# Cost-revenue analysis of using a haemoadsorbent membrane in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass and ticagrelor

Benjamin Mathat, Youssouf Compaore, Charles-Henri David, Valery-Pierre Riche, Maël Ryan, Mickaël Vourc'H, Nicolas Mauduit, Johann Clouet, Julien Cadiet, Fabien Nativel, et al.

► To cite this version:

Benjamin Mathat, Youssouf Compaore, Charles-Henri David, Valery-Pierre Riche, Maël Ryan, et al. Cost-revenue analysis of using a haemoadsorbent membrane in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass and ticagrelor. Archives of cardiovascular diseases, 2026, 119 (2), pp.115-122. 10.1016/j.acvd.2025.07.011. hal-05533967

HAL Id: hal-05533967

https://hal.science/hal-05533967v1

Submitted on 3 Mar 2026

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
<figure><img src="image_2.png" /></figure>

Clinical research

# Cost-revenue analysis of using a haemoadsorbent membrane in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass and ticagrelor

Benjamin Mathat<sup>a</sup>, Youssouf Compaore<sup>b</sup>, Charles-Henri David<sup>c</sup>, Valery-Pierre Riche<sup>b</sup>, Maël Ryan<sup>c</sup>, Mickaël Vourc'h<sup>d</sup>, Nicolas Mauduit<sup>e</sup>, Johann Clouet<sup>a,f</sup>, Julien Cadiet<sup>d,1</sup>, Fabien Nativel<sup>a,f,*,1</sup>

<figure><img src="image_3.png" /></figure>

## ARTICLE INFO

**Article history:**

Received 18 February 2025

Received in revised form 18 June 2025

Accepted 21 July 2025

Available online 2 September 2025

**Keywords:**

Coronary artery bypass grafting

Ticagrelor

Cardiopulmonary bypass

Haemoadsorbent membrane

Cost-revenue analysis

## ABSTRACT

**Background:** Patients with acute coronary syndrome requiring coronary artery bypass graft surgery while on ticagrelor face a high risk of perioperative bleeding because of its strong antiplatelet effect. The Cytosorb® haemoadsorbent membrane (CytoSorbents Corporation, Princeton, NJ, USA), which is CE marked for ticagrelor removal, may help to mitigate this risk.

**Aim:** To evaluate the cost-revenue impact of the use of Cytosorb® membrane over two different time periods in a high-volume French hospital.

**Methods:** A retrospective cohort of patients who underwent coronary artery bypass grafting with ticagrelor without the use of Cytosorb® and a prospective cohort of patients of the same type undergoing coronary artery bypass grafting with the use of Cytosorb® were compared. The primary outcome was the budget impact of using Cytosorb® in patients undergoing coronary artery bypass grafting with ticagrelor. Secondary outcomes included morbidity criteria and the length of stay in different hospital departments.

**Results:** Among 40 patients, the cost difference favoured the cohort without Cytosorb® by €2670. However, the Cytosorb® group generated €635 more revenue per patient. Operative variables (duration, cardiopulmonary bypass time, transfusions) were similar, but the Cytosorb® group had a shorter stay in the intensive care unit. Sensitivity analysis highlighted membrane cost as the most influential factor in the overall cost difference.

**Conclusion:** In the French financial context, the use of the Cytosorb® in coronary artery bypass graft surgery with ticagrelor leads to additional costs, despite a slight revenue increase and the potential benefit of a shorter stay in the intensive care unit.

© 2025 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## 1. Abbreviations

CABG Coronary artery bypass grafting

CI Confidence interval

CPB Cardiopulmonary bypass

DRG Diagnosis-related group

IPW Inverse probability weighting

NCS French National Common Cost Study 2019 Version 2021

## 2. Background

Cardiovascular disease is the leading cause of death worldwide. An estimated 17.7 million deaths are attributable to cardiovascular disease, accounting for 31% of all deaths worldwide [1]. In France, cardiovascular disease is the second leading cause of death after

<footnote><sup>a</sup> Nantes Université, CHU Nantes, Pharmacie, 44000 Nantes, France</footnote>

<footnote><sup>b</sup> Nantes Université, CHU Nantes, Direction de la Recherche et de l'Innovation, 44000 Nantes, France</footnote>

<footnote><sup>c</sup> Nantes Université, CHU Nantes, Unité de Chirurgie Thoracique et Cardio-Vasculaire, 44800 Nantes, France</footnote>

<footnote><sup>d</sup> Nantes Université, CHU Nantes, Service d'Anesthésie et Réanimation, 44800 Nantes, France</footnote>

<footnote><sup>e</sup> Nantes Université, CHU Nantes, Service d'Information Médicale, 44000 Nantes, France</footnote>

<footnote><sup>f</sup> Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, 44000 Nantes, France</footnote>

<footnote>* Corresponding author. Pharmacie, Nantes Université, CHU de Nantes, 5, allée de l'Île Gloriette, 44000 Nantes, France.</footnote>

<footnote>E-mail address: fabien.nativel@univ-nantes.fr (F. Nativel).</footnote>

<footnote n="1">¹ These authors contributed equally.</footnote>
cancer, with more than 140,000 deaths per year, and it is the leading
cause of death among the elderly and women of all ages [2]. In 2019,
around 100,000 people in France were treated for an acute coronary
syndrome in France, with 20% experiencing a second ischaemic
event within 5 years [3].

