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

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/jval

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; 4Universite de Bourgogne,
Dijon, France

AB ST RAC T

Objectives: Proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) present varying pharmacological efficacy in preventing
stress ulcer bleeding (SUB) in intensive care units. The literature also
reports disparate rates of ventilator-assisted pneumonia (VAP) as side
effects of these treatments. We compared the cost-effectiveness of
these two prophylactic pharmacological options. Methods: We constructed a decision tree with a 60-day time horizon for patients at
high risk for developing SUB, receiving either PPIs or H2RAs. For each
treatment strategy, patients could be in one of three states of health:
SUB, VAP, or no complication. Contemporary, clinically relevant
probabilities were obtained from a broad literature search. Costs were
estimated by using a representative US countrywide database. A
third-party payer perspective was adopted. Cost-effectiveness and
univariate and multivariate sensitivity analyses were performed.
Results: Probabilities of SUB and VAP were 1.3% and 10.3% for PPIs

versus 6.6% and 10.3% for H2RAs, respectively. Lengths of stay and per
diem costs were 24 days and US $2764 for SUB, 42 days and US $3310
for VAP, and 14 days and US $2993 for patients without complications.
Average costs per no complication were US $58,700 for PPIs and US
$63,920 for H2RAs. The H2RA strategy was dominated by PPIs.
Sensitivity analysis showed that these findings were sensitive to
VAP rates but PPIs remain cost-effective. The acceptability curve
shows the stability of the probabilistic results according to varying
willingness-to-pay values. Conclusion: PPI prophylaxis is the most
efficient prophylactic strategy in patients at high risk of developing
SUB when compared with using H2RAs.
Keywords: cost-effectiveness, H2RA, proton pump inhibitors, stress
ulcer bleeding.

Introduction

Methods

Stress-related mucosal disease in the form of stress ulcer bleeding

(SUB) remains an important clinical problem. Although it is a small
proportion of patients who bleed [1,2], the clinical factors that predict
a higher risk of rebleeding are increasingly found among patients
admitted to an intensive care unit (ICU) setting [13]. Proton pump
inhibitors (PPIs) have been found efficacious in preventing stressrelated mucosal disease (also referred to as stress ulcer) bleeding (SUB)
in the ICU setting, as have H2-receptor antagonists (H2RAs) [14]. Their
comparative efficacies and the possible development of ventilatorassisted pneumonia (VAP) remain subjects of controversy with disparate data in the literature. Recent meta-analyses have suggested the
superiority of PPIs [5,6], but the low incidence of SUB coupled to the
high costs of this complication underline the need for a cost-effective
analysis comparing PPIs with H2RAs. We therefore performed an
economic analysis to better quantify the cost-effectiveness impact of
these two therapeutic prophylactic approaches.

Copyright & 2013, International Society for Pharmacoeconomics and

Outcomes Research (ISPOR). Published by Elsevier Inc.

Study Population
The study population comprised patients at high risk of developing SUB in the ICU setting. These patients were identified by
using the Nationwide Inpatient Sample (NIS) 2008 [7] that is
supported by the Agency for Healthcare Research and Quality
from the U.S. Department of Health and Human Services. This
national hospitalization database comprises 8 million hospitalizations in more than 1000 hospitals located in 42 states from the
United States. Hospitalizations of patients who died during the
hospital stay or who were younger than 18 years were excluded
from the analysis. We included only those hospitalizations that were
recorded with Medicare, Medicaid, or a private insurance as the
primary payer. We selected specific diagnoses to define a representative group of patients at risk of SUB. The list of all diagnoses
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, Montreal, Quebec 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

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Table 1 Probability estimates used in the model.

Probability among the entire study population (%)
SUB
SUB
VAP
VAP

with
with
with
with

Point estimate

Source

Low bound

High bound

1.34
6.61
10.33
10.32

[819,22]
[819,22]
[8,11,1315,18,19]
[8,11,1315,18,19]

0.7
4
8
7

3
9
14
14

PPI treatment
H2RA treatment
PPI treatment
H2RA treatment

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 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 [819]

and was validated by a clinician expert (A.B.). We used the
principal diagnosis and 14 other possible secondary diagnoses
that were expressed as International Classification of Diseases,
Ninth Revision, Clinical Modification (ICD-9-CM) codes and the
indicator of occurrence of major operating room procedure to
select the hospitalizations from the NIS database. We focused
on the principal diagnosis to define patient eligibility (except for
septicemia that could appear as a nonprincipal diagnosis). The
diagnoses were extracted from ICD-9 coding among all the
available diagnoses recorded in the NIS database. The list of
selected diagnoses is shown in Table 2.

