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Prevention of Complicated Ulcer Disease Among Chronic Users of Nonsteroidal Anti-inflammatory Drugs
The Use of a Nomogram in Cost-effectiveness Analysis
Hashem B. El-Serag, MD, MPH;
David Y. Graham, MD;
Peter Richardson, PhD;
John M. Inadomi, MD
Arch Intern Med. 2002;162:2105-2110.
ABSTRACT
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Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an
increased risk of clinical upper gastrointestinal tract (UGI) events, namely,
symptomatic ulcer, perforation, bleeding, and obstruction. Our objective in
this study was to compare the cost-effectiveness of several strategies aimed
at reducing the risk of clinical UGI events in NSAID users.
Methods A decision tree model was used for patients requiring long-term treatment
with NSAIDs to compare conventional NSAID therapy alone with 7 other treatment
strategies to reduce the risk of NSAID-related clinical UGI events (cotherapy
with proton-pump inhibitor, cotherapy with misoprostol, cyclooxygenase [COX]-2–selective
NSAID therapy, or Helicobacter pylori treatment followed
by each of the previous strategies, including conventional NSAID treatment,
respectively). The outcome measure is the incremental cost per clinical UGI
event prevented compared with conventional NSAID treatment over 1 year.
Results The use of a COX-2–selective NSAID and cotherapy with proton-pump
inhibitors were the 2 most cost-effective strategies. However, the incremental
cost associated with these strategies was high (>$35 000) in persons
with a low risk of clinical UGI event with conventional NSAIDs (eg, 2.5% per
year). If the baseline risk of clinical UGI events is moderately high (eg,
6.5%), using a COX-2–selective NSAID becomes the most effective and
least costly (dominant) treatment strategy, followed closely by cotherapy
with a daily proton-pump inhibitor. Because small changes in costs or assumed
efficacy of these drugs could change the conclusions, the incremental cost-effectiveness
ratios between any 2 strategies were presented in a nomogram that allows the
flexible use of a wide range of values for costs and rates of clinical UGI
events.
Conclusions The risk of clinical UGI events in NSAID users depends on their baseline
risk, the added risk associated with the individual NSAID, and the protection
conferred by cotherapy. A nomogram can be used to incorporate these factors
and derive estimates regarding cost-effectiveness of competing strategies
aimed at reducing the risk of clinical UGI events.
INTRODUCTION
NONSTEROIDAL anti-inflammatory drugs (NSAIDs) are commonly used to relieve
symptoms of arthritis and soft tissue inflammation. It is estimated that in
2000, there were more than 111 million NSAID prescriptions filled in the United
States at a cost of approximately $4.8 billion.1 The
NSAIDs have been associated with an increased risk of clinical upper gastrointestinal
tract (UGI) events, namely, symptomatic ulcer, bleeding, perforation, and
obstruction.2-3 The frequency
of these complications in average-risk persons is relatively low (1%-5% per
year of drug use).3-8 Several
risk factors increase the risk of clinical UGI events associated with NSAID
use. These include older age, history of peptic ulcer disease, use of anticoagulants
or steroids, and possibly Helicobacter pylori infection.6, 9-16
Various measures have been used to reduce the risk of clinical UGI events
in NSAID users.4 Medical cotherapy with high-dose
histamine2 receptor blockers, proton inhibitors, or misoprostol
reduces the incidence of endoscopic duodenal and gastric ulcers.6, 17-21 Misoprostol,
in addition, reduces the risk of NSAID-associated clinical events.6 Recently, treatment with cyclooxygenase-2–selective
NSAIDs (coxibs) have been shown in double-blind, randomized, controlled trials
to be associated with a significant reduction in frequency of clinical UGI
events compared with conventional NSAID therapy.7-8 Finally,
treatment and eradication of H pylori among infected
individuals might reduce the frequency of complications related to peptic
ulcer disease.22
In the presence of several effective strategies that reduce the number
of NSAID-related UGI clinical events, cost becomes an important factor in
choosing the optimal strategy.23 Several cost-effectiveness
studies have addressed this issue.4, 24-27 Typically,
cost-effectiveness studies present their results for a set of assumptions
regarding the magnitude of risk of clinical UGI events, the reduction in frequency
of complications associated with the use of a certain strategy, and the cost
of that strategy. Difficulty arises when one attempts to apply results of
published cost-effectiveness studies to an individual case because (1) the
risk of developing clinical UGI events in individual NSAID users ranges between
1% in low-risk patients and 50% in patients with several risk factors; (2)
costs differ among hospitals, pharmacies, and countries, and costs of drugs
change over time; (3) the estimates for the efficacy of the strategies outlined
above in reducing the number of clinical UGI events may vary significantly
in the published literature; and (4) most cost-effectiveness studies predate
the introduction of coxibs.
