VALUE IN HEALTH 16 (2013) 14–22

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ORIGINAL RESEARCH Economic Evaluation Cost-Effectiveness Analysis: 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 1Division 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

ABSTRACT

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 -assisted (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 (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, Montre´al, Que´bec H3G 1A4, Canada. E-mail: [email protected]. 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 VALUE IN HEALTH 16 (2013) 14–22 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] 49 VAP with PPI treatment 10.33 [8,11,13–15,18,19] 814 VAP with H2RA treatment 10.32 [8,11,13–15,18,19] 714

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)codesandthe 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 VALUE IN HEALTH 16 (2013) 14–22

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 78559 Shock W/O trauma nec 99592 Sys inflam/infecti W organ dysfuncti Septicemia 0380 Streptococcal septicemia Acute 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 ) 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 SUBÃ 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 ; 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 consideredincludedinthehospitalcosts. 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 VALUE IN HEALTH 16 (2013) 14–22 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 foracomplicatedoruncomplicatedhospital 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. averagecost-to-chargeratiowasapplied.Thisgroupaveragecost- 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 VALUE IN HEALTH 16 (2013) 14–22

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 One-way sensitivity analysis majority of scenarios. 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 VALUE IN HEALTH 16 (2013) 14–22 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 VALUE IN HEALTH 16 (2013) 14–22

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 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 REFERENCES 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. 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