An acute coronary syndrome results from a partial or complete occlusion of one or more coronary arteries caused by the rupture of atherosclerotic plaques. Revascularization may be performed by angioplasty in interventional cardiology or by coronary bypass in cardiac surgery. The decision is based on a number of variables, including the time elapsed since the onset of pain, the extent of the lesions and the Global Registry of Adverse Cardiac Events (GRACE) score, which assesses the risk of ischaemia [4]. Angioplasty is chosen as the first-line treatment for patients with a single coronary stenosis. Coronary artery bypass grafting (CABG) is preferred over percutaneous coronary intervention in patients with multitruncular stenosis, those with diabetes or when the lesions are long or close to bifurcation points that are not accessible with percutaneous coronary intervention [5].

The simultaneous administration of aspirin and a P2Y₁₂ receptor inhibitor (clopidogrel, ticagrelor, prasugrel) is frequently found in the European Society of Cardiology recommendations for the management of acute coronary syndromes [6]. Discontinuation of this treatment should be discussed before CABG in order to assess the balance between ischaemic and haemorrhagic risk.

Ticagrelor (Brilique®; AstraZeneca, Cambridge, UK) has a direct, selective and reversible mechanism of action at the P2Y₁₂ receptor [7]. As there is no specific reversible agent for ticagrelor, platelet transfusions are often used in emergency situations, but their efficacy is controversial and depends on the time since the last dose of ticagrelor. It has been shown that platelet transfusions within 48 hours of taking the drug cannot restore platelet function. In conjunction with the excretion mechanisms of ticagrelor metabolites and the drug itself, a delay of at least 48 hours for platelet transfusion appears to be required to allow recovery of platelet function [8,9]. Studies and recommendations indicate that discontinuation of ticagrelor less than 5 days before surgery is associated with an increased risk of major bleeding complications and the administration of blood products [10,11].

A Cytosorb® haemoadsorbent membrane (CytoSorbents Corporation, Princeton, NJ, USA) can be used to reduce the effect of medication more quickly; this is a medical device composed of polymer beads (cross-linked divinylbenzene/polyvinylpyrrolidone) providing selectivity for molecule sizes <55 kDA [12]. When placed in cardiopulmonary bypass (CPB), it is CE marked for ticagrelor removal, thereby reducing the risk of intra- and postoperative bleeding, as evidenced by a significantly lower incidence of bleeding complications, shorter operation times, lower drainage volumes, reduced transfusions requirements and a shorter duration of hospitalization [13]. At the same time, the preliminary report from the Safe and Timely Antithrombotic Removal (STAR) registry underlines the value of this simple, safe approach, which can help to reduce the risk of bleeding in patients undergoing cardiac surgery and receiving antithrombotic therapy [14].

The aim of this study was to perform a comparative cost-revenue
analysis of the use of the Cytosorb® membrane in patients under-
going CABG surgery with ticagrelor over two different time periods
in a high-volume French hospital.

3. Methods

3.1. Study design

This was a single-centre comparative before-and-after
cohort study conducted in the Department of Anaesthesia and

Resuscitation in the Thoracic and Cardiovascular Surgery Unit in
Nantes University Hospital. Clinical data were collected in our
local database.

Two cohorts were used for this study: a retrospective cohort (control) including patients who underwent CABG surgery with ticagrelor without the use of the Cytosorb® membrane between January 2016 and December 2019; and a prospective cohort including patients undergoing the same type of operation with the use of Cytosorb® membrane between June 2021 and January 2023.

The study was approved by the local Nantes ethics committee (n° 2021.08.24). This report does not contain any personal information that could lead to the identification of the patients.

3.2. Study patients

Patients aged > 18 years who underwent CABG surgery with CPB associated with uninterrupted ticagrelor treatment or ticagrelor treatment interrupted for < 48 hours were included. The exclusion criteria were all other surgical operations and/or early discontinuation (> 48 hours) of ticagrelor treatment.

3.3. Cost-revenue analysis

After patient inclusion, data concerning the diagnosis-related
groups (DRGs) and the level of severity associated with the stays
were extracted by the Medical Information Department of Nantes
University Hospital. According to the DRG classification, CABGs
were coded 05C04 if coronary angiography was performed and
05C05 if not. Thus, 05C04X corresponds to coronary artery bypass
surgery with cardiac catheterization or coronary angiography rang-
ing from severity level 2 to severity level 4 (specifically 05C042
and 05C044), and 05C05X corresponds to coronary artery bypass
surgery without cardiac catheterization or coronary angiography,
ranging from severity level 2 to severity level 4 (specifically 05C052
and 05C054).

DRG costs were then estimated using the adjusted French National Common Cost Study 2019 Version 2021 (NCS) method; this takes into account the average national costs calculated in the NCS, to which are added the costs measured in our study by microcosting.

In general, hospital costs are divided into four categories:

* clinical cost, which encompasses all expenses associated with the hospital care unit;

* medicotechnical cost, which covers all expenses related to the aortocoronary bypass procedure, including laboratory tests and imaging exams – it also includes medical and paramedical expenses during the intervention, as well as maintenance and depreciation costs of medical equipment;

* logistical cost, which includes expenses related to medical logistics (pharmaceutical and hygiene products) as well as general logistics costs (laundry, food and administration);

* direct cost, which includes the price of medical devices, drugs and other consumables.

For each patient included in this study, we considered three
categories of expenses: fixed costs; costs related to the length of
hospitalization (or allocated costs); and variable costs.

Fixed costs encompass medical-technical expenses, such as
medical staff and medical tests (e.g. imaging), as well as various
direct charges, including medications and non-specific medical
devices that were not subject to detailed assessment through
microcosting analysis. These fixed costs were estimated using the
NCS for each severity level of DRG, and they are uniform for all
patients within the same severity level.
Daily allocated costs of hospitalization encompass expenses associated with care units and logistics, as they vary depending on the patient's length of stay. These costs were subtracted from the funding provided by the French NCS. For each stay, a fixed daily cost was then calculated by dividing the average cost per stay in the DRG pricing category by the average length of stay, and multiplying this result by the actual duration of the patient's hospitalization.

Finally, variable costs include directly measured medical costs obtained during the study, which were acquired through a micro-costing approach. Microcosting was used to estimate the cost of blood products, blood-derived drugs and medical implantable devices reimbursed only, in addition to the DRG tariff. As the procedure was similar in both groups, the other costs were equivalent.

Hospital revenue data was collected utilizing the Medical Information Systems Programme (PMSI) furnished by the Medical Information Department of Nantes University Hospital.

## 3.4. Outcomes

The primary outcome was the budget impact of using this haemoadsorbent membrane in patients undergoing CABG surgery with ticagrelor. The balance for each episode was estimated using the following equation: net result = income – total hospitalization costs. This balance corresponds to the gap between the average cost of the DRG from the hospital's perspective and the average fee for the DRG as set by the health insurance. The net result for the activity during the study period was obtained by summing up the calculated gaps for all the established DRGs.

The secondary outcomes were divided into clinical outcome and economic outcome. The clinical outcome included the duration of use of the operating room and associated CPB time, the length of stay in conventional care, the duration of hospitalization in the continuous monitoring unit, intensive care and resuscitation units and the use of labile blood products during and after the operation (red blood cells, fresh frozen plasma, platelets). The economic outcome studied was cost distribution, to identify the most important expense items.

## 3.5. Inverse probability weighting: adjusting for confounding bias

In order to control for possible confounding factors and to estimate the marginal causal effect, inverse probability weighting (IPW) was applied [15]. The propensity score was estimated using multivariable logistic regression, incorporating the confounding variables identified by clinical expertise. To limit excessive variability in weights and ensure an effective sample size close to that of the original population, stabilized weights were used [16]. The IPW method was used to recreate a pseudorandomization within the study population, and to estimate the differences in costs, revenues and benefits between the groups. The 95% confidence intervals (CIs) were calculated using a non-parametric bootstrap with 10,000 replications.

## 3.6. Sensitivity analysis

A univariate sensitivity analysis was performed using a tornado diagram to assess the impact of variations in certain variables on the cost differential between the two groups. This analysis explored variations in the daily cost of hospitalization (€128.8), by modifying it at €100 and then at €200, as well as variations in the cost of the membrane (€1,368), by testing it at €1000 and €1500. The aim of this approach is to assess the robustness of the results obtained, by incorporating the uncertainty associated with these variables. Analyses were carried out using Stata software, version 16 (StataCorp, College Station, TX, USA).

## 3.7. Statistical analysis

GraphPad 8® software (GraphPad Software Inc., La Jolla, CA, USA) was used for all other statistical analyses. All results are reported as mean ± standard error of the mean, and were compared using the multiple *t* test. A two-way unpaired analysis of variance (ANOVA) test was used, with *P*-values adjusted for multiple comparisons, to compare specifical clinical characteristics of the study population. A *P*-value < 0.05 was considered statistically significant.

# 4. Results

## 4.1. Characteristics of the study population

Between January 2016 and December 2019, 20 patients were included in the control cohort, and 20 patients were included between June 2021 and January 2023 in the cohort with the Cytosorb® membrane. Various factors were collected to calculate the EuroSCORE II, which assesses the risk of cardiac surgery before intervention, and the expected risk of death in this type of patient [17]. Patient characteristics are presented in Table 1. Seven patients were excluded. Of these, four patients were excluded because of the indication (valve replacement or aortic dissection), two patients were treated with direct oral anticoagulants (rivaroxaban) and, in the last patient, ticagrelor was discontinued 5 days before surgery. The comparison of CABGs with and without Cytosorb® showed no significant differences in most patient-related factors, with the exception of a lower percentage of cases with recent myocardial infarction in the Cytosorb® group (15% vs. 45%; *P* < 0.05). Renal dysfunction occurred significantly more frequently in the Cytosorb® group, with 35% having moderate or severe renal failure. There was also no significant difference regarding the intraoperative placement of an intra-aortic balloon pump (20% for CABG alone group versus 10% for the Cytosorb® group), a severity criterion to consider because of its potential clinical consequences. Cardiac factors showed a lower prevalence of severe conditions in the Cytosorb® group, including fewer patients with Canadian Cardiovascular Society (CCS) score IV and high mean pulmonary artery systolic pressure (*P* < 0.0001). The distribution of surgical emergencies differed slightly, with more salvage cases in the CABG alone group (10% vs. 0%). The Cytosorb® group had a higher proportion of patients classified under DRG 05C052 (40% vs. 10%) and a lower proportion of patients classified under DRG 05C042 (15% vs. 45%), indicating potential differences in case complexity.

## 4.2. Primary economic outcome

The mean costs for CABG with ticagrelor and Cytosorb® were €19,226 (95% CI €14,210 to €24, 241) whereas costs without Cytosorb® were lower at €16,556 (95% CI €13,645 to €19,467). The cost difference of €2670 (95% CI € – 2673 to €8013) shows that costs are higher with Cytosorb®.

In terms of revenue, procedures using Cytosorb® generated a mean of €21,391 (95% CI €18,104 to €24,678) compared with procedures without Cytosorb®, which generated €20,756 (95% CI €17,802 to €23,710). The difference in revenue of €635 (95% CI € – 3428 to €4697) shows an increase in revenue with the use of Cytosorb®.

Finally, the mean net results associated with CABG with ticagrelor and Cytosorb® were €2165 (95% CI € – 808 to €5139) whereas procedures without Cytosorb® showed a higher mean net result of €4201 (95% CI €3097 to €5304). The difference between the two groups was €2035 (95% CI € – 4887 to €817), highlighting a lower net result with the use of Cytosorb®.
<table><caption>**Table 1**

Characteristics of the study population.</caption><thead><tr><th></th><th>CABG (n=20)</th><th>CABG + Cytosorb® (n=20)</th><th>P</th></tr></thead><tbody><tr><td>Patient-related factors</td><td></td><td></td><td></td></tr><tr><td>Age (years)</td><td>63.45</td><td>68.55</td><td>0.13</td></tr><tr><td>Male sex</td><td>75</td><td>85</td><td>0.44</td></tr><tr><td>EuroSCORE II</td><td>2.69</td><td>1.86</td><td>0.31</td></tr><tr><td>Extracardiac arteriopathy</td><td>5</td><td>20</td><td>0.16</td></tr><tr><td>Redo (previous cardiac surgery)</td><td>0</td><td>0</td><td></td></tr><tr><td>Chronic pulmonary dysfunction</td><td>0</td><td>0</td><td></td></tr><tr><td>Active endocarditis</td><td>0</td><td>0</td><td></td></tr><tr><td>Recent myocardial infarction</td><td>45</td><td>15</td><td>&lt;0.05</td></tr><tr><td>Critical preoperative state</td><td>15</td><td>30</td><td>0.27</td></tr><tr><td>IDDM</td><td>5</td><td>0</td><td>0.32</td></tr><tr><td>Poor mobility</td><td>0</td><td>10</td><td>0.15</td></tr><tr><td>Renal dysfunction</td><td></td><td></td><td></td></tr><tr><td>CC &gt; 85 mL/min/m²</td><td>100</td><td>65</td><td>&lt;0.0001</td></tr><tr><td>CC 51-85 mL/min/m²</td><td>0</td><td>20</td><td></td></tr><tr><td>CC ≤ 0 mL/min/m²</td><td>0</td><td>15</td><td></td></tr><tr><td>On dialysis</td><td>0</td><td>0</td><td></td></tr><tr><td>Cardiac-related factors</td><td></td><td></td><td></td></tr><tr><td>CCS score IV</td><td>35</td><td>10</td><td>0.06</td></tr><tr><td>NYHA class</td><td></td><td></td><td>0.16</td></tr><tr><td>≤ II</td><td>90</td><td>100</td><td></td></tr><tr><td>III</td><td>0</td><td>0</td><td></td></tr><tr><td>IV</td><td>10</td><td>0</td><td></td></tr><tr><td>LVEF</td><td></td><td></td><td></td></tr><tr><td>&lt; 51%</td><td>45</td><td>40</td><td>&lt;0.0001</td></tr><tr><td>31-50%</td><td>45</td><td>50</td><td></td></tr><tr><td>21-30%</td><td>10</td><td>10</td><td></td></tr><tr><td>&lt; 20%</td><td>0</td><td>0</td><td></td></tr><tr><td>PA systolic pressure</td><td></td><td></td><td></td></tr><tr><td>≥ 55 mmHg</td><td>0</td><td>15</td><td>&lt;0.0001</td></tr><tr><td>30-55 mmHg</td><td>0</td><td>5</td><td></td></tr><tr><td>&lt; 30 mmHg</td><td>100</td><td>80</td><td></td></tr><tr><td>Operation-related factors</td><td></td><td></td><td></td></tr><tr><td>Urgency</td><td></td><td></td><td></td></tr><tr><td>Elective</td><td>35</td><td>40</td><td>&lt;0.005</td></tr><tr><td>Urgent</td><td>40</td><td>35</td><td></td></tr><tr><td>Emergency</td><td>15</td><td>25</td><td></td></tr><tr><td>Salvage</td><td>10</td><td>0</td><td></td></tr><tr><td>Number of CABG per procedure</td><td>2.9</td><td>3</td><td>0.52</td></tr><tr><td>Diagnosis-related groups</td><td></td><td></td><td></td></tr><tr><td>05C042</td><td>45</td><td>15</td><td>&lt;0.05</td></tr><tr><td>05C052</td><td>10</td><td>40</td><td></td></tr><tr><td>05C043</td><td>25</td><td>25</td><td></td></tr><tr><td>05C053</td><td>5</td><td>5</td><td></td></tr><tr><td>05C044</td><td>15</td><td>5</td><td></td></tr><tr><td>05C054</td><td>0</td><td>10</td><td></td></tr></tbody></table>

Data are expressed as mean or %. CABG: coronary artery bypass grafting; CC: creatinine clearance; CCS: Canadian Cardiovascular Society; IDDM: insulin-dependent diabetes mellitus; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association score; PA: pulmonary artery.

<table><caption>**Table 2**

Distribution of fixed, allocated and variable costs per cohort with or without the use of Cytosorb® membrane.</caption><thead><tr><th>Expenses</th><th>CABG (n=20)</th><th>CABG + Cytosorb® (n=20)</th><th>Difference</th></tr></thead><tbody><tr><td>Fixed costs (€)</td><td>9697 (8228 to 11,166)</td><td>9738 (7737 to 11,738)</td><td>40 (-2253 to 2338)</td></tr><tr><td>Average allocated costs (€)</td><td>6115 (4771 to 7458)</td><td>7272 (4587 to 9957)</td><td>1158 (-1595 to 3911)</td></tr><tr><td>Average variable costs (€)</td><td>745 (246 to 1243)</td><td>2216 (1639 to 2793)</td><td>1471 (756 to 2186)</td></tr></tbody></table>

Data are expressed as mean (95% confidence interval). The cost study was carried out by using the adjusted French National Common Cost Study 2019 Version 2021 method. CABG: coronary artery bypass grafting.

### 4.3. Secondary outcomes

The distribution of costs is presented in Table 2. The comparison of costs between CABG with ticagrelor with or without Cytosorb® showed no significant difference in fixed and allocated costs, as their confidence intervals included zero. However, variable costs were significantly higher with Cytosorb® (€1471), confirming a real additional expense.

Morbidity criteria and length of stay are presented in Table 3. The data from both cohorts were non-significantly different during the operation (operating time, CPB time and transfusions). A significant difference was observed in the duration of stay in the

continuous monitoring unit (0.9 ± 0.3 days for CABG group alone vs. 2.4 ± 0.6 days for the Cytosorb® group). No deaths were observed at 30 days.

### 4.4. Sensitivity analysis

The tornado graph (Fig. 1) shows the impact of variations in the daily hospital cost and the cost of the membrane on the difference in cost between the two groups. The cost differential used as the base value for the comparisons was €2670. Two variables were evaluated: the daily cost of hospitalization and the cost of the
<table><caption>**Table 3**
Lengths of stay in different hospital departments and morbidity criteria per cohort with or without the use of Cytosorb® membrane.</caption><thead><tr><th></th><th>CABG (n=20)</th><th>CABG + Cytosorb® (n=20)</th><th>P</th></tr></thead><tbody><tr><td>Surgery duration (minutes)</td><td>353.5 ± 15.2</td><td>360.1 ± 15.3</td><td>0.74</td></tr><tr><td>Cardiopulmonary bypass time (minutes)</td><td>87.9 ± 6.5</td><td>87.7 ± 5.4</td><td>0.98</td></tr><tr><td>Length of stay (days)</td><td></td><td></td><td></td></tr><tr><td>In conventional care</td><td>8 ± 0.8</td><td>8.9 ± 1.5</td><td>0.59</td></tr><tr><td>In continuous monitoring unit</td><td>0.9 ± 0.3</td><td>2.4 ± 0.6</td><td>&lt; 0.05</td></tr><tr><td>In intensive care unit</td><td>2.6 ± 0.6</td><td>1.2 ± 0.6</td><td>0.13</td></tr><tr><td>In resuscitation unit</td><td>2.7 ± 0.6</td><td>2.6 ± 0.4</td><td>0.9</td></tr><tr><td>Total duration of hospitalization</td><td>14.3 ± 1.1</td><td>15.3 ± 1.9</td><td>0.64</td></tr><tr><td>Transfusions (number/patient)</td><td></td><td></td><td></td></tr><tr><td>Red blood cell concentrate</td><td>1.45 ± 0.4</td><td>1.35 ± 0.4</td><td>0.87</td></tr><tr><td>Fresh frozen plasma</td><td>0.9 ± 0.4</td><td>1.0 ± 0.4</td><td>0.84</td></tr><tr><td>Pooled platelet concentrate</td><td>0.6 ± 0.2</td><td>0.65 ± 0.2</td><td>0.66</td></tr><tr><td>Apheresis platelet concentrate</td><td>0.05 ± 0.05</td><td>0.15 ± 0.08</td><td>0.3</td></tr></tbody></table>

Data are expressed as mean ± standard error of the mean. CABG: coronary artery bypass grafting.

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Cost differences arising from variations in daily hospital and membrane costs.</figcaption></figure>

membrane, each adjusted in 'low' and 'high' scenarios to measure their influence on the cost differential.

The cost of the membrane (in blue in Fig. 1 for the low value of €1000 and in red for the high value of €1500) had the greatest influence on the cost differential, with values ranging from €2302 to €2802. Variations in the cost of the membrane can have an impact on the cost differential. The daily hospital cost (also shown in blue in Fig. 1 for the low value of €100 and in red for the high value of €200) has a smaller influence, with variations in the cost differential between €2625 and €2802.

## 5. Discussion

In surgical procedures, the risk of bleeding is a critical variable that, in most cases, determines the time required for surgical treatment. This bleeding risk is associated with a significantly higher increase in morbidity and deaths in emergency surgical procedures [18]. Patients requiring coronary bypass surgery who are being treated with ticagrelor for coronary artery disease are particularly susceptible to this bleeding risk. The Cytosorb® membrane, thanks to its intraoperative adsorption mechanism, offers a solution to this problem in cardiac surgery when ticagrelor is not discontinued or is discontinued for < 5 days.

Given the specificities of the French healthcare system, a cost-revenue analysis is needed to assess the value of this therapy in the treatment of patients undergoing coronary bypass surgery. Several studies have shown that the use of Cytosorb® membrane in patients undergoing coronary bypass surgery while receiving ticagrelor offers an economic advantage in different countries with

different healthcare and financing systems: in the UK, Javanbakht et al. demonstrated a difference of £3941 between treatment with and without the Cytosorb® membrane as a result of red blood cell and platelet transfusions and surgical revision [19]. In the USA, Cohen et al. showed savings of $3434 between the two procedures [20]. In France, the financing model used is the activity-based funding Tarification à l'Activité (T2A). This is a healthcare facility financing mechanism that links their funding to the actual medical activity produced and reported. This hospital activity is described with the help of the DRG. Each patient's stay is associated with a DRG, which identifies a specific healthcare service provided for a particular patient profile. The amount for each DRG is determined from the average costs, and is published once a year as a DRG tariff by the French Ministry of Health. However, this financing model has its limitation, in particular regarding innovation, because the valuation of stays is based on past data. Consequently, it is possible that the revenues generated by stays related to expensive innovations no longer cover the expenses, which could pose challenges for healthcare facilities, as has already been demonstrated in studies carried out in other disciplines, such as interventional cardiology [21,22] and interventional neuroradiology [23]. To address this limitation, a supplementary billing system to the activity-based funding has been implemented, which allows reimbursed medical devices (or drugs) in addition to the DRG tariff. Therefore, to our knowledge, our study stands as a first analysis of cost-revenue and a first analysis of the various costs associated with hospital stays when using the Cytosorb® membrane perioperatively in a high-volume French hospital.
The characteristics of our studied population are representative of patients treated with CABG, as already reported by Ter Woorst et al., with 77.6% being male, with an average age of 67.7 ± 9.4 years, and 22.4% being female, with an average age of 63.9 ± 9.6 years [2].

The aim of this study was to evaluate the impact of using Cytosorb® membrane in CABG surgery in patients receiving ticagrelor therapy. The study design was based on a single-centre comparative cohort approach carried out in a thoracic and cardiovascular surgery unit. Two cohorts were compared: a retrospective cohort including patients operated on without Cytosorb® between January 2016 and December 2019; and a prospective cohort including patients operated on with Cytosorb® between June 2021 and January 2023. In this study, a total of 40 patients were included: 20 patients in the intervention group (who underwent CABG with the use of Cytosorb® membrane); and 20 patients in the control group (who underwent CABG without the use of Cytosorb®). Rigorous data collection methods, based on a local database and an IPW approach, enabled potential confounders to be controlled, and cost, income and benefit differentials between the two groups to be estimated.

The results of this study show that the differences in costs, revenues and benefits between the groups, although present, are not statistically significant, as shown by the CIs encompassing the zero value. This finding indicates a high degree of uncertainty about the economic impact of using Cytosorb®, and suggests that the relatively small sample size may be to blame.

A more detailed analysis of economic criteria reveals a trend toward higher healthcare costs in the membrane group across all three cost categories, with a statistically significant increase in variable costs, including medical costs measured directly during the study (i.e. the cost of medical devices). Additionally, the net financial result during hospitalization was much lower in the Cytosorb® group compared with the standard of care. Sensitivity analysis, illustrated by a tornado diagram, confirmed these findings.

The analysis of the morbidity criteria revealed an increase in the length of stay in the continuous monitoring unit. Patients are transferred to this department in the postoperative period to conduct weaning off noradrenaline and dobutamine in cases of persistent hypoxia or rhythm disorders, particularly atrial fibrillation, which affects approximately 30-40% of postoperative cardiac surgery patients [24]. However, the increase in length of stay in continuous monitoring in the Cytosorb® membrane cohort was not associated with an increase in the overall length of stay in hospital, which was not associated with an increase in the risk of morbidity or death. Another morbidity criterion that was analysed was the need for transfusions. An analysis of the annual consumption of labile blood products for the cardiac surgery operating room in our institution during the study period showed a 22% increase in the consumption of platelet concentrates between 2017 and 2023. Compared with our cohort, the consumption of the included patients remained stable during the same period. Thus, the results of a previous study

[13], which showed a significant reduction in platelet transfusions with the use of the Cytosorb® membrane, appear consistent.

The extended patient inclusion period (from 2016 to 2023) was not considered a bias in the study as there were no changes in medical or surgical management, or in patient pathways for those undergoing CABG during this period. However, inclusion was delayed during the transition to the European Society of Cardiology guidelines for the treatment of ST-segment elevation myocardial infarction [6], which now recommend the use of prasugrel instead of ticagrelor for patients requiring angioplasty. In addition, pretreatment with an anti-P2Y₁₂ agent is no longer recommended for rapidly performed coronary angiography (<24 hours).

This risk of bleeding remains a problem in the management of patients treated with dual antiplatelet therapy. Two studies have shown that it is beneficial to discontinue ticagrelor 72 hours before surgery without increasing the risk of bleeding. In addition, an inhibitor of ticagrelor, bentracimab, is currently under evaluation, and appears to offer the possibility of reversing the effect of ticagrelor [25-27].

## 5.1. Study limitations

This single-centre retrospective non-randomized study included only 40 patients, which limits its statistical power and the generalizability of its results. Temporal biases are possible, because of the evolution of coding practices, previously performed by surgeons and then transferred to the Medical Information Department. Furthermore, disparities in economic severity between patients, particularly related to transfers from centres without surgical capacity, may have influenced coding and billing. Despite statistical adjustments, imbalances persist between groups (in particular, recent myocardial infarction and renal dysfunction), exposing them to confounding bias. Although the use of Cytosorb® in this indication appears to generate additional hospital costs, its true cost-effectiveness or cost-utility remains to be determined. In France, the lack of reimbursement in addition to the DRG tariff penalizes its economic evaluation. A multicentre randomized controlled trial, with an expanded sample and economic modelling integrating quality of life data and long-term follow-up, will consolidate these results and inform public health decision-makers.

## 6. Conclusions

Intraoperative use of the haemoadsorbent membrane Cytosorb® does not provide economic benefits compared with standard of care for patients undergoing CABG while receiving ticagrelor. Although data are available from other countries, the benefits of the membrane have yet to be confirmed in the French healthcare financing system (Central Illustration).
<figure><img src="image_5.png" /><figcaption>**Central Illustration.** The use of Cytosorb® in coronary artery bypass grafting with ticagrelor increases costs (+€2670 per patient) despite a slight increase in revenue (+€635 per patient).</figcaption></figure>

## Sources of funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

## Disclosure of interest

The authors declare that they have no competing interest.

## References

[1] Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics - 2013 update: a report from the American Heart Association. Circulation 2013;127:e6-245, http://dx.doi.org/10.1161/CIR.0b013e31828124ad.

[2] ter Woorst JF, Olsthoorn JR, Houterman S, van Straten BHM, Soliman-Hamad MA, et al. Sex difference in long-term survival after coronary artery bypass grafting is age-dependent. J Cardiothorac Vasc Anesth 2022;36:1288-95, http://dx.doi.org/10.1053/j.jvca.2021.08.104.

[3] Alkhaili M. Mechanistic insights to target atherosclerosis residual risk. Curr Probl Cardiol 2021;46:100432, http://dx.doi.org/10.1016/j.cpcardiol.2019.06.004.

[4] Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119-77, http://dx.doi.org/10.1093/eurheartj/ehx393.

[5] Neumann F-J., Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019;40:87-165, http://dx.doi.org/10.1093/eurheartj/ehy394.

[6] Collet J-P, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2021;42:1289-367, http://dx.doi.org/10.1093/eurheartj/ehaa575.

[7] Goel D. Ticagrelor: the first approved reversible oral antiplatelet agent. Int J Appl Basic Med Res 2013;3:19-21, http://dx.doi.org/10.4103/2229-516X.112234.

[8] Teng R, Carlson GF, Nylander S, Andersson TLG. Effects of autologous platelet transfusion on platelet inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost 2016;14:2342-52, http://dx.doi.org/10.1111/jth.13511.

[9] Zafar MU, Smith DA, Baber U, Sartori S, Chen K, Lam DW, et al. Impact of timing on the functional recovery achieved with platelet supplementation after treatment with ticagrelor. Circ Cardiovasc Interv 2017;10:e005120, http://dx.doi.org/10.1161/CIRCINTERVENTIONS.117.005120.

[10] Gherli R, Mariscalco G, Dalén M, Onorati F, Perrotti A, Chocron S, et al. Safety of preoperative use of ticagrelor with or without aspirin compared with aspirin alone in patients with acute coronary syndromes undergoing coronary artery bypass grafting. JAMA Cardiol 2016;1:921-8, http://dx.doi.org/10.1001/jamacardio.2016.3028.

[11] Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57, http://dx.doi.org/10.1056/NEJMoa0904327.

[12] Ankawi G, Xie Y, Yang B, Xie Y, Xie P, Ronco C. What have we learned about the use of cytosorb adsorption columns? Blood Purif 2019;48:196-202, http://dx.doi.org/10.1159/000500013.

[13] Hassan K, Kannmacher J, Wohlmuth P, Budde U, Schmoeckel M, Geidel S. Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding. Ann Thorac Surg 2019;108:45-51, http://dx.doi.org/10.1016/j.athoracsur.2018.12.032.

[14] Schmoeckel M, Thielmann M, Hassan K, Geidel S, Schmitto J, Meyer AL, et al. Intraoperative haemoadsorption for antithrombotic drug removal during cardiac surgery: initial report of the international safe and timely antithrombotic removal (STAR) registry. J Thromb Thrombolysis 2024;57:888-97, http://dx.doi.org/10.1007/s11239-024-02996-x.

[15] Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70:41-55, http://dx.doi.org/10.2307/2335942.

[16] Robins JM, Hernán MÁ, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000;11:550.

[17] Nashef SAM, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, et al. EuroSCORE II. Eur J Cardiothorac Surg 2012;41:734-45, http://dx.doi.org/10.1093/ejcts/ezs043.

[18] Kreuziger LB, Karkouti K, Tweddell J, Massicotte MP. Antithrombotic therapy management of adult and pediatric cardiac surgery patients. J Thromb Haemost 2018;16:2133-46, http://dx.doi.org/10.1111/jth.14276.

[19] Javanbakht M, Trevor M, Rezaei Hemami M, Rahimi K, Branagan-Harris M, Degener F, et al. Ticagrelor removal by CytoSorb® in patients requiring emergent or urgent cardiac surgery: a UK-based cost-utility analysis. Pharmacoeco Open 2020;4:307-19, http://dx.doi.org/10.1007/s41669-019-00183-w.

[20] Cohen BG, Chinguanco F, Zhang J, Reid NM, Lee V, Hong J, et al. Cost-effectiveness and budget impact of a novel antithrombotic drug removal system to reduce bleeding risk in patients on preoperative ticagrelor undergoing cardiac surgery. Am J Cardiovasc Drugs 2023;23:429-40, http://dx.doi.org/10.1007/s40256-023-00587-4.

[21] Huchet F, d'Acremont F, Letocart V, Guerin P, Grimandi G, Manigold T. Is transcatheter aortic valve replacement a profitable procedure in a high-volume French hospital? Arch Cardiovasc Dis 2018;111:534-40, http://dx.doi.org/10.1016/j.acvd.2018.01.003.
[22] Mahdjoub I, d'Acremont F, Mauduit N, Grimandi G, Rondeau F, Letocart V, et al. Is the MitraClip® procedure profitable in a high-volume French hospital? Arch Cardiovasc Dis 2019;112:691–8, http://dx.doi.org/10.1016/j.acvd.2019.07.002.

[23] Nativel F, Detraz L, Mauduit N, Riche V-P, Desal H, Grimandi G. Economic challenges of using innovative medical devices in major public health pathologies: example of acute ischemic stroke management by mechanical thrombectomy. Rev Epidemiol Sante Publique 2019;67:361–8, http://dx.doi.org/10.1016/j.respe.2019.08.003.

[24] Baeza-Herrera LA, Rojas-Velasco G, Márquez-Murillo MF, del Portillo-Romero AR, Medina-Paz L, et al., Álvarez-Álvarez RJ, et al. Atrial fibrillation in cardiac surgery. Arch Cardiol Mex 2019;89:348–59.

[25] Tomšič A, Schotborgh MA, Manshanden JSJ, Li WWL, de Mol BAJM. Coronary artery bypass grafting-related bleeding complications in patients treated with dual antiplatelet treatment. Eur J Cardiothorac Surg 2016;50:849–56, http://dx.doi.org/10.1093/ejcts/ezw149.

[26] Hansson EC, Jidéus L, Åberg B, Bjursten H, Dreifaldt M, Holmgren A, et al. Coronary artery bypass grafting-related bleeding complications in patients treated with ticagrelor or clopidogrel: a nationwide study. Eur Heart J 2016;37:189–97, http://dx.doi.org/10.1093/eurheartj/ehv381.

[27] Ortega-Paz L, Giordano S, Franchi F, Rollini F, Pollack CV, Bhatt DL, et al. Clinical and pre-clinical pharmacokinetics and pharmacodynamics of bentracimab. Clin Pharmacokinet 2023;62:673–92, http://dx.doi.org/10.1007/s40262-023-01245-3.