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Canadian Coordinating Office for Health Technology Assessment
SELECTIVE SEROTONIN
REUPTAKE INHIBITORS (SSRIs)
FOR MAJOR DEPRESSION
PART II
THE COST-EFFECTIVENESS OF SSRIs IN
TREATMENT OF DEPRESSION
CCOHTA Report 1997: 4E
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit
organization, funded by the federal, provincial and territorial governments. It was established to encourage
the appropriate use of health technology by influencing decision-makers through the scientific evaluation
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health are examined.
This report should be cited as:
Canadian Coordinating Office for Health Technology Assessment. Selective serotonin reuptake
inhibitors (SSRIs) for major depression. Part II. The cost-effectiveness of SSRIs in treatment of
depression. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 1997.
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National Library of Canada
ISBN 1-895561-54-X
Canadian Coordinating Office for Health Technology Assessment
SELECTIVE SEROTONIN
REUPTAKE INHIBITORS (SSRIs)
FOR MAJOR DEPRESSION
PART II
THE COST-EFFECTIVENESS OF SSRIs IN
TREATMENT OF DEPRESSION
PROJECT DIRECTOR:
Jean-François Baladi
AUGUST 1997
REVIEWERS
External Reviewers
Dr. Sten Thelander
Psychiatrist, Swedish Council on Technology
Assessment in Health Care
Stockholm, Sweden
Dr. Gilbert Pinard
Director, Department of Psychology
McGill University
Montreal, Quebec
SmithKline Beecham Inc.
Oakville, Ontario
Eli Lilly Canada Inc.
Scarborough, Ontario
This report was reviewed by external
reviewers and by members of a subcommittee
of CCOHTA’s Scientific Advisory Panel.
These individuals kindly provided comments
on drafts of this report. This final document
incorporates most of the Reviewers comments,
however, the authors take sole responsibility
for its form and content.
Pfizer Canada Inc.
Pointe-Claire, Dorval, Quebec
Solvay Pharma Inc.
Scarborough, Ontario
Subcommittee Members
Dr. Bernie O’Brien
Associate Professor, McMaster University
Centre for Evaluation of Medicines
St. Joseph’s Hospital
Hamilton, Ontario
Dr. Murray Krahn
Staff Physician
Division of General Internal Medicine &
Clinical Epidemiology
The Toronto Hospital
Toronto, Ontario
Dr. Ingrid Sketris
College of Pharmacy, Dalhousie University
Halifax, Nova Scotia
Canadian Coordinating Office for Health Technology Assessment
EXECUTIVE SUMMARY
Recent years have witnessed large increases in expenditures on antidepressants. This has coincided with
the introduction and the widespread use of a new class of antidepressants, the selective serotonin
reuptake inhibitors (SSRIs). SSRIs are substantially more expensive than the older tricyclic
antidepressants (TCAs), but have a different adverse effect profile and are better tolerated. This study
examines the cost-effectiveness of this new class of antidepressants as compared to TCAs in the
outpatient treatment of depression. It assesses whether SSRIs, with their higher price, have the ability to
enhance the success of antidepressive treatments, can lead to savings in other health care expenditures
and can improve quality of life for patients.
A decision model is built in order to compare three different strategies. The first strategy consists of an
SSRI followed by a TCA in case of failure, the second strategy consists of a TCA followed by an SSRI in
case of failure, and the third strategy consists of TCA only. The decision model incorporates the possibility
of dropping out of therapy or a relapse or recurrence of depressive symptoms. Success is defined simply
as having stayed on treatment without dropping out of it. Clinical data concerning treatment efficacy is
obtained from a meta-analysis of randomized controlled trials. Resource use is estimated by the research
team from the literature and from discussions held with a number of practitioners. Costs of resources are
obtained from a variety of Canadian sources. The cost of SSRIs and TCAs used, generic fluoxetine and
generic imipramine, respectively, is the cost of the cheapest drug in each class. Health related quality of
life is introduced into the model with the incorporation of utility values. Utility values taken from the
literature are varied within the sensitivity analysis. The analysis is carried out from a Ministry of Health
perspective and extended over a nine month time horizon.
Although simple in construct, the decision model allows the derivation of some interesting conclusions
regarding the cost, success rate, and utility of the different strategies examined. The model indicates that
the success rate of a short term treatment with an SSRI is higher than one with a TCA, but is also more
expensive. However, as maintenance therapy is initiated, and the switch of medications is allowed for
those who drop out of a treatment, the cumulative success rate of the SSRI first strategy becomes very
similar to that of the TCA first strategy, but the cost of the SSRI first strategy increases over time. In
comparison, when estimates of drop-out rates taken from studies conducted in naturalistic environments
are substituted for clinical trial rates, this additional cost becomes increasingly small. When the cost of
a more expensive TCA is used (such as desipramine), the difference in the expected costs of treatment
tend to disappear. If quality of life is considered, the SSRI first strategy offers improved quality of life over
the TCA first strategy. In other words, an SSRI first-line strategy is dominant over a TCA only strategy,
and an SSRI first-line strategy compared to a SSRI second-line strategy produces QALYs at an acceptable
cost by current standards. Sensitivity analysis shows that these results are robust.
This analysis allows us to conclude that a treatment strategy which can rely on SSRIs leads to higher
success rate than one which relies on TCAs alone. When both drug classes are considered as part of a
treatment, the SSRI first strategy has similar success rate as a TCA first therapy and is more costly.
However, this cost may likely be offset by improved quality of life of patients.
Canadian Coordinating Office for Health Technology Assessment
TABLE OF CONTENTS
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2
Therapeutic Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3
Indications for which Economic Evaluation is being done . . . . . . . . . . . . . . . . . . . . . .
1.4
Objectives of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1
2
2
2
2. OVERVIEW OF PREVIOUS WORK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. METHODS
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
4. RESULTS
4.1
4.2
4.3
4.4
................................................................... 5
Type of analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Target Audience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Viewpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Comparator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Time Horizon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
The Decision Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Utilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Resource Measurement and Cost Valuation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Uncertainty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
...................................................................
Cost-Minimization Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cost-Effectiveness and Cost-Utility Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sensitivity Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Equity Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
15
15
17
20
5. DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
6. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
APPENDIX
Canadian Coordinating Office for Health Technology Assessment
TABLES
Table 1:
Table 2:
Table 3:
Table 4:
Table 5:
Table 6:
Table 7:
Table 8:
Table 9:
Table 10:
Major Determinants of Cost-Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Probabilities Used and Sources of Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Comparison of Drop Out Rates Obtained by Different Meta-Analyses . . . . . . . . . . . . . . . 10
Utility Values Used in This Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Resource Use
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Cost Estimates
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Price Comparison of Selected SSRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Baseline Case Results
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Sensitivity Analysis Results Around Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Sensitivity Analysis Results Around Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
FIGURES
Figure 1a: The Treatment Path with SSRI as a First Line Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1b: The Treatment Path with TCA as a First Line Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1c: The Treatment Path with TCA as the Only Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ABBREVIATIONS
AHCPR
CIHI
CMG
GP
HMO
HRQOL
ICES
QALY
QOL
MT
NIH
RCT
SSRI
ST
TCA
Agency for Health Care Policy and Research
Canadian Institute for Health Information
Case Mix Group
General practitioner
Health Maintenance Organization
Health related quality of life
Institute for Clinical Evaluative Sciences in Ontario
Quality Adjusted Life Years
Quality of Life
Medium term
National Institute of Health (U.S.)
Randomized controlled trial
Selective serotonin reuptake inhibitors
Short term
Tricyclic Antidepressants
Canadian Coordinating Office for Health Technology Assessment
1.
INTRODUCTION
1.1
Background
Recent years have witnessed a substantial growth in the expenditures for antidepressants. For example,
the Institute for Clinical Evaluative Sciences in Ontario (ICES) reported that the amount spent on
antidepressants per elderly resident of Ontario increased by 120%, from $6.00 to $13.25 per person,
between 1990-91 and 1994-95.1 In themselves, increased expenditures for antidepressants are not
necessarily undesirable. Effective treatment of depression can dramatically improve quality of life and
social function. In addition, it can affect the burden of illness by reducing direct and indirect costs
associated with depression. In other words, there may be economic reasons as well as social benefits
behind a society’s decision to accept increased expenditures on antidepressants.
This growing expenditure has been the result of two factors; a rise in the quantity of antidepressants used
and an increase in the average cost per dose of antidepressant prescribed. The utilization of
antidepressants could have expanded as a result of the availability of SSRIs. Indications for SSRIs are
slightly different than those for TCAs since SSRIs may be used for psychiatric disorders other than
depression. Also, conditions which were previously untreated are being treated more often with SSRIs
(possibly because of improved recognition of mental illness). Adverse effect profiles of SSRIs differ from
those of TCAs thereby making them suitable for a greater number of patients. As a result, prescribers
could be more at ease with SSRIs than with TCAs.
The increased expenditures on antidepressants may also be due to the switch from the use of tricyclic
antidepressants (TCA) to the more expensive selective serotonin reuptake inhibitors (SSRI). The per capita
expenditure on TCAs declined in Ontario from $3.40 to $3.13 from the period 1990-91 to the period 199495 (by - 8%), and the per capita expenditure on SSRIs increased by nearly 5 fold (by +488%) in the same
period from $1.52 to $8.94.1
Many studies have shown that the use of SSRIs is as, or even more, cost effective than the use of TCAs
(see Section 2. Overview of Previous Work). If this is true, this means that although medication costs have
increased over time due to the switch from TCAs to SSRIs, the overall direct cost of treatments (including
expenditures such as physicians, laboratory, monitoring costs and hospitalization), may not necessarily
have increased. Therefore, a switch from TCAs to SSRIs cannot be regarded as the sole reason for
increases in expenditures. In all likelihood, the utilization of antidepressants has expanded as a result of
the availability of SSRIs.
Ideally, therefore, an investigation into the cost effectiveness of SSRIs should be undertaken both in those
situations where SSRIs are used as an alternative to TCAs, and in those situations where SSRIs are
replacing no treatment at all. The cost-effectiveness of SSRIs depends on their use in actual practice, and
the consequences of this use on quality of life and the burden of illness of depression.
As a first step in an analysis of the cost-effectiveness of SSRIs, this study focuses on an analysis of the
cost-effectiveness of SSRIs when they are used as an alternative to TCAs. This study has not been
designed to investigate the use of SSRIs.
Part 12 of this project investigated the efficacy, adverse effect profiles and drop-out rates of SSRIs. The
present study employs a decision-analytic model. Estimates of probabilities for the decision tree branches
were obtained from the meta-analyses presented in Part 1, 2 as well as from other sources. Costs are
estimated using a variety of Canadian sources.
1.2
Therapeutic Classification
Canadian Coordinating Office for Health Technology Assessment
1
Selective serotonin reuptake inhibitors are classified as antidepressants. Some of them may also be used
as anti-obsessional, antibulimic and antipanic agents.
1.3
Indications for which Economic Evaluation is being done
The present analysis examines the cost-effectiveness of SSRIs in the treatment of major depression.
However, since this study is a comparative analysis of two treatments, its conclusions apply only in cases
where these treatments (SSRIs and their comparators) are indeed options. There may be patients for
whom one of the treatments considered is not a valid option due to co-morbidity or drug interactions. For
these individuals, results of this evaluation are not applicable. For example, SSRIs are generally preferred
in patients at particular risk from some TCA adverse effects, e.g patients at risk of heart disease or urinary
retention, or patients unable to tolerate orthostatic hypotension. Also, this analysis does not differentiate
between mild, moderate or severe forms of depression even though randomized controlled trials (RCTs),
upon which many estimates of this analysis are based, have a tendency to preferentially enroll patients
with severe forms of depression.
1.4
Objectives of the Study
This study is undertaken primarily to help Canadian Provincial drug plan managers in their formulary
decisions. This study attempts to determine:
(a) whether SSRIs are a cost-effective alternative to TCAs in the treatment of depression (as
outlined in 1.3 above)
(b) and whether their use as a first line therapy, or second line treatment influences their costeffectiveness.
The least costly SSRI is also determined.
2
Canadian Coordinating Office for Health Technology Assessment
2.
OVERVIEW OF PREVIOUS WORK
A number of economic studies have been performed comparing SSRIs to TCAs. Some studies were costminimization, for example, the Sclar et al3 study, in which fluoxetine was compared to amitryptiline,
nortriptyline or desipramine. Some studies were cost-effectiveness studies, for example, Lapierre et al,4
and Jönsson and Bebbington,5 compared paroxetine and imipramine. Some studies were cost-utility in
which patient preferences were taken into account.6, 7 Some studies were cost-benefit analyses in which
cost and outcomes were measured in pecuniary terms.8
Researchers have used different techniques such as decision modeling4, 9 or Markov chains7 in which
probability estimates were obtained from the literature. In other studies, there was retrospective analysis
of patient charts in health maintenance organization (HMO) and regression analysis was used to assess
whether total expenditures were related to the type of drug used as first line therapy.10, 3 One study
prospectively analyzed resource use and outcomes for HMO patients randomly allocated to fluoxetine,
imipramine or desipramine.11
Researchers accounted for and measured different types of resources; especially with respect to the cost
of treatment failures, the cost of the treatment of adverse events, and indirect costs. The inclusion of these
costs in the published analyses was variable.
The time horizon for these studies has also been diverse, ranging from episodic treatment5
maintenance or prophylactic therapy over a life-time.7
to
In general, authors concluded that SSRIs are equally, or more, cost-effective than TCAs, their higher drug
cost being counterbalanced by a reduction in the consumption of other health care resources such as
physician visits or hospitalization. Cost-utility ratios are within the range of acceptable cost per QualityAdjusted-Life Years (QALY) figures.12 However, these conclusions were not unanimous or fully robust and
were based on different qualities of evidence. Sensitivity analyses conducted in the various studies have
shown that there are some variables which are crucially important for the conclusions. They are: drop out
and relapse/recurrence rates, as well as resource use and the cost of treatment failures.
In Table 1, we try to summarize what is known about the determinants of the cost-effectiveness of SSRI
treatment compared with TCA treatment. With this background, we have built a decision model to examine
the impact of variables that have been shown to be critical to the cost-effectiveness conclusions, i.e. drop
out and relapse/recurrence rates and resource use.
Canadian Coordinating Office for Health Technology Assessment
3
Table 1:
Major Determinants of Cost-Effectiveness
Determinant of Costeffectiveness
Present State of Knowledge
Favor
SSRI or TCA
Drug efficacy
It is generally agreed that no one antidepressant is
clearly more effective than another. This has been
confirmed in RCTs as well as retrospective studies
Both equally
Adverse events profile
RCTs as well as retrospective studies have generally
concluded that TCAs and SSRIs have different adverse
events profiles. Compared to TCAs, SSRIs have fewer
anticholinergic, sedative and cardiovascular adverse
effects but have more gastro-intestinal side effects.
Depends on
preferences.
Adverse events
profile is different
Drug acceptability and
compliance
RCTs have found that drop out due to adverse effects is
more important with TCAs, but differences in total drop
out have not always been statistically significant.
Studies conducted in naturalistic environments generally
agree that compliance is higher with SSRIs, but it is not
known whether these differences are sustained in the
long term.
SSRIs
Relapse and recurrence
rates
Although there are some doubts regarding the long-term
efficacy of TCAs in the prevention of relapse, there is no
strong evidence regarding which of SSRIs or TCAs is
more effective in this respect.
Still unknown
Health related quality of life
(HRQOL) and patient
preferences
The fact that adverse event profile is different between
the two classes of drug does not imply that one is
preferred to another. However, the apparent higher
acceptability of SSRIs suggests that SSRIs are
preferable on average. Also, studies have found that
SSRIs are associated with improved HRQOL.
Tends towards
SSRIs
Drug acquisition costs
SSRIs are generally more expensive than TCAs, but
large price differences exist among TCAs
TCAs
Resource use during
treatment
Generally the same for SSRIs and TCAs. However,
depending on patient conditions, TCAs may require
more physician visits and laboratory tests for dosage
adjustment and close follow-up. Hospitalization is not
believed to be related to treatment with one or another
class of drug unless the treatment results in failure.
Tends towards
SSRIs
Safety in overdose
Although SSRIs are regarded as safer in overdose and
in case of overdose may require shorter length of stay,
the view that completed suicide depends on the
willingness to commit suicide rather than on the drug
cannot be ruled out. Long-term studies are lacking.
SSRIs
Indirect costs
To the extent that indirect costs are related to the
prevalence of depression, indirect costs will be less
important the more a treatment is efficacious and
adhered to.
Both equally.
(Faced with no
better evidence)
4
Canadian Coordinating Office for Health Technology Assessment
3.
METHODS
3.1
Type of Analysis
Cost-Minimization Among SSRIs
The meta-analysis presented in Part 12 of this study established that there are no statistical significant
differences among SSRIs in terms of efficacy, adverse effect profiles or compliance. Accordingly, a costminimization analysis among SSRIs is presented first. Whether these non-significant statistical differences
reflect a lack of clinically important differences among SSRIs is debatable. However, all SSRIs are
generally considered equally efficacious, although their pharmacodynamic and pharmacokinetic properties
differ. Health related quality of life may also differ for patients on these drugs.
This analysis is conducted for the sole purpose of selecting the least costly drug among the SSRIs at a
defined daily dose, so that this drug price can be used in the subsequent cost-effectiveness analysis.
Cost-Effectiveness of SSRIs Compared to TCAs
After the brief review of the current evidence in the preceding section, general considerations regarding
decision analytic models are presented. Next, a cost-effectiveness model is built in order to compare the
cost-effectiveness of SSRIs to that of TCAs, and to highlight the main determinants of cost-effectiveness.
Incorporating Patient Preferences - Cost-Utility Analysis
Health related quality of life (HRQOL) and patient preferences are incorporated into the decision model.
They are included principally because the side effect profiles of the two classes of drugs are different,
although the total drop out rate due to these side effects may not be very different.
3.2
Target Audience
The results of this analysis are intended primarily for decision makers within Canadian provincial drug
plans, and secondarily for decision makers in institutions and third party payers. However, most aspects
of this analysis would also be of interest to practitioners as well.
3.3
Viewpoint
In view of the target audience of this analysis, the perspective taken is that of a provincial payer. Costs
are measured from a health care system viewpoint. However, patient preferences are incorporated at a
later stage in the analysis and the impact of taking a societal perspective is discussed.
3.4
Comparator
This study compared SSRIs to TCAs. TCA is a common treatment option for patients with depression.
It is also the treatment option for which medication costs are currently the least expensive.
More specifically, the model outlined below compares a treatment strategy which consists of SSRI first
followed by TCA, with one which consists of TCA first and SSRI second. The third strategy consists of TCA
only. Therefore, there are two comparator strategies to the SSRI first strategy.
Canadian Coordinating Office for Health Technology Assessment
5
The rationale for using strategies that consist of more than one drug is to reflect actual practice in which
patients are switched from one drug to another when the first drug fails. This design more closely
approaches the purpose of cost-effectiveness analysis which is to investigate the cost-effectiveness of
treatment strategies. The third comparative strategy, which consists of TCA alone, is examined in order
to investigate the incremental cost-effectiveness of a treatment which includes SSRIs over a treatment in
which SSRIs would not be available.
3.5
Time Horizon
The decision model extends over a nine month period, mainly because current treatment guidelines
recommend maintenance therapy for patients who respond favourably.13, 14 However, the decision model
is also run with a short term time horizon of three months. The short term time horizon of three months
analyzes the episodic treatment of depression with either an SSRI or a TCA. By extending the length of
treatment by six additional months, the cost-effectiveness of short term treatment plus maintenance
treatment is then captured. In the longer term analysis drug substitution, relapses and recurrences were
allowed. Splitting the decision model into two time periods allows us to investigate the effect of the length
of the treatment period upon cost-effectiveness. Therefore, inferences can be made about the impact of
extending treatments by six month intervals.
3.6
The Decision Model
Description of the Model
As outlined in Section 3.4 above, the model compares three treatment paths; one in which the first-line
treatment is an SSRI, and two others where it is a TCA. The model compares these three alternative
treatment options, and calculates the cumulative success, expected costs and cost-effectiveness of each
alternative over the specified time period.
This decision model was formulated by the research team following consultation with four psychiatrists,
statisticians, and reviewers. It was run using Data 2-6® and calculations were performed using an Excel®
spreadsheet.
The decision model is depicted in Figures 1a, 1b and 1c. It focuses on specific elements which are
believed to influence the cost-effectiveness of SSRIs and TCAs, namely; drop-out rates and
relapse/recurrence rates.1 The probabilities that appear in these figures are explained below.
The model simulates patients who might follow one of three treatment arms. The first, the SSRI-TCA case,
depicts a treatment strategy which starts with an SSRI and then switches to a TCA in the case of a drop
out. Relapses while on maintenance therapy could occur. The second arm, the TCA-SSRI option, depicts
a strategy of starting with a TCA and then switching to an SSRI in the event of a drop out. Relapses are
also possible while on maintenance therapy. The third arm, the TCA only strategy, depicts a strategy in
which only TCAs are available. The possibility for spontaneous remission or recurrence of symptoms
under all three arms is also incorporated.
1
6
The model is built around drop out rates, but in actual life non-compliance may take many
different forms, such as patients renewing their refulls more slowly.
Canadian Coordinating Office for Health Technology Assessment
Switchovers that are allowed in two treatment arms give some rigidity in the model since the cumulative
probabilities of success and failures will be very similar (see for example the results of the sensitivity
analysis below). This may be considered a limitation of the model, but the alternative of not allowing for
such switchovers would, in our opinion, reduce the validity of the model. Another simplification is that
switches from one SSRI (TCA) to another SSRI (TCA) are not considered.
Outcome Measures
In this analysis, outcomes are measured first as successes or failures, and second as quality adjusted life
years. Success means that a patient did not drop out at the end of the time horizon, and failure means
that a patient dropped out of the sequence of treatments. This definition of success assumes that patients
who stay for the course of their therapy experience an effect, do not experience bothersome side effects
that cause them to drop out (reported drop out rates usually encompass drop out due to adverse events
as well as drop out because of a lack of efficacy), and do not relapse. It is acknowledged that some
patients could remain on the drug without deriving any benefit from it. However, building a model that
assumes this situation to be prevalent would be difficult. The model is extended to include health-relatedquality-of-life and patient preferences by incorporating utility values found in the literature. In the cost-utility
analysis, outcome is expressed in terms of quality adjusted life years (QALY).
Canadian Coordinating Office for Health Technology Assessment
7
Figure 1a. The Treatment Path with SSRI as a First Line Therapy
Figure 1b. The Treatment Path with TCA as a First Line Therapy
No relapse - success
Do not drop
#
Do not drop - success
#
Relapse - inc. dose
0.13
#
Drop - failure
0.385
TCA
No relapse - success
#
Do not drop SSRI
Do not drop - success
#
Drop
Relapse - inc. dose
0.13
Switch to SSRI
#
Drop - failure
0.329
0.385
No recurrence
Drop SSRI
0.329
#
Recurrence - failure
0.38
Figure 1c. The Treatment Path with TCA as the Only Therapy
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Canadian Coordinating Office for Health Technology Assessment
Characteristics of Treatment Arms
The model has the following characteristics:
i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
x.
Once a patients is put on a drug, he/she may drop out or not.
If the patient does not drop out, he/she may either relapse or stay on the drug for the nine
month period. A relapse is defined as a reported worsening of symptoms while on
medication.
If the patient relapses while on the first line drug, the dose of the drug is increased.
Following the increased dose, the patient again may either drop out or stay on the drug.
If a patient drops out, therapy is switched, except in the TCA only arm.
After a switch of therapy, a patient either drops out or continues treatment.
Those who drop out following a switch of therapy may experience a recurrence of
symptoms, otherwise their symptoms remit. A recurrence is defined in this study as a
worsening of symptoms while not on medication.
In the TCA only arm also, those patients who drop out may or may not experience a
recurrence.
Those patients who have dropped out are considered failures, otherwise the treatment is
considered a success.
The short-term analysis extends over the first three months during which neither a relapse
nor a switch of medication occurs.
Probabilities and Sources of Information
The probabilities of the events included in the decision model as well as the sources are indicated in
Table 2.
Table 2:
Probabilities Used and Sources of Information
SSRI drop out
SSRI relapse
TCA drop out
TCA relapse
Recurrence
Estimate
Confidence Interval
32.9%
13.0%
38.5%
13.0%
38.0%
28.8 - 37.3
n.a.
32.4 - 45.3
n.a.
n.a.
Source
Meta analysis in Part 1, Section 6.2.32
Doogan & Caillard, 199215
Meta analysis in Part 1*, Section 6.2.32
Assumed to be equal to that of SSRIs
Mueller 1996,16 Keller 1982,17
n.a.: not available
*
Part 1 has selected for the purpose of meta-analysis, only a subset of published studies of TCAs (which included all
head-to-head studies between SSRIs and TCAs) versus a more complete set of studies involving SSRIs. However, it is
assumed that this subset of TCA studies is representative of the larger set of TCA studies. The results of other metaanalyses are tested within the sensitivity analysis.
Canadian Coordinating Office for Health Technology Assessment
9
Assumption
The major assumption made in this model is that drop out rates of TCAs and SSRIs do not depend on
previous therapy. However, we are not aware of any other evidence, and Part 1, Section 6.1.52 suggested
this assumption. The impact of relaxing this assumption will be discussed below. Also, since the drop out
rates used in the decision model are those that prevailed at 12 weeks in RCTs, the model approaches a
cost-efficacy analysis rather than a cost effectiveness analysis. However, in an attempt to more closely
represent real life situations, a number of special cases that rely on estimates coming from naturalistic
studies are modeled within the sensitivity analyses.
In this decision model, the probability of drop out plays a central role. For comparison Table 3 compares
the drop out rates obtained by other meta-analyses.
Table 3:
Comparison of Drop Out Rates Obtained by Different Meta-Analyses
Study
Drop Out Rate
SSRI
Montgomery et al (1994)18
Song et al (1993)19
Dunbar et al (1991)20
Anderson & Tomenson (1995)21
Part 12
19%
32%
42%
31%
33%
Montgomery et al (1994)18
Song et al (1993)19
Dunbar et al (1991)20
Anderson & Tomenson (1995)21
Part 12
27%
33%
54%
33%
39%
Difference between SSRI and TCA
Montgomery et al (1994)18
Song et al (1993)19
Dunbar et al (1991)20
Anderson & Tomenson (1995)21
Part 12
- 8%
- 1%
- 12%
- 2%
- 6%
TCA
3.7
Utilities
Utilities used in this model were derived from published literature. In a recent article, Revicki et al (1995)7
used utility values obtained by applying standard gamble scaling methods to 70 patients with major
depressive disorders. The following utility values were taken from that article and used in this analysis
(Table 4). It should, however, be noted that these utility values were derived from a single study with a
limited number of patients. Despite the increasing acceptance of utility values, there is still debate about
the methods used to elicit such values and the equity assumptions on which they rest.
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Canadian Coordinating Office for Health Technology Assessment
Table 4:
Utility Values Used in This Model
Health state in Revicki et al (1995)7
Utility
Values
Health states in our
model for which
Revicki et al values are
applied
Utility values
used in
sensitivity
analysis
Acute episode, fluoxetine treatment a
3 months treatment, fluoxetineb
Prophylaxis, fluoxetine c
0.725
0.795
0.859
1st 3 months on SSRI
2nd 3 months on SSRI
3rd 3 months on SSRI
0.8625
0.8975
0.9295
Acute episode, imipramine treatmenta
3 months treatment, imipramineb
Prophylaxis, imipraminec
0.667
0.734
0.797
1st 3 months on TCA
2nd 3 months on TCA
3rd 3 months on TCA
0.8335
0.8670
0.8985
Untreated depression
0.306
Therapy failure
No recurrence
0.6530
0.9295
a
b
c
3.8
Utility after 1 month of treatment.
Utility after 3 months of treatment.
Utility after 6 months of prophylaxis.
Resource Measurement and Cost Valuation
Resource Use
Estimates of resource consumption were determined following consultation with the clinical experts
mentioned above. They are based on the following assumptions:
i.
ii.
iii.
iv.
v.
vi.
When neither a drop out nor a relapse occurs, four general practitioner (GP) visits and one set
of laboratory tests are required during the nine month period in addition to the cost of
medication.
TCA treatment requires one additional GP visit for dose adjustment.
Following a relapse or a drop out, a patient is treated by a psychiatrist instead of a GP.
When there is a switch of medication, one psychiatric consultation is added.
If the switch is to a TCA, one set of laboratory tests is added.
Treatment failures are assumed to require hospitalization.
In view of the primary audience of this analysis and the controversy regarding the net loss to society of
productivity losses related to morbidity, only direct health care costs to the health care system are
considered. However, the impact of patient costs and indirect costs (time and productivity losses) will be
discussed. For example, all failures are assumed to require hospitalization. This simplification is made
in order to account for the diverse costs of treatment failures. There is indeed some evidence that shows
that depressed patients who are not treated, consume more health care resources and are less productive
than those who are treated.11, 22 No cost is attributed to the management and treatment of adverse effects
except within sensitivity analysis. Adverse effects are assumed to lead to drop out only.
Table 5 lists the estimates of resource used for each treatment arm possibility.
Canadian Coordinating Office for Health Technology Assessment
11
Table 5:
Resource Use
SSRI-TCA
End Nodes from Top to Bottom on the Tree
2
3
4
5
6
7
1
1
1
1
1
1
3
3
3
4
4
2
1
1
2
2
2
1
3
3
3
3
3
3
6
6
0
0
0
0
0
0
6
3
3
3
0
0
0
3
3
0
0
20*
0
0
20*
0
No. of GP visits
No. of psychiatrist visits
No. of lab test sets
Months on 1st SSRI
Months on increased SSRI dose
Months on TCA
Months on increased TCA dose
Days hospitalized
1
4
0
1
9
0
0
0
0
TCA-SSRI
No. of GP visits
No. of psychiatrist visits
No. of lab test sets
Months on 1st TCA
Months on increased TCA dose
Months on SSRI
Months on increased SSRI dose
Days hospitalized
1
5
0
1
9
0
0
0
0
2
2
3
1
3
6
0
0
0
3
2
3
1
3
6
0
0
20*
4
2
3
1
3
0
6
0
0
5
2
4
1
3
0
3
3
0
TCA only
No. of GP visits
No. of psychiatrists visits
No. of Lab test sets
Months on 1st TCA
Months on increased TCA
Months on SSRI
Months on increased SSRI dose
Days hospitalized
1
5
0
1
9
0
0
0
0
2
2
3
1
3
6
0
0
0
3
2
3
1
3
6
0
0
20*
4
2
0
1
3
0
0
0
0
5
2
1
1
3
0
0
0
20*
6
2
4
1
3
0
3
3
20*
7
2
2
1
3
0
3
0
0
8
1
3
1
3
0
3
0
20*
8
2
3
1
3
0
3
0
20*
* 20 days hospital stay: Case Mix Group (CMG) 765 23
Cost Valuation
Table 6 indicates the dollar values of the resources necessary for the decision analysis.
Table 6:
Cost Estimates
SSRI daily dose: 20 mg generic fluoxetine
SSRI increased daily dose: 40 mg generic fluoxetine
TCA daily dose: 50 mg tid generic imipramine
TCA increased daily dose: 100mg tid generic imipramine
Hospital day: daily cost of 1 hospital day for standard CMG
765 (Depressive mood disorders, no ECT W AX3)H 23
General practitioner visit
Psychiatrist consultation
Laboratory tests
Estimate
$1.2035
$2.4070
$0.0558
$0.1116
$380
$58.90
$75.00
$25
Source
Quebec formulary*24
Quebec formulary*24
Quebec formulary*24
Quebec formulary*24
CIHI (personal communication) - Cost
estimated by case costing
Quebec rate **
Quebec rate **
Author’s estimate
* Formulary prices of generic drugs are very similar across Canada
** Provincial fee schedule provided by CIHI
Fluoxetine and imipramine costs are used since they have the lowest cost within their class. Other product
prices are used within the sensitivity analysis. Quebec rates for GP and psychiatric visits are chosen
because they are neither the highest nor the lowest in Canada, and also to be consistent with the drug
prices.
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Canadian Coordinating Office for Health Technology Assessment
The same cost is attributed to GP and psychiatric visits and consultation. This reflects the present
Canadian health care system in which a single fee is attached to a physician visit. In reality, some visits
consume less physician time than others, thus freeing up more time for the physician to treat other
patients. From the point of view of society’s opportunity cost, the two visits are different. Ideally, a more
detailed costing method should be used. However, considering the perspective from which costs are
measured in this study, this “case mix bias”25 is acceptable, since all these physician fees will result in the
same cost to the Ministry of Health.
3.9
Uncertainty
Uncertainty in this model derives from the use of estimates as well as from the use of assumptions. The
uncertainty surrounding each of the estimates and assumptions used in this model is addressed by
sensitivity analysis. Sensitivity analysis is performed using the upper and lower bounds of the 95%
confidence interval of estimates when available, or from values derived from other sources. Uncertainty
about assumptions is handled by running the model with different assumptions.
Sensitivity Analysis Around Estimates
The following variables are changed within the sensitivity analysis, and the values used are:
i.
ii.
iii.
iv.
v.
vi.
*
Drop out rates: 95% confidence interval used (Table 2), as well as drop out rates obtained in two
other meta-analyses ( SSRI: 42%, TCA 54%, Dunbar20 and SSRI: 32.3%, TCA: 33.4%, Song19).
These two meta-analyses are chosen because the differences in reported rates between SSRIs
and TCAs are at different extremes.
Relapse rates: +/- 50%
Physician and psychiatric costs: Newfoundland fees are used instead of Quebec fees: GP
$34.50, psychiatrist $110.65. (Newfoundland has the lowest GP rate, and one of the highest
psychiatrist rates, whereas Quebec has the highest GP rate)*
Drug costs: the cost of 150 mg of desipramine and 50 mg of sertraline, respectively $1.2676 and
$1.5364, are used instead of the costs of imipramine and fluoxetine
Hospitalization: length of stay is increased from 20 days to 60 days (length of stay for elderly
patients in psychiatric hospitals)
Utility values: utility values are increased by half the difference between the utility value and 1 (to
raise the utility values and reduce the impact of quality of life)
(Source: provincial fee schedule costs provided by CIHI)
Sensitivity Analysis Around Assumptions
In addition to the sensitivity analysis described above, the following scenarios are considered in
order to integrate additional evidence regarding actual real life performance of antidepressant
therapies.
Special Case 1: The prescription of TCA in subtherapeutic doses. It has been argued that TCAs
are often prescribed in subtherapeutic doses in general practice with the result that they become less
efficacious.26 For example, in a study on the cost implication of treatment failures, McCombs et al27,
26
excluded 45% of patient charts from further analysis because of subtherapeutic levels. To account
for this, we use the relapse rate obtained for placebo (45.7%)15 in the TCA arm.
Special Case 2: Different drop out rates than those observed in RCTs. It is often argued that the
discontinuation rates of SSRIs, and especially TCAs, are higher in actual life than those observed
Canadian Coordinating Office for Health Technology Assessment
13
in controlled trials. To address this issue, we use drop out rates taken from the review article by
Revicki and Luce28; TCA 69.5% and SSRI 50%.
Special Case 3: An increased use of resources for patients treated with TCAs. Patients using TCAs
are often said to consume more health care resources due to dose adjustment and to management
of adverse effects. One physician visit and one lab test are added in this special case.
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Canadian Coordinating Office for Health Technology Assessment
4.
RESULTS
4.1
Cost-Minimization Analysis
Table 7 shows the lowest price per daily dose of each SSRI reimbursed by Canadian drug plans. Note that
these dosages may not reflect actual clinical practice and should therefore be interpreted with care. A
comparison based on actual clinical practice dosages may yield different results. Note also that pharmacist
dispensing fees are not included.
Generic fluoxetine appears to be the cheapest alternative among the different SSRIs. This comparison
holds only for the present time in Canada, since the table compares prices of generic versions with prices
of brand name versions.
Table 7:
Price Comparison of Selected SSRIs
Generic Name
Brand Name
Daily Dose
29
Generic Version
Price 24
Brand Name Price 24
Fluoxetine
Prozac
20 mg
$1.2035
$1.6050
Fluvoxamine
Luvox
100 mg
n.a.
$1.4130
Paroxetine
Paxil
20 mg
n.a.
$1.5900
Sertraline
Zoloft
50 mg
n.a.
$1.5364
n.a.: not available
Studies comparing the cost of treatments with different SSRIs have been published. An econometric
model by Sclar et al30 compared direct costs of treatment of HMO patients treated with fluoxetine,
paroxetine or sertraline (taking into account medication costs, physician visits, laboratory testing, and
hospitalization) and concluded that fluoxetine was associated with lower total costs than the other SSRIs
examined. However, another study found that the total direct costs per patient were lower for sertraline
relative to fluoxetine.31 Similarly, a retrospective study in 1997 by Singletary et al,32 which compared the
medication costs to a medical centre for fluoxetine, sertraline, and paroxetine revealed that the average
daily medication cost with sertraline was lower than that of fluoxetine and paroxetine. Undoubtedly, these
findings reflect in large part differences in the unit price of the drugs in the different settings. For example,
generic fluoxetine may not be available in other countries. As far as the present Canadian situation is
concerned generic fluoxetine appears to have the least acquisition cost among the SSRIs.
4.2
Cost-Effectiveness and Cost-Utility Analyses
The Baseline Case
Baseline case results are obtained by using the decision model represented in Figures 1a, 1b, and 1c with
the assumptions, probability estimates, and costs described in Section 3. The cumulative expected
probability of success for a patient started either on SSRI or on TCA therapy is calculated. The expected
cost of treating each patient over the defined time period and expected utility of each treatment arm is also
estimated.
The results of the baseline case analysis (i.e. the short and medium term expected probabilities of success
as well as the expected utility and cost) are presented in Table 8. Although an incremental cost per
successfully treated patient can be calculated, this result is not displayed due to its high imprecision. The
Canadian Coordinating Office for Health Technology Assessment
15
denominator of such an incremental cost per successfully treated patient would be the difference between
the expected probabilities of success at the end of treatment arms in the two branches. In our case, these
probabilities are very similar and have large variances. Therefore the precise number is practically
meaningless. Sufficient information can be obtained by considering the similarity between the success
rates, on one hand, and cost and utility differences between the treatment branches on the other hand.
Table 8:
Baseline Case Results
SSRI-TCA
vs
TCA-SSRI
SSRI-TCA
vs
TCA only
Probability of success
ST incremental success
MT incremental success
5.6%
0.3%
5.6%
9%
Expected cost
ST incremental cost
MT incremental cost
$44
$110
$44
-$406
Expected incremental utility (MT)
0.039
0.042
Expected cost per QALY gained (MT)
$2,818
Dominant
ST: Short term, MT: Medium term
The short-term analysis reveals that the probability of success of an SSRI therapy is greater than that of
a TCA therapy (as expected from the meta analysis of drop out rates presented in Part 1 of this study)2
and its expected cost is slightly higher. However, when extended over an additional six months, during
which relapses, recurrences, and switch of therapies are allowed, the probability of success of an SSRITCA therapy is very close to that of a TCA-SSRI therapy, but higher than a TCA only therapy by 9%.
In terms of costs, the short-term SSRI first therapy has a slightly higher expected cost than the TCA first
therapy ($44), and this cost differential increases as the time horizon is increased to nine months ($110).
However, compared to the TCA only therapy, the SSRI first therapy is less costly due to the built-in cost
of treatment failures. These incremental costs of $44 and $110 are NOT the incremental costs of
successfully treating one more patient with an SSRI instead of a TCA. They are the expected incremental
costs of treating one patient with an SSRI rather than a TCA over a period of three and nine months,
knowing that the probability of success is similar with the two drugs.
When patient preferences are incorporated into the analysis via the use of utility values, the SSRI first
therapy provides, on average, increased health related quality of life over the TCA first therapy, and even
more quality of life benefits over the TCA only therapy. The cost per QALY is estimated at $3,000.
In summary, the SSRI-TCA treatment yields the same success rate as the TCA-SSRI treatment option
(0.3% difference), offers improved health related quality of life to patients, but is slightly more costly. This
cost tends to increase over time as treatment is maintained. However, compared to a TCA-only therapy,
the SSRI-TCA treatment is a dominant strategy. It is both more successful and less costly, and offers
increased health related quality of life.
The detailed results (expected costs and probabilities) are displayed in Figure A1a, A1b and A1c in
Appendix 1.
16
Canadian Coordinating Office for Health Technology Assessment
4.3
Sensitivity Analysis
The robustness of the above conclusions to different probability estimates and to changes in assumptions
is examined by using one-way sensitivity analyses as detailed in section 3.9 above.
Sensitivity Analysis Around Estimates
The results of the one-way sensitivity analyses are presented in Table 9.
Sensitivity analysis results show the following:
i.
Short term success rates: except in the case where the drop out rate for TCA is at its lowest
value, the expected short term success rate of the SSRI therapy is higher than that of TCA.
ii. Medium term success rate: In all cases, the success rates achieved by the SSRI-TCA treatment
are not significantly different than that of the TCA-SSRI strategy. Compared to the TCA only
strategy, the SSRI-TCA strategy always has a higher expected probability of success varying
between 7% and 11%, depending on the case.
iii. Short term cost: In all cases, the short term expected cost of the SSRI-TCA strategy is higher
than that of the TCA-SSRI strategy except when sertraline and desipramine costs are used. In
this case, the SSRI-TCA strategy is less expensive.
iv. Medium term cost: In all cases, the medium term expected cost of the SSRI-TCA strategy is
higher than that of the TCA-SSRI strategy. However, in the cases where either the drop out rate
for TCA is at its upper bound, Dunbar20 values are used, the length of hospital stay is high, or
where sertraline and desipramine costs are used; the increase in cost, between the short and the
medium term, is less than proportional to the increase in length of time (i.e. in these cases,
incremental costs would tend to fade as treatment extends over time, other things remaining
equal).
v. Utility gained and cost-utility ratios: In all cases, the SSRI-TCA strategy leads to increased health
related quality of life over the TCA-SSRI case. In all cases also, it leads to even greater
increases over the TCA only case, except when higher utility values are used for all health states
examined. Costs per QALY gained range between $1,500 and $6,000. In the case where
sertraline and desipramine costs are used, the QALY gained is accompanied by reduced cost.
It may therefore be argued that the conclusions reached in the baseline case are robust.
Canadian Coordinating Office for Health Technology Assessment
17
Table 9:
Sensitivity Analysis Results Around Estimates
SSRI-TCA
v/s
TCA-SSRI
TCA high drop out rate
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.124
0.006
$44
$72
0.049
$1,476
TCA low drop out rate
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
-0.005
0
$44
$150
0.031
$4,922
SSRI high drop out rate
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.012
0.001
$44
$123
0.03
$4,140
SSRI low drop out rate
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.097
0.006
$44
$96
0.048
$2,006
Dunbar20 values TCA drop 54%, SSRI drop: 42%
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.12
0.004
$44
$55
0.042
$1,297
Song19 Values TCA drop: 33.4% SSRI drop 32.3%
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.011
0.001
$44
$141
0.033
$4,254
18
SSRI-TCA
v/s
TCA only
0.108
-$536
0.052
Dominant
0.073
-$284
0.032
Dominant
0.081
-$342
0.029
Dominant
0.099
-$469
0.053
Dominant
0.106
-$525
0.036
Dominant
0.077
-$313
0.036
Dominant
Canadian Coordinating Office for Health Technology Assessment
SSRI-TCA
v/s
TCA only
SSRI-TCA
v/s
TCA-SSRI
Low relapse rate
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.056
0.002
$44
$115
0.039
$2,918
High relapse rate
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.056
0.005
$44
$106
0.039
$2,717
Newfoundland rate
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.056
0.003
$69
$126
0.039
$3,210
Desipramine and sertraline costs
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.056
0.003
-$35
-$34
0.039
-$873
Lengthy hospitalization
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.056
0.003
$44
$65
0.039
$1,653
Higher utilities
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
0.056
0.003
$44
$110
0.02
$5,636
ST: Short term
0.094
-$447
0.043
Dominant
0.086
-$365
0.04
Dominant
0.09
-$356
0.041
Dominant
0.09
-$530
0.042
Dominant
0.09
-$1,776
0.042
Dominant
0.09
-$406
0.023
Dominant
MT: Medium term
Canadian Coordinating Office for Health Technology Assessment
19
Sensitivity Analysis Around Assumptions
Results of varying assumptions under special cases are displayed in Table 10.
Table 10:
Sensitivity Analysis Results Around Assumptions
SSRI-TCA v/s
TCA-SSRI1st
Subtherapeutic doses of TCA
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
Real life drop out: TCA 69.5%, SSRI 50%
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
More resource use for TCA
ST increased success rate
MT increased success rate
ST increased cost
MT increased cost
Utility gained
Increased cost per QALY gained
SSRI-TCA v/s
TCA only
0.056
0.055
$44
-$291
0.054
Dominant
0.195
0.004
$44
$13
0.048
$276
0.056
0.003
$15
$52
0.039
$1,316
0.142
-$807
0.057
Dominant
0.113
-$577
0.03
Dominant
0.09
-$465
0.042
-$11,859
In all these cases, results are more favorable to the SSRI-TCA strategy than in the baseline case.
Conclusions regarding the similarity of success rates between the SSRI first and the TCA first strategy
remain unchanged but the medium term expected cost of the SSRI-TCA strategy is in these cases, much
lower than the baseline case. When TCA is administered in subtherapeutic doses, the expected cost of
the SSRI-TCA strategy is even less than that of TCA-SSRI. Similarly, costs per QALY gained are within
the ranges obtained in the sensitivity analyses outlined above. When TCA is administered in
subtherapeutic doses increased health related quality of life is obtained at lower cost. Therefore, under
these special cases, conclusions are more favorable to the SSRI-TCA strategy than the baseline case.
The baseline case assumes that prescribers use the appropriate dose for each drug. Here too, when
different assumptions are used, the baseline case yields results that are more favorable to the SSRI first
strategy.
4.4
Equity Issues
Equity considerations should be borne in mind when tradeoffs between health care interventions are
examined. In this study, one of the most important equity issues results from the fact that the adverse
effect profiles of SSRIs and TCAs are different, even though the difference in the total drop out rates
associated with these drugs, upon which this decision analysis rests, is not statistically significant at a
certain level of significance. The equity issue that would arise if these two classes of drugs are considered
equivalent on the basis of efficacy and drop out rates cannot be disregarded. Performing a cost
minimization analysis between the two classes, while at the same time acknowledging that the adverse
effects that lead to drop out are different between the two classes of drugs, is problematic. Such an
analysis would favor those who might suffer from the adverse effects associated with the least expensive
drug while penalizing those who might suffer from the adverse effects of the most expensive drug.
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Canadian Coordinating Office for Health Technology Assessment
5.
DISCUSSION
General
This economic evaluation of SSRIs in comparison to TCAs uses decision modeling to derive conclusions
regarding the cost-effectiveness of SSRIs when used as a first or second line therapy in the treatment of
depression. The comparators are TCAs, used either alone or supplemented by SSRIs whenever the TCAs
failed. The decision model is derived after discussions with practitioners and reviewers. Health related
quality of life is incorporated by using published utility values derived from actual patients using standard
gamble techniques. Conclusions apply only to instances where SSRIs and TCAs are valid options for the
treatment of depression. Due to co-morbidities, drug interactions, or possible adverse effects, either TCAs
or SSRIs may not be valid options.
Based on this model, it is concluded that the success rate of an episodic treatment with an SSRI (as
defined by the non-drop out) is higher than one with a TCA, but is also more expensive. However, as
maintenance therapy is initiated, and switch of medications is allowed for those who drop out of a
treatment, the cumulative success rate of the SSRI first strategy becomes very similar to that of the TCA
first strategy, but its cost increases over time. Compared to a therapy using only TCAs, the SSRI-TCA
strategy is dominant since it has a higher probability of success and costs less.
The model reveals that the aggregate cumulative probability of success with the different therapies is very
similar. This is not surprising given the construct of the model. The fact that patients are modeled to
switch between one therapy and another when the first therapy fails, combined with the fact that the
success of therapies does not depend on the previous therapies, and that relapses are not a function of
the therapies, causes this rigidity. This feature can be desirable, since repeated trials have shown that
SSRIs and TCAs are equally efficacious, as measured for example by the Hamilton Depression Rating
Scale. A recent study that traced a cohort of patients has indeed found that a number of patients switched
therapies, and that the overall success rates were not statistically different between those who were started
on an SSRI or on a TCA.11
The expected incremental cost of SSRI-TCA versus TCA-SSRI increases as the time horizon is increased.
This indicates that maintaining responsive patients on an SSRI therapy adds to the expected cost of a
treatment (if we assume the above relapse, recurrence and drop out rates as well as therapy switches that
might occur during a six month interval).
Compared to the TCA only therapy, the SSRI first therapy is less costly due to the built-in cost of treatment
failures. This is acceptable given the cost of depression and if one assumes that the availability of SSRIs
will enable the treatment of an increased number of patients. Many studies have documented the direct
and the indirect cost of depression. Depressed individuals tend to consume more health care resources
and are less productive than patients without depression (burden of illness studies).26, 33 This issue is
partially addressed by our assumption that all failures are hospitalized. Although highly simplifying, this
assumption is made to capture the cost of treatment failures. In the comparison between the SSRI-TCA
and the TCA-SSRI strategies, this assumption has little impact since the probability of hospitalization will
be very similar between these two treatment branches.
Compared to other cost-effectiveness studies, the baseline analysis of this study is somewhat less
favorable to SSRIs. Other cost-effectiveness studies have found that the cost of treatment success is less
costly with SSRIs than with TCA.4, 5, 7 These studies use a different decision model, different estimates,
include the cost of managing adverse effects or suicide costs - items which are not accounted for in this
Canadian Coordinating Office for Health Technology Assessment
21
study. The use of different drug costs could also explain dissimilar results. Sensitivity analysis reveals that
drug costs are an important determinant of the incremental cost of treatments in this analysis. The
conclusions of these previously published cost-effectiveness studies are also slightly different than those
reached in the Simon et al11 study in which HMO patients were randomized to receive either fluoxetine,
imipramine or desipramine. When patients were allowed to switch drugs if one drug failed, the study
showed that at the end of six months the total health care costs were similar between the three groups,
as was quality of life measured by the SF-36. But those patients originally on fluoxetine were less likely
to switch medication.
Studies which investigated health-related quality of life have generally concluded that SSRIs offer improved
quality of life over TCAs. As many meta-analyses have demonstrated, SSRIs have different adverse effect
profiles and overall, patients seem to rate adverse effects associated with SSRIs less unfavorably than
those associated with TCAs. This is reflected by the higher utility values obtained from patients and by
opinions of psychiatrists. This improved quality of life comes at a cost; a cost which is nevertheless low
compared to other health interventions (approximately $3,000 per QALY gained). These values are very
close to those obtained by other studies. For example, Hatziandreu et al6 obtained a value of $US3,692
for the cost-utility of sertraline versus dothiepin, and Revicki et al’s7 cost-utility ratios range between
negative amounts to $17,326 for nefazodone compared to imipramine. In the Simon study11 which
followed two cohorts of patients, there was no statistical differences in quality of life between the two
cohorts as measured by the SF-36 questionnaire. However, more patients who had started with TCAs
switched therapies than those who started on SSRIs. One could conclude from the results presented
above that an SSRI first-line strategy is dominant over a TCA only strategy, and that an SSRI first-line
strategy compared to a SSRI second-line strategy produces QALYs at an acceptable cost compared with
other interventions.
It should, however, be noted that the utility values that were used in this study were taken from a single
study which relied on a limited number of patients.7 Despite the increasing acceptance of utility values in
economic analyses, the methods used to elicit them are still subjects of research and debate, and
controversy still remains as to the equity assumptions on which they rest. Conclusions derived from the
use of such values should therefore be taken with caution. In this case, the basic message behind using
utility values is not the precise cost per QALY figure that was obtained, it is the fact that the existing
(although limited) evidence points to the fact that quality of life seems higher with SSRIs than with TCAs.
This being the case, SSRIs tend to look more advantageous than TCAs whenever quality of life
considerations are introduced into the analysis. The stronger the belief that SSRI improves health related
quality of life compared to TCAs, the lower the incremental cost-utility ratio between the two drugs.
Limitations
As in any cost-effectiveness analysis that uses modeling, this study has limitations. Sensitivity analysis
is used to test the validity of our conclusions with respect to changes in estimates and assumptions. The
conclusions appear robust. The following is a brief discussion of the limitations of the study that should be
borne in mind when looking at the conclusions and possibly acting upon them.
The major limitation relates to the structure of the decision tree itself and its assumptions. In actual life
treatment paths and outcomes are not so stylized. The decision model used in this study is very simple
and does not allow for differences in success rates to occur over time, especially for the comparison
between the SSRI-TCA and the TCA-SSRI strategy. This is because, first, the efficacy of SSRIs and TCAs
are not significantly different from each other. Second, the model assumes that the efficacy of the different
drugs are not altered by prior treatment (i.e. the efficacies of SSRIs and TCAs are not affected by a prior
treatment with a TCA or an SSRI). Third, it is assumed that all drop outs are switched to the other therapy
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Canadian Coordinating Office for Health Technology Assessment
and all patients who relapse are put on another course of the same therapy. Had any of these
assumptions been relaxed, the conclusions would have tended to be more favorable to the SSRIs because
they are associated with fewer drop outs.
This analysis is actually a cost-efficacy study. Clinical information on the success of therapies and dropout has been taken, in the baseline case, from RCTs. RCTs do not fully mirror the real world environment.
In addition, RCTs eliminate many types of patients such as those with psychotic disorders, concurrent
symptoms, or suicidal tendencies; in other words they eliminate many psychiatrists’ regular patients.
Compliance also may not be adequately estimated by RCT drop out rates. The measure of acceptability
used might not reflect actual life. This is why sensitivity analyses examine the case where drop out rates
are derived from actual follow up of patients. Results in such a case are more favorable to the SSRI first
strategy than the baseline case.
The baseline case also assumes that prescribers use the appropriate dose for each drug. Here too, when
different assumptions are used in the decision model, the baseline case yields more favorable results than
the SSRI first strategy.
The long term efficacy, and also effectiveness, of the different drugs is unknown. This is also true for the
long-term drop out rates and relapse rates (which contribute to the effectiveness of the drug). RCTs
usually extend over a maximum period of 12 weeks. The true cost effectiveness of treatments for
depression depends on the success of a treatment in the long run: whether it will prevent patient relapse
or recurrences, whether it will reduce resource use or increase the quality of life of patients. While studies
have shed some light on the impact of different treatments on resource use, quality of life, and to a lesser
degree on relapses while on treatment, we still do not know whether one treatment rather than another will
reduce recurrence in the future (whether the recurrence is related or not to an earlier episode of
depression).
This analysis has taken a limited Ministry of Health perspective2 instead of the broader, and presumably
more appropriate, societal perspective. This means that direct costs borne by patients, time costs borne
by patients and society’s indirect costs in terms of lost production and lost productivity (all of which in the
case of depression can be substantial) have been excluded. If these costs are more important with the
use of TCAs, then their inclusion would show results more favorable towards SSRIs. This trend is
indicated in the sensitivity analysis when the resource use associated with TCAs is increased. Our model
also excludes the possibility of suicide and the associated costs. Here again, this possibility is more readily
attributable to TCA due to its safety profile in overdose, and the inclusion of these costs in the analysis
would have favored SSRIs.
The model incorporates estimates of relapse and recurrence rates that were derived from different
sources. These rates could include relapse and recurrences which may not be attributable to the first
depressive episode or its treatment. Although, in a strict sense, some would argue that a decision model
should only consider those relapses that are consequent to the first depressive episode, this is not possible
here, since estimates are lacking and possibly empirically impossible to determine (and perhaps
meaningless in view of the recurrent nature of depression). Finally, the model does not take into
consideration time to symptom improvement.
6.
CONCLUSIONS
2
Pharmacy mark-ups and dispensing fees are ignored.
Canadian Coordinating Office for Health Technology Assessment
23
Our analysis indicates that the strategy of starting a treatment for depression with an SSRI is as successful
as, but more costlier than, a strategy which starts with a TCA; success being measured as not having
terminated treatment due to adverse events or other causes. However, it is more efficacious and less
costly than a strategy in which SSRIs cannot be relied upon as a second line treatment. This result is
dependent upon various estimates most of which are derived from clinical trials. When information derived
from naturalistic environments or health related QOL considerations are incorporated, conclusions tend
to be more favorable towards SSRIs. When a more comprehensive perspective than the Ministry of
Health is taken, the SSRI first option tends to be less costly. In short, this study concludes that an SSRI
first-line strategy is dominant over a TCA only strategy, and that an SSRI first-line strategy compared to
a SSRI second-line strategy produces QALYs at an acceptable cost by current standards.
If only direct costs to the Ministry of Health are considered, then TCA first appears to be the cheapest
alternative with SSRIs playing the role of a fall back strategy. However, when quality of life considerations
and costs borne by patients are taken into account, then SSRIs would be the choice of patients and
practitioners. This will likely come at a cost to a Ministry of Health which might increase over time as
maintenance therapy becomes more prevalent. However, this cost may be balanced by the improved
quality of life and productivity of the individuals concerned.
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APPENDIX A1a
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APPENDIX A1b
Canadian Coordinating Office for Health Technology Assessment
29
APPENDIX A1c
No relapse
$335; P=0.535
0.870
Do not drop
$723
0.615
Efficacious
Relapse - inc. dose
$393; P=0.049
0.615
$3,319
0.130
TCA
$1,624
Failure
$7,993; P=0.031
0.385
No recurrence
$148; P=0.239
Drop
$3,065
0.385
0.620
Recurrence - failure
$7,823; P=0.l46
0.380
30
Canadian Coordinating Office for Health Technology Assessment
Canadian Coordinating Office for Health Technology Assessment
110-955 Green Valley Crescent
Ottawa, Ontario, Canada K2C 3V4
Canadian Coordinating Office for Health Technology Assessment