Model Design
A decision tree model was constructed by using the software
program TreeAge Pro Suite 2011 (TreeAge Software, Inc.,
Williamstown, MA) to present the use of PPIs versus H2RAs
during the hospitalization for a patient at high risk of developing
SUB. Treatment in the PPI group included bolus intravenous or
oral omeprazole 40 mg daily. The H2RA regimen was famotidine
40 mg intravenously twice daily.
In each treatment, patients were stratified into those with
complications and those with no complication. Complications
were divided into two categories: SUB and VAP. The adopted time
horizon was 2 months (60 days), as justified by clinical arguments
below. We also adopted a third-party-payer perspective.

Probabilities
Probabilities were provided by a literature search spanning 1990
to September 2011. Computerized medical literature searches

were done by using Ovid MEDLINE (1990 to September Week 2,

2011), EMBASE (1990 to 2011 Week 37), CENTRAL (fourth quarter
2011), and (ISI) Web of knowledge 4.3. All abstracts from Digestive
Disease Week and United European Gastroenterology Week were
also searched as were clinical trials databases [20]. Articles were
selected by using a search strategy to identify reports of randomized controlled trials (RCTs) [21] with a combination of Medical
Subject Headings and text words related to 1) PPI, 2) stress ulcer,
3) gastric bleeding in a, 4) clinical ill patient setting treated with
either PPI, or 5) a treatment of PPIs or H2RAs. Treatment group as
well as RCTs were required and three of the other aforementioned criteria for selection. Recursive searches and crossreferencing were also carried out by using a similar articles
function; hand searches of articles were identified after an initial
search. We included all adult human studies in French or English,
published as full article or abstracts. Trials comparing only
different dosing regimens of the same molecule were excluded.
Studies assessing solely or mainly pediatric patients, or whose
only outcomes were gastric pH measurements, were also
excluded. All selected model probabilities were validated by an
expert clinician (A.B.).
Our literature search identified 489 articles. Eight fully published articles [810,1416,19,22] were included as well as five
abstracts [1113,17,18] (we evaluated the English abstract of De
Azevedo et al. trial and not the full Spanish publication in
keeping with the a priori limits chosen for language selection)
as reported in a recently published quantitive meta-analysis by
our group [23]. The resulting probabilities of SUB were 1.34% and
6.61% and those of VAP were 10.33% and 10.32% among all
patients at risk for SUB following the PPI and H2RA treatments,
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 SUB and VAP.

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Table 2 List of ICD-9-CM codes.

Category of patients
Category of chosen diagnosis

ICD-9-CM code

Description of the code as they appear in the ICD-9

coding system

Risk for SUB

Major trauma
850-854
860-869
925-929

Intracranial injury, excluding those with skull fracture

Internal injury of thorax, abdomen, and pelvis
Crushing injury

Hypovolemic shock
78559

Shock W/O trauma nec

99592

Sys inflam/infecti W organ dysfuncti

0380

Streptococcal septicemia

51881

Respiratory failure

Sepsis
Septicemia
Acute respiratory failure
Extensive burns
(30% of the body and more)
Acute renal failure

9483-9489
5846
5847
5848
5849

Burns classified according to extent of body surface involved

Ac renal fail-cort necr
Ac ren fail-medull necr
Ac renal failure nec
Acute renal failure nos

Shock
5185
6395
66910-66914
9584
9980

Shock lung (pulmonary insufficiency following trauma and surgery)

Shock: circulatory collapse after complications classifiable to 630-638
Shock during or following labor and delivery (obstretric shock)
Traumatic shock (shock following injury)
Postoperative shock

Severe acute pancreatitis

5770

Diseases of pancreas acute pancreatitis

74685
99603
74685
99603

Coronary artery anomaly

Due to coronary bypass graft
Coronary artery anomaly
Malfunc coron bypass grf

53021
53100
53120
53400
53420
5780
5781
53200
53220

Ulcer of esophagus with bleeding

Gastric ulcer: acute with hemorrhage
Gastric ulcer: acute with hemorrhage and perforation
Gastrojejunal ulcer: acute with hemorrhage
Gastrojejunal ulcer: acute with hemorrhage and perforation
Gastrointestinal hemorrhage: hematemesis
Gastrointestinal hemorrhage: blood in stool
Duodenal ulceracute with hemorrhage
Duodenal ulceracute with hemorrhage and perforation

99731

Vent assoc pneumonia

Coronary artery bypass graft surgery

Complication cases among the risk for SUB

SUB

VAP

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

A specific length of stay and per diem were assigned to each of the
three groups of patients. Only hospital costs were included. All
pharmaceutical costs were considered included in the hospital costs.
Lengths of stay and costs were obtained from the NIS 2008 [7] by
using a validated methodology [24] and relevant specific ICD-9-CM

codes (Table 2). Two strategies were used to cost out the hospital stay
of patients with complications: The VAP hospitalizations were
selected among all the available diagnoses in NIS (from the 1st to
the 15th diagnosis for a given patient), whereas SUB hospitalizations
were selected among all the available diagnoses relating to upper
gastrointestinal bleeding in NIS, excluding these when appearing as
a principal diagnosis. The no-complication category was represented

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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
With VAP
No complication

2764
3310
2993

2542
3035
2915

2986
3586
3072

Length of stay (d)

With SUB during the hospitalization
With VAP
No complication

23.7
41.8
13.9

20
33
13

27
51
15

Notes. Source of the point estimate: NIS2008 [7]. All bounds were computed on the basis of 95% CI. Complication 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
groups. In addition, only hospitalizations with major operating room
procedures reported on the discharge record were considered to be
eligible to represent the three subgroups of patients at risk for SUB
(SUB, VAP, and no complication). Costs were computed on the basis
of average charges combined with a cost-to-charge ratio, which was
for the most part specific to the hospital where the hospitalization
took place. More precisely, a cost-to-charge ratio specific to the
hospital was used when available, and if not, a recommended group
average cost-to-charge ratio was applied. Per-diem cost was the ratio
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
account for cases in which cost estimates were missing, as
suggested by the NIS). All US$ values were expressed in 2010 US
dollars by using the consumer price index for the medical care
services published by the U.S. Department of Labor [25].
The diagnoses identified to represent the patient at risk for SUB
and the three subgroups (SUB, VAP, and no complication) are listed in
Table 2. Respecting the inclusion criteria, the weighted results
present 94,865 hospitalizations in the no-complication group, 1,088
in the SUB group, and 235 in the VAP group.
In 87% of the hospitalizations that we selected from the NIS,
we used a cost-to-charge specific to the hospital where the hospitalization occurred. For the other hospitalizations (where a specific
cost-to-charge ratio was not available), the recommended group
average cost-to-charge ratio was applied. This group average costto-charge ratio is defined according to several characteristics of the
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,
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
relevant; it justified our adoption of a 60-day time horizon for the
model. The average hospitalization costs were US $41,600 (nocomplication patients), US $65,500 (SUB), and US $137,700 (VAP). All
costs and lengths of stay used in the model are presented in Table 3.

Cost-Effectiveness Analysis
The effectiveness was expressed as the probability of no complication
occurring during the hospitalization. The costs were those tabulated
for a complicated or uncomplicated hospital stay. The main outcome
was the cost per averted complication. Results are reported as cost,
effectiveness, and incremental cost-effectiveness ratio if a strategy is
more effective but also more costly than another; if not, the model
simply points out the strategy that is dominated (the dominated
strategy is the one that is both less effective and more costly) and
shows therefore the one that is preferred.

Sensitivity and Threshold Analyses

One-way sensitivity analyses were performed on all variables
used in the model to investigate the robustness of the results and
to determine which factors influence these results the most; a
two-way analysis assessing pneumonia incidence in the PPI and
in the H2RA treatment was also performed. Each variable was
varied across its respective 95% [26] confidence interval range. We
produced a tornado diagram [2729] to display in a single graph
each of the one-way results as a single bar and to highlight which
parameters have the greatest influence on the model [30].
Threshold analyses were also performed for select variables.
The adoption of a willingness-to-pay threshold was arbitrary
because we do not use quality-adjusted life-years (QALYs) as
units of effectiveness.
A probabilistic sensitivity analysis was also performed by
using the Monte Carlo method [30].

Results
Base-Case Analysis
The cost-effectiveness analysis shows that the PPI strategy
exhibits a US $1250 lower average cost per patient with a greater
probability of not developing a complication (SUB and VAP) than the
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
H2RA

51,849
53,099

0
1,250

0.8833
0.8307

0
0.0526

58,699
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.

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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
(Table 4). In other words, H2RAs are strictly dominated by PPIs.

Sensitivity Analysis
One-way sensitivity analysis
Figure 2 shows the Tornado diagram using the percentage of the
variation of the base-case incremental cost-effectiveness ratio
when we alter the variables inside their respective 95% confidence
intervals. The probability of developing VAP is what most influences the incremental cost-effectiveness ratio. Univariate sensitivity analysis demonstrates a change in the conclusions only
when varying the probability of pneumonia: H2RA ceases to be
dominated if this probability (which is fixed at 10.3% in the base
case for both pharmacological strategies; see Table 1) rises above
11.6% in the PPI group or if it drops below 9% in the H2RA group.
Across the clinically relevant range of each of these variables, the
PPI strategy becomes more expensive but remains more effective
because of its greater effect on bleeding prevention.

Threshold analysis
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
dominated. The SUB probability has to increase by more than 5%
for the PPI strategy (or drop by more than 5% in the H2RA
approach) for the PPI approach to lose its dominance over the
H2RA strategy. Other threshold values on costs were very unlikely
to occur in order to alter results in any clinically plausible way:
The hospitalization cost for no complication would need to
increase by more than US $1700 per day for H2RAs to become
no longer dominated. Similarly, for the PPI approach to lose its
dominance, the length of stay in patients with no complications
or those developing SUB would need to rise by almost 60% or drop
by 40%, respectively. The analysis did not identify any other
threshold values.

Two-ways sensitivity analysis

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
for an empirically set willingness to pay of US $50,000 in the
majority of scenarios.

Probabilistic sensitivity analysis

A Monte-Carlo analysis was performed with 10,000 simulations
assuming gamma distributions for the per-diem costs and the
lengths of stay and beta distributions for all the probabilities. PPI
treatment was dominant in 49% of the simulations and remained
cost-effective (more effective yet more costly according to a
maximum willingness to pay of US $50,000 per no complication
case) in another 9% of the simulations. On average, the cost of PPI
treatment was almost US $1500 lower than that of H2RA (median
difference of US $3000). Similarly, the gain in mean effectiveness
favored the PPI approach (88.5% vs. H2RA 83%). The corresponding 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
is shown in Figure 5.

Discussion
Both PPIs and H2RAs are used as antisecretory agents in a
number of acid-related diseases in clinical practice [14].
Although cost-effectiveness models have been reported in therapeutic areas such as gastroesophageal reflux disease or in the
context of peptic ulcer bleeding (either before or following
gastroscopy), there exist very few fully published cost analyses
targeting patients in the ICU at risk of developing either a
gastrointestinal bleed or a VAP. Only Schupp et al. [31] performed
such an analysis, but unfortunately limited the economic outcomes to sole drug acquisition costs. As PPIs are more expensive
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

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

VAP in the two groups. Base-case estimates are represented
by the 2 broken lines by pointed lines. Willingness-to-pay
US$50,000 per no complication case. H2RA, H2-receptor
antagonists; PPI, proton pump inhibitors; VAP, ventilatorassisted pneumonia.

patients who receive PPIs rather than H2RAs, we felt that there
were arguments for a full cost-effectiveness analysis, also providing for a more precise documentation of cost implications.
Indeed, the drug costs are magnitudes smaller than the

Fig. 4 Monte-Carlo simulation distribution plot:

incremental cost-effectiveness of PPI versus H2RA
approaches. Probabilistic sensitivity analysis by using
10,000 trials. The slope of the scatterplot represents
willingness to pay of US$50,000 per no complication case.
The interrupted lines indicate the base-case values for
incremental cost and incremental effectiveness. H2RA,
H2-receptor antagonists; PPI, proton pump inhibitors.

19

Fig. 5 Cost-acceptability curves. Maximum willingness to

pay US$50,000 per no complication case. H2RA, H2receptor antagonists; PPI, proton pump inhibitors.

additional hospitalization costs attributable to potential complications ($15$400 [31] vs. $65,000 for the cost of hospitalization of
a bleeding complication in this patient population). Furthermore,
sensitivity analyses in this cost-effectiveness report also allow us
to assess the diverging associations of bleeding and pneumonia
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 [3235], 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
published RCTs assessing SUB [6,37,38]. We did not identify
patients simultaneously experiencing both SUB and VAP as outcomes as these would represent a very small group, and one for
whom it was nearly impossible to identify relevant data in the
NIS notwithstanding the possibility of synchronous complications, whereby the resulting length of stay may not be additive;
these are included in the SUB or VAP complication groups in
our model.

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The choice of NIS assured us of a broad generalizability of

results with regard to not only geographic variation but also the
contemporary nature of care [7].
We chose a decision tree approach as the best way to model
the decisional impact of treating patients at risk for SUB [3942],
considering the short clinically pertinent time horizon and the
chosen outcome [43]. Furthermore, because there was no necessity to focus on recursive health states involving back and forth
movements in the time, decision tree appeared more indicated
than opting for a Markov model [44].
There exist no QALYs described for this condition to the best
of our knowledge. The choice of the unit of effectiveness of cost
per averted complication is in keeping with the nature of the
medical complications that are self-limited, and usually devoid of
prolonged impact beyond the 60-day time horizon. If the outcome of bleeding or pneumonia is now an unusual one, bleeding
or pneumonia-related mortality represents only a proportion of
these rates, with an even smaller number of patients, thus
limiting its choice as an outcome of interest. The chosen outcome of averted complication is in keeping with other costeffectiveness analyses of similar short-term clinical outcomes
[39,4548] and is in keeping with methodological suggestions
published in the literature [27,49].
We did not model for a strategy that used sucralfate in our
analysis because this medication is an older, now little used
method of SUB prophylaxis. Furthermore, some comparative
trials, most of which date back up to 21 years (close to the start
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 exploratory analysis that included all three prophylactic strategies (PPI,
H2RA, and sucralfate) did not alter the findings of PPI dominance
[50]. We do not include these data as we feel they are less
clinically useful for the aforementioned reasons, and may even
be misleading with regard to the final estimates of costs and
effectiveness. Although there exist wide clinical heterogeneity in
the RCTs, our probability assumptions are taken from the available contemporary literature [818,32,5161], including a recent
robust meta-analysis [38]; we did include all relevant trials.
Table 3 reports a per-diem hospitalization cost of US $2993 for
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
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
hospitalization costs are greater for this group (due to the
markedly greater length of stay). This has been previously
reported [24].
Additional choices of point-estimates also deserve discussion:
the PPI and H2RA treatment strategies were associated with SUB
and VAP probabilities of 1.34% and 6.61% and 10.33% and 10.32%,
respectively. Higher VAP rates can be found in the literature: Eom
et al. [62] computed a risk of 19.3% for patients treated with
H2RAs. Contrarily to our more contemporary estimates, however,
this research group included in their calculations trials as old as
1985. We did not consider such older studies as it is well accepted
that VAP rates have decreased significantly in more recent years
[13,15,18,19]. Even though our conclusions are sensitive to VAP
rate estimations, the adopted confidence intervals we use are
already very wide (7%14%) given the contemporary practice of
medicine [13,15,18,19].
To ensure the robustness of the results, we performed many
sensitivity analyses. One-way sensitivity analysis was performed
to explore the impact of the different assumptions across their
broad adopted ranges on the results of the model (also in keeping
with ISPOR recommendations [27]). Two-way analysis varying

both the SUB and VAP probabilities synchronously confirmed the

robustness of the conclusions. Probabilistic sensitivity analysis
additionally tested the uncertainty of all variables simultaneously across 10,000 simulations of the model. The resulting
cost-acceptability curve showed how the willingness to pay failed
to have a significant impact on the strategic choice. Threshold
analyses suggested that only clinically irrelevant values could
alter these conclusions.
The plotting of cost-acceptability curves remains complex and
somewhat subjective whatever the outcome as disparate
willingness-to-pay thresholds are reported in the literature
[6367]. Furthermore, we could not use a reference based on
willingness to pay per QALY because we did not adopt QALYs as
units of effectiveness. The nearest content-relevant examples we
could find were those of Enns et al. [39] who worked with a
willingness to pay per rebleed averted and Briggs et al. [68] who
adopted a willingness to pay per no gastroesophageal reflux
disease symptoms. There are no references in the literature for
a willingness to pay per complication averted in the context of
SUB prophylaxis [39] that we could find. Ubel et al. [67] suggest
that the choices of willingness to pay usually are underestimates
among published cost-effectiveness analyses, at least as it
pertains to the use of QALYs as a measure of effectiveness. We,
therefore, granted arbitrarily as most, fixed a cutoff point at US
$50,000. This value is consistent with the order of magnitude of
the average cost of treatment as noted in our analysis, as some
have suggested to do [39,67,68].

Conclusion
Based on available current data both from RCTs and from a large
contemporary observational administrative database informing
our probability and cost estimates, a strategy of PPI prophylaxis is
the most efficient approach in patients at high risk of developing
SUB when compared with using H2RAs.
Source of financial support: Dr Alan Barkun is a consultant for
Astra Zeneca Canada and Takeda Canada. He also serves as an
expert witness for Merck. There are no other relevant conflicts to
report.
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