs for all economic outcomes were
calculated in Camdim dollars from the perspective of the Ontario Health Insurance Plan.
4.3 Materials and Methods
The material analysed in the present study was collected as part of a 1-year randomized
double blind comparison of leflunomide, methotrexate and placebo in 482 US patients with
rheumatoid arthritis (76). Patients with active RA aged 18 years or older were eligible for
treatment if they met the American College of Rheumatology (ACR) criteria for having RA for 6
months or longer. Patients could not have previously received methotrexate, other DMARDs had
to be discontinued for at least 30 days. Patients were assigned to 1 of 3 treatment groups in a
3:2:3 randomization: leflunomide treatment (20 mg/d), placebo, or methobexate treatment (up to
15 mglwk). Patients identified on or after week 16 as non-responders according to ACR response
criteria (2) were allowed to switch to alternate therapy: methotrexate and placebo patients
switched to leflunornide and leflunomide patients to methotrexate.
Clinical data and information on costs were collected biweekly from weeks 4 to 12 and
monthly thereafter. Questionnaires examining health related quality of life and interviews
eliciting patients' utilities were applied at baseline, week 24 and 52, or at study exit. The intent-
to treat analysis included all patients who received drug and had at least one follow-up visit.
Clinical study results have been published elsewhere (76).
Utilities
Patients' utilities for their current health status at baseline, week 24, 52 or at study exit
were elicited through rating scale and standard gamble (SG) measurements. Patients were
initially asked to rate their health on a rating scale anchored by perfect health (1 00) and
immediate death (0). In the SG interview, patients were asked to make a choice between their
current health as a certain outcome or a gamble involving death and perfect health as the
uncertain outcomes. Patients were then told to imagine a treatment leading to either death or
perfect health. The chances of treatment success, i.e. perfect health, were varied systematically
from 100% downwards, and the chance of perfect health that made patients insecure as to
whether they preferred their current health state or the gamble was then recorded as the SG utility
for the patient's current health state. Utilities for patients who rated their own health worse than
death were considered 0 for the purpose of this analysis.
Costs
Treatment or disease related costs were quantified by asking the patient about: 1) any
health resources used that were not specified by the clinical protocol and that were associated
with an adverse event; 2) any expenses incurred by the patient out of her own pocket because of
the disease or treatment related adverse events; and 3) any loss in the patient or her caregiver's
productivity or the performance of social or leisure activities including costs resulting as a
consequence of a loss in productivity.
Health resource utilization questions inquired about 1) the number and duration of
hospital, intensive care unit (ICU) or nursing home stays, 2) the number of office or emergency
room visits to health professionals, 3) the number and type of outpatient diagnostic tests and
laboratory tests received and 4) the number and type of outpatient procedures performed.
Personal expense questions asked for any out of pocket costs for health services, transportation
costs, costs for meals on wheels and the type and costs of equipment purchased in order to cope
with the disease or adverse events related to the study drug. Finally, patients were asked about
the amount of work time they or their caregivers lost, the extra time incurred through performing
additional chores, the amount of lost leisure time and the costs incurred by hiring extra help to
perform daily chores.
Canadian costs were estimated for all resource utilization and cost items. Hospitalizations
were coded into case mix group (CMG) codes according to the C M G ~ 1998 Directory for use
with ~lx". Average 1998 daily hospitalization costs by CMG were then derived From a mid-size
inner-city teaching hospital's database of hospitalization costs for over 18,000 patient encounters.
These were multiplied by the patient's length of stay in order to obtain the full hospitalization
costs. Average daily hospitalization costs across all CMGs were used for three patients whose
CMG codes did not appear in the hospital's database. The physician component of the
hospitalization costs were obtained from the Ontario Health Insurance Plan (OHIP) Schedule of
Benefits (SOB), 1999 version. All hospitalizations were classified by the study physicians on
whether they were not, possibly or probably related to the drugs under investigation. All
hospitalizations rated by the study physicians as possibly or probably related were considered
related for the purpose of this analysis.
Costs of office or emergency room visits to health professionals and costs for imaging
procedures were obtained from the OHIP SOB. Costs for laboratory tests were derived &om the
Ontario Schedule of Benefits for Laboratory Services, 1999 version. A standard request including
CBC, transaminases, creatinine, BUN was used to cost performance of laboratory tests
independent of the number indicated by the patient. The OHIP SOB was also used to cost
outpatient procedures such as endoscopy, skin biopsy or pulmonary function test, assuming the
assessment conducted most frequently under routine conditions. Personal expenses incurred by
patients during the trial were converted from US to Canadian dollars using 1997 Purchasing
Power Parities published for 1997 by the Organization for Economic Cooperation and
Development. Costs for productivity time lost to the patient by age and gender were derived from
1996 Canadian Census data using the average 1995 yearly income for each age and gender group.
Costs for productivity time lost to the caregiver were calculated using the average 1995 yearly
income of the total population, as age and gender information was not provided for the caregiver.
Costs for lost leisure time were not calculated.
Costs for the routine monitoring of patients on leflunomide or methotrexate were
calculated according to monitoring guidelines published in the product monograph of each drug
in the Compendium of Pharmaceuticals and Specialties. Wholesale costs of drugs were increased
by the 10% maximum allowable markup and a prescription fee of 56.1 1 was added for each 6-
month prescription. All costs were updated to 1999 levels using the the respective portions of the
Canadian Consumer Price Index.
Analysis
Patient's utilities derived from the Feeling Thermometer and Standard Gamble
questionnaire for the baseline, week 24 and week 52 or study exit measurement were weighted
by the time period covered, according to the trapezoidal rule, and divided by the total time of
observation in order to obtain a utility per person-year of observation. Utilities between study
groups were compared using analysis of variance, with Tukey'studentized range test for painvise
comparisons.
Costs for medical procedures and visits unrelated to the disease, such as dental visit were
excluded from hrther analysis. Costs for services, tests, procedures and hospital visits (medical
costs) and patients' out of pocket costs (non-medical costs) formed the direct cost component,
patient time and productivity costs, excluding leisure time, the indirect medical cost component.
Each individual patient's direct medical costs and indirect costs were then added over the study
period and further adjusted by the total time of follow-up in order to obtain an annualized cost
estimate.
The statistical analysis of cost data is being debated in the literature, with some experts
arguing for non-parametric tests on often transformed costs, due to the heavily skewed
distributions of cost values (77), and others for parametric tests, which are thought to be
sufficiently robust with larger sample sizes (78). Several statistical comparisons were made thus
in the absence of a consensus on the appropriate statistical tests to be used in cost-comparisons
(79): 1) Student's t-test on untransformed costs to compare means between two groups; 2)
Student's t-test on untransformed costs with reference to 200 bootstrap samples; 3) Wilcoxon test
on log-transformed cost data; 4) Student's t-test on log-transformed costs; 5) a 2-Score test
statistic, proposed by Zhou et al. (80) was calculated to adjust for possible inequalities of
variances; and 6) an analysis of log-transformed costs in an ordinary least squares regression
model with adjustment for age and gender. Expected values, still on a log-transformed scale,
were then back transformed, using a nonparametric smearing estimate that takes into account the
residuals remaining from the least squares estimation (8 1).
Statistical comparisons were performed on: 1) all costs, to form a societal perspective, 2)
direct healthcare costs only and 3) direct healthcare costs excluding, arbitrarily, the top 1%
extreme outliers to perform the cost comparison
4.4 Results
01485 patients enrolled, 482 received at least one dose of a study drug or placebo and
were evaluated for safety; 480 had at least one follow-up visit to evaluate efficacy (1 82 patients
received leflunomide therapy, 180 received methotrexate therapy and 1 18 received placebo). All
patients were similar in the measured demographic and prognostic variables (Table 4.1). The
efficacy results, published elsewhere (76), are briefly recaptured here: Both leflunomide and
methotrexate achieved statistically equivalent response rates with 52% and 46%, respectively
being considered successful responders as defined by the American College of Rheumatology
preliminary criteria for 20% improvement (ACR20) (2). Furthermore, 41 % and 35% of
leflunomide and methotrexate patients sustained ACR20 response status until study end at 52
weeks. Patients on leflunomide fared better than methotrexate patients from a functional
perspective, with statistically significant differences favouring leflunomide in the HAQ disability
index and 2 of 8 subscores of the SF-36. Leflunomide is also statistically significantly superior to
placebo in retarding disease progression as measured by x-ray analysis of both erosions and joint
space narrowing but no consistent differences were noted between leflunomide and methotrexate
on assessments of joint damage.
Table 4.1: Demographic and disease chiuacteristics of the study patients at baseline (76).
