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VA L U E I N H E A LT H 1 6 ( 2 0 1 3 ) 1 4 – 2 2

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ORIGINAL RESEARCH
Economic Evaluation
Cost-Effectiveness Analysis: Stress Ulcer Bleeding Prophylaxis with
Proton Pump Inhibitors, H2 Receptor Antagonists
Alan N. Barkun, MD, MSc1,2,*, Viviane Adam, MSc1, Myriam Martel, BSc1, Marc Bardou, MD, PhD3,4
1
Division of Gastroenterology, McGill University Health Center, McGill University, Montreal, Canada; 2Division of Epidemiology, Biostatistics and Occupational
Health, McGill University Health Center, McGill University, Montreal, Canada; 3INSERM CIC-P 803, CHU de Dijon, Dijon, France; 4Université de Bourgogne,
Dijon, France

AB ST RAC T

Objectives: Proton pump inhibitors (PPIs) and H2-receptor antago- versus 6.6% and 10.3% for H2RAs, respectively. Lengths of stay and per
nists (H2RAs) present varying pharmacological efficacy in preventing diem costs were 24 days and US $2764 for SUB, 42 days and US $3310
stress ulcer bleeding (SUB) in intensive care units. The literature also for VAP, and 14 days and US $2993 for patients without complications.
reports disparate rates of ventilator-assisted pneumonia (VAP) as side Average costs per no complication were US $58,700 for PPIs and US
$63,920 for H2RAs. The H2RA strategy was dominated by PPIs.
effects of these treatments. We compared the cost-effectiveness of
Sensitivity analysis showed that these findings were sensitive to
these two prophylactic pharmacological options. Methods: We con-
VAP rates but PPIs remain cost-effective. The acceptability curve
structed a decision tree with a 60-day time horizon for patients at
shows the stability of the probabilistic results according to varying
high risk for developing SUB, receiving either PPIs or H2RAs. For each
willingness-to-pay values. Conclusion: PPI prophylaxis is the most
treatment strategy, patients could be in one of three states of health:
efficient prophylactic strategy in patients at high risk of developing
SUB, VAP, or no complication. Contemporary, clinically relevant
SUB when compared with using H2RAs.
probabilities were obtained from a broad literature search. Costs were
Keywords: cost-effectiveness, H2RA, proton pump inhibitors, stress
estimated by using a representative US countrywide database. A
ulcer bleeding.
third-party payer perspective was adopted. Cost-effectiveness and
univariate and multivariate sensitivity analyses were performed. Copyright & 2013, International Society for Pharmacoeconomics and
Results: Probabilities of SUB and VAP were 1.3% and 10.3% for PPIs Outcomes Research (ISPOR). Published by Elsevier Inc.

Introduction Methods
Stress-related mucosal disease in the form of stress ulcer bleeding
(SUB) remains an important clinical problem. Although it is a small Study Population
proportion of patients who bleed [1,2], the clinical factors that predict The study population comprised patients at high risk of devel-
a higher risk of rebleeding are increasingly found among patients oping SUB in the ICU setting. These patients were identified by
admitted to an intensive care unit (ICU) setting [1–3]. Proton pump using the Nationwide Inpatient Sample (NIS) 2008 [7] that is
inhibitors (PPIs) have been found efficacious in preventing stress- supported by the Agency for Healthcare Research and Quality
related mucosal disease (also referred to as stress ulcer) bleeding (SUB) from the U.S. Department of Health and Human Services. This
in the ICU setting, as have H2-receptor antagonists (H2RAs) [1–4]. Their national hospitalization database comprises 8 million hospitali-
comparative efficacies and the possible development of ventilator- zations in more than 1000 hospitals located in 42 states from the
assisted pneumonia (VAP) remain subjects of controversy with dis- United States. Hospitalizations of patients who died during the
parate data in the literature. Recent meta-analyses have suggested the hospital stay or who were younger than 18 years were excluded
superiority of PPIs [5,6], but the low incidence of SUB coupled to the from the analysis. We included only those hospitalizations that were
high costs of this complication underline the need for a cost-effective recorded with Medicare, Medicaid, or a private insurance as the
analysis comparing PPIs with H2RAs. We therefore performed an primary payer. We selected specific diagnoses to define a represen-
economic analysis to better quantify the cost-effectiveness impact of tative group of patients at risk of SUB. The list of all diagnoses
these two therapeutic prophylactic approaches. chosen was based on the included patient populations from

* Address correspondence to: Alan N. Barkun, Division of Gastroenterology, McGill University Health Center, Montreal General Hospital
Site, Room D7-346, 1650 Cedar Avenue, Montréal, Québec H3G 1A4, Canada.
E-mail: alan.barkun@muhc.mcgill.ca.
1098-3015/$36.00 – see front matter Copyright & 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.jval.2012.08.2213
VA L U E I N H E A LT H 1 6 ( 2 0 1 3 ) 1 4 – 2 2 15

Table 1 – Probability estimates used in the model.


Probability among the entire study population (%) Point estimate Source Low bound High bound

SUB with PPI treatment 1.34 [8–19,22] 0.7 3


SUB with H2RA treatment 6.61 [8–19,22] 4 9
VAP with PPI treatment 10.33 [8,11,13–15,18,19] 8 14
VAP with H2RA treatment 10.32 [8,11,13–15,18,19] 7 14

Notes. The only probabilities in the model are the overall complication rates (for PPI and H2RA groups), and the proportion of these that represent
either an outcome of SUB or VAP. From the above, the probabilities as they appear in Figure 1 include the complication rates in the PPI arm
(11.67%) and the H2RA path (16.93%), and the proportions of complications that are SUB or VAP in the PPI arm (11.5% and 88.5%) and the H2RA
group (39% and 61%), respectively. Complication ¼ SUB and VAP. All bounds were computed on the basis of 95% CI.
CI, confidence interval; H2RA, H2-receptor antagonist; PPI, proton pump inhibitor; SUB, stress ulcer bleeding; VAP, ventilator-assisted pneumonia.

randomized trials on this topic published in the literature [8–19] were done by using Ovid MEDLINE (1990 to September Week 2,
and was validated by a clinician expert (A.B.). We used the 2011), EMBASE (1990 to 2011 Week 37), CENTRAL (fourth quarter
principal diagnosis and 14 other possible secondary diagnoses 2011), and (ISI) Web of knowledge 4.3. All abstracts from Digestive
that were expressed as International Classification of Diseases, Disease Week and United European Gastroenterology Week were
Ninth Revision, Clinical Modification (ICD-9-CM) codes and the also searched as were clinical trials databases [20]. Articles were
indicator of occurrence of major operating room procedure to selected by using a search strategy to identify reports of rando-
select the hospitalizations from the NIS database. We focused mized controlled trials (RCTs) [21] with a combination of Medical
on the principal diagnosis to define patient eligibility (except for Subject Headings and text words related to 1) PPI, 2) stress ulcer,
septicemia that could appear as a nonprincipal diagnosis). The 3) gastric bleeding in a, 4) clinical ill patient setting treated with
diagnoses were extracted from ICD-9 coding among all the either PPI, or 5) a treatment of PPIs or H2RAs. Treatment group as
available diagnoses recorded in the NIS database. The list of well as RCTs were required and three of the other aforemen-
selected diagnoses is shown in Table 2. tioned criteria for selection. Recursive searches and cross-
referencing were also carried out by using a ‘‘similar articles’’
Model Design function; hand searches of articles were identified after an initial
search. We included all adult human studies in French or English,
A decision tree model was constructed by using the software
published as full article or abstracts. Trials comparing only
program TreeAge Pro Suite 2011 (TreeAge Software, Inc.,
different dosing regimens of the same molecule were excluded.
Williamstown, MA) to present the use of PPIs versus H2RAs
Studies assessing solely or mainly pediatric patients, or whose
during the hospitalization for a patient at high risk of developing
only outcomes were gastric pH measurements, were also
SUB. Treatment in the PPI group included bolus intravenous or
excluded. All selected model probabilities were validated by an
oral omeprazole 40 mg daily. The H2RA regimen was famotidine
expert clinician (A.B.).
40 mg intravenously twice daily.
Our literature search identified 489 articles. Eight fully pub-
In each treatment, patients were stratified into those with
lished articles [8–10,14–16,19,22] were included as well as five
complications and those with no complication. Complications
abstracts [11–13,17,18] (we evaluated the English abstract of De
were divided into two categories: SUB and VAP. The adopted time
Azevedo et al. trial and not the full Spanish publication in
horizon was 2 months (60 days), as justified by clinical arguments
keeping with the a priori limits chosen for language selection)
below. We also adopted a third-party-payer perspective.
as reported in a recently published quantitive meta-analysis by
our group [23]. The resulting probabilities of SUB were 1.34% and
Probabilities 6.61% and those of VAP were 10.33% and 10.32% among all
Probabilities were provided by a literature search spanning 1990 patients at risk for SUB following the PPI and H2RA treatments,
to September 2011. Computerized medical literature searches respectively (Table 1).

Fig. 1 – Decision tree schema. H2RA, H2-receptor antagonist; P, probability; PPI, proton pump inhibitor; SUB, stress ulcer
bleeding; VAP, ventilator-assisted pneumonia. Complication ¼ SUB and VAP.
16 VA L U E I N H E A LT H 1 6 ( 2 0 1 3 ) 1 4 – 2 2

Table 2 – List of ICD-9-CM codes.


Category of patients ICD-9-CM code Description of the code as they appear in the ICD-9
Category of chosen diagnosis coding system

Risk for SUB


Major trauma
850-854 Intracranial injury, excluding those with skull fracture
860-869 Internal injury of thorax, abdomen, and pelvis
925-929 Crushing injury
Hypovolemic shock
78559 Shock W/O trauma nec
Sepsis
99592 Sys inflam/infecti W organ dysfuncti
Septicemia
0380 Streptococcal septicemia
Acute respiratory failure
51881 Respiratory failure
Extensive burns
(30% of the body and more) 9483-9489 Burns classified according to extent of body surface involved
Acute renal failure
5846 Ac renal fail-cort necr
5847 Ac ren fail-medull necr
5848 Ac renal failure nec
5849 Acute renal failure nos
Shock
5185 Shock lung (pulmonary insufficiency following trauma and surgery)
6395 Shock: circulatory collapse after complications classifiable to 630-638
66910-66914 Shock during or following labor and delivery (obstretric shock)
9584 Traumatic shock (shock following injury)
9980 Postoperative shock
Severe acute pancreatitis
5770 Diseases of pancreas acute pancreatitis
Coronary artery bypass graft surgery
74685 Coronary artery anomaly
99603 Due to coronary bypass graft
74685 Coronary artery anomaly
99603 Malfunc coron bypass grf
Complication cases among the risk for SUB
SUB
53021 Ulcer of esophagus with bleeding
53100 Gastric ulcer: acute with hemorrhage
53120 Gastric ulcer: acute with hemorrhage and perforation
53400 Gastrojejunal ulcer: acute with hemorrhage
53420 Gastrojejunal ulcer: acute with hemorrhage and perforation
5780 Gastrointestinal hemorrhage: hematemesis
5781 Gastrointestinal hemorrhage: blood in stool
53200 Duodenal ulcer—acute with hemorrhage
53220 Duodenal ulcer—acute with hemorrhage and perforation
VAP
99731 Vent assoc pneumonia

Note. Major operating room procedure reported on discharge record was a condition to represent the risk for SUB.
ac renal fail- cort necr, acute renal failure – cortical necrosis; ac ren fail- medull necr, acute renal failure – medullary necrosis; ac renal failure
nec, acute renal failure with necrosis; acute renal failure nos, acute renal failure not otherwise specified; ICD-9-CM, International Classification of
Diseases, Clinical Modification, malfunc coron bypass grf, malfunction of coronary artery bypass graft; shock w/o trauma nec, shock without
trauma or necrosis; SUB, stress ulcer bleeding; sys inflam/infecti w organ dysfuncti, systemic inflammation/infection with organ dysfunction;
VAP, ventilator-assisted pneumonia; vent assoc pneumonia; ventilator associated pneumonia.
* The no-complication patients were defined as all the patients in the ‘‘high risk for SUB’’ group who were not in the SUB or VAP groups.

Lengths of Stay and Costs codes (Table 2). Two strategies were used to cost out the hospital stay
of patients with complications: The VAP hospitalizations were
A specific length of stay and per diem were assigned to each of the
selected among all the available diagnoses in NIS (from the 1st to
three groups of patients. Only hospital costs were included. All
the 15th diagnosis for a given patient), whereas SUB hospitalizations
pharmaceutical costs were considered included in the hospital costs. were selected among all the available diagnoses relating to upper
Lengths of stay and costs were obtained from the NIS 2008 [7] by gastrointestinal bleeding in NIS, excluding these when appearing as
using a validated methodology [24] and relevant specific ICD-9-CM a principal diagnosis. The no-complication category was represented
VA L U E I N H E A LT H 1 6 ( 2 0 1 3 ) 1 4 – 2 2 17

Table 3 – Cost and length of stay estimates used in the model.


Point estimate Low bound High bound

Per-diem cost for patients at high risk for SUB


(US$, year 2010 values)
With SUB during the hospitalization 2764 2542 2986
With VAP 3310 3035 3586
No complication 2993 2915 3072

Length of stay (d)


With SUB during the hospitalization 23.7 20 27
With VAP 41.8 33 51
No complication 13.9 13 15

Notes. Source of the point estimate: NIS2008 [7]. All bounds were computed on the basis of 95% CI. Complication ¼ SUB and VAP.
CI, confidence interval; SUB, stress ulcer bleeding; VAP, ventilator-assisted pneumonia.

by all the patients at risk for SUB who were not in the SUB or VAP Cost-Effectiveness Analysis
groups. In addition, only hospitalizations with major operating room
The effectiveness was expressed as the probability of no complication
procedures reported on the discharge record were considered to be
occurring during the hospitalization. The costs were those tabulated
eligible to represent the three subgroups of patients at risk for SUB
for a complicated or uncomplicated hospital stay. The main outcome
(SUB, VAP, and no complication). Costs were computed on the basis
was the cost per averted complication. Results are reported as cost,
of average charges combined with a cost-to-charge ratio, which was
effectiveness, and incremental cost-effectiveness ratio if a strategy is
for the most part specific to the hospital where the hospitalization
more effective but also more costly than another; if not, the model
took place. More precisely, a cost-to-charge ratio specific to the
simply points out the strategy that is dominated (the dominated
hospital was used when available, and if not, a recommended group
strategy is the one that is both less effective and more costly) and
average cost-to-charge ratio was applied. Per-diem cost was the ratio
shows therefore the one that is preferred.
of the average cost per hospitalization to the average length of stay
per hospitalization. To obtain valid national cost estimates, we used
discharge weights in our computation (weights were corrected to Sensitivity and Threshold Analyses
account for cases in which cost estimates were missing, as One-way sensitivity analyses were performed on all variables
suggested by the NIS). All US$ values were expressed in 2010 US used in the model to investigate the robustness of the results and
dollars by using the consumer price index for the medical care to determine which factors influence these results the most; a
services published by the U.S. Department of Labor [25]. two-way analysis assessing pneumonia incidence in the PPI and
The diagnoses identified to represent the patient at risk for SUB in the H2RA treatment was also performed. Each variable was
and the three subgroups (SUB, VAP, and no complication) are listed in varied across its respective 95% [26] confidence interval range. We
Table 2. Respecting the inclusion criteria, the weighted results produced a tornado diagram [27–29] to display in a single graph
present 94,865 hospitalizations in the no-complication group, 1,088 each of the one-way results as a single bar and to highlight which
in the SUB group, and 235 in the VAP group. parameters have the greatest influence on the model [30].
In 87% of the hospitalizations that we selected from the NIS, Threshold analyses were also performed for select variables.
we used a cost-to-charge specific to the hospital where the hospita- The adoption of a willingness-to-pay threshold was arbitrary
lization occurred. For the other hospitalizations (where a specific because we do not use quality-adjusted life-years (QALYs) as
cost-to-charge ratio was not available), the recommended group units of effectiveness.
average cost-to-charge ratio was applied. This group average cost- A probabilistic sensitivity analysis was also performed by
to-charge ratio is defined according to several characteristics of the using the Monte Carlo method [30].
hospital (state, urban or rural localization, ownership of the hospital,
and bedsize). By using this NIS, we found that the mean length of
stay was 24 days for the SUB patients, 42 days for the VAP patients,
Results
and 14 days for the no-complication patients. Overall, a full 97.6% of
the patients at risk for SUB in the NIS database were hospitalized for
60 days or fewer. This observation was clinically plausible and Base-Case Analysis
relevant; it justified our adoption of a 60-day time horizon for the The cost-effectiveness analysis shows that the PPI strategy
model. The average hospitalization costs were US $41,600 (no- exhibits a US $1250 lower average cost per patient with a greater
complication patients), US $65,500 (SUB), and US $137,700 (VAP). All probability of not developing a complication (SUB and VAP) than the
costs and lengths of stay used in the model are presented in Table 3. H2RA strategy. More precisely, average costs per no-complication

Table 4 – Results of cost-effectiveness analysis.


Strategy Cost Incremental cost Effectiveness Incremental effectiveness C/E ratio ICER

PPI 51,849 0 0.8833 0 58,699 —


H2RA 53,099 1,250 0.8307 0.0526 63,921 Dominated

Note. US $, year 2010 values.


C/E, cost-effectiveness ratio; ICER, incremental cost-effectiveness ratio; PPI, proton pump inhibitor; H2RA, H2-receptor antagonist.
18 VA L U E I N H E A LT H 1 6 ( 2 0 1 3 ) 1 4 – 2 2

Fig. 2 – Tornado diagram: univariate analysis. The horizontal bars represent variability in the model estimates. Each bar
represent one-way sensitivity analysis of influential variables in the model across a range of possible outcomes, with the
range of values listed in Tables 1 and 3. All variables present the characteristics of patients at risk for SUB. The base-case
ICER of PPI versus H2RA is –$23,767. Values of the input variables are varied across their 95% confidence intervals. US$, year
2010 value. H2RA, H2-receptor antagonists; ICER, incremental cost-effectiveness ratio; LOS, length of stay; PPI, proton pump
inhibitors; SUB, stress ulcer bleeding; VAP, ventilator-assisted pneumonia.

patient are US $58,700 for PPIs versus US $63,921 for H2RAs Two-ways sensitivity analysis
(Table 4). In other words, H2RAs are strictly dominated by PPIs. Figure 3 illustrates which treatment is more cost-effective when
we simultaneously vary the two probabilities of VAP in the PPI
and H2RA groups. The PPI approach remains more cost-effective
Sensitivity Analysis for an empirically set willingness to pay of US $50,000 in the
majority of scenarios.
One-way sensitivity analysis
Figure 2 shows the Tornado diagram using the percentage of the
variation of the base-case incremental cost-effectiveness ratio Probabilistic sensitivity analysis
when we alter the variables inside their respective 95% confidence A Monte-Carlo analysis was performed with 10,000 simulations
intervals. The probability of developing VAP is what most influ- assuming gamma distributions for the per-diem costs and the
ences the incremental cost-effectiveness ratio. Univariate sensi- lengths of stay and beta distributions for all the probabilities. PPI
tivity analysis demonstrates a change in the conclusions only treatment was dominant in 49% of the simulations and remained
when varying the probability of pneumonia: H2RA ceases to be cost-effective (more effective yet more costly according to a
dominated if this probability (which is fixed at 10.3% in the base maximum willingness to pay of US $50,000 per no complication
case for both pharmacological strategies; see Table 1) rises above case) in another 9% of the simulations. On average, the cost of PPI
11.6% in the PPI group or if it drops below 9% in the H2RA group. treatment was almost US $1500 lower than that of H2RA (median
Across the clinically relevant range of each of these variables, the difference of US $3000). Similarly, the gain in mean effectiveness
PPI strategy becomes more expensive but remains more effective favored the PPI approach (88.5% vs. H2RA 83%). The correspond-
because of its greater effect on bleeding prevention. ing cloud diagram is shown in Figure 4. The line represents the
willingness-to-pay value fixed at US $50,000. Varying the
willingness-to-pay line leads to the cost-acceptability curve that
Threshold analysis is shown in Figure 5.
Threshold analysis for the probability of VAP shows that only
when this variable exceeds 15.6% for the PPI patients or drops
below 5% for the H2RA patients does the PPI strategy become Discussion
dominated. The SUB probability has to increase by more than 5%
for the PPI strategy (or drop by more than 5% in the H2RA Both PPIs and H2RAs are used as antisecretory agents in a
approach) for the PPI approach to lose its dominance over the number of acid-related diseases in clinical practice [1–4].
H2RA strategy. Other threshold values on costs were very unlikely Although cost-effectiveness models have been reported in ther-
to occur in order to alter results in any clinically plausible way: apeutic areas such as gastroesophageal reflux disease or in the
The hospitalization cost for no complication would need to context of peptic ulcer bleeding (either before or following
increase by more than US $1700 per day for H2RAs to become gastroscopy), there exist very few fully published cost analyses
no longer dominated. Similarly, for the PPI approach to lose its targeting patients in the ICU at risk of developing either a
dominance, the length of stay in patients with no complications gastrointestinal bleed or a VAP. Only Schupp et al. [31] performed
or those developing SUB would need to rise by almost 60% or drop such an analysis, but unfortunately limited the economic out-
by 40%, respectively. The analysis did not identify any other comes to sole drug acquisition costs. As PPIs are more expensive
threshold values. than H2RA and simultaneously the risk of SUB is lower for
VA L U E I N H E A LT H 1 6 ( 2 0 1 3 ) 1 4 – 2 2 19

Fig. 3 – Two-way sensitivity analysis on the probability of


Fig. 5 – Cost-acceptability curves. Maximum willingness to
VAP in the two groups. Base-case estimates are represented
pay ¼ US$50,000 per no complication case. H2RA, H2-
by the 2 broken lines by pointed lines. Willingness-to-pay¼
receptor antagonists; PPI, proton pump inhibitors.
US$50,000 per no complication case. H2RA, H2-receptor
antagonists; PPI, proton pump inhibitors; VAP, ventilator-
assisted pneumonia.
additional hospitalization costs attributable to potential compli-
cations ($15–$400 [31] vs. $65,000 for the cost of hospitalization of
patients who receive PPIs rather than H2RAs, we felt that there a bleeding complication in this patient population). Furthermore,
were arguments for a full cost-effectiveness analysis, also pro- sensitivity analyses in this cost-effectiveness report also allow us
viding for a more precise documentation of cost implications. to assess the diverging associations of bleeding and pneumonia
Indeed, the drug costs are magnitudes smaller than the for a given pharmacological option, and the identification of
possible thresholds for decision taking.
The present cost-effective analysis suggests the economic
dominance of a prophylactic approach utilizing PPIs in an ICU
setting compared with H2RAs. Indeed, we found that lengths of
stay and per-diem costs were 14 days and US $2,993 for patients
developing no complication, 24 days and US $2,764 for SUB, and
42 days and US $3,310 for VAP. Average costs per no complication
were US $58,700 for PPIs and US $63,921 for H2RAs. A number of
methodological decisions that can affect the interpretation of
these results need to be discussed.
As it is only a subgroup of patients who are at high risk of
developing SUB [32–35], we attempted to identify this target
population by reviewing pertinent diagnoses and severity indices
as they appeared in the NIS database, using our clinical expertise
to determine such a selection (Table 2). We were unable to enter
all relevant diagnoses that could represent a patient in this target
population (i.e., patients who are at high risk of developing SUB)
because of a lack of precision in the ICD-9 coding. We chose,
however, a large number of diagnoses that emulate those of
identified risk factors [36] or of previously included populations in
Fig. 4 – Monte-Carlo simulation distribution plot: published RCTs assessing SUB [6,37,38]. We did not identify
incremental cost-effectiveness of PPI versus H2RA patients simultaneously experiencing both SUB and VAP as out-
approaches. Probabilistic sensitivity analysis by using comes as these would represent a very small group, and one for
10,000 trials. The slope of the scatterplot represents whom it was nearly impossible to identify relevant data in the
willingness to pay of US$50,000 per no complication case. NIS notwithstanding the possibility of synchronous complica-
The interrupted lines indicate the base-case values for tions, whereby the resulting length of stay may not be additive;
incremental cost and incremental effectiveness. H2RA, these are included in the SUB or VAP complication groups in
H2-receptor antagonists; PPI, proton pump inhibitors. our model.
20 VA L U E I N H E A LT H 1 6 ( 2 0 1 3 ) 1 4 – 2 2

The choice of NIS assured us of a broad generalizability of both the SUB and VAP probabilities synchronously confirmed the
results with regard to not only geographic variation but also the robustness of the conclusions. Probabilistic sensitivity analysis
contemporary nature of care [7]. additionally tested the uncertainty of all variables simulta-
We chose a decision tree approach as the best way to model neously across 10,000 simulations of the model. The resulting
the decisional impact of treating patients at risk for SUB [39–42], cost-acceptability curve showed how the willingness to pay failed
considering the short clinically pertinent time horizon and the to have a significant impact on the strategic choice. Threshold
chosen outcome [43]. Furthermore, because there was no neces- analyses suggested that only clinically irrelevant values could
sity to focus on recursive health states involving back and forth alter these conclusions.
movements in the time, decision tree appeared more indicated The plotting of cost-acceptability curves remains complex and
than opting for a Markov model [44]. somewhat subjective whatever the outcome as disparate
There exist no QALYs described for this condition to the best willingness-to-pay thresholds are reported in the literature
of our knowledge. The choice of the unit of effectiveness of cost [63–67]. Furthermore, we could not use a reference based on
per averted complication is in keeping with the nature of the willingness to pay per QALY because we did not adopt QALYs as
medical complications that are self-limited, and usually devoid of units of effectiveness. The nearest content-relevant examples we
prolonged impact beyond the 60-day time horizon. If the out- could find were those of Enns et al. [39] who worked with a
come of bleeding or pneumonia is now an unusual one, bleeding willingness to pay per rebleed averted and Briggs et al. [68] who
or pneumonia-related mortality represents only a proportion of adopted a willingness to pay per no gastroesophageal reflux
these rates, with an even smaller number of patients, thus disease symptoms. There are no references in the literature for
limiting its choice as an outcome of interest. The chosen out- a willingness to pay per complication averted in the context of
come of averted complication is in keeping with other cost- SUB prophylaxis [39] that we could find. Ubel et al. [67] suggest
effectiveness analyses of similar short-term clinical outcomes that the choices of willingness to pay usually are underestimates
[39,45–48] and is in keeping with methodological suggestions among published cost-effectiveness analyses, at least as it
published in the literature [27,49]. pertains to the use of QALYs as a measure of effectiveness. We,
We did not model for a strategy that used sucralfate in our therefore, granted arbitrarily as most, fixed a cutoff point at US
analysis because this medication is an older, now little used $50,000. This value is consistent with the order of magnitude of
method of SUB prophylaxis. Furthermore, some comparative the average cost of treatment as noted in our analysis, as some
trials, most of which date back up to 21 years (close to the start have suggested to do [39,67,68].
of intravenous PPI availability), can be misleading as there have
been major advances in supportive care that have significantly
decreased SUB and VAP, as further discussed below. An explora-
tory analysis that included all three prophylactic strategies (PPI, Conclusion
H2RA, and sucralfate) did not alter the findings of PPI dominance
Based on available current data both from RCTs and from a large
[50]. We do not include these data as we feel they are less
contemporary observational administrative database informing
clinically useful for the aforementioned reasons, and may even
our probability and cost estimates, a strategy of PPI prophylaxis is
be misleading with regard to the final estimates of costs and
the most efficient approach in patients at high risk of developing
effectiveness. Although there exist wide clinical heterogeneity in
SUB when compared with using H2RAs.
the RCTs, our probability assumptions are taken from the avail-
Source of financial support: Dr Alan Barkun is a consultant for
able contemporary literature [8–18,32,51–61], including a recent
Astra Zeneca Canada and Takeda Canada. He also serves as an
robust meta-analysis [38]; we did include all relevant trials.
expert witness for Merck. There are no other relevant conflicts to
Table 3 reports a per-diem hospitalization cost of US $2993 for
report.
no-complication patients and US $2764 for patients with SUB
during their hospitalization. Although counterintuitive, because
the first days of a hospitalization usually require more medical R EF E R EN C E S
and human resources, the per-diem cost is lower for patients
with longer hospitalizations, as is the case for patients who
develop complications during hospitalization. Of course, the total [1] Spirt MJ. Stress-related mucosal disease: risk factors and prophylactic
hospitalization costs are greater for this group (due to the therapy. Clin Ther 2004;26:197–213.
markedly greater length of stay). This has been previously [2] Stollman N, Metz DC. Pathophysiology and prophylaxis of stress ulcer
in intensive care unit patients. J Crit Care 2005;20:35–45.
reported [24].
[3] Laine L, Curtis SP, Langman M, et al. Lower gastrointestinal events in a
Additional choices of point-estimates also deserve discussion: double-blind trial of the cyclo-oxygenase-2 selective inhibitor
the PPI and H2RA treatment strategies were associated with SUB etoricoxib and the traditional nonsteroidal anti-inflammatory drug
and VAP probabilities of 1.34% and 6.61% and 10.33% and 10.32%, diclofenac. Gastroenterology 2008;135:1517–25.
[4] Kuipers EJ, Sung JJ, Barkun A, et al. Safety and tolerability of high-dose
respectively. Higher VAP rates can be found in the literature: Eom
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