Hai-Feng Wang
email: haifeng.wang@obspm.fr

Francois Hammer
email: francois.hammer@obspm.fr

Yan-Bin Yang
email: yanbin.yang@obspm.fr

Jian-Ling Wang

Typeset using

Keywords: Sagittarius dwarf spheroidal galaxy, Milky Way disk, Galaxy dynamics

The infall of the Sagittarius (Sgr) Dwarf Spheroidal Galaxy in the Milky Way halo is an unique opportunity to understand how the different components of a dwarf galaxy could be tidally removed. In this work, we reconstruct the Sgr core morphology and kinematics on the basis of a model that has already successfully reproduced the Sgr stream. Here we use a very high resolution model that almost resolves individual stars in the Sgr core. It reproduces most of the observed morphology and kinematic properties, without specific fine-tuning. We also show that the dark matter may have been almost entirely stripped by Milky Way tides after two passages at pericenter. Finally the model predicts that the Sgr core will be fully disrupted within the next 2 Gyr.

INTRODUCTION

Our understanding of the formation and evolution of massive galaxies has been limited for a while by the question of disk formation (White & Rees 1978;Navarro et al. 1995). This has substantially progressed in the last decade by the discovery that many massive galactic disks are rejuvenated by major mergers (Hammer et al. 2005(Hammer et al. , 2009;;Robertson & Bullock 2008;Stewart et al. 2009). However, the formation and evolution of dwarf galaxies is still a matter of debate. For example, the proximity of MW dwarfs to their pericenters (Simon 2019;Hammer et al. 2020) may question their dark matter content. Dwarf galaxies may reveal important properties of their matter content when they are observed in a merging process such as that experienced by the Sgr dwarf galaxy. Since this ongoing minor merger event was discovered by Ibata et al. (1994), Sagittarius core or remnant has been investigated by many studies (Ibata et al. 1995;Lokas et al. 2010;Penarrubia et al. 2010;Vasiliev et al. 2020Vasiliev et al. , 2021;;del Pino et al. 2021). This dwarf galaxy may help to probe the Milky Way potential and may have affected the Milky Way disc (Antoja et al. 2018;Wang et al. 2018aWang et al. ,b, 2019Wang et al. , 2020a,c,d;,c,d;López-Corredoira et al. 2020;Yu et al. 2021;Bland-Hawthorn et al. 2021;Yang et al. 2022;Laporte et al. 2018Laporte et al. , 2019Laporte et al. , 2020)). There are also globular clusters associated to the Sgr system such as M 54, Ter 8, Ter 7, Arp 2 inside or near the main body of the Sagittarius dwarf spheroidal galaxy, and Pal 12, Whiting 1 that belong to the trailing arm (Bellazzini et al. 2020).

Using N-body simulations under the framework of tidal stripping scenario, Lokas et al. (2010) presented the first model for the evolution of the Sgr dwarf considering the observed elliptical shape, and suggested that the total mass nowadays within 5 kpc is 5.2 × 10 8 M with small intrinsic rotation left. del Pino et al. (2021) showed that the Sgr core has a S-shape morphology and shows a mild rotation. This has been done on the basis of a machine learning method for Gaia DR2 RR Lyrae stars and of a N-body model whose progenitor is a flattened rotating disk. However, the model is based on a Sgr-like dwarf and a relatively massive Milky Way, which could be quite different from the real Sgr orbiting around the real Milky Way.

Many properties of the Sgr remnant or core are still under debate, e.g., the Sgr core mass and its dynamical state, which is likely affected by MW tides. Vasiliev et al. (2020) showed that a tidally disrupted Sgr making 2.5 orbits around the Milky Way could reproduce well the core observational properties, for which they found a present-day core mass of 4.0 × 10 8 M within a 5 kpc radius. Recently, Wang et al. (2022) considered a Milky Way mass of 5.2 × 10 11 M and an initial Sgr mass of 9.3 × 10 8 M with a similar initial orbit than that used by Vasiliev et al. (2021) and for which they assumed a total MW mass of 9 × 10 11 M . To retrieve the Sgr stream, Wang et al. (2022) have scaled down many mass properties of Vasiliev et al. (2020Vasiliev et al. ( , 2021)), and adopt a rotating disk for the Sgr progenitor, together with a dark matter scale length of 1.6 kpc.

They have also been able to reproduce as well 3D spatial features of Sgr stream, including its leading and trailing arms. Moreover and conversely to the Vasiliev et al. (2020) model, Wang et al. (2022) model is able to reproduce the observed north and south bifurcations, which were firstly discovered in Belokurov et al. (2006) and Koposov et al. (2012), respectively (see also Oria et al. 2022).