Leflunomide Placebo Methotrexate
-- --- - (n= 182) (n=118) (n= 1 82) -- -
Female, % 72.5 70.3 75.3
Age, years ' 54.1 k 12.0 54.6 10.7 53.3 k 1 1.8
Rheumatoid Arthritis, duration, y ' 7.0 5 8.6 6.9 k 8.0 6.5 * 8.1
Rheumatoid Anhritis, s 2 years, % 3 9 33.3 40.1
Rheumatoid factor positive, % 64.8 60.2 59.4
No. of DMARDs that failed ' 0.8 5 1.0 0.9 i 0.9 0.9 -C 1 .O
No prior DMARD treatment, O/o 44.5 39.8 44
Taking concomitant NSAIDs, % 75.2 65.2 69.7
Taking concomitant steroids, % 53.8 55.1 52.7
No. of tender joints (range, 0-28) 15.5 k 6.4 16.5 = 6.3 15.8 i 6.9
Patients' global assessment of 5.6 * 2.2 5.8 i 2.2 5.4 i 2.3 disease activity (10 point VAS)
Modified health assessment 0.8 k 0.6 0.9 = 0.5 0.8 * 0.5 questionnaire scores
ESR, mm/hr 38.4 2 26.8 - - - - - -- - - -
37.3 i 28.7 -
33.8 = 25.4 -- - - --
.t Values are mean * Standard Deviation
DMARD: Disease modifying anti-rheumatic drug; VAS: Visual analogue scale; ESR: Erythrocyte sedimentation
Utilities
Rating scale values were missing for 19, 1 1, and 1 1 patients in the leflunomide,
methotrexate and placebo group respectively, and SG utilities were missing for 2 1, 12, and 1 1
patients, respectively. Missing values exclusively occurred in patients who were considered non-
responders, with the exception of l patient in the leflunomide group and 1 in the rnethotrexate
group who were responders. Analysis of variance showed no statistically significant differences
between leflunomide and methotrexate (Table 4.2). Rating scale values for both leflunomide
(67.7) and methotrexate (64.8) were significantly different fiom placebo (57.5) [p < .05]. In
addition, standard gamble results were statistically significantly different between methotrexate
(83.2) and placebo (77.0) [p < .05], but not between leflunomide (80.2) and placebo (Table 4.2).
Table 4.2: Standard gamble and rating scale values for 480 patients participating in a 12-month randomized controlled trial comparing leflunornide to methotrexate and placebo.
Leflunomide Placebo Methotrexate
n = I63 (RS) and 16 1 (SG) N = 107 (RS and SG) N = 169 (RS) and 168 (SG)
Mean Med. IQR Mean bled. IQR Mean Med. IQR -- -
Rating Scale 67.7 4 70.3 57.5 - 80.4 57.5 57.5 44.0 72.5 64.8 67.9 55.0- 78.1
Standard Gamble 80.2 86.3 72.5 - 96.5 77 83.5 65.0 - 92.7 83.2 ' 89 75.5 -96.3 -- - - -- - - - - - - - - - - - - - --
IQR: Inter-quartile range; $5: statistically significantly different from placebo, p < .05 RS: Rating Scale SG: Standard Gamble
Costs
Among the 480 trial participants there were 234 (48.8%) patients who incurred direct medical
costs, including hospitalizations, related to the study drugs or the underlying disease (Table 4.3).
Hospitalizations judged to be related to the drug or RA occurred in 2, 3 and 2 patients in the
leflunomide, methotrexate and placebo groups, respectively.
Table 43: Number of patients incurring costs in the three cost categories. -- - - - - .- -- . - - - - - -- - - - - - - -- - - - - - - - -- - - - - -- A . -
-- - - - - - - LEF (N= 182) hlTX (N= 180) PBO (N=118) . - - - - - - - - - . - - -- - - - - - - - -- - -. - -
Direct medicaI costs 95 52.2% 93 51.7% 45 38.1%
Hospitalizations Cj udged related by study physicians) 2 1.1% 3 1.7% 2 1.7%
Direct nonmedical costs (out of pocket) 13 7.1% 5 2.8% 8 6.8%
Indirect costs (patient time 1 productivity) - -- . 55 30.2% 50 27.8% - . - - - -- - - -- --
42 35.6% -- --- - - A
LEF: leflunomide; MTX: methotrexate; PBO: placebo
Resource utilization episodes, such as the number of hospitalizations (all), outpatient physician
visits and the number of separately ordered laboratory tests, occurred more frequently in the
leflunomide group, while the number of outpatient diagnostic imaging tests and the number of
outpatient procedures were similar in the leflunomide, methotrexate and placebo groups (Table
4.4). These observations also hold when resource utilization episodes are annualized. The
annualized direct costs and indirect costs exhibit markedly skewed distributions: almost 50% of
patients incurred no costs, and a few patients incurred extremely high costs (Table 4.5).
Table 4.4: Health Care Resource Utilization Items Incurred by patients over the 52 week study period, unadjusted, and adjusted by total time of follow up as number of events per person-year
- - - - - -
Leflunomide .Methotrexate PIacebo Items Unadj. per person- Unadj. per person- Unadj. per person-
-- -- - -- year year year Total person-years of observation 126.1 135.1 65.8
Hospital or Nursing Home Stays 3 5 0.28 6 0.04 10 0.15
Outpatient Physician Visits 288 2.28 209 1.55 110 1.67
Outpatient Diagnostic Imaging 94 0.75 90 0.67 5 7 0.87
Lab tests (No. separately ordered) 205 1.63 67 0.50 45 0.68
Outpatient Procedures - - - - -- - 42 0.33 50 0.37 26 0.39 -- - - -- -- - - - -
# 1 10' py : Number of events per 1000 person-years of observation
Table 4.5: Descriptive Statistics of annualized total, direct, indirect, non-medical costs and estimated yearly drug acquisition and monitoring costs by treatment group - - - - - - -- - - -- - - - - - - - - - - - - -
Leflunomide Methotrexate Placebo
-- - - - - - - - - - - Mean Median M iMean Median Max Mean Median Max - - - - - - - - - - - - - -. -- - - - - - - -. - - - - -. - - . -- - -
Totalcosts(excl.drugand $1,761 5171 $54,216 $1,280 $107 $78,925 $1,324 9132 520,315 monitoring costs) Direct costs $753 $54 $49,566 $620 $51 $78,925 S336 S167 37.31 1
Direct costs (excl. top 1%) $420 S53 $9,885 $173 550 $1,654 5227 SO $4,218
Direct non-medical costs $22 $0 $1,030 S2 SO $170 $66 SO $3,181 Indirect costs $986 SO $33,474 $660 $0 $39,553 $921 SO $20,147
Monitoring costs $483 - $599 - $55 - Drug acquisition costs $3,853 5258 - - - -- - - - - - -- - - - - - - - - - - -- - * -- - - - - - - -- - - - - - - - - -- - - -
Statistical analyses of the annualized total costs, representing the societal perspective, revealed
no statistically significant differences between leflunomide and methotrexate, or in comparison
of these two agents with placebo (Table 4.6 - Following page). Analysis of direct medical costs
only, representing the perspective of the Provincial Health Insurance Plan, also revealed an
absence of a statistically significant difference between leflunomide and methotrexate. However,
direct annualized medical costs associated with leflunornide were statistically significantly higher
than placebo in the statistical comparisons of the log-transformed costs: Wilcoxon Rank Sum, t-
test and regression on log-transformed costs. Direct annualized medical costs associated with
methotrexate were significantly higher than placebo in the regression analysis on log transformed
cost data. The differences in direct costs between leflunomide and placebo persisted after
arbitrarily trimming all costs by the top 1%.
Table 4.6: Statistical Evaluation of total costs, direct costs and direct costs trimmed by the highest 1%. Results of statistical tests on untransformed and Iog- transfomed costs.
LEF vs. MTX LEF vs. PBO MTX vs. PBO
Total Costs
t-test
Bootstrap
Wilcoxon Rank Sum
T-test (log S + 1 )
Z-score (log $ + 1 .)
Regression (log $ + 1 )
Direct Costs
t- tes t
Bootstrap
Wilcoxon Rank Sum
T-test (log S + I )
Z-score (log S + 1 )
Regression (log $ + 1 )
Direct Costs (1% trim)
Wilcoxon Rank Sum
T-test (log $ + 1)
Z-score (log S + 1 )
$9: with adjustment for age and gender
LEF: leflunornide; MTX: methotrexate; PBO: placebo
Mean costs adjusted for age and gender were calculated by "back-transforming" the
regression analysis results. The "back-transformed costs" demonstrate only a slight difference to
the original costs, suggesting that age and gender have marginal influence on total or direct costs
(results not shown).
Incremental cost-effectiveness and cost-utility ratios were calculated using the total costs
provided in Table 4.5, the previously reported ACR20 response rates and the SG utilities
reported in Table 4.2. The marginal societal benefit of LEF in comparison to placebo was valued
at $21,445 per ACR.20 responder gained and S 147,438 per quality-adjusted life-year (QALY)
gained (Table 4.7). The marginal benefit of MTX was 54,738 per A C E 0 responder gained and
f 12,226 per QALY gained. While MTX was associated with less costs and higher utilities, LEF
achieved a higher percentage of AC R20 responders, leading to a cost-effectiveness ratio of
$66,000 per ACE220 responder gained in comparison to MTX. Cost-effectiveness and cost-utility
ratios were similar when calculated £?om the provincial payer's perspective.
Table 4.7:Calculation of cost per ACR.20 responder and quality-adjusted life-year (QALY) gained. - - -. - - -- .- . .
