Cost-effectiveness analysis of immune-modulating nutritional support for gastrointestinal cancer patients

Clinical Nutrition 33 (2014) 649e654

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Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu

Original article

Cost-effectiveness analysis of immune-modulating nutritional support for gastrointestinal cancer patientsq Hélène Chevrou-Séverac a, *, Christophe Pinget b, Yannick Cerantola c, Nicolas Demartines c, Jean-Blaise Wasserfallen b, Markus Schäfer c a b c

Nestlé Health Science, Avenue Nestlé 55, BP 353, CH-1800 Vevey, Switzerland University Hospital of Lausanne (CHUV), Medical Direction, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland University Hospital of Lausanne (CHUV), Department of Visceral Surgery, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland

a r t i c l e i n f o

s u m m a r y

Article history: Received 27 March 2013 Accepted 5 September 2013

Background & aim: Immune-modulating nutritional formula containing arginine, omega-3 fatty acids and nucleotides has been demonstrated to decrease complications and length of stay in surgical patients. This study aims at assessing the impact of immune-modulating formula on hospital costs in gastrointestinal cancer surgical patients in Switzerland. Method: Based on a previously published meta-analysis, the relative risks of overall and infectious complications with immune-modulating versus standard nutrition formula were computed. Swiss hospital costs of patients undergoing gastrointestinal cancer surgery were retrieved. A method was developed to compute the patients’ severity level, not taking into account the complications from the surgery. Incremental costs of complications were computed for both treatment groups, and sensitivity analyses were carried out. Results: Relative risk of complications with pre-, peri- and post-operative use of immune-modulating formula was 0.69 (95%CI 0.58e0.83), 0.62 (95%CI 0.53e0.73) and 0.73 (95%CI 0.35e0.96) respectively. The estimated average contribution of complications to the cost of stay was CHF 14,949 (V10,901) per patient (95%CI 10,712e19,186), independently of case’s severity. Based on this cost, immune-modulating nutritional support decreased costs of hospital stay by CHF 1638 to CHF 2488 per patient (V1195 eV1814). Net hospital savings were present for baseline complications rates as low as 5%. Conclusion: Immune-modulating nutritional solution is a cost-saving intervention in gastrointestinal cancer patients. The additional cost of immune-modulating formula are more than offset by savings associated with decreased treatment of complications. Ó 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Immune-modulating formula Post-surgical complication risk Cost-effectiveness analysis Gastrointestinal cancer surgery

1. Introduction Complications following gastrointestinal (GI) cancer surgery are still an important issue and significantly impact on patient’s outcome, length of hospital stay (LOS) and costs.1,2 Reported postNon-standard abbreviations: IMF, immune-modulating formula; GI, gastrointestinal; DRG, diagnostic-related group; RR, relative risk; LOS, length of hospital stay; CHF, Swiss franc. q Conferences presentations: This paper has been presented as: (1) A poster presentation at the 24th Annual Congress, European Society of Intensive Care Medicine, October 1e5, 2011, Berlin, Germany. (2) An oral presentation at the 23rd Annual Congress ALASS (Association latine d’analyse des systèmes de santé), September 9e11 of 2012, Lisboa, Portugal. (3) An oral presentation at the 9th HTAi conference (Health Technology Assessment international), June 25e27th of 2012, Bilbao, Spain. * Corresponding author. Tel.: þ41 21 924 79 22. E-mail address: [email protected] (H. Chevrou-Séverac).

operative complication rates for GI cancer surgery are ranging from 15% to 54%,3e7 with infectious complications being the most frequent ones (including wound infections, abdominal abscess, pneumonia, anastomotic dehiscence, urinary tract infections, and sepsis). Policies to prevent and reduce post-operative complications generally focus on pathogen eradication, e.g. peri-operative antibiotic prophylaxis, reduction of surgical trauma and intraoperative contamination, as well as improvement in the hospital environment.8 Only recently, improving host defense mechanisms have become a target of interest. Adequate nutrition is strongly linked with immune competence and risk reduction of infections5,7; hence any nutritional deprivation increases patient’s risk. Immune-modulating nutritional formulas (IMF) have been studied in multiple randomized clinical trials. Most of them have shown a reduction in post-operative infectious and non-infectious complications as well as LOS in patients

0261-5614/$ e see front matter Ó 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. http://dx.doi.org/10.1016/j.clnu.2013.09.001

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undergoing GI cancer surgery. Although some studies were not conclusive due to either the IMF used, as formulas are not identical and therefore don’t reach the same clinical efficacy,6 or compliance issues,9,10 when studies were pulled together in meta-analyses, results have been consistently showing benefit of IMF in GI surgical patients.3e7,11 The most recent meta-analyses of RCTs in GI surgery are the ones of Cerantola et al. (2011),5 Marimuthu et al. (2012)7 and Zhang et al. (2012).11 Cerantola’s study focused on all GI cancer surgeries, whereas Marimuthu’s one assessed only major open GI surgery; while Zhang and coauthors focused on surgeries for GI cancer patients. In addition of meta-analyses3e7,11 demonstrating the efficacy of IMF versus standard of care (SoC, i.e. nil-by-mouth and/or standard enteral nutrition depending on the IMF regimen), several costeffectiveness analyses and cost impact studies of IMF have been published.1,12e14 The impact of IMF on hospital costs has been studied in GI cancer surgery in Germany,12 Italy1,13 and the US.14 All these trials demonstrated that IMF is a cost-effective and costsaving intervention, independent of the IMF regimen. However, none of these studies took into account the patients’ severity level to isolate cost of care related to the index disease and interventions. The goal of this study was to fill this gap by assessing the costeffectiveness of IMF from a Swiss hospital diagnostic-related group (DRG) cost database, while discarding the impact of patients’ severity level on these costs. 2. Methods 2.1. Clinical outcomes This cost-effectiveness analysis of IMF in GI patients used the clinical evidence from the Cerantola’s meta-analysis5 in order to have clinical practice close to one of the Swiss hospital from which cost data were extracted for the economic analysis. We used the same 21 RCTs as included in this meta-analysis of RCTs comparing IMF versus SoC (standard enteral nutrition or nil-by-mouth) in GI cancer patients undergoing elective surgery,5 to determine the relative risks (RR) of overall and infectious complications of IMF compared to SoC. Among these 21 studies, 6 focused on preoperative use of IMF, 12 on post-operative use of IMF and 6 on peri-operative administration of IMF (see Cerantola et al.5 for more details). The studies selected by Cerantola and coauthors are not presented in this publication. The RR computed here are just complementary results to this meta-analysis in order to be used in a straightforward way into the cost-effectiveness analysis. The computation of RR was performed using Review Manager Software for WindowsÒ (RevManÒ 5.0.23; The Nordic Cochrane Centre, Copenhagen Denmark), by a treatment effects analysis, with 95% confidence intervals (CI). Data across studies were pooled using fixed-effects (inverse variance) and random-effects models. 2.2. Cost outcomes 2.2.1. Hospital cost database Cost data were obtained from the university hospital of Lausanne (CHUV) from its accounting and diagnostic-related group (DRG) database (thereafter, hospital database) for the years 2006e 2010. Based on their diagnostic (ICD-10-CMd) and intervention codes (ICD-9-CMe), hospital records of patients matching with the

d International Classification Disease, 10th revision, Clinical Modification, World Health Organization, http://www.who.int/classifications/icd/en/. e International Classification Disease, 9th revision, Clinical Modification, World Health Organization.

Table 1 ICD codes related to GI cancer patients. Main diagnostic ICD-10 codes (C15) Malignant neoplasm of esophagus (ICD-10 codes selected: C15.0; C15.4e5; C15.8e9) (C16) Malignant neoplasm of stomach (ICD-10 codes selected: C16.0e9 except C16.7) (C17) Malignant neoplasm of small intestine (ICD-10 codes selected: C17.0e2 and C17.8e9) (C18) Malignant neoplasm of colon (ICD-10 codes selected: C18.0e9) (C19) Malignant neoplasm of rectosigmoid junction (C20) Malignant neoplasm of rectum (C25) Malignant neoplasm of pancreas (ICD-10 codes selected: C25.0e3 and C25.8e9) (C26) Malignant neoplasm of other and ill-defined digestive organs (ICD-10 codes selected: C26.8e9) (C78.7) Secondary malignant neoplasm of liver

ones included into the meta-analysis of Cerantola et al.5 were retrieved (see Tables 1 and 2 for the list of GI cancer diagnoses and surgical interventions). Their medical records provided information on diagnoses, interventions, comorbidities, LOS, costs and DRG codes. Patients with overall and infectious complications linked to surgery that were potentially preventable with IMF intervention were coded as patients with complications (see Table 3 for the selected complications). Based on the meta-analysis of Waitzberg et al. (2006),3 these likely preventable complications with IMF were identified to be wound infections, anastomotic leaks and their consequent infections, pneumonia and abdominal abscesses. From this database extraction, average costs of hospital stay for the GI cancer surgical patients with and without complications were computed. 2.2.2. Disease severity and cost of stay due to complications In order to distinguish between costs related to treating complications from costs linked to the patient’s comorbidities and/or disease severity, corrected cost-weights were computed by using Diagnosis Related Groups (DRG) to derive an exogenous severity score for each patient stay. In a DRG system, patient stays are classified in homogeneous groups on the basis of age, gender, diagnostic and intervention codes. Patient stays grouped in the same DRG are assumed to have comparable costs. To each DRG, a severity score called cost-weight (CW) is assigned. This CW was used to derive the patient’s exogenous severity score. For patients without complications, the exogenous severity score is equal to the current CW. However for the patients with complications, the CW they would have had in absence of complication was calculated to identify their exogenous severity score (meaning independent of the complications studied). The relevant complication codes were discarded from the patients’ record and a new DRG computed which represents the severity of patient’s profile independent of his/her complications. Finally the contributions of complications and of patient’s severity level to the cost of hospital stay were both estimated by regression analysis using Stata Statistical Software: Release 11 (StataCorp 2009).

Table 2 ICD codes related to GI surgeries. List of interventions code ICD 9: GI surgeries 42.19 42.59 43.89 45.61 45.91 50.26

42.33 42.62 43.91 45.62 45.92 52.01

42.39 42.63 43.99 45.71 45.93 52.09

42.4 42.65 45.31 45.73 45.94 52.22

42.41 42.69 45.33 45.74 45.95 52.51

42.42 42.99 45.34 45.75 46.99 52.52

42.52 43.5 45.41 45.76 49.99 52.53

42.54 43.6 45.43 45.79 50.23 52.7

42.58 43.7 45.49 45.8 50.25 52.96

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Table 3 ICD codes used to classify complications likely preventable with IMF. ICD-10 diagnostic codes used to identify complications and infections Sepsis Infections Pneumopathies Other complications

A41.1 A49.0 J15.0 K91.3

A41.2 A49.1 J15.2 K91.8

A41.5 A49.8 J15.6

A41.51 A49.9 J18.0

2.2.3. Hospital cost impact and cost-effectiveness analyses The resulting estimated treatment cost of complications was then used to compute the impact of IMF versus SoC on hospital costs for GI cancer patients undergoing surgery. For each patient’s group, the costs of complications were computed by multiplying the percentage of patients presenting with overall complications by the cost of treating these complications. The hospitalization costs related to exogenous patient’s severity score were not taken into account, as assumed to be unrelated to the effect of IMF. Finally, the cost-effectiveness of IMF intervention compared to SoC was computed by comparing both cost of complications and medical nutrition and complications rates between the two treatment groups. 2.2.4. Sensitivity analyses In order to also assess the robustness of the model, sensitivity analyses were performed. First, results were computed around the baseline complication rate which was varied between 0% and 60%. The difference in hospital cost per patient were computed for each complication rate and plotted against the baseline complications rate for each IMF regimen. The baseline complication rate at which difference in costs between groups was null (also called costneutrality) was also estimated for the three regimen of IMF use. Second, results were estimated for RR of infectious complications to get a crude estimate of the impact of IMF regimen on cost of infections. Here as well, the initial infection rate, making INF a costneutral intervention was computed. Finally, uncertainty in parameters was also taken into account by one-way sensitivity analysis using 95% confidence interval values for the RR of complications and the RR of infections.

3. Results 3.1. Clinical outcomes (Tables 4 and 5) RR of infectious complications and overall complications based on the 21 trials included in the meta-analysis by Cerantola and coauthors5 are displayed in Tables 4 and 5. The decreases in risks of complications were always statistically significant, but more important for infectious complications (RR ¼ 0.48e0.65) than for overall complications (RR ¼ 0.62e0.73). The effect of IMF to reduce the overall complication rate was more important when IMF was used peri-operatively (RR of 0.62, with 95%CI 0.53e0.73); whereas for infectious complications, the decrease was more important when IMF was administered pre-operatively (RR of 0.48, with 95% CI 0.35e0.66).

Table 4 Relative risk of overall complications for the 3 regimen of IMF; computed by metaanalysis.

A41.52

A41.58

J18.1

J18.9

A41.8

A41.9

N39.0

R65.0

3.2. Hospital cost data and case’s severity Four hundred and twenty patients with diagnosis and operation codes related to GI cancer and surgery were extracted from the hospital DRG database. These patients were selected based on the diagnostic and intervention codes related to major GI surgery related to use of IMF as recommended in ESPEN Guidelines (Grade A recommendation).15 These patients underwent major GI surgery into this hospital between January 2006 and December 2010. All patients underwent routine pre-operative nutritional assessment at the outpatient department by using the Nutritional Risk Score (NRS).16 Patients having a NRS 3 were further assessed and treated by the clinical nutrition team according to ESPEN guidelines.15 If necessary, surgery was delayed up to two weeks. In addition between October 2007 and September 2010, 152 of these patients were included into a randomized clinical trial assessing the efficacy of pre-operative IMF compared to standard enteral nutrition on post-operative complications rate in patients at nutritional risk.9 Consequently some of these patients might have used less healthcare resources than a true control group due to either the usual standard nutrition protocol or to the trial done. Therefore using cost data from this hospital was a conservative approach, as it may have driven the hospital costs estimation down. This assumption was confirmed as only 64 patients over the 420 selected presented with complications giving a post-operative complication rate of 15.2%, far below the rates usually seen in control groups of RCTs (ranging from 31% to 95% for overall complications when considering the RCTs included in Cerantola’s meta-analysis5). From these DRG data, the average exogenous severity scores were estimated to amount to 4.05 (SD 1.85) for the 64 patients presenting with at least one complication, and 2.84 (SD 1.21) for patients without complication. This difference demonstrates that patients with complications are more severely ill than those without it, independently of the complications studied. The average cost of hospital stay for the 420 cancer patients (with and without infectious complications) undergoing lower and upper GI surgery was CHF 33,549 (SD 21,955) per patient-stay (V24,464). The mean hospital cost of stay for patients without and with complications was CHF 29,499 (SD 17,587) and CHF 56,072 (SD 29,239) per patient-stay respectively (V21,511 and V40,889). Patients without complications staid on average 12.76 days (with SD of 7.11) into hospital; while patients with complications staid 22.92 days (10.32). The contribution to the cost of hospital stay of treating complications was estimated by a regression analysis taking into account the severity scores of the patients: it led to additional CHF 14,949 (V10,901) per patient-stay (95%CI CHF 10,712e19,186) (see Table 6). Table 5 Relative risk of infectious complications for the 3 regimen of IMF; computed by meta-analysis.

IMF regimen

Relative risk of complications

95% confidence interval

Pooled complication rate  control

IMF regimen interval

Relative risk of infections

95% confidence interval

Pooled infection rate  control

Pre-operative Post-operative Peri-operative

0.69 0.73 0.62

0.58e0.83 0.35e0.96 0.53e0.73

53% 50% 54%

Pre-operative Post-operative Peri-operative

0.48 0.65 0.50

0.35e0.66 0.53e0.79 0.38e0.66

36% 29% 29%

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Table 6 Estimated cost of hospital stay due to case’s severity and complications (estimated by regression analysis).

Exogenous severity score Complications

Estimated costs

95% confidence interval

P

CHF 9637

CHF 8546; 10,728

<0.001

CHF 14,949

CHF 10,712; 19,186

<0.001

For non-malnourished patients, IMF is recommended to be taken orally 3 times a day prior to surgery for 5e7 days; whereas for malnourished patients the recommended intake is 3 times a day orally for 5e7 days prior to surgery and 5 times a day orally (or 2 to 3 enteral pouches) for minimum 7 days. Thus the cost of IMF for well-nourished patients was CHF 200 for the pre-operative regimen for 5 days and a minimum of CHF 580 for the peri-operative regimen (either oral or enteral) for malnourished patients for 5 days pre- and minimum 7 days post-surgery (Nestlé Health Science list prices as of 2010). 3.3. Cost-effectiveness analysis Treatment costs of complications were computed for patients in the IMF and control groups (Table 7). Considering the pre-operative use of IMF therapy, in the SoC group, the pooled average complication rate was estimated to be 53%. Hence, based on the marginal costs of CHF 14,949 (V10,901) for treating complications, this cost of treating complication were multiplied by the complication rate of the control group leading to an incremental average costs of treating complications in the control group of CHF 7923 (5778V) per patient. With the use of IMF, complications decreased from 53.0% in SoC to 36.6% (RR 0.69). The average incremental cost of treating complications in the IMF group was computed like in the control group while adding cost of IMF: it led to CHF 5667 (V4132) per patient including costs of IMF. Thus, hospitals could save CHF 2256 (V1645) per patient’s hospitalization (95%CI [CHF 1560; 2952]) by decreasing the risk of overall complications with the prescription of IMF pre-operatively. When doing the same calculation for peri-operative use of IMF, the estimated savings amounted to an average of CHF 2488 (V1814) per patient (95%CI [CHF 1618; 3357]) and to an average of CHF 1638 (V1195) per patient with post-operative use of IMF (95%CI [CHF 1066; 2210]) (Table 7). Thus in the three IMF regimen, overall complications as well as treatment costs decreased, making IMF a more effective and cost-saving intervention compared to Soc. 3.4. Sensitivity analyses In real life, baseline complications rates in the control group could be different, depending on medical practice in different

Table 7 Hospital cost of stay in the IMF and control groups based on relative risk of complications. IMF Complication rate regimen RR SoC IMF

Pre-op Peri-op Post-op

Fig. 1. Estimated cost-savings depending on the initial complications rate in the control group (pre-operative regimen). Vertical axe’s title: Savings per patient’s stay in Swiss francs. Horizontal axe’s title: Baseline complication rate.

hospitals. Considering pre-operative use of IMF, hospitals can still achieve net savings of CHF32 (V23) per patient if baseline infections rate in GI cancer surgical patient is as low as 5% (see Fig. 1). The baseline complication rates at which there is no difference in cost of complications (also called cost-neutral baseline rate) between the control and the intervention groups were estimated to be 4.32%, 10.21% and 9.41% for the pre-, peri- and post-operative regimen of IMF. For initial complication rates above these thresholds, introducing IMF in the protocol of care for treating GI cancer patients undergoing surgery could generate savings in hospital costs (Table 8). When considering only the infectious complications into the cost-effectiveness analysis, here as well IMF was deemed as a dominant intervention as it decreased risk of infection and cost of care. The savings were respectively CHF 2598, CHF 1588 and CHF 1137 per patient for the pre-, peri- and post-operative use of IMF respectively (respectively V1895; V1158 and V829). Similarly when making the baseline infection rates varied in the control group, the cost-neutral baseline infection rates was found to be 2.57%, 7.76% and 7.27% for pre-, peri- and post-operative use of IMF (Figs. 1e3). For initial infection rate above these thresholds, hospitals are expected to make savings when introducing IMF in their medical practice (Table 8). Finally, when taking into account 95%CI of RR of complications, the range of cost of stay for treating complication always demonstrated savings for pre and peri-operative use of IMF, whereas it wasn’t the case for post-operative use; while when considering 95% CI of RR of infections, the range of hospital cost shown that the IMF intervention was always cost-saving (Table 8). 4. Discussion This study demonstrated that IMF, by decreasing complications, decreased net hospital cost, making it a more effective and costsaving intervention compared to SoC (called also dominant intervention). Indeed, costs of IMF were offset by the savings due to the decrease in hospital complications costs. Table 8 Results of the sensitivity analyses for the pre-, peri- and post-operative use of IMF. Pre-operative Peri-operative Post-operative regimen regimen regimen

Marginal hospital costs SoC (95%CI)

0.69 53.0% 36.6% CHF 7923 (5677; 10,169) 0.62 54.0% 33.5% CHF 8072 (5784; 10,360) 0.73 50.0% 36.5% CHF 7475 (5356; 9593)

IMF (95%CI)

CHF 5667 (4117; 7216) CHF 5585 (4166; 7003) CHF 5836 (4290; 7383)

Difference (IMF  Soc) (95%CI) CHF 2256 (1560; 2952) CHF 2488 (1618; 3357) CHF 1638 (1066; 2210)

Cost-neutral baseline complication rate Savings per patient based on 95%CI of RR of complications Savings based on infection rate per patient (95%CI) Cost-neutral baseline infection rate Savings based on 95%CI of RR of infections

4.32%

10.21%

9.41%

CHF 1147; 3128 CHF 2598 (1805; 3392) 2.57%

CHF 1600; 3214 CHF 1588 (973; 2202) 7.76%

CHF 81; þ4478 CHF 1137 (707; 1567) 7.27%

CHF 1630; 3298

CHF 894; 2108

CHF 530; 1658

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Fig. 2. Estimated cost-savings depending on the initial complication rate in the control group (peri-operative regimen). Vertical axe’s title: Savings per patient’s stay in Swiss francs. Horizontal axe’s title: Baseline complication rate.

Our results are in concordance with four other studies assessing the cost-effectiveness and impact on hospital costs of IMF in GI cancer patients’ population undergoing elective surgery. Braga and Gianotti13 and Braga et al.1 used hospital costs data gathered from GI cancer surgical patients included in a randomized controlled trial performed in an Italian hospital setting. Both analyses concluded that IMF was an effective and cost-saving nutritional therapy. These results confirmed a previous study using German cost data.12 Furthermore, Mauskopf et al.14 estimated the impact of IMF on US hospital costs. Although they showed that IMF was costsaving compared to SoC in GI cancer surgery, they did not focus on incremental costs due to complications. Our study is limited by the fact that hospitalization costs were not collected by micro-costing method or alongside clinical trials, which might reduce its accuracy. Nevertheless, our results are comparable to the ones of Senkal12 and Braga,1 who both used more detailed micro-costing methods to compute complications costs. In both studies, costs of IMF for all patients were offset by the savings due to the decrease in complication rates. In addition, our approach of taking into account exogenous severity score of the patients allowed for isolating the hospital costs attributed to the complications partially preventable by the use of IMF. Despite the lack of micro-costing hospital cost data, our approach allowed to compute the hospital costs for treating complications partly preventable with IMF. Thus correcting for case’s severity into DRG hospital database can be an option to identify hospital costs attributable to specific diseases, interventions or comorbidities. Our analysis used the clinical outcomes from the meta-analysis of Cerantola and coauthors which mixed different IMF formulas.5 Therefore, a comparison between the different IMF formulas could be of interest as well. However, Drover and coauthors have already done this comparison and demonstrated that the IMF

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containing arginine, omega-3 fatty acids and nucleotide had the strongest efficacy on risk of infections and hospital LOS.6 IMF containing arginine, fish oil and nucleotides has been constantly demonstrating its efficacy when taken accordingly to recommended intake in well-nourished and malnourished GI cancer patients undergoing surgery; and has received a grade A recommendation into ESPEN Guidelines on Enteral Nutrition for Surgery including organ transplantation.15 The clinical benefit of IMF has been shown on decreasing risk of overall complications, infectious complications and LOS. However, the role of IMF on prevention of infections with multi-resistant strains has not been demonstrated. This lack of data is probably related to the fact that infections caused by multi-resistant strains have gained clinical importance only during recent years. In almost all Western countries, healthcare costs are rapidly increasing and the increasing gap between costs and available resources has become a serious issue,17 especially during economic downturns. The development and implementation of effective cost containment measures represent an ongoing major challenge involving all players in the healthcare market. Pre-operative assessment of surgical risk and interventions aiming at decreasing the post-operative complications and infections risk are the two potentially successful approaches. Among pre-operative surgical risk, malnutrition is a well-known risk factor for all kind of postoperative complications. In post-operative period, malnourished patients are indeed more vulnerable to infection and present delayed wound healing.18,19 Therefore screening for malnutrition risk and intervening with medical nutrition are two assets in preventing and fighting hospital-acquired infection, especially in a context of increasing bacteria resistance. In addition, IMF nutritional intervention in well-nourished patients has also been demonstrated to be an asset in decreasing the risk of post-operative complications.3e7,11 Hence independently of the nutritional status, this study and the previous available cost-effectiveness analyses and meta-analyses of RCTs on IMF have demonstrated that immune-modulating nutritional intervention when taken accordingly to recommendations is also an asset to support patients’ recovery after GI cancer surgery. By decreasing the risk of complications by 27%e48%, IMF could allow hospitals to make net savings ranging between CHF 1638 and 2488 per patients. Therefore, IMF can be considered as a dominant intervention in GI cancer patients undergoing elective surgery: it is a more effective and a cost-saving nutritional intervention compared to nil-by-mouth or standard enteral nutrition. As IMF is a very simple intervention in an era of high technology, it should be recommended to hospitals willing to decrease infectious complications as well as to control hospital costs. Conflict of interest Since the initiation of this publication, JBW, ND and MS have been invited from time to time by Nestlé Health Science to present into symposium on topics realted to medical nutrition and/or into experts panel. Acknowledgment

Fig. 3. Estimated cost-savings depending on the initial complications rate in the control group (post-operative regimen). Vertical axe’s title: Savings per patient’s stay in Swiss francs. Horizontal axe’s title: Baseline complication rate.

Funding: HCS works for Nestlé Health Science, as Global Head of the Health Economics. CP and JBW were consultants for Nestlé Health Science for this study. YC, MS and ND didn’t receive any financial incentive or support to collaborate to the study. Authors’ contribution: HCS initiated the project and wrote the abstract and manuscript. CP realized the DRG cost database analysis and reviewed the manuscript. YC computed the relative risk of infectious and non-infectious complications based on the same

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data has the Cerantola et al. (2011) meta-analysis. MS and YC brought their medical expertise to carefully select the cost data for patients matching their meta-analysis (i.e. GI cancer patients undergoing major GI surgery). CP, YC, MS, JBW and ND actively reviewed and contributed to the abstract and manuscript.

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