Here we follow the Wang et al. ( 2022) study, using a much higher resolution version of their model, in order to generate the detailed Sgr core physics, including kinematics, and the way stars and dark matter have been stripped.

This paper is structured as it follows. In Section 2, we focus on the modeling details. In Section 3 we discuss how the core properties are reproduced, and we also show the dark matter stripping history, then we show the stellar or dark matter distribution at the present time. The last Section includes the discussion and then the conclusions.

MODELING PARAMETERS

Here we give a concise review of our high resolution modeling for which the mass resolution for dwarf galaxy is one hundred times better than the fiducial model in Wang et al. (2022), i.e., 13.75 solar mass per Sgr particle instead of 1375 solar mass . The Milky Way model has been constructed following Barnes et al. (2002), and it includes a bulge, an exponential stellar disc, and a core dark matter halo, while the Sgr dwarf galaxy is made of a dark matter halo and of a disc (see Table 1). The halo density profile is converging at large radii. More details about the modeling components could be found in Barnes et al. (2002) and in Wang et al. (2022). The modeling is realized using GIZMO (Hopkins et al. 2015) and Table 1 gives the initial conditions. In order to avoid numerical/artificial kick between heavy MW particles and light dwarf galaxy particles, the technique of adaptive gravity softening (AGS, Hopkins et al. 2018) has been adopted. The minimal softening is set to 2.5 pc (e.g., for interactions between light particles), which allows a full-resolution of dynamics within the core scalelength (300 pc) of Sgr dwarf galaxy.

However, the adaptive softening is not a magic fix for having very different particle masses (see Table 1). We have first verified the absence of anomalous motions especially during the pericenter passages. Second, we have replaced the Milky Way (bulge, disk, and halo) particles by an analytic potential having precisely the same initial parameters (sizes and masses), and have verified whether the velocity dispersion of stars has been affected by numerical heating. The latter is detected only during the short-time scale passages to the pericenter, after which values of our model cannot be distinguished from that of the analytic potential. Third, we have ran a simulation with a higher resolution, in which the mass of MW particles has been divided by 10. We retrieve the same results, i.e., numerical heating mildly affects stellar velocity for short time, during pericenter passages. We then conclude that our simulations can be well representative of the Sgr core kinematics and morphology (See Appendix Figure 5).

In this work the core/stream is projected in a righthanded Galactocentric cartesian coordinates (van der Marel et al. 2002, X, Y, and Z). We have adopted the solar motion from Drimmel & Poggio (2018) with [U V W ] = [12.9, 12.6, 7.78] km s -1 . The circular speed of the Local Standard of Rest is adopted to be 233 km s -1 (Drimmel & Poggio 2018). The distance of the Sun from the Galactic center is chosen to be R = 8.277 kpc (GRAVITY Collaboration et al. 2022) and Z = 20.8 pc (Bennett & Bovy 2019), and we have verified that different solar motions and coordinates would not change our final conclusions. We have also verified that our models remain stable when evolved in isolation for several Gyr.

RESULTS

Figure 1 shows the 3D stellar density and 3D kinematics distributions of the Sgr core for both modelling (left panels) and observations (right panels) from del Pino et al. (2021, see, their Fig. 10). The top panels reveal the S-shape in the x-z plane, which is surrounded by star motions indicated by black arrows that indicate stellar motions (v x , v z ) after subtraction of the COM (centre of mass) velocity. It suggests that tidal stripping becomes prominent at 2 kpc from the Sgr center, where the stars of the Sgr core are progressively removed from the main body to feed the stream. By accounting for this mechanism, the simulations reproduce well the observed morphology and kinematics of the Sgr core in the x-z plane. Similarly, simulations shown in the middle left panel (x-y plane) present an almost circular shape as it is observed, as well as a relatively chaotic distribution of velocities shown as black arrows based on v x , v y . Black arrows in the z-y plane indicate an expansion of the stars in the outskirts of the core for both data and modeling (see bottom panels). Besides this, in the z-y plane the morphology of the modeled Sgr core appears to be more elongated than the observed one. We also note that the S-shape is caused by the later tidal disruption and it is not a long lived structure. A more detailed map of the Sgr core stellar motions is given in the Appendix (Figure 4).

In Figure 1 the large blue arrow shows the projection of the internal angular momentum, for which a good agreement is found between observations and modeling, except perhaps in the x-z plane (top panel) for which their orientations differ by ∼ 30 degrees. The large orange arrow represents the COM velocity direction, for which observations and modeling agrees within 5 degrees. In the x-z and y-z planes the core shows a counter-clockwise and clockwise rotation, respectively. It appears that the model reproducing well the whole Sgr stream compares quite well with the observations of the Sgr core of del Pino et al. ( 2021) for both morphology and kinematics. However the dynamics, and in particular for the internal angular momentum direction, is not fully recovered, and to reach a perfect matching between modeling and observations would require some further fine tuning.