Costs Costs % A 0 QALYs Cost per ACR Cost per QALY
-- --- - -. - - --- - - -- -- - - - - - - - - 20 responder
Le flunomide $6,097 S5,089 41% 0.80
Methotreme $2,137 $1,477 35% 0.83
Societal Perspective
~Methotrexate vs. Placebo $4,738 S 12,226
Leflunomide vs. Placebo $2 1,445 S 147,437
Leflunomide vs. Methotrexate $66,000 MTX dominates
Payer's Perspective
Methotrexate vs. Placebo S6,788 S 17.5 16
Leflunomide vs. Placebo $21,355 $146,812
Leflunomide vs. Methotrexate --
$60,200 MTX dominates -
ACR20: Response status by American College of Rheumatology Criteria for Improvement of at least 20%
4.5 Discussion
[n this investigation we compared, from the perspective of a Canadian health insurance
plan, the economic consequences and health utilities of RA patients treated with leflunornide,
methotrexate or placebo. All data were collected during the first 12 months of a North American
randomized controlled trial which was conducted in 482 patients with rheumatoid arthritis. The
results of this analysis demonstrate that, when excluding drug monitoring and acquisition costs,
leflunomide has an othenvise similar economic profile compared to the best alternative
methotrexate. In comparison to placebo, leflunomide costs an extra $147,437 per QALY gained
and methotrexate S12,226. Although no statistically significant differences were found in health
state utilities between leflunomide and methotrexate, methotrexate is both less expensive than
leflunomide and produces higher utilities. However, more patients on leflunomide achieved an
ACMO response status at a cost of $66,000 per responder gained in comparison to methotrexate.
This is one of the few economic evaluations in rheumatology, where economic data were
collected concurrently to a randomized controlled trial. Both patient and investigator were
blinded to treatment assignment and data collection procedures were identical in each treatment
arm, which lends support to the conclusion that the economic consequences were similar
between the two active treatments. It is unclear, however, how high the economic consequences
would have been, had this study been performed under routine treatment conditions similar to the
daily practice of the rheumatologists in the study.
Because a portion of medical resource consumption was mandated by the protocol, it was
not possible to determine the full costs that would have occurred in the absence of protocol-
related monitoring. Treatment or disease-related resource consumption was collected in a fairly
detailed way, but no attempt was made at collecting resource utilization data at a micro level.
Additionally, the use of healthcare resources unrelated to the treatment of RA was not
documented and thus not included in the costing process. Even though some unrelated costs
might have been documented due to judgmental errors on part of the investigator, these are
probably distributed fairly evenly and unlikely to influence the final comparison.
Consumption of medical resources, in the present study, occurred to US patients in a US
healthcare setting but these resources were costed in Canadian dollars. There is sufficient
evidence from other diseases that US utilization of healthcare may be up to twice as intense as
that in Canada (82). Overall direct costs are thus inflated compared to potential Canadian costs
and the already non-significant difference between leflunomide and methotrexate would have
been smaller than the one observed had this study been conducted in a Canadian setting. A
differential effect on the direct costs in both treatment arms is unlikely given the fact that these
data were collected in a randomized controlled trial.
Methotrexate is considered the standard therapy in the management of RA and, among
DMARD monotherapies, patients on methotrexate achieve the highest relative response. Thus
the requirement of regulatory agencies to use methotrexate as the active comparator in clinical
trials of new therapies. In Canada, methotrexate is also one of the least expensive DMARDs,
which makes it one appropriate comparator for a direct economic comparison. Other comparators
could have been conceivable as well, particularly those DMARDs that are chosen if a patient
fails or presents adverse events to methotrexate. Because methotrexate is considered both the
least expensive and most effective DMARD, the cost-effectiveness and cost-utility ratios of
leflunomide in comparison to other DMARDs are likely to be more favourable than the present
values in comparison to methotrexate.
There are only few studies to which we can compare the results of the present study. The
closest, and most recent study is the one by Verhoeven and associates (83) who compared the
cost-effectiveness and cost-utility of combined step-down prednisolone, methotrexate and
sulphasalazine, to sulphasalazine alone in a Dutch setting. The authors found a not statistically
significantly better economic profile and a significantly better clinical profile in favour of
combination therapy. Measurement of costs in this study were comprehensive, including costs
unrelated to the disease. This explains the higher total costs oFUS$5,500 - US$6,500 incurred by
the study patients. Even though the combination therapy arm was clinically superior to the
sulfasalazine arm, the economic consequences were not statistically significantly different.
Althoug it is unknown, how much clinically superior a new therapy has to be, in order to produce
more favourable economic consequences in comparison to methotrexate, it is likely that this is
difficult to achieve given the low costs of this drug and its high effectiveness.
Before the approval of leflunomide by the FDA in 1998, there was a decade without new
treatments that physicians could offer to patients with RA. Recently, several new drugs have
been approved and rheumatologists face better treatment choices than before. Our study showed
that leflunomide has an economic profile that is similar to methotrexate and that the extra costs
faced by policymakers are fixed treatment costs that, however, are higher than the costs of
generic drugs, such as methotrexate. From an economic perspective, leflunomide imposes itself
as an alternative once methotrexate fails, due to its equally high efficacy. But leflunomide might
also be a drug of first choice, provided that drug acquisition costs are covered.
CHAPTER 5
An estimation of the i y e a r cost effectiveness of adding Leflunomide to a strategy of
conventional disease modifying antirheumatic drugs in patients with RA
5.1 Preface
This chapter reports the results of the model-based economic evaluation of leflunomide as
an element of a typical treatment strategy for patients with more aggressive rheumatoid arthritis.
Data that were collected in the surveys (Chapter 2), the meta-analysis (Chapter 3) and the
randomized clinical trial (Chapter 4) were used to support a decision-analysis-model. The model
runs over 5 years with cycles of 6 months duration and evaluates the cost-effectiveness and cost-
utility of adding leflunomide to a typical DMARD-strategy.
5.2 Introduction
The last decade has seen an intense debate about appropriate treatment strategies in the
management of patients with RA. A consensus seems to have emerged that patients with
moderate or aggressive RA should be treated early and aggressively, if possible by combining
several disease modifying anti-rheumatic drugs (DMARDs). However, these recommendations
were made in the absence of potent therapeutic alternatives. Fortunately, several new therapies
were recently approved for the treatment of patients with RA, which now add powerfbl options
to the management of RA. In 1998, leflunomide (LEF) was the first disease modifying drug
approved in over a decade by the US Food and Drug Administration (FDA), soluble TNFa
receptor and monoclonal anti-TNFa antibodies followed. However, compared to existing
therapies, which may cost as low as USS300 per year, these new agents cost between US$3,500
and US$13,000 per year. Thus, their therapeutic potential needs to be measured not only by their
ability to slow or halt disease progression, but also by their share in decreasing the healthcare
costs incurred by patients with RA. Reimbursement approval for these new agents will likely
depend on their demonstrated cost-effectiveness.
The costs of illness associated with RA are compounded by a disease that often starts
early in life, that can lead to severe disability and frequently requires hospitalization and intense
medical and surgical treatment. The yearly costs of RA vary, but have been estimated to be
approximately US$8,416 per patient in 1996 dollan. Direct medical and non-medical costs and
indirect costs, such as losses in productivity, share equal parts of this sum. In Canada, the annual
costs incurred by RA patients were calculated to average CAD$6,253 (1 994 dollars) (22), with
direct costs responsible for 74% ($4,656) of the total and prescription drugs for - 20% of the
direct costs. Extrapolating these costs to the 0.5% to 1% of the Canadian population estimated to
be affected by RA would leads to an estimate of the total healthcare costs of RA patients in
Canada between 0.9 and 1.75 billion dollars (1994 Cdn.).
The relationship between costs and effectiveness of old or new anti-rheumatic therapies
has been examined in only very few economic evaluations (73-79, and all of these compared one
therapy to another over a short time-period. There have been two attempts to model the disease
over longer time horizons (84;85) but without the required efficacy data to study the costs and
benefits within a therapeutic framework. The present study is an attempt to examine the
incremental cost-effectiveness and cost-utility of LEF, a novel disease modifying antirheumatic
drug, within a realistic sequence of DMARDs modelled over a 5-year time horizon in patients
with active RA, from a Canadian payer's perspective.
5.3 Methods
Decision Analysis Model
A decision analysis model was developed to represent the events that occur as a
consequence of taking DMARDs (Figure 5.1 - following page). Several models were available
from the literature (73;74), but none of the models allowed for a combination of data from
observational studies - which primarily report on the proportion of patients maintaining therapy
and randomized controlled trials (RCTs) - which primarily report on the degree of treatment
response, e.g. the American College of Rheumatology composite criteria for 20% improvement
(ACR20) (2).
Adverse Event -.: Sty tnew DhMRD
I tack o f Efficacy .'. Stan new DMARD
Minor Adverse Event Clinical Response I --. : Continue same D W R D (ACUO)
i 1 1 1 No Adverse Event
- ' Continue same D W R D !