In the present cost-effectiveness study, we have presented the results
in a nomogram that enables physicians to tailor the treatment strategy to
each patient's specific circumstances and to compare the cost-effectiveness
of any 2 strategies aimed at reducing the risk of clinical UGI events. The
values in the nomogram include a wide range of possibilities for the risk
of clinical UGI events, the assumed efficacy of the treatment strategy, and
the cost of the drug and/or strategy. We provide several clinical examples
to illustrate the use of the nomogram as an aid to clinical decision making.
METHODS
BASE CASE ASSUMPTIONS
A decision tree model was created using Excel (Microsoft, Redmond, Wash)28 to determine the most cost-effective strategy for
reducing the risk of clinical UGI events (symptomatic ulcer, perforation,
bleeding, and obstruction) in NSAID users under base case assumptions. A time
frame of 1 year was used, and therefore we did not adjust dollar amounts to
reflect the time value of money by assigning lower values to dollars paid
in the future than to dollars paid in the present. The perspective of the
analysis is that of a third-party payer.
The base case scenario involves a 55-year-old person with osteoarthritis
who requires NSAID therapy for 1 year. The overall risk of clinical UGI events,
which is assumed to be 2.5%, equals the baseline risk combined with the risk
conferred by conventional NSAID intake.4 The
following alternative strategies of NSAID treatment were compared: (1) conventional
NSAID (800 mg of ibuprofen 3 times daily—this is the conventional NSAID
used throughout the present study); (2) conventional NSAID plus a single dose
of regular-strength proton-pump inhibitor (PPI; 30 mg of lansoprazole daily—this
is the PPI used throughout the present study); (3) conventional NSAID plus
200 µg of misoprostol 3 times daily; (4) coxib (100 mg of celecoxib
twice daily); and (5) through (8), bismuth subsalicylate/metronidazole/tetracycline
combination (Helidac; Prometheus Laboratories Inc, San Diego, Calif) and PPI
treatment for H pylori twice daily for 2 weeks followed
by each of the first 4 treatment strategies, respectively.
These treatment strategies were assumed to have similar anti-inflammatory
efficacy and a similar degree of osteoarthritis pain relief. The 3 main outcomes
of all the strategies were the total number of clinical UGI events, the total
cost of drugs, and the total cost of the strategy when the cost of a clinical
UGI event is considered. The probability of clinical UGI events associated
with each strategy and cost of drugs is outlined in Table 1. We also calculated the incremental cost-effectiveness ratios
between strategy 1 (reference strategy, conventional NSAID therapy alone)
and each of the other 7 strategies. The incremental cost-effectiveness ratio
is the extra cost incurred by using an alternative strategy to reduce a single
clinical UGI event. For example, the incremental cost-effectiveness ratio
between strategy 2 and strategy 1 is calculated as the cost of strategy 2
minus the cost of strategy 2 divided by number of clinical UGI events prevented
in strategy 2 minus the number of clinical UGI events prevented in strategy
1.29
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Table 1. Assumptions Regarding Costs Used in the Base Case Scenario
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All the assumptions of costs and probabilities were made for the 1-year
time frame. The assumptions concerning the incidence of clinical UGI events
in different settings were derived from published literature, and in cases
of significant differences in these estimates, the opinion of an expert (D.Y.G.)