However, we think that the most important change to be done would be to introduce the gas in the Sgr progenitor, since it is likely a gas-rich irregular dwarf. Gas stripping history was revealed by Tepper-García & Bland-Hawthorn et al. (2018), showing that the gas has been lost about 1 Gyr ago. If adding gas could not improve the modeling, one may consider to increase the number of parameters, e.g., by adding an extra massive LMC or considering a non-spherical Milky Way halo, For example, Vasiliev et al. (2021) have added a mas-sive LMC and a twisted halo, which helped them in reproducing the Sgr stream.

Our modeling suggests a current Sgr core deficient in dark matter as it is shown in Figure 2, which gives the time evolution of both dark and stellar matter within a radius of 5 kpc (top panels) and 2 kpc (bottom panels). The left panels show the evolution of the dark matter/stellar mass ratio that varies from an initial value of 20 (13 in the bottom panel) to almost 0 after 4.7 Gyr evolution. During the same elapsed time, the stellar mass decreases from 3×10 7 M to 1.4 (1.1)×10 7 M , corresponding to a mass loss rate of 53% (63%) as seen in the middle panel of Figure 2. This stellar mass loss contrasts with that of the dark matter, for which the mass is decreasing from 6 (4)×10 8 M to almost 0 according to the right panels of Figure 2. In other words, almost all the dark matter content of Sgr has been lost from its core, and Sgr becomes almost dark matter free at the present epoch.

We also note that the model of Vasiliev et al. ( 2020) leads to a smaller elapsed time for the Sgr disruption, while also fitting the stream very well. This mainly comes from their MW model that is more massive than ours, leading to larger gravitational forces and then shorter times. Other differences are due to different choices in implementing the Sgr progenitor (e.g., disk or a spheroid, intial abundance of dark matter).

Moreover, it appears that dark matter losses occurred mostly during pericenter passages, which suffices to almost fully empty it, 3 Gyr ago. Dark matter studies of dwarf galaxies have often excluded Sgr because of its strong interaction with the Milky Way. Such guesses are robustly confirmed by our study that suggests a dark matter deficient Sgr core, for which most properties are led by the Milky Way tidal forces.

Figure 3 shows the leading, trailing, north and south bifurcation of the Sgr stellar stream in the (X, Z) plane. It also evidences how the distribution of dark matter particles (bottom panel) differs from that of the stars forming the Sgr stream (top panel). This illustrates well that dark matter populating galactic halo do not interact through gravitational torques and let the stream be almost only populated by stars.

DISCUSSION & CONCLUSIONS

In their modeling Vasiliev et al. (2020) found a remnant stellar mass within a 5 kpc radius of 10 8 M assuming few kpc for the dark matter scale radius. In this work we give the evolution history of both dark matter and stellar masses within 2 or 5 kpc in Figure 2 while the initial dark matter scale length is 1.6 kpc. This contrasts with our finding of only 1.4 ×10 7 M within the same radius. Determining the stellar mass of the Sgr core is not a simple exercise, because (i) it lies near the MW disk leading to severe extinction and confusion effects, and (ii) the core limits are not easy to determine as it is directly linked to the stream (see Figure 1) as expected from the Sgr tidally disrupted nature. For example, Majewski et al. (2003, see also Simon 2019) found that Sgr has a V-band luminosity of 2.1 ×10 7 L , which contrast with the much larger value found by Niederste-Ostholt et al. (2010), who made an intensive stellar count study and find around 10 (9.6-13.2) ×10 7 L for which 30% is associated to the the Sgr core and 70% to the stream. Assuming a factor 1.5 for converting luminosity into stellar mass for a galaxy containing intermediate-age stars, one can find 3 ×10 7 M from Simon 2019, and 4.5 ×10 7

Figure 2. It shows the dark matter and stellar mass evolution history during our simulation over a 4.7 Gyr duration (top panels: within a radius of 5 kpc; bottom panels: within a 2 kpc radius). The left, middle, and right panels show the ratio of dark matter to the stellar mass, the stellar stripping history of the core, and that of the dark matter.

M for the core mass of Sgr from Niederste-Ostholt et al. (2010), which is likely an upper limit since their estimates includes stars lying up to 10 kpc (see their Figure 9) instead of the 5 kpc radius adopted by Vasiliev et al. (2020). Given the above observational limits, it means that the core mass (10 8 M ) recovered from the model of Vasiliev et al. (2020) may overestimate while this paper (1.4 ×10 7 M ) may underestimate the core stellar mass by a factor between 2 to 3, respectively. Perhaps more important for our modelling is the good agreement that predicts the correct fraction of stars in the stream and in the core (see Figure 2).