Minor Adverse Event 1 No Clinical Response ; - - ' Continue same DMARD I (ACR2O) P
'4 No Advcne Event : Continue same D M R D
6 Months - _ _ _ _ _ ___--__. . _ _ _ _ _ _ .___
Figure 5.1: Events occurring during a 6-month period as a consequence of taking a DMARD. Patients who stop one DMARD start a new one and repeat the cycle with the new DMARD.
To conform with available data from observational studies and RCTs, the decision tree is
designed so that patients may experience three types of events during a 6-month treatment period
(Figure 5.1): 1) they continue therapy, 2) they stop therapy because of adverse events or 3) they
stop therapy because it is lacking or losing efficacy. Furthermore, continuing patients may be
classified clinically with regard to the quality of the response to treatment - here defined as
meeting the A C E 0 criteria - and whether they experience minor adverse events. Because this
analysis is limited by the type of data available from the literature, a more detailed classification
of adverse events by type and severity could not be utilized.
Overall, two DMARD strategies were compared, one including LEF and the other
excluding it (Figure 5.2). Both strategies try to emulate treatment as it happens in real life, which
means that patients cycle through different treatment regimens when they encounter toxicity or
lack or loss of efficacy. A new treatment regimen is chosen for those patients who fail the
previous regimen.
Lack of Egicocy +
Methotrexate
Strategy with /"\ Strategy without leflunomide ,I leflunomide
/
Leflunomide Gold
Toxicity / i Lack of Eflcacyf
v Gold
Toxicity / Lack of Eflcad
v Cyclosporine
Methotrexate/ Sulfasalazine/ H ydroxychloroquine
/ Toxicity / Lack of Eflcacy
Toxicity / Lack of Eflcacy
v Cyclosporine
- - -.A- - - - - - -- - - - - -- - - - - - - - - - - - . - - - . --
Figure 5.2: Sequence of DMARDs chosen for the strategies modeIled in the analysis. One strategy includes LEF.
The choice of treatment strategies is supported by results of a mailed survey using case
scenarios of patients with RA (9). The treatment strategy ercklding LEF is modelled to start with
methotrexate (MTX) followed by combinations of MTX and sulfasalazine (SSZ), and MTX, SSZ
and hydroxychloroquine (HCQ) in case of efficacy failure, while patients developing toxicity to
MTX are modelled to take gold afterwards. Patients failing gold then receive cyclosporine
(CYA) as a last alternative (Figure 5.2). The treatment strategy including LEF is modeled to
allow the patient to take LEF before gold when they can no longer take MTX because of toxicity
or lack of efficacy. In technical terms this representation of the treatment strategies is considered
a Markov model, which covers a 5-year time horizon and is split into 10 intervals of 6 months
duration.
Probabilities
Outcome information for each DMARD was derived from a systematic review of
observational studies and RCTs of DMARDs, the detailed results of which are reported
elsewhere (46). A systematic search of the Medline database was performed Erom t 966 to August
1997 by combining the keyword 'rheumatoid arthritis' with textwords and keywords for MTX,
gold, auranofin, HCQ, chloroquine, CYA and azathioprine. Synonyms of these agents were
included as well. All abstracts were scanned for relevance and resulted in a set of 1387 references
which was further complemented by 1035 references from a broader literature search conducted
by the RA subgroup of the Cochrane Musculoskeletal Review Group. Both searches gave a total
of 2422 references.
Outcome information to be abstracted £?om these references included:
1) Maintenance of DMARDs: percentage of patients maintaining DMARDs and reasons for
withdrawal including adverse events and lack or loss of efficacy,
2) ACR20 response status: percentage of patients meeting ACR preliminary criteria for 20%
improvement (2) , and
3) Percentage of patients suffering one or more adverse events and the type of adverse event.
Maintenance of DMARDs
Of the 2422 references, a total of 445 investigations were found that provided information
on treatment withdrawal. Studies that documented the experience of patients from the day
therapy was initiated, and that provided withdrawal information for one of the four therapies in
patients with RA were included in the published meta-analysis. References for CYA and various
combinations of DMARDs were searched according to the same criteria for the purpose of this
economic evaluation. Studies published after 1997 and reporting withdrawals with the
above-mentioned drugs were added on an ongoing basis. Information on treatment withdrawals
was abstracted according to a standardized questionnaire. Combined withdrawal rates and 95%
confidence intervals were obtained using parametric regression assuming an exponential hazard
function. Withdrawal rates were converted to 6-month treatment withdrawal probabilities for use
in the decision analysis model.
ACWO response status
All 2422 references were further searched for observational studies and RCTs that were
published after 1990 and used explicit response criteria. Possible response criteria included the
ACR preliminary criteria for 20%, 50% and 70% improvement (2), the Paulus criteria for 20%,
50% and 70% improvement (86)and the European League for Rheumatism (EULAR) criteria for
good response (87) which are based on the disease activity score (DAS). The cut-off date was
chosen because it coincided with the publication of the Paulus response criteria. Papen reporting
any one of the above-mentioned criteria were retained and the respective values were abstracted
for the therapies of interest.
Percentage of ~atients suffering one or more adverse events
All studies which provided withdrawal information were also screened for the reporting
of adverse events, in particular the number and percentage of patients suffering one or more
adverse events. The frequency or percentage of patients suffering one or more adverse events
were then abstracted and combined for all studies of each respective DMARD or combination of
DMARDs.
Utilities
Standard gamble (SG) utilities for responder and non-responder status were obtained From the
MTX and LEF treatment groups of the North American study of LEF (76). Utilities were
collected at baseline, week 24 and week 52 or at discontinuation of the study. Utilities obtained
from all patients on LEF or MTX, and who were classified as a treatment success or failure by
ACR20 response criteria at the end of the study period, were used as utilities for DMARD
treatment success or failure in the model. This was considered justified, since the quality of
response to the other comparators could be assumed to be similar to the quality of response
achieved with MTX or LEF.
Costs
Costs of Manaeine Adverse Events
Costs of managing averse events occurring in patients on DMARDs had to be estimated
by gathering information on how rheumatologists would typically manage these events. A
questionnaire was developed, inquiring about rheumatologists' typical management of adverse
events occurring on MTX, gold, SSZ, HCQ and CYA. The type and frequency (per 1000
person-years) of these advene events were derived from the observational studies and RCTs
included in the database. Where possible, adverse events were collapsed into a common category.
In the questionnaire, advene events were categorized into two classes of severity: 1)
severe enough to cause treatment withdrawal or 2) mild adverse event, not necessitating
treatment withdrawal. The questionnaire consisted of a total of 2 19 adverse event management
sections (MTX: 28 withdrawal events/ 38 continuations; gold: 27/23; SSZ 23/18; HCQ 7/20;
CYA: 17/19). The questionnaire was sent to five rheurnatologists in Toronto: two community
rheumatologists and three with academic affiliations. Specifically, they were asked to indicate
whether they would deal with each type of adverse event over the phone, see the patient in the
office or recommend immediate hospitalization. They were also asked to indicate how they
would typically manage this type of adverse event, i.e.: 1) what type of instructions they would
give to the patient including prescriptions of medications and change of anti-rheumatic
medication; 2) which investigations or tests they would order, and 3) whether they would refer to
other specialists, or plan follow up and how often in their own practice
Data from all completed questionnaires were entered into a database to carry out the
costing of all management items. Costs of physician visits, procedures and laboratory tests were
derived from the Ontario Schedule of Physician and Laboratory Benefits, September 1999
version (88). Costs of prescription and over the counter medications were obtained from the
catalogue of a large wholesaler providing the majority of hospital pharmacies in Toronto. A
maximum mark-up of 10% allowable for patients insured under the Ontario Drug Benefit Plan
was added to the price of each drug (prescription and over the counter). A prescription fee of
$6.1 1 was W e r added to the price of each prescription. Costs of hospitalizations were provided
by the Ontario Case Cost Project database based on the ICD9-CM code for the respective adverse
event.
A single cost estimate for the management of each advene event was obtained by
averaging the five respondents' costs for each event. Furthermore, a cost per generic adverse
event episode associated with each treatment was then obtained by weighting each adverse
event's associated cost by the fraction of its incidence relative to the overall incidence of adverse
events, and adding these weighted costs. The same procedure was repeated with the lowest and
highest management costs for each advene event to obtain confidence limits. Costs for the
management of advene events associated with DMARD-combinations were calculated by
assuming that physicians' management of an adverse event on DMARD combination would be
identical to the same adverse event reported for single drugs.
Costs of Monitoring
Costs of monitoring patients on DMARDs were derived from the Canadian Compendium
of Pharmaceuticals and Specialties (CPS) by costing all management steps required when
fo1lowing monitoring directions issued under precautions for each drug. Monitoring costs were
divided into baseline monitoring, i.e. one-time investigations necessary to implement the
medication and check for absence of contraindications. Routine monitoring costs were calculated
separately as these do not change over time. Costs of physician services, procedures and
laboratory services were derived from the Ontario Schedules of Benefit for physician and
laboratory services (88). Monitoring for combinations of DMARDs were combined and all
overlapping monitoring items were eliminated.
