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Cost‐Effectiveness of Parenteral Nutrition Containing ω‐3 Fatty Acids in Hospitalized Adult Patients From 5 European Countries and the US

Abstract Background ω‐3 Fatty acid (FA)–containing parenteral nutrition (PN) is associated with improvements in patient outcomes and with reductions in hospital length of stay (HLOS) vs standard PN regimens (containing non–ω‐3 FA lipid emulsions). We present a cost‐effectiveness analysis of ω‐3 FA–containing PN vs standard PN in 5 European countries (France, Germany, Italy, Spain, UK) and the US. Methods This pharmacoeconomic model was based on estimates of ω‐3 efficacy reported in a recent meta‐analysis and data from country‐specific sources. It utilized a probabilistic discrete event simulation model to compare ω‐3 FA–containing PN with standard PN in a population of critically ill and general ward patients. The influence of model parameters was evaluated using probabilistic and deterministic sensitivity analyses. Results Overall costs were reduced with ω‐3 FA–containing PN in all 6 countries compared with standard PN, ranging from €1741 (±€1284) in Italy to €5576 (±€4193) in the US. Expenses for infections and HLOS were lower in all countries for ω‐3 FA–containing PN vs standard PN, with the largest cost differences for both in the US (infection: €825 ± €4001; HLOS: €4879 ± €1208) and the smallest savings in the UK for infections and in Spain for HLOS (€63 ± €426 and €1636 ± €372, respectively). Conclusion This cost‐effectiveness analysis in 6 countries demonstrates that the superior clinical efficacy of ω‐3 FA–containing PN translates into significant decreases in mean treatment cost, rendering it an attractive cost‐saving alternative to standard PN across different healthcare systems.


Background
Hospitalized critically ill and surgical patients typically receive parenteral nutrition (PN) if oral or enteral nutrition is contraindicated or insufficient. A complete all-in-one PN admixture comprises amino acids/protein, glucose, elec-trolytes (depending on patient condition), lipid, micronutrients (such as vitamins), and trace elements to sustain or improve patient nutrition status and clinical outcomes. Lipid is an integral part of PN, as it is a dense source of energy and supplies the building blocks for cell membranes and essential fatty acids (FAs) in PN to prevent deficiencies. 1 Traditionally, the lipid added to PN in the form of a lipid emulsion was derived from soybean oil. 2 Soybean oil emulsions, however, contain high concentrations of linoleic acid and other ω-6 polyunsaturated FAs, which may have detrimental properties. 1 Following concerns that ω-6 FA may promote inflammation and immunosuppression, lipid emulsions with balanced mixtures of different oil sources, such as soybean oil, medium-chain triglycerides, olive oil, and fish oil, were developed for use in PN. 1 There is a strong body of evidence that ω-3 FAs derived from fish oil, especially eicosapentaenoic acid, docosahexaenoic acid, and their respective metabolites, possess beneficial antiinflammatory and immunomodulatory properties and play a key role in the resolution of inflammation across a wide range of patient groups, including surgical, critically ill, and cancer groups. 1,3 This attenuation of proinflammatory processes could contribute to the trend observed across several studies and meta-analyses that report decreases in hospital and intensive care unit (ICU) length of stay (LOS) when using PN regimens containing ω-3 FA-containing lipid emulsions. [4][5][6][7][8][9][10] In general, decreases in hospital LOS (HLOS) are associated with a lower risk of infection, 11 and a shorter ICU LOS reduces general deconditioning due to prolonged bed rest, sedation, and immobilization, with overall improvements in patient quality of life. 12 A number of clinical trials and meta-analyses in hospitalized patients demonstrated that PN containing ω-3 FA is associated with better clinical outcomes than standard PN regimens (PN with lipid emulsions not containing ω-3 FA; ie, derived from sources such as soybean oil and/or olive oil), including decreases in morbidity and mortality, 6,13 shortened HLOS [4][5][6][7][8][9]14 and ICU LOS, 15 and reduced infection rates. 4,5,8,9 In a previously published clinical meta-analysis and subsequent pharmacoeconomic analysis, ω-3 FA-containing PN was shown to be more clinically effective and more cost-effective than standard PN in both ICU and non-ICU patients. 16,17 Based on Italian outcome data, this pharmacoeconomic analysis modeled the cost-effectiveness of PN with and without ω-3 FA in 4 countries (France, Germany, Italy, UK) and found that infection rates, overall LOS, and total cost per patient were reduced with the use of ω-3 FA-containing PN. The higher treatment costs for ω-3 FA-containing PN were completely offset by the lower overall costs, demonstrating that PN containing ω-3 FA was cost-effective in French, German, Italian, and UK hospitals.
A more recent meta-analysis, 4 which included 49 randomized controlled trials and a total of 3641 patients, re-ported a significantly lower relative risk of infection (40%), a 56% reduced risk of sepsis, and a nonsignificant 16% reduction in mortality in patients receiving PN containing ω-3 FA compared with standard PN. In addition to decreases in mean length of ICU and hospital stays, the analysis also showed significant reductions in the relative risk of infection and sepsis. 4 Whereas the positive clinical effects of ω-3 FA-containing PN found in a previous analysis 17 were confirmed in the recent analysis adhering to current study quality standards, the evaluation of the economic impact of ω-3 FA-containing PN remains to be updated.
The aim of the present study was to investigate the cost-effectiveness of ω-3 FA-containing PN compared with standard PN without fish oil based on a recent metaanalysis. 4 Here, we present the results of 6 country-specific cost-effectiveness models comparing the utilization of ω-3 FA-containing PN with standard PN from the perspective of a hospital in France, Germany, Italy, Spain, the UK, and the US.

Methods
This analysis modeled the cost-effectiveness of ω-3 FAcontaining and standard PN based on country-specific data sources for 6 countries (France, Germany, Italy, Spain, UK, and the US).

Model Structure
Six separate cost-effectiveness models comparing ω-3 FAcontaining PN with standard PN without fish oil were developed and simulated for hospitals in France, Germany, Italy, Spain, the UK, and the US. Overall, the model generation included the following steps: (1) conceptualization of a logical structure for both patient cohorts (critically ill cohort  of country-specific clinical outcomes for patients receiving standard PN in both cohorts; (3) identification of countryspecific sources for drug acquisition and hospital service costs; (4) simulation of country-specific clinical outcomes for patients receiving ω-3 FA-containing PN by applying the ω-3 efficacy estimates from the recent meta-analysis to (2); (5) calculation of the country-specific total cost per simulated patient; (6) analysis of the result's sensitivity to input parameter uncertainty via deterministic and probabilistic sensitivity analyses (PSAs).
The models were based on a probabilistic discrete event simulation technique and developed in Excel (Microsoft Corporation, Redmond, WA, USA). Simulations were run over 10,000 iterations, with each iteration representing 1 patient.

Patient Population and Epidemiological Data
On the patient level, all models included 2 treatment arms (ω-3 FA-containing PN and standard PN) with each patient passing simultaneously through both arms, thus enabling both alternative simulations to run on the same cohort ( Figure 1). The simulated hospitalized patients were sent to CR and GE pathways and could receive either PN treatment option (ω-3 FA-containing PN or standard PN). In the present pharmacoeconomic analysis, patients from both settings (CR and GE) were combined to evaluate the costeffectiveness of ω-3 FA-containing PN in a mixed adult population of CR and GE patients.

Model Inputs and Data Sources
Relative treatment effects for patients receiving ω-3 FAcontaining PN were derived from a recent meta-analysis. 4 Economic data such as daily costs, costs per infection, and costs for PN treatment were extracted from published sources for each country and treatment arm (Table 1). 4, The models also included inputs on the clinical outcomes nosocomial infections, HLOS, and mortality. The latter 2 parameters defined the end of the patient pathway, whereas the first reflected only costs. Mean HLOS and mean incidence of infection with ω-3 FA-containing PN and standard PN without ω-3 FA varied widely between countries (Table 2), with the shortest mean HLOS and the lowest incidence of infection for both treatment groups in the US and Germany, respectively. For inclusion of time-to-event parameters, such as HLOS, in the model, a Weibull distribution fitting was performed, with population parameters estimated using the method of moments.
For the 5 European countries, the daily costs of PN were estimated based on current market shares, the daily number of PN bags per patient, and current market prices. For the estimation of daily costs in the US, a model was created to approximate daily lipid requirements based on patient age distribution 43 and patient weight in genderand age-specific groups. 48 The cost of lipid emulsions was based on the lowest cost for standard PN while using the manufacturer price for ω-3 FA-containing PN, thus leading to a conservative estimate of the latter. Costs were modeled according to local currencies in each country but converted into euros (EUR) to facilitate comparability. Pound sterling (GBP) and US dollar (USD) were converted to EUR using the mean exchange rates for January 2020: GBP-EUR: 1.1759; USD-EUR: 0.9005. Exchange rates were derived from https://www.oanda.com/. No discount rate was applied to the costs, because of the short time frame of the simulation. 1162 (1290) 21 2006 (2228) 26 1855 (2060) 34 2085 (2315)

Sensitivity Analysis
The influence of model parameters on calculated estimates was evaluated using probabilistic and deterministic sensitivity approaches.
In the PSA, 1000 sets of unique parameter combinations are created, drawing each model parameter within the extremes of its probability distribution. In case of missing data on uncertainty, a 20% standard deviation of the mean value was used and an appropriate probability distribution according to the shape of the data was chosen.
In the deterministic sensitivity analyses, simulations were repeated with variations of parameter values to the lower and upper confidence interval limits, while keeping the remaining parameter values constant.
In summary, ω-3 FA-containing PN demonstrated superior efficacy with a concurrent overall cost reduction in all countries compared with standard PN without ω-3 FA via reductions in mean length of ICU and hospital stays, as well as lower incidences of infection and sepsis.

Sensitivity Analyses
Sensitivity analyses demonstrated the stability and robustness of the outcomes in this pharmacoeconomic assessment to parameter changes. For all 6 countries, ω-3 FAcontaining PN was associated with cost savings compared with standard PN in 100% of the simulations. Our analyses showed that in order to achieve an average cost saving of  Figure 2 display the results of 1000 ICER estimates and thus the cost required to avoid 1 case of infection using the most effective strategy. For all 6 countries, the incremental costs for avoided infections were negative, including the entirety of the 95% confidence interval ellipses. Hence, each avoided infection with ω-3 FA-containing PN was associated with a reduction in total cost, which is referred to as dominance in pharmacoeconomic terms (ie, better clinical outcomes at a lower cost).
The results of the deterministic sensitivity analyses are displayed as tornado diagrams, which show the influence of variations in key parameters on cost savings per patient (Figure 3). These graphs indicate that for both treatment options (ω-3 FA-containing PN and standard PN), the most influential parameter for cost savings across all 6 countries was mean difference of HLOS (topmost bars). In France, Germany, the UK, and the US, the second most influential factor was the cost of caring for critically ill patients, whereas in Italy and Spain the cost of ω-3 FAcontaining PN was ranked second.
On average, the use of ω-3 FA-containing PN was demonstrated to be a cost-saving strategy under the circumstances and conditions of the model.

Discussion
According to the US guidelines on the provision and assessment of nutrition support therapy in adult critically ill patients, PN has evolved from mere nutrition support to nutrition therapy. 49 Adequately fed patients are thought to benefit from improvements in a range of clinical factors, such as attenuation of the metabolic response to stress, prevention of oxidative cellular injury, and favorable modulation of immune responses. 49 ω-3 FA-containing PN in particular has been associated with significantly improved patient outcomes [4][5][6][7][8][9]13,14,50 and, as shown in the present pharmacoeconomic analysis, concurrent cost savings.
This cost-effectiveness analysis builds on a previously published model 16 but includes a wider country scope, country-specific analyses, and a more sophisticated source selection. Using a robust model and country-specific data from 6 countries (France, Germany, Italy, Spain, UK, US), we demonstrate that PN containing ω-3 FA is, with very great likelihood, a dominant alternative to standard PN for a mixed population of CR and GE patients in terms of treatment cost. Despite the higher acquisition cost of ω-3 FA-containing PN in comparison with standard PN in nearly all of the countries analyzed, the superior efficacy with regard to patient outcomes renders it a cost-saving alternative to standard PN.
Since economic models are built on data from various sources with the objective of creating an accurate cost estimate, their results are limited by the availability of valid data inputs and the overall assumptions upon which the models are built. The limitations of the presented models are mainly centered around input data sources. Although some data were available, more research evaluating clinical outcomes, particularly in CR patients, would be indicated. The literature, at least for some countries, was incomplete (none for GE patients in the UK) and, in part, outdated. Specifically, some of the data sources for CR patients in France, Germany, Italy, and Spain were more than a decade old.
Accurate economic inputs are just as important as clinical information to achieve accurate cost estimates. Updated and valid sources for hospital cost data are not easily available, especially at the desired level of detail in the breakdown by components. Some data elaboration and assumptions were necessary also in this study; nevertheless, we are confident in the main conclusions, for 2 main reasons. Firstly, when there was the need for an assumption, we have always adopted the most conservative. Secondly, sensitivity analyses consistently show expected savings across countries and assumptions.  This model, in conjunction with a recently published meta-analysis, 4 has shown that ω-3 FA-containing PN is beneficial for patients in terms of improved clinical outcomes as well as for healthcare systems because of lower overall costs. The higher acquisition cost for ω-3 FAcontaining PN compared with standard PN is offset by cost reductions due to shorter HLOS and fewer infections, demonstrating that not only acquisition costs but overall treatment costs should influence the choice of treatment option. We would like to place particular emphasis on the fact that clinical interventions that improve patient outcomes while providing saving costs are very rare and support the use of ω-3 FA-containing PN in appropriate settings.
The accumulating evidence regarding the improvement of clinical outcomes with ω-3 FA-containing PN in comparison with standard PN in adult hospitalized patients 4-9,13,14,50 may contribute to evidence-based treatment decisions and future guideline development. Concurrent cost savings with PN containing ω-3 FA, as shown in this cost-effectiveness analysis, may provide an additional benefit in this regard.
In summary, we demonstrate that ω-3 FA-containing PN is likely a dominant alternative to standard PN from a hospital point of view, with a decrease in mean costs for all 6 countries evaluated (France, Germany, Italy, Spain, UK, US). With regard to the positive clinical and economic outcomes demonstrated in the present analysis and in the recent meta-analysis 4 on which this pharmacoeconomic evaluation is built, we suggest that ω-3 FA-containing PN be considered as standard of care and suggest using the present publication and that by Pradelli et al 4 as a reference for guideline recommendations.