In summary, the model presented by Wang et al. (2022) that reproduces the Sgr stream including its bifurcation behavior is also able to successfully reproduce most of the Sgr core properties as it is shown in this work. Without specific fine-tuning, the modeling reproduces most of the core morphology, including the S-shape, as well as most of its kinematics, including the tidally removed stars at its S-shape edges, which are forming the Sgr stream. We are however aware that there are some discrepancies between the modeling and the observations, and these are mostly linked to the internal angular momentum poles, which may suggest to investigate an initially gas-rich Sgr.

As another result, this study shows how stars and dark matter are tidally removed from the core, the dark matter being almost completely stripped as it is expected from theory. This model also predicts that the Sgr core will disappear within 2 Gyr, letting only its central cluster intact1 . . It compares our full-particle simulation presented in the paper and this simulation with the analytical MW (see the blue and red dots respectively). The latter is assumed without numerical heating, since it does not possess massive particles. From top to bottom: the velocity dispersion perpendicular to the orbital plane, as it is a quantity that could be only affected by the Sgr disk particle motions; the distance of dwarf galaxy from the MW center; the number of massive MW particles within the Sgr core (with a radius of 2 kpc). For a double check, we ran a new simulation by increasing the resolution of MW by a factor of 10, see the green dots. It shows a very smooth evolution in the velocity dispersion perpendicular to the orbital plane of dwarf galaxy, which verifies the concern that using less massive MW particles reduces the artificial kicking. These tests confirm that the artificial kicking happens only for short durations near the pericenter passage, and has a marginal impact to the results and conclusions of the paper.

Figure 1 .

 1 Figure 1. Left column: Sgr core density and kinematics of the model projected on the Galactocentric x-z, x-y, and z-y planes. Stellar density is shown by black contours and coloured from yellow to blue. The projected tangential velocities after subtraction of the COM velocity are shown by the black arrows and the orange arrows indicate the projected bulk velocity of the COM region. The blue arrow shows the projection of the internal angular momentum. The direction towards the MW center is indicated by the white dashed line. All arrows are scaled in order to be clearly shown for physical discussion. Right column: The observational results from del Pino et al. (2021, see, their Fig. 10) that are shown for comparison. A more detailed view of the stellar motions is shown in the Appendix Figure 4.

Figure 3 .

 3 Figure 3. It shows stellar and dark matter tracks at the present time after 4.7 Gyr evolution. The top panel shows the stellar leading, trailing arm, core, north and south bifurcation. The bottom panel indicates how the dark matter may distribute differently than stars.

Figure 4 .

 4 Figure 4. Similar to Figure 1, but with more arrows and points to make the rotation and expansion in the outskirts clearer. Left column: Sgr core density and kinematics of the model projected on the Galactic centric x-z, x-y, and z-y planes. Right column: the observational results from del Pino et al. (2021, see, their Fig. 10)that are shown for more comparison.

APPENDIXA.

  Figure5. It compares our full-particle simulation presented in the paper and this simulation with the analytical MW (see the blue and red dots respectively). The latter is assumed without numerical heating, since it does not possess massive particles. From top to bottom: the velocity dispersion perpendicular to the orbital plane, as it is a quantity that could be only affected by the Sgr disk particle motions; the distance of dwarf galaxy from the MW center; the number of massive MW particles within the Sgr core (with a radius of 2 kpc). For a double check, we ran a new simulation by increasing the resolution of MW by a factor of 10, see the green dots. It shows a very smooth evolution in the velocity dispersion perpendicular to the orbital plane of dwarf galaxy, which verifies the concern that using less massive MW particles reduces the artificial kicking. These tests confirm that the artificial kicking happens only for short durations near the pericenter passage, and has a marginal impact to the results and conclusions of the paper.

Table 1 .

 1 Initial condition parameters in this high resolution dynamical simulation.

	Parameter	Milky Way	Sagittarius	Units
	Particle mass (star/dark matter) 1.375(5.575)×10 5 13.75(55.13) M
	Dark Matter mass	4.8×10 11	9.0×10 8	M
	Dark Matter scale	9.1	1.6	kpc
	Stellar disc mass	3.58×10 10	3.0×10 7	M
	Stellar scale length	2.4	0.3	kpc
	Stellar scale height	0.24	0.15	kpc
	Bulge mass	1.12×10 10	N/A	M
	Bulge scale	0.4	N/A	kpc
	Number of particle	1.2	18	Million
	Initial Position		(66, -9, 27)	kpc
	Initial Velocity		(-48, -17, 65) km s -1

This can be seen in a video showing the evolution of star particles as shown in the top of Figure3: https://youtu.be/ EqjEQpWaeIU.

ACKNOWLEDGMENTS

The author gratefully acknowledges the support of K.C. Wong Education Foundation. We appreciate the support of the International Research Program Tianguan, which is an agreement between the CNRS in France, NAOC, IHEP, and the Yunnan Univ. in China. YY thanks the National Natural Foundation of China (NSFC No. 11973042). Simulations in this work were performed at the High-performent calculation (HPC) resources MesoPSL financed by the project Equip@Meso (reference ANR-10-EQPX-29-01) of the program "Investissements d'Avenir" supervised by the 'Agence Nationale de la Recherche'. We are very grateful to Gary Mamon, Eugene Vasiliev, Frederic Arenou, Carine Babusiaux, Piercarlo Bonifacio, Jiang Chang, Yongjun Jiao and Marcel Pawlowski for the numerous and illuminating discussions we have had on the Sgr simulation. We thank the referee for giving us precious advices and suggestions that have seriously improved the manuscript. HFW acknowledge the science research grants from the China Manned Space Project with NO. CMS-CSST-2021-B03. We are grateful to Phil Hopkins who kindly shared with us the access to the Gizmo code.

DATA AVAILABILITY

The data underlying this article will be shared on reasonable request to the corresponding author.


Pascal Colson1
email: p-colson@chu-montpellier.fr

Jean-Luc Fellahi

; Philippe Gaudard

Sophie Provenchère

Bertrand Rozec

Arcothova Group

Cost Analysis of Aprotinin Reintroduction in French Cardiac Surgery Centres: A Real-World Data-Based Analysis

Keywords: Budget impact, France, Cardiac surgery, ICU stay, Aprotinin, Tranexamic acid

Introduction:

The European Medicines Agency restored aprotinin (APR) use for preventing blood loss in patients undergoing isolated coronary artery bypass graft (iCABG) in 2016 but requested the collection of patient and surgery data in a registry (NAPaR). The aim of this analysis was to evaluate the impact of APR reintroduction in France on the main hospital costs (operating room, transfusion and intensive unit stay) compared to the current use of tranexamic acid (TXA), which was the only antifibrinolytic available before APR reinstatement.

Methods:

A multicenter before-after post-hoc analysis to compare APR and TXA was carried out in four French university hospitals. APR use followed the ARCOTHOVA (French Association of Cardiothoracic and Vascular Anesthetists) protocol, which had framed three main indications in 2018. Data from 236 APR patients were retrieved from the NAPaR (N = 874); 223 TXA patients were retrospectively retrieved from each center database and matched to APR patients upon indication classes. Budget impact was evaluated using both direct costs associated with antifibrinolytics and transfusion products (within the first 48 h) and other costs such as surgery duration and ICU stay.

Results:

The 459 collected patients were distributed as: 17% on-label; 83% off-label. Mean cost per patient until ICU discharge tended to be lower in the APR group versus the TXA group, which resulted in an estimated gross saving of €3136 per patient. These savings concerned operating room and transfusion costs but were mainly driven by reduced ICU stays. When extrapolated to the whole French NAPaR population, the total savings of the therapeutic switch was estimated at around €3 million.

Conclusion:

The budget impact projected that using APR according to ARCOTHOVA protocol resulted in decreased requirement for transfusion and complications related to surgery. Both were associated with substantial cost savings from the hospital's perspective compared with exclusive use of TXA.