Costs of Drugs
Costs of drugs were derived £iom the wholesale price catalogue of a supplier to the
majority of hospital-based pharmacies in Toronto. A mark-up of 10% was added to the price of
each drug and a prescription fee of $6.1 1. The average price per month was based on the
recommended dosage to be given to patients. High and low drug costs were calculated depending
on the maximally and minimally therapeutic dosage for each drug.
Un certainiy
Uncertainty was dealt with by employing second order Monte Carlo simulations. A cohort
of 5000 patients was simulated to go through each DMARD sequence for the full 5-year period.
Costs and utilities were discounted by 3%. Values for the probabilities and costs incorporated
into the model were randomly chosen at each cycle from realistic distributions specified
beforehand. Distributions for cost items were specified to be triangular in shape with the mean
value to be the most likeliest and the minimum and maximum values to be the least likely.
Distributions for probabilities and utilities were assumed to approximate the normal distribution
shaped by the standard deviation For each respective value. The Monte Carlo method then
proceeds such that a value is picked from the distributions whereby values around the average are
picked more frequently than values at the extremes of the distributions, with the probability of
being picked determined by the shape of each distribution. A confidence interval for the resulting
cost-effectiveness ratio was arbitrarily set as the cost effectiveness ratio of each values mean plus
or minus its standard deviation (89).
5.4 Results
Pro babiiities
Detailed withdrawal information for the comparators was provided by 119 studies entered
into the original meta-analysis (46) . Findings From 7 studies published after 1997 were added
later for the purpose of this economic evaluation. Thus, a total of 126 studies provided
information on single agent therapy with MTX, gold, SSZ, HCQ, CYA and LEF, and
combination therapy MTX and SSZ, and MTX, HCQ and SSZ. All 126 studies contributed 158
treatment arms, of which 141 arms were contributing information for the therapeutic strategies
used in the model. Probabilities of withdrawal From therapy and the subset of toxicity
withdrawals were combined across studies for each drug (Table 5.1). The conditional probability
of failing due to toxicity (Table 5.1) was derived by dividing the toxicity failure rate by the
general failure rate. Percent response was obtained and combined across studies from the intent
to treat findings of relevant RCTs of the respective therapies.
Table 5.1: Probabilities of treatment withdrawals, overall and due to toxicity, adverse events in continuing
patients and ACWO response rates. - - -- - - -- - -
Toxicity Withdrawals Adverse Events Drug as percentage of all among patients AC wo response
(%) withdrawals continuing therapy
MTX (SE) 13.5 (2.8) 49.2 (1.6) 18 74.2 (3.2)
MTX & SSZ (SE) 12.5 (4.0) 68 (3.1) 92.9 79.3 (4.5)
MTxlSSZJHCQ (SE) 3.6 ( I .3) 23.5 (6) 72.1 80.9 (4.2)
LEF (SE) 3 1.6 (7.3) 52 (4.5) 29.6 72.9 (2.8)
Gold (SE) 26 (4.3) 71 (3.5) 27 59.4 (6.0)
CY A (SE) 19.3 (4.4) 47.5 (2.6) 46.4 41.3 (5.6)
MTX: methotrexate; SSZ: sulfasalazine; HCQ: hydroxychloroquine; ACR.20: American College of
Rheurnatology criteria of 20% improvement ; SE: standard error
The values obtained for the percentage of patients experiencing one or more adverse
events that do not lead to treatment withdrawal, are only approximate estimates without
confidence intervals, due to the special reporting of adverse events. In RCTs, adverse events are
generally reported as the number of events which makes it impossible to know how many
patients had one or more events. Furthermore, advene events are not reported on a
time-dependent basis, obscuring whether they occurred simultaneously or not. These findings
have management implications, and it was thus assumed that all events receive separate
management, which likely overestimates the costs of managing advene events.
Costs
Questionnaires collecting data on the management of advene events with gold, MTX,
SSZ, HCQ and CYA were completed by all five rheumatologists (Table 5.2). Costs are presented
separately for advene events, mild enough not to lead to treatment withdrawal. and for severe
adverse events that cause treatment withdrawal.
Table 5.2: Average, minimum and maximum costs per type and incidence weighted adverse event.
Severe adverse events are those that cause treatment withdrawals, while events that let patients
continue on therapy are considered mild*. - - .. . . - . - - -
Continuations Withdrawals
Average Minimum Maximum Average Minimum Maximum
LEF $83.69 $69.34 S 101 2 2 $253.00 S 199.65 $296.47
Gold $62.88 $16.98 $107.99 $146.18 547.50 $23 1.59
CYA $100.87 $30.86 $208.62 $265.04 $68.07 S400.49
* as determined by answers of five rheurnatologists to a detailed questionnaire
Costs for baseline and routine monitoring were derived from specifications accompanying
the product monographs in the Canadian Compendium of Pharmaceuticals and Specialties (Table
5.3 - following page); no minimum and maximum was calculated for the baseline monitoring as
there were no ranges provided for the numbers of test and investigations to be done at baseline.
Costs of drugs were calculated £iom the perspective of the Ontario Drug Benefit Plan (Table 5.3).
Tabte 53: Costs of Monitoring DMARDs at baseline and during routine follow-up in a 6-
month period. -
- -- - - - - . - - - -- Baseline Routine (Average & Range) Drug costs
MTX 9 137.06 $230.72 ($156.45 - $304.99) $ 129.22
MTXfHCQtSSZ $266.39 $266.76 (S 159.04 - $374.47) $642.85
LEF $ 140.50 $171.33 ($125.16-5217.50) $1,926.36
Gold 562.68 $419.24 ($384.06-5454-41) $518.62
Ut if it ies
Of 364 patients in the active treatment arms in the North American study of LEF, there
were 329 patients who participated at the utility interviews; 135 were defined as treatment
success, and 195 as not a treatment success by ACR20 criteria. SG utilities for success were
8 1-62 * 22.79 (mean * standard deviation) and 82.37 * 27.99 for patients considered not a
success (difference of 0.75 no statistically significant).
Cost-effectiveness and cost -141 ility rest clts including sensitivity analysis
Results of the cost-effectiveness analysis over a 5 year period, i.e. ten 6-month cycles,
show that the strategy including LEF would cost approximately 37,675 dollars per 5-year period
and a strategy excluding LEF would cost approximately $6,6 10, a difference of 5 1,065 over the 5
year period (Table 5.4). Patients in the sequence of DMARDs that includes LEF would, on
average, be in a state of response for 3.04 years over the 5-year period, gaining an extra 36.5 days
compared to patients in the sequence that excludes LEF, who would be in a state of response for
2.94 years. These findings translate into a cost-effectiveness ratio of $10,682 for each additional
year of response. Confidence intervals for the cost-effectiveness ratio were calculated from the
output of the simulations as ratios of the costs and effects plus/minus one standard deviation.
Adding or subtracting one standard deviation provided a range of $3,380 to $21,018 per year of
response. This cost-utility analysis shows that patients in the strategy including LEF gain 0.058
quality adjusted life-years (3.636 QALYs vs. 3.578 QALYs) which with the above mentioned
costs per strategy would provide a cost-utility ratio of S 18,474 per QALY gained (Confidence
interval i I standard deviation: 54,178 - $83,6 14).
Table 5.4: Expected costs, numbers of cycles patients respond to therapy, time spent on active therapy and cost per responder. Table shows point estimates and mean +/- one standard deviation as determined by Monte Carlo simulations with 5000 runs.
-- - -- - - - - - - - - -- - . -
Mean SD Minus SD Plus SD -- -- - -- - - - - - - -- -
Costs
Inc. Lef
Excl. Lef
Years in ACR2O response
Inc. Lef Excl. Lef
QALYs
Inc. Lef.
Exc. Lef
Cost per responder
fnc. vs. ExcI.
Cost per QALY
Inc. vs. Excl.
5.5 Discussion
In this investigation we compared, from the perspective of a Canadian health insurance
plan, the cost-effectiveness and cost-utility of adding LEF to a realistic treatment strategy in the
management of patients with active RA, as supported by data gathered through a systematic
review of the literature and surveys of Canadian rheumatologists. Evaluation over a 5-year period
shows that adding LEF as a therapeutic option increases the management costs by S 1,085
compared to the strategy without LEF with a cost-effectiveness ratio of $10,682 per additional
year of response to treatment gained, and a cost-utility ratio of $18,474 per QALY gained.
The model-based cost effectiveness approach was selected to demonstrate the added
value of LEF when introduced in a management approach adopted by Canadian rheumatologists
in their usual management of patients with active RA. This approach emulates the management
of EL4 patients in real life where they cycIe through different treatment regimens upon
experiencing toxicity or lack of efficacy. There are several advantages to this type of analysis.
The modelling approach allows estimation of the expected performance of the drug in the real
world and theoretically provides a better estimate of the cost-effectiveness of new interventions.
Furthermore, the impact of LEF can be assessed over a time horizon that exceeds the limited
time-horizons adopted in clinical trials. Within that more realistic framework, the addition of
LEF as a new treatment alternative for patients requiring a new therapy extends the time patients
may benefit from DMARDs.
The strategy modelled in this investigation was identified by means of a survey of
Canadian rheumatologists, which showed that MTX discontinuation is followed by prescriptions
of MTX combinations, gold, or immunosuppressants such as CYA (9) These treatment choices
were therefore incorporated into the model-based cost effectiveness analysis. The choice of
sequence was limited, on one hand by technical considerations, imposed by the type of model
used, and on the other hand by the availability of information which needed to be retrieved from
a systematic review of the literature. Even though it is clear that different rheumatologists will
opt for different treatment sequences, only the sequence thought to be most representative of
rheumatologists' treatment choices for patients with more aggressive RA was chosen for the
comparison. In addition, the choice of sequence was limited by the availability of emcacy data,
i.e. ACR.20 response, in the literature. For example, the survey of Canadian rheumatologists
identified the combination of MTX and HCQ to be more frequently used than that of MTX and
SSZ. However, the combination of MTX and HCQ could not be modeled, as there is no study
reporting ACWO response rates for this treatment strategy. Because the MTX-HCQ combination
is perceived in practice to be equally efficacious to the methotraxate-sulphasaiazine combination,
the substitution of one for the other in the model was not expected to change the conclusions of
the analysis.
The advantage of choosing a sequence of DMARDs was that the results could be
presented in a setting that is more realistic than single-agent comparisons of LEF to other
DMARDs or DMARD-combinations. Furthermore, the incremental cost-effectiveness of single
agent comparisons, for example LEF vs. CYA or gold would be lower than the cost-effectiveness
resulting from a comparison of treatment sequences. This is because the costs and efEects of each
treatment sequence were proportionally influenced by the time patients spend on the drugs in
each sequence. Indeed, given the relatively lower discontinuation rate, MTX and MTX
combinations were contributing more to the costs and effects than drugs that appear later in the
sequence, such as gold and CYA.
The analysis was conducted over a five-year time-horizon based on the 2-year
information available for LEF and information available in the literature for the other DMARDs.
Having to extrapolate from the 2-year data is a limitation of the model that does not Favor LEF.
For example, long-time experience with MTX showed that approximately 14% of patients
discontinue during a 6-month period. When referring to the North American trial comparing LEF
to MTX, the clinical trial setting points to a discontinuation rate of 32% with no difference in
discontinuation rates between the two agents (76).
Other outcomes, such as improvement in ACR criteria by 50%, would also have been
plausible choices for the model. This is especially important as the newer DMARDs may be
more potent and probably qualitatively superior to existing therapies, however, very few studies
in the literature report on ACRSO outcomes. Although here is little reason to suspect qualitatively
superior responses among the comparators used in the present study, this cannot be entirely
excluded, and would likely bias against leflunornide.
While it is likely that, with more exposure to the drug, discontinuation rates in real life
will fall to the level observed For MTX, the model used a 32% discontinuation rate for LEF
because of lack of other values. This also implies an underestimation of the time patients spend
on LEF and thus a possible overestimation of the cost-effectiveness ratio (i.e. overestimation of
the cost per additional year of response gained and cost per QALY) given the higher costs and
lower response rates of the following DMARDs.
Direct medical costs estimated for the purpose of the model-based comparison are only an
approximation of the costs likely to be encountered in real life. It is conceivable, that costs will
be lower in real life. First, monitoring costs were derived from monitoring recommendations
provided in the product monographs. In real life, physicians will likely monitor less, the more
they gain experience with each drug. Similarly, costs of managing adverse events were derived
kom a literature-based survey of 5 Toronto rheumatologists. Costing of the adverse events was
based on the answers provided in the swey , which may deviate from physicians' behaviour in
real practice. Physicians responding to the questionnaire may have adopted a more cautious
approach, not knowing the precise clinical circumstances accompanying the adverse event.
The majority of data supporting the model-based comparison were derived from the
literature. The literature, however, is sparse for much of the data needed. For example, only 35%
of the observational studies studying maintenance of DMARDs provide data needed for the
model. Similarly, only approximately 30% of RCTs or observational studies provide information
on the number of patients suffering one or more adverse events. Explicit response criteria have
only recently been used in RCTs and are seldom used in observational studies. For these reasons,
the data used in our model do not represent all studies that were conducted with the respective
drugs.
Research into the economics of DMARDs is complicated by the chronic nature of RA.
There is not one drug to treat RA, but a multitude and all of them are failing with time. This
makes modeling more complicated, in particular if combinations of drugs are used. Of Further
importance for modeling RA is the severity and stage of the disease, as a differential response
may be expected from patients with mild RA or those who try MTX as first drug or after
previous failure of other drugs, such as SSZ or HCQ. These details were impossible to consider
in the present modeling framework.
The results of this study confirm that leflunomide has a place in the management of
patients with RA and that its integration into the therapeutic armamentarium comes at reasonable
cost. The exact therapeutic value of leflunomide in the routine management of patients with RA
needs to be Further established. As rheumatologists gain more experience with leflunomide, the
drug's effectiveness will likely improve and further enhance its economic profile.
CHAPTER 6
Epilogue
Pharmacoeconomic evaluations of pharmaceuticals often depend on information that needs to be
collected in routine care settings, and often country-specific. Data from randomized controlled
trials, observational studies and administrative databases, and those collected from experts need
to be integrated in an appropriate way to adequately estimate the pharmacoeconomic
characteristics of a given drug in a country-specific setting. The methods of economic evaluation
are inexact and often leave sufficient room for specific decisions or assumptions to influence the
final findings. Consequently, results of economic evaluations are preferably seen as supporting
reimbursement decisions rather than guiding them.
This thesis presents a comprehensive assessment of the pharmacoeconomic properties of
leflunomide, a novel disease-modifying anti-rheumatic drug. Several studies, surveys and rneta-
analyses were undertaken to put this economic evaluation on a more stable foundation. The
physician survey was necessary to understand treatment preferences and their sequences in
patients who are similar to those receiving leflunomide. Furthennore, to not just provide head to
head comparisons to methotrexate or other DMARDs, an understanding of the long-term
behaviour of patients on these DMARDs was required. The meta-analysis of DMARDs provided
this quantitative information from published studies of these DMARDs under clinical trial and
routine care conditions. These data made it possible to model the management of patients with
RA in the long-term and to align treatments in a sequence that is close to what physicians would
do in their routine care of patients with RA. Review of these published studies also provided
sufficient information about the incidence and severity of adverse events under routine care
conditions.
However, the information derived fkom observational studies needed to be supplemented by data
collected in randomized controlled trial settings. For example the standard gamble utilities
measured in the randomized controlled trial of leflunomide, methotrexate and placebo were
required to assess the cost-effectiveness of leflunomide in terms of cost per quality adjusted life-
year gained. Equally important were the ACR response rates. Therefore, this combination of trial
data, data derived fiom systematic reviews and separately conducted surveys corroborated the
treatment model underlying this economic evaluation fiom various perspectives, that of the
routine care setting and that of a clinical trial setting.
The separately conducted analysis of the immediate economic consequences of methotrexate,
leflunomide and placebo, as collected alongside the randomized controlled trial, provided a
further understanding of the pharmaco-economic properties of leflunomide. The results showed
that decision makers can count on economic consequences that are similar to methotrexate and
therefore assist decision maken in gaining a better understanding about the costs of leflunomide,
should they opt for Full or restricted reimbursement.
Leflunomide is a much needed DMARD that enables patients to delay the need for much more
aggressive therapies or even surgery. Its overall profile, including efficacy and adverse events, is
equal to that of rnethotrexate, at present the standard treatment for patients with rheumatoid
arthritis. It comes at an extra costs that decision makers need to assess in their particular
circumstances. The results of this thesis may provide helpful assistance.
References
[I] Amen FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The
American Rheumatism Association 1987 revised criteria for the classification of rheumatoid
arkitis. Arthritis Rheum 1988; 3 1(3):3 15-324.
[2] Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C et al. American
College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis.
Arthritis Rheum 1995; 38(6):727-735.
[3] Felson DT, Anderson JJ, Lange ML, Wells G, LaValley MP. Should improvement in
rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in
core set measures, rather than twenty percent? Arthritis Rheum 1998; 4 l(9): 1564- 1570.
[4] Fries JF. The hierarchy olquality-of-life assessment, the Health Assessment Questionnaire
(HAQ), and issues mandating development of a toxicity index. Controlled Clin Trials 199 1 ; l2(4
Suppl): 106s- 1 17s.
[5] Pincus T, Summey JA, Soraci SA, Jr., Wallston KA, Hurnmon NP. Assessment of patient
satisfaction in activities of daily living using a modified Stanford Health Assessment
Questionnaire. Arthritis Rheum 1983; 26(1l): 1346- 1353.
[6] Wiles N, Symmons DP, Harrison B, Barrett E, Barrett JH, Scott DG et al. Estimating the
incidence of rheumatoid arthritis: trying to hit a moving target? Arthritis Rheum 1999;
42(7): 1339-1 346.
[7] Symmons DP, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with
rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998; X(6): 1072- 107%
[8] Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal
antiinflammatory drugs [review]. N Engl J Med 1999; 340(24): 1 888- 1 899.
[9] Maetzel A, Bombardier C, Strand V, Tugwell P, Wells G. How US and Canadian
rheumatologists treat moderate or aggressive rheumatoid arthritis: a survey. J Rheumatol 1998;
25:233 1-2338.
[lo] Guidelines for the management of rheumatoid arthritis. American College of Rheurnatology
Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39(5):7 13-722.
[ l 11 Kinvan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The
Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group [see comments]. N
Engl l Med 1995; 333(3): 142-146.
[El Kirwan JR, B a h t G, Szebenyi B. Anniversary: 50 years of glucocorticoid treatment in
rheumatoid arthritis [editorial]. Rheumatology (Oxford) 1999; 38(2): 100- 102.
[13] Kirwan JR, Russell AS. Systemic glucocorticoid treatment in rheumatoid arthritis--a debate
[editorial]. Scand I Rheumatol 1998; 27(4):247-25 1.
[14] Jiang Y, Genant HK, Watt I, Cobby M, Bresnihan B, Aitchison R et al. A multicenter,
double-blind, dose-ranging, randomized, placebo- controlled study of recombinant human
interleukin- 1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and
correlation of Genant and Lanen scores. Arthritis Rheum 2000; 43(5): 100 1 - 1009.
[15] Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan 2, Emery P et al.
Treatment of rheumatoid arthritis with recombinant human interleukin-l receptor antagonist [see
comments]. Arthritis Rheum 1 998; 4 1(12):2 196-2204.
[16] Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ et
al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med
1999; 130(6):478-486.
[17] Weinblatt ME, Kremer SM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI et al. A
trial of etanercept, a recombinant tumor necrosis factor receptor:Fc hsion protein, in patients
with rheumatoid arthritis receiving methotrexate [see comments]. N Engl J Med 1999;
340(4):253-259.
[I81 Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M et al. Infliximab
(chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid
arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRKT
Study Group. Lancet 1999; 354(9194): 1932-1939.
[19] Finck B., Martin R., Fleischmann R., Moreland LW, Schiff M, Bathon J. A Phase EI Trial
of Etanercept vs. Methotrexate (MTX) In Early Rheumatoid Arthritis (Enbrel (33 ERA Trial).
Arthritis & Rheumatism 42[9 (Supp.)], S 1 17. 1999.
Ref Type: Abstract
[20] Badley EM. The economic burden of musculoskeletal disorders in Canada is similar to that
for cancer, and may be higher [editorial]. J Rheumatol 1995; 22(2):204-206.
[21] Coyte PC, Asche C, Croxford R, Wu K. The Economic Cost of Arthritis and Rheumatism
in Canada. In: Williams JI, Badley EM, editors. Patterns of Health Care in Ontario: Arthritis and
Related Conditions. Toronto: Institute for Clinical Evaluative Sciences, 1998: 27-34.
[22] Clarke AE, Zowall H, Levinton C, Assirnakopoulos H, Sibley JT, Haga M et al. Direct and
indirect medical costs incurred by Canadian patients with rheumatoid arthritis: a 12 year study. J
Rheumatol 1997; 24(6): 105 1 - 1060.
[23] Strand V, Cohen SJ, Schiff M, Weaver A, Fleischmann RM, Cannon G et al. Treatment of
Active Rheumatoid Arthritis With Leflunomide Compared With Placebo and Methotrexate. Arch
Intern Med 1999; 1 S9(2 l):2542-2550.
[24] Smolen JS, Kalden IR, Scott DL, Rozrnan B, Kvien TK, Larsen A et al. Efficacy and safety
of leflunornide compared with placebo and sulphasalazine in active rheumatoid arthritis: a
double-blind, randomised, multicentre trial. European Leflunomide Study Group [see
comments]. Lancet 1999; 353(9149):259-266.
[25] Wilke WS, Sweeney TJ, Calabrese LH. Early, aggressive therapy for rheumatoid arthritis:
concerns, descriptions, and estimate of outcome. [Review]. Semin Arthritis Rheum 1993; 23(2
Suppl l):26-41.
[26] McCarty DJ. Suppress rheumatoid inflammation early and leave the pyramid to the
Egyptians [editorial]. J Rheumatol 1990; 17(9): 1 1 15-1 1 18.
[27] Suarez-Almazor ME, Soskolne CL, Saunden LD, Russell AS. Use of second line h g s for
the treatment of rheumatoid arthritis in Edmonton, Alberta. Patterns of prescription and longterm
effectiveness. J Rheumatol 1995; 22(5):836-843.
[28] Collins D, Bellarny N, Campbell J. A Canadian survey of current methotrexate prescribing
practices in rheumatoid arthritis. J Rheumatol 1994; 2 1 : 1220- 1223.
[29] Bellamy N, Brooks PM, Campbell J, Drane D, Dupen F. An Australian survey of current
prescribing practices of methotrexate in rheumatoid arthritis. Aust N Z I Med 1994; 2 4 2 14-2 16.
[30] Criswell LA, Henke CJ. What explains the variation among rheumatologists in their use of
prednisone and second line agents for the treatment of rheumatoid arthritis? J Rheumatol 1995;
22(5):829-835.
[3 11 Wolfe F, Haw ley DJ, Cathey MA. Termination of slow acting antirheurnatic therapy in
rheumatoid arthritis: a i 4-year prospective evaluation of 10 1 7 consecutive starts. J Rheumatol
1990; 1 7:994- 1002.
[32] Pincus T, Marcum SB, Callahan LF. Longterm drug therapy for rheumatoid arthritis in
seven rheumatology private practices: II. Second line drugs and prednisone. I Rheumatol 1992;
19: 1885-1 894.
[33] Alarcon GS, Tracy IC, Strand GM, Singh K, Macaluso M. Survival and drug
discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients.
Ann Rheum Dis 1995; S4(9):708-7 12.
[34] Morand EF, McCloud PI, Littlejohn GO. Life table analysis of 879 treatment episodes with
slow acting antirheurnatic drugs in community rheumatology practice [published erratum appears
in J Rheumatol 1992 Dec; lg(I2): 19981. J Rheumatol 19%; l9:704-708.
[35] O'Dell JR, Haire CE, Erikson N, Dryrnalski W, Palmer W, Eckhoff PI et al. Treatment of
rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a
combination of all three medications. N Engl J Med 1996; 334(20): 1287-1 29 1.
[36] Jones TV, Gerrity MS, Earp J. Written case simulations: do they predict physicians'
behavior? [see comments]. J Clin Epidemiol 1990; 43:805-8 15.
[37] Rethans JJ, van Boven CP. Simulated patients in general practice: a different look at the
consultation. Br Med J 1987; 294:809-8 12.
[38] Kirwan JR, Chaput de Saintonge DM, Joyce CR, Currey HL. Clinical judgment in
rheumatoid arthritis. I. Rheumatologists' opinions and the development of 'paper patients'. Ann
Rheum Dis 1983; 42:644-647.
[39] Kirwan JR, Bellamy N, Condon H, Buchanan WW, Barnes CG. Judging "current disease
activity" in rheumatoid arthritis--an international comparison. J Rheumatol 1983; 1 O:9O 1-905.
[40] Holt WS, Jr., Mazzuca SA. A written case simulation of osteoarthritis as a predictor of
prescribing behavior among family practitioners. Acad Med 1992; 67:4 14-4 15.
[41] Wolfe F, Pincus T, Fries JF, US Inception Cohort Group. Use of second line "Disease
Modifying" anti-rheumatic drugs (DMARDs) within 5 months of disease onset by 64% of 750
rheumatoid arthritis patients under care of 142 US rheumatologists: an inception cohort study.
Arthritis & Rheumatism 40[9], S2 18. 1997.
Ref Type: Abstract
[42] Prashker MJ, Meenan R E The total costs of drug therapy for rheumatoid arthritis. A model
based on costs of drug, monitoring, and toxicity. Arthritis Rheum 1995; 38:3 18-325.
[43] Moreland LW, Kimberly RP, Alarcon GS. European (EU) and US rheumatologists
(RHEUM) agree in triple but not on double of single early DMARD choice for different types of
RA. Arthritis & Rheumatism 40[9 (Supplement)], S218. 1997.
Ref Type: Abstract
[44] O'Dell JR, Rheumatoid Arthritis Investigational Network. Combination therapy for
rheumatoid arthritis: Apparent universal zcceptance. Arthritis & Rheumatism 40[9
(Supplement)], SSO. 1997.
Ref Type: Abstract
[45] Asch DA, Jedrziewski MK, Christakis NA. Response rates to mail surveys published in
medical journals. J Clin Epidemiol 1997; SO(1O): 1 129- 1 1 36.
[46] Maetzel A, Wong A, Strand V, Tugwell P, Wells G, Bombardier C. Meta-analysis of
treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-
rheumatic drugs. Rheumatology 2000; 39(9):xx-xx.
[47] Felson DT, Anderson JJ, Boers M, Bombardier C, Chemoff M, Fried B et al. The American
College of Rheurnatology preliminary core set of disease activity measures for rheumatoid
arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical
Trials. Arthritis Rheum 1993; 36:729-740.
[48] Hawley DJ, Wolfe F. Are the results of controlled clinical trials and observational studies
of second line therapy in rheumatoid arthritis valid and generalizable as measures of rheumatoid
arthritis outcome: analysis of 122 studies [see comments]. J Rheurnatol 199 1 ; 18: 1008- 10 14.
[49] Pincus T, Stein CM. What is the best source of useful data on the treatment of rheumatoid
arthritis: clinical trials, clinical observations, or clinical protocols? [editorial; comment]. J
Rheumatol 1995; 22(9):1611-1617.
[50] Jenkins DP, Cooke MW, Glucksman EE. Audit of upper limb fracture management in an
accident and emergency department. Journal of Accident & Emergency Medicine 1994; 1 1 : 105-
108.
[51] Kirklin JW, Blackstone EH, Nafiel DC, Turner ME. Influence of study goals on study
design and execution. Controlled Clin Trials 1997; 18(6):488-493.
[52] Herman J. Advancing the standards of clinical research: the urgent need for new methods
and better data. Journal of Evaluation in Clinical Practice 1997; 3(3):223-227.
[53] Black N. Why we need observational studies to evaluate the effectiveness of health care.
BMJ 1996; 312(7040):1215-1218.
1541 Streiner DL. Stayin' alive: an introduction to swiva l analysis. Canadian Journal of
Psychiatry - Revue Canadieme de Psychiatric 1995; 40(8):439-444.
[55] Caspi D, Tishler M, Yaron M. Association between gold induced skin rash and remission
in patients with rheumatoid arthritis [see comments]. Ann Rheum Dis 1989; 48(9):730-732.
[56] Felson DT, Anderson IJ, Meenan RF. The comparative efficacy and toxicity of second-line
drugs in rheumatoid arthritis. Results of two metaanalyses [see comments]. Arthritis Rheum
1990; 33: 1449-1461.
[57] Wolfe F. The epidemiology oldrug treatment failure in rheumatoid arthritis. [Review].
Baillieres Clin Rheumatol 1995; 9(4):6 19-632.
[58] Ferraccioli GF, Salaffi F, Nervetti A, Manganelli P. Long-term outcome with gold
thiosulphate and tiopronin in 200 rheumatoid patients. Clin Exp Rheumatol 1989; 7(6):577-58 1.
[59] Porter DR. M c h e s I, Hunter I, Capell HA. Outcome of second line therapy in rheumatoid
arthritis. Ann Rheum Dis 1994; 53(12):8 12-8 15.
[60] McEntegart A, Porter D, Capell HA, Thomson EA. Sulfasalazine has a better
efficacy/toxicity profile than auranofin--evidence from a 5 year prospective, randomized trial. J
Rheumatol 1996; 23(7 1): 1887-1 890.
[6 11 KO fheister RT. Methotrexate therapy in rheumatoid arthritis: 15 yean experience. Am J
Med 1983; 75:69-73.
[62] Scully CJ, Anderson CJ, Cannon GW. Long-term methotrexate therapy for rheumatoid
arthritis. [Review]. Semin Arthritis Rheum 199 1 ; 20:3 1 7-33 1.
[63] Weinblatt ME, Kaplan H, Germain BF, Block S, Solomon SD, Memman RCWF et al.
Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study. Arthritis Rheum
1994; 3 7: 1492- 1498.
[64] Rau R, Herbom G, Karger T, Menninger H, Elhardt D, Schmitt J. A double blind
randomized parallel trial of intramuscular methotrexate and gold sodium thiomalate in early
erosive rheumatoid arthritis. J Rheumatol 1991 ; 18:328-333.
[65] Rau R, Herbom G, Meminger H, Blechschmidt J. comparison of intramuscular
methotrexate and gold sodium thiomalate in the treatment of early erosive rheumatoid arthritis:
12 month data of a double-blind parallel study of 174 patients. Br J Rheumatol 1997; 36(3):345-
[66] Fries IF, Spitz PW, Mitchell DM, Roth SH, Wolfe F, Bloch DA. Impact of specific therapy
upon rheumatoid arthritis. Arthritis Rheum 1986; 29(5):620-627.
[67] Wolfe F, Hawley DJ. Cathey MA. Measurement of gold treatment effect in clinical
practice: evidence for effectiveness of intramuscular gold therapy. J Rheurnatol 1993; 20(5):797-
802.
[68] Klinkhoff AV, Teufel A. How low can you go? Use of very low dosage of gold in patients
with mucocutaneous reactions. J Rheumatol 1995; 22(9): 1657- 1659.
[69] Klinkhoff AV, Teufel A. The second course of gold. J Rheumatol 1995; 22(9): 1655- 1656.
[70] Svensson A, Theander J. Skin rashes and stomatitis due to parenteral treatment of
rheumatoid arthritis with sodium aurothiomalate. Ann Rheum Dis 1992; 5 1 (3):326-329.
[71] Sander 0, Herbom G, Bock E, Rau R. Prospective six year follow up of patients withdrawn
fiom a randomised study comparing parenteral gold salt and methotrexate. Ann Rheum Dis
1999; 58(5):28 1-287.
[72] Utley M, Gallivan S, Young A, Cox N, Davies P, Dixey J et al. Potential bias in Kaplan-
Meier survival analysis applied to rheumatology drug studies. Rheumatology 2000; 39: 1-2.
[73] Anis AH, Tugwell PX, Wells GA, Stewart DG. A cost effectiveness analysis of
cyclosporine in rheumatoid arthritis. J Rheumatol 1996; 23(4):609-6 16.
[74] Kavanaugh A, Heudebert G, Cush J, Jain R. Cost evaluation of novel therapeutics in
rheumatoid arthritis (CENTRA): a decision analysis model. Semin Arthritis Rheum 1996;
25(5):297-307.
[75] Verhoeven AC, Bibo JC, Boers M, Engel GL, van der LS. Cost-effectiveness and cost-
utility of combination therapy in early rheumatoid arthritis: randomized comparison of combined
step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone. COBRA
Trial Group. Combinatietherapie Bij Reumatoide Artritis. Br J Rheumatol 1998; 37(10): 1 102-
1 109.
[76] Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G et al. Treatment of
active rheumatoid arthritis with leflunomide compared with placebo and methotrexate.
Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999; 159(2 1):2542-
2550.
[77] Coyle D. Statistical analysis in pharmacoeconomic studies. A review of current issues and
standards [see comments]. Pharmacoeconomics 1996; 9(6):506-5 1 6.
[78] Thompson SG, Barber JA. How should cost data in pragmatic randornised trials be
analysed? BMJ 2000; 320(7243): 1 197-1 200.
[79] Barber JA, Thompson SG. Analysis and interpretation of cost data in randomised
controlled trials: review of published studies [see comments]. BMJ 1998; 3 17(7 167): 1 195- 1200.
[80] Zhou XH, Melfi CA, Hui SL. Methods for comparison of cost data. Ann Intern Med 1997;
l27(8 Pt 2):752-756.
[8 11 Rutten-van Molken MP, van Doorslaer EK, van Vliet RC. Statistical analysis of cost
outcomes in a randomized controlled clinical trial. Health Econ 1994; 3(5):333-345.
[82] Gironimi G, Clarke AE, Hamilton VH, Danoff DS, Bloch DA, Fries JF et al. Why health
care costs more in the US: comparing health care expenditures between systemic lupus
erythematosus patients in Stanford and Montreal. Arthritis Rheum 1996; 39(6):979-987.
[83] Verhoeven AC, Bibo JC, Boers M, Engel GL, van der Linden S. Cost-effectiveness and
cost-utility of combination therapy in early rheumatoid arthritis: randomized comparison of
combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone.
COBRA Trial Group. Cornbinatietherapie Bij Reurnatoide Artritis. Br J Rheumatol 1998;
37(10):1102-1109.
[84] Albert DA, Aksentijevich S, Hurst S, Fries JF, Wolfe F. Modeling therapeutic strategies in
rheumatoid arthritis: use of decision analysis and Markov models. J Rheumatol2000; 27(3):644-
652.
[85] Kobelt G, Eberhardt K, Jonsson L, Jonsson B. Economic consequences of the progression
of rheumatoid arthritis in Sweden. Arthritis Rheum 1999; 42(2):347-356.
[86] Paulus HE, Egger MJ, Ward JR, Williams HI. Analysis of improvement in individual
rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the
findings in patients treated with placebo. The Cooperative Systematic Studies of Rheumatic
Diseases Group [see comments]. Arthritis Rheum 1990; 33(4):477-484.
[87] van Gestel AM, Prevoo ML, van't Hof MA, van Rijswijk MH, van de Putte LB, van Riel
PL. Development and validation of the European League Against Rheumatism response criteria
for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology
and the World Health Organizationhtemational League Against Rheumatism Criteria. Arthritis
Rheum 1996; 39(1):34-40.
[88] Ontario Ministry of Health. Schedule of Benefits. Physician Services under the Health
Insurance Act. Toronto: Ontario Ministry of Health, 1998.
[89] S t i ~ e t t AA, Paltiel AD. Estimating CE ratios under second-order uncertainty: the mean
ratio versus the ratio of means. Med Deck Making 1997; 17(4):483-489.