on the published literature was used (Table
1). The costs of drugs were reported from the Red Book30 for 1999 (Table 1) and the cost of clinical UGI events from Laine.4
SENSITIVITY ANALYSIS AND THE NOMOGRAM
The 3 variables included in the sensitivity analyses were (1) the baseline
risk of clinical UGI events with conventional NSAID use alone; (2) the risk
of clinical UGI events with other strategies of NSAID therapy; and (3) the
cost of the drugs. The overall risk of clinical UGI events equals the baseline
risk of clinical UGI events with conventional NSAID use multiplied by the
risk reduction conferred by using alternative NSAID strategies. Incremental
cost-effectiveness ratios were calculated for a wide continuous range of possibilities
for risk of clinical UGI events (2 variables) and the cost of the drugs (1
variable). A 3-way sensitivity analysis is presented as a nomogram. The overall
difference between any 2 strategies in the risk of UGI events varied between
0.1% and 5% while the difference in cost varied between $10 and $2000 (cost
in 1 year).
A wide range of values for the difference in clinical UGI events, difference
in cost, and incremental cost-effectiveness ratio was presented. The functional
relationship z = x/y can be linearized by a transformation of variables as
log(z) = log(x) - log(y). Hence, depiction of this relationship by a
nomogram requires an exponential scaling of the axes representing the values
of x, y, and z (the first 2 increasing and the third decreasing). Once the
position of 1 labeled value for each of 2 of these axes is chosen (eg, x and
y) and the length of a doubling interval on 1 of these 2 is chosen, the exact
scalings for all 3 axes are uniquely determined.
To facilitate the estimation of the overall risk of UGI events in a
given individual, we have provided risk estimates associated with older age
and history of peptic ulcer disease, H pylori infection,
use of steroids, and use of anticoagulants (Table 2). These estimates were based on our interpretation of published
literature. The effect of these variables was assumed to be additive (ie,
no interactions). However, different assumptions can be substituted by the
user within the ranges presented in the nomogram.
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Table 2. Estimating the Annual Risk of Clinical UGI Event in an Individual
Patient by Risk Stratification*
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RESULTS
ASSUMPTIONS AND FINDINGS
Table 3 outlines the annual
cost when only the cost of the drugs used in the 8 treatment strategies is
considered. These estimates are presented for the base case assumption of
2.5% annual risk with the use of conventional NSAIDs. The same table includes
data on the frequency of clinical UGI events prevented and the incremental
effectiveness (in reducing clinical UGI events) between strategy 1 and all
alternative strategies. The cost-effectiveness is expressed as the incremental
cost-effectiveness ratio between strategy 1 and each of the alternative strategies.
The cost of strategies was the lowest for a conventional NSAID (strategy 1)
and highest for a combination of a conventional NSAID and a daily PPI (strategies
2 and 6). The frequency of clinical UGI events was highest for conventional
NSAID (strategy 1) and equally low for a combination of conventional NSAID
and a daily PPI (strategy 2) or a coxib (strategy 4). However, the incremental
cost-effectiveness ratio was lowest for coxib (strategy 4) and highest for
a combination of conventional NSAID and PPI (strategies 2 and 6).
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Table 3. Cost-effectiveness of Reducing Clinical UGI Events by Drug
Costs Only*
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Changes in the baseline risk of clinical UGI events resulted in large
changes in the estimated effectiveness and cost-effectiveness measures. For
example, if the baseline risk of clinical UGI events is moderately high (6.5%),
the incremental cost-effectiveness ratio is lowest with strategies 4 and 5
(ie, most cost-effective in reducing clinical UGI events). This example is
illustrated in the right 3 columns of Table
3.
Table 4 outlines incremental
cost-effectiveness ratios for the different strategies when the cost of clinical
UGI events is considered in addition to the cost of the drugs (ie, different
values from Table 3). At an assumed
cost of $28 000 for each clinical UGI event, the incremental cost-effectiveness
ratio was $69 600 between strategies 1 and 3 and $35 200 between
1 and 4. In other words, adding misoprostol to a conventional NSAID treatment
regimen (strategy 3) prevents 1 clinical UGI event at an additional cost of
$69 600, while using coxib (strategy 4) instead of a conventional NSAID
prevents a single UGI event at an additional cost of $35 200.
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Table 4. Cost-effectiveness of Reducing Clinical UGI Events by Drug
Costs and Costs of Clinical UGI Events*
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The estimates for incremental cost-effectiveness ratio in Table 4 differ from those in Table 3 by a fixed value of $28 000, which is the assumed cost
of a clinical UGI event. Therefore, we chose to present the cost of the drugs
(rather than the cost of the strategy) in the sensitivity analyses.
SENSITIVITY ANALYSIS
The nomogram (Figure 1) consists
of 3 vertical lines representing (A) the difference in the annual cost of
the drugs, (B) the difference in the annual risk of clinical UGI events between
any 2 strategies, and (C) the incremental cost-effectiveness ratio, or additional
cost per clinical UGI event prevented between the strategies. Estimates for
risk factors of clinical UGI events among NSAID users based on the published
literature are presented as fold increase in risk in Table 2. These estimates can be used to calculate the value in Figure 1B (difference in risk of clinical
UGI events).
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Figure 1. The results of the decision tree
are presented in a nomogram: A, the difference in the annual cost between
any 2 strategies of nonsteroidal anti-inflammatory drug (NSAID) use; B, the
difference in the annual rate of clinical upper gastrointestinal tract (UGI)
events (symptomatic ulcer, perforation, bleeding, or obstruction) between
any 2 strategies of NSAID use; and C, the incremental cost-effectiveness ratio,
which is the additional cost per clinical UGI event prevented. An incremental
cost-effectiveness ratio that incorporates the cost of clinical UGI events
(in addition to the cost of the drugs) can be obtained by deducting the assumed
cost of a UGI event.
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The following example serves to illustrate the use of the nomogram in
comparing the cost-effectiveness of 2 competing strategies for NSAID use in
reducing clinical UGI events (Figure 2).
A 50-year-old man with a history of bleeding peptic ulcer disease has a 25%
annual risk of a clinical UGI event while undergoing therapy with 375 mg of
Naprosyn (Roche Pharmaceuticals, Nutley, NJ) 3 times daily (2.5% baseline
risk with conventional NSAID x 10). Naprosyn is assumed to cost $654
per year. The same person has a 12.5% risk of a clinical UGI event if Naprosyn
is combined with 20 mg of omeprazole daily (an assumed 50% reduction). At
health maintenance organization (HMO) A, the additional cost of omeprazole
is $1393 per year (Figure 2A), and
the difference in the annual rate of clinical UGI events is 12.5% (Figure 2B); therefore the incremental cost-effectiveness
ratio is $11 144 (calculated by connecting the marks on Figure 2A and Figure 2B
and extending the line to intersect with Figure 2C). Alternatively, this person could be given a coxib, 100
mg of Celebrex (G.D. Searle & Co, Skokie, Ill) twice daily, at an annual
cost of $1029 (Figure 2A) with the
same reduction in clinical UGI events (12.5% on Figure 2B) and therefore an incremental cost-effectiveness ratio
of $9700. If the same patient receives his care at a different HMO (B) where
omperazole is offered at a lower annual cost of $900 (Figure 2A), then the calculated incremental cost-effectiveness ratio
becomes $7200 (Figure 2C), and adding
omeprazole to the regimen becomes a more cost-effective strategy. Similarly,
if the user disagrees with the 50% reduction in clinical events with coxib
and assumes a 70% reduction rate instead, the point on Figure 2B changes to 19.3%, and the incremental cost-effectiveness
ratio will be calculated at $5322.
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Figure 2. A hypothetical example of how
to use the nomogram pictured in Figure 1 (see "Results" section for details).
Strategies with smaller incremental cost-effectiveness ratios are more cost-effective.
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The nomogram in Figure 1 includes
only the annual cost of drugs. An incremental cost-effectiveness ratio that
incorporates the cost of clinical UGI events can be obtained by simply deducting
the assumed cost of a UGI event from the incremental cost-effectiveness ratio
in the nomogram. For example, if the cost of a clinical UGI event in the previous
case scenario is $15 000, then the incremental cost-effectiveness ratio
of omeprazole (at HMO A) is $3573. In this case, the coxib strategy becomes
the most effective and least costly (dominant) strategy.
COMMENT
Three variables affected the cost-effectiveness estimates for reducing
clinical UGI events in long-term NSAID users: (1)the cost of drugs, (2) the
baseline risk of clinical UGI events with conventional NSAID therapy, and
(3) the degree of protection conferred by alternative strategies. We have
presented the results of this model in a user-friendly nomogram. In constructing
the nomogram, we used a wide range of probabilities for these influential
variables that allow the user to obtain an instant estimation of the incremental
cost-effectiveness ratio of reducing clinical UGI events between any 2 competing
strategies of NSAID treatment (the additional cost needed to prevent 1 event).
The incremental cost-effectiveness ratio between strategies was the outcome
of the model and the nomogram. The incremental cost-effectiveness ratio is
an important measure of cost-effectiveness29;
in the present study it refers to the additional cost of alternative strategies
to avoid 1 clinical UGI event compared with the use of conventional NSAID
therapy.
We assumed that once a clinical UGI event, for example a bleeding ulcer,
develops in an NSAID user, the clinical course is similar regardless of the
initial strategy of NSAID use. Therefore, for practical purposes, all the
"downstream" events (hospitalizations, endoscopy, consultations, or death)
and their associated costs will be determined by the probability of developing
a clinical UGI event. We have shown that the calculated incremental cost-effectiveness
ratios follow the same trend whether we use only the cost of drugs or the
overall cost of the strategies including the cost of UGI events. The costs
of drugs are obtained more easily and accurately and will provide the user
with readily calculated incremental cost-effectiveness ratios. However, to
obtain an incremental cost-effectiveness ratio that incorporates the cost
of clinical UGI events, these costs could be simply deducted from the incremental
cost-effectiveness ratio obtained in the nomogram. The cost of clinical UGI
events ranges between $20 000 and $30 000 and could vary greatly
between practitioners, institutions, and countries.25-26
This model has several advantages. It can be used as a simple cost-minimization
model to determine the least expensive drug(s) to prevent a clinical UGI event
in NSAID users. Most important, however, the model is constructed to make
this determination for patients with a wide range of baseline risks for clinical
UGI events. The attractiveness of this method of presentation is in its universality:
it can be applied to existing drugs, new drugs, and combinations of drugs.
In addition, while the decision tree uses specific predefined estimates based
on our interpretation of published literature, users of the nomogram can enter
whatever assumptions they wish based on their own interpretation of the literature
and cost estimates in their own practice settings. The relative simplicity
of the model in having only 2 predicting variables has made the nomogram presentation
possible. The presence of more than 2 predicting variables would have made
the linear presentation impossible. Therefore, this type of presentation may
not be applicable to more complex models.
The overall finding of this study is rather straightforward: it is cost-effective
to use relatively expensive medications such as coxibs or to add a PPI to
regimens for patients with a high risk for clinical UGI events. Including
the cost of clinical UGI events in the analysis strengthens the argument further.
Even in persons with an intermediate risk of clinical UGI events with conventional
NSAIDs (6.5% per year), the use of coxibs becomes a more effective and less
costly strategy than conventional NSAID therapy. We assumed in this model
that coxibs were slightly less expensive than adding a PPI to a conventional
NSAID regimen, but these costs are similar, and it is possible that in some
practice settings a certain PPI would be less expensive. The use of the nomogram
could determine the most cost-effective strategy in these settings.
AUTHOR INFORMATION
Accepted for publication February 27, 2002.
Dr El-Serag is the recipient of Veterans Affairs Health Services Research
& Development Career Development Award RCD00-013-2.
Corresponding author and reprints: Hashem B. El-Serag, MD, MPH, Department
of Veterans Affairs Medical Center, 2002 Holcombe Blvd (152), Houston, TX
77030 (e-mail: hasheme{at}bcm.tmc.edu).
From the Health Services Research Sections, Houston Center for Quality
of Care & Utilization Studies (Drs El-Serag and Richardson), and the Gastroenterology
Section (Dr Graham), The Houston Department of Veterans Affairs Medical Center
and Baylor College of Medicine, Houston, Tex; the Department of Veterans Affairs
Medical Center & Health Services Research and Development Service and
the University of Michigan, Ann Arbor (Dr Inadomi).
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