INTRODUCTION

Perioperative bleeding is a major concern in cardiac surgery as it is associated with the risks of exposure to allogeneic blood transfusion, prolonged lengths of hospital stay and increased mortality [START_REF] Paone | Transfusion of 1 and 2 units of red blood cells is associated with increased morbidity and mortality[END_REF][START_REF] Koch | Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting[END_REF][START_REF] Vlot | Intra-operative red blood cell transfusion and mortality after cardiac surgery[END_REF][START_REF] Agostino | The society of thoracic surgeons adult cardiac surgery database: 2019 update on outcomes and quality[END_REF][START_REF] Colson | Impact of red blood cell transfusion on inhospital mortality of isolated coronary artery bypass graft surgery. A retrospective observational study of french nationwide 3-year cohort[END_REF]. The definition of a patient at high risk of bleeding or autologous transfusion involves multiple factors including the patient's ability to initiate and sustain adequate haemostasis and the characteristics of surgery. These factors are used as key criteria in a broad range of predictive scores [START_REF] Alghamdi | Development and validation of Transfusion Risk Understanding Scoring Tool (TRUST) to stratify cardiac surgery patients according to their blood transfusion needs[END_REF][START_REF] Vuylsteke | The Papworth Bleeding Risk Score: a stratification scheme for identifying cardiac surgery patients at risk of excessive early postoperative bleeding[END_REF][START_REF] Goudie | Risk scores to facilitate preoperative prediction of transfusion and large volume blood transfusion associated with adult cardiac surgery[END_REF][START_REF] Klein | The ACTA PORTscore for predicting perioperative risk of blood transfusion for adult cardiac surgery[END_REF]. Nonetheless, the incidence of allogenic blood exposure remains high even when a restrictive transfusion strategy is applied, approximately 50% [START_REF] Murphy | Liberal or restrictive transfusion after cardiac surgery[END_REF][START_REF] Mazer | Restrictive or liberal redcell transfusion for cardiac surgery[END_REF].

Overall awareness of the need to reduce exposure to blood product is supported by international guidelines on patient blood management (PBM) [START_REF] Task Force ; Ferraris | The Society of Thoracic Surgeons Blood Conservation Guideline Task Force. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline[END_REF][START_REF] Pagano | EACTS/EACTA guidelines on patient blood management for adult cardiac surgery[END_REF][START_REF] Raphael | Society of cardiovascular anesthesiologists clinical practice improvement advisory for management of perioperative bleeding and hemostasis in cardiac surgery patients[END_REF]. Among the intraoperative strategies of PBM, antifibrinolytic therapy is recommended to reduce bleeding and transfusions of blood products and reoperations for bleeding (Class I, Level A) [START_REF] Pagano | EACTS/EACTA guidelines on patient blood management for adult cardiac surgery[END_REF]. Antifibrinolytics are a class of haemostatic agents used to prevent excessive blood loss associated with degradation of intravascular fibrin clots by action of plasmin [START_REF] Koster | Antifibrinolytic therapy for cardiac surgery: an update[END_REF]. The lysine analogues epsilon aminocaproic acid (EACA, also referred as aminocaproic acid, not available in France) and tranexamic acid (TXA) specifically inhibit the conversion of plasminogen to plasmin. APR, a naturally occurring polypeptide, is an inhibitor of serine proteases. It has a broad range of targets such as plasmin, trypsin and kallikrein [START_REF] Koster | Antifibrinolytic therapy for cardiac surgery: an update[END_REF]. Concerns regarding APR safety in cardiac surgery arose in 2005 and culminated in 2008 with the publication of the BART study [START_REF] Fergusson | BART investigators: a comparison of aprotinin and lysine analogues in high-risk cardiac surgery[END_REF]. Following BART results, APR was withdrawn from the market at the request of various National health authorities and the EMA. However, further analysis reported several problems with the way the BART study was conducted, which cast doubt on the previous conclusions. Moreover, overall data available showed that APR's benefits are greater than its risks in restricted indications [START_REF]Assessment report Antifibrinolytics containing aprotinin, aminocaproic acid and tranexamic acid aprotinin [Internet[END_REF]. Therefore, the EMA lifted the suspension of APR from the market in 2012 [START_REF]Assessment report Antifibrinolytics containing aprotinin, aminocaproic acid and tranexamic acid aprotinin [Internet[END_REF].

The debate on APR withdrawal/reinstatement spread confusion among clinicians regarding its role and place. To clarify the situation, the European Society of Anaesthesiology set up a task force to assess the current evidence and provide a summarised definition of high-risk patients for whom APR might be beneficial [START_REF]The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesia. Aprotinin: is it time to reconsider?[END_REF]. This expert opinion to target APR indication was followed by national expert groups such as Aprotinin-ARCOTHOVA experts [START_REF] Amour | L'ordonnance type du groupe de travail Aprotinine-ARCOTHOVA[END_REF]. Besides, a European post-authorisation marketing authorisation safety study was part of the risk minimisation measures associated with APR's lifting of suspension. This Nordic Aprotinin Patient Registry (NAPaR) was established to collect real-world data on APR use and investigate specific safety concerns in the patient population not included in the current indication. This registry was expected to record information on virtually all patients exposed to Nordic Aprotinin.

The impact of APR on the economic burden of bleeding and transfusion started to be investigated before the product withdrawal [START_REF] Ray | Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass[END_REF][START_REF] Smith | Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials[END_REF][START_REF] Meyerson | Medical and economic impact of aprotinin use in adult cardiac surgery[END_REF][START_REF] Robinson | A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit[END_REF]. After years of absence, the expectation regarding the benefits of APR was no longer restricted to its clinical efficacy but also to its cost efficiency. Also, very few APR data were available after its reinstatement in cardiac units. Therefore, to assess the overall financial impact of APR reinstatement, four teaching hospital centres pooled their anonymised data to develop a budget impact model (BIM) comparing the costs associated with surgery, bleeding, transfusion and ICU stay for 1:1 matched patients treated with TXA or APR.

METHODS

This is a multicentre retrospective analysis using real-world databases from French academic hospitals, selected on the basis they had performed at least 50 adult (age>/= 18 years) cardiac surgery cases under APR between December 2018 (first patient in) and December 2020 (interim database lock). APR use followed the three indication groups defined by the French Society of Anaesthesiologists in Thoracic and Cardiac Surgery (ARCOTHOVA: Anesthésie-Réanimation Coeur-Thorax-Vaisseaux) [START_REF] Amour | L'ordonnance type du groupe de travail Aprotinine-ARCOTHOVA[END_REF]:

• Indication 1: isolated coronary artery bypass graft under cardiopulmonary bypass (iCABG) with bleeding risk [ongoing active antiplatelet therapy or previous sternotomy (redo)]

• Indication 2: High-risk cardiac surgery other than iCABG in patients with at least three of the TRUST SCORE risk factors [START_REF] Alghamdi | Development and validation of Transfusion Risk Understanding Scoring Tool (TRUST) to stratify cardiac surgery patients according to their blood transfusion needs[END_REF] including age >/= 75 years, complex surgery with or without aortic repair or replacement, cardiac transplant, non-elective surgery, platelet impairment and BMI < 25.

• Indication 3: High-risk cardiac surgery other than those defined in indications 1 and 2 including redo (except iCABG), infectious endocarditis, aortic dissection or mechanical heart device.

Patients in APR groups were retrieved from the French NAPaR registry (EU PAS register number: EUPAS11384). They defined the proportion of patients in the three indication groups. To compare patients treated with APR to those treated with TXA, APR and TXA patients were matched following their bleeding risk according to the three indication groups.

Patients in the TXA group were retrieved from the pharmacy and services database of each institution, where data from patients treated by TXA are routinely collected for accounting. From the lists of these patients, matching was used to recruit patients in the study according to the three indications, with similar proportions in each indication for APR group. To obtain matching as close as possible to 1:1, TXA patients were retrospectively collected over a longer period from May 2016 to October 2019. All anonymised data were then transferred and centralised for analysis by our statistician partner CEMKA.

As data were retrospectively analysed, the use of antifibrinolytics followed routine practice. Unlike TXA, APR benefits from a standardized protocol published by ARCOTHOVA: halfdose regimen (patient's loading dose, 1.10 6 KIU; pump priming, 1.10 6 KIU; continuous infusion, 0.25.10 6 KIU/h), a dose regimen that was advised in 2018 by the representative cardiac anaesthetist group in France (ARCOTHOVA).

The main objectives were to compare the costs associated with the patient journey in cardiac surgery departments according to the selected prophylactic antifibrinolytics and to assess the overall budget impact of APR reintroduction from the hospital perspective. The secondary objectives were to characterize patients exposed to APR following ARCOTHOVA prescription criteria, quantify the use of hospital resources in a patient journey and assess the cost of a patient journey according to ARCOTHOVA indications.

Only the data needed for the matching process (i.e., ARCOTHOVA criteria: type of surgery, platelet impairment, redo, age >/= 75 years, BMI < 25, complex surgery, aortic surgery, endocarditis, transplant, emergency, etc.) and for the cost analysis [number of antifibrinolytics, time in the operating room (OR) for the main surgery and, when applicable, for the reoperation for bleeding, number of transfusion products, intensive care unit (ICU) length of stay and postoperative survival) were available in pooled databases.

As the main registry contributors provided the sample used in this model, the sample is assumed to be representative and no sample size was determined prior to the analysis.

Fig. 1 Scenario assessed in the budget impact model

Direct costs were analysed in euros (€) from the hospital perspective including antifibrinolytic use, length of surgical procedure (operation and possible reoperation), need for blood product transfusion and ICU stay. When carried out, reinterventions were included in length of surgery. Any other complications, regardless of the type, that occurred during a hospital stay and were managed in ICU were included in ICU stay costs to avoid duplication. As the ICU stay depended on postoperative complications, including acute renal failure, low cardiac output syndrome, pulmonary dysfunction, thromboembolic events, sepsis complications and others, the length of the ICU stay was considered a surrogate of a composite outcome, which would have included each above-mentioned complication.

In addition, a cardiac complication following cardiac surgery was counted as an extension of the ICU stay instead of a new hospitalisation. These above-mentioned costs were collected from the public databases of the French Ministry of Health and the Agency for Hospital Information as well as published unit value from the French official journal. Hospital costs were analysed using the 2019 basis and were inflated to those of 2021 (Supplementary materials, Table S1). It was assumed that the inflation rate for 2021 was equivalent to that of 2020 for medical services. Patients deceased during the hospital stay including the OR or ICU were excluded from the cost analysis. The total population was therefore analysed to estimate resource utilization during the hospital stay.

A budget impact model (Fig. 1) was developed in Microsoft R Excel R (Microsoft 365 MSO V.2203) to compare the costs associated with the use of APR versus TXA in patients undergoing high risk of bleeding cardiac surgery from the hospital perspective in France. The model compared the difference in overall cost between two scenarios for the management of patients in the population of interest:

• A scenario WITHOUT aprotinin (Scenario 1): treatment with TXA, which was considered as the standard antifibrinolytic therapy for cardiac surgery to prevent major bleeding.

• A scenario WITH aprotinin (Scenario 2): the expected changes in patient management if APR were to completely replace TXA (full substitution hypothesis).

We assumed that the distribution of patients among the three indications was strictly equivalent in the two scenarios (scenario with aprotinin and scenario without aprotinin). The budget impact represented the cost difference between these two scenarios. One-way sensitivity analyses were performed by changing the base case parameters of the model and a variability of ± 20% of the central value was assumed to be a reasonably wide range as approved by the leading clinical experts. The modelling of clinical pathways and the identification of healthcare resource utilization were developed in collaboration with all four authors, each referent for the NAPaR in their health institutions.

The statistical analysis was performed using SAS R V9.4 software (North Carolina, USA). Quantitative and qualitative variables were undergoing high risk of bleeding cardiac surgery from the hospital perspective in France. The model compared the difference in overall cost between two scenarios for the management of patients in the population of interest:

• A scenario WITHOUT aprotinin (Scenario 1): treatment with TXA, which was considered as the standard antifibrinolytic therapy for cardiac surgery to prevent major bleeding.

• A scenario WITH aprotinin (Scenario 2): the expected changes in patient management if APR were to completely replace TXA (full substitution hypothesis).

We assumed that the distribution of patients among the three indications was strictly equivalent in the two scenarios (scenario with aprotinin and scenario without aprotinin). The budget impact represented the cost difference between these two scenarios. One-way sensitivity analyses were performed by changing the base case parameters of the model and a variability of ± 20% of the central value was assumed to be a reasonably wide range as approved by the leading clinical experts. The modelling of clinical pathways and the identification of healthcare resource utilization were developed in collaboration with all four authors, each referent for the NAPaR in their health institutions.

The statistical analysis was performed using SAS R V9.4 software (North Carolina, USA). Quantitative and qualitative variables were described for each group and for the total population. Quantitative variables were expressed as mean ± standard deviation (SD), median, or range and qualitative variables as percentages. A subgroup analysis was conducted to compare the two treatment arms according to the three ARCOTHOVA indication groups using the chisquare test for qualitative variables, and t test or analysis of variance was performed for quantitative variables when the distribution was close to normal (Shapiro-Wilk test not significant). Otherwise, Wilcoxon's non-parametric test was used. The association between ''antifibrinolytic treatment'' and ''indication'' was assessed by the chi-square test to ensure that the three ARCOTHOVA indications were distributed similarly between the two treatment arms.

RESULTS

Of the 874 APR patients recorded in the French NAPaR between December 2018 and December 2020, 399 patients were treated in the 4 participating centres including Public Assistance Hospitals of Paris (Bichat-Claude Bernard), University Hospital of Nantes (Laennec), University Hospital of Montpellier (Arnaud de Villeneuve) and University Hospital of Lyon (Louis Pradel). Since 163 patients had missing data and were excluded, the 236 remaining patients (60%) defined the APR group. These patients were retrospectively matched to 223 TXA patients who underwent similar high risk cardiac surgeries between May 2016 and October 2019. A total of 459 adult patients were enrolled in the study (Fig. 2). Patients' characteristics were not statistically different between the APR and tranexamic groups (Table 1).

Resource Utilisation

When considering the two groups, irrespective of the three indications, there were no statistical differences in any of the mean resource utilizations except for the antifibrinolytic used between the APR and TXA groups. More than half of the analysed patients (53%) were transfused with an average of 2.4 units of RBC. Overall transfusion rate for other bloodderived products was around 39% for both fresh frozen plasma (FFP) and platelets and 32% for fibrinogen. The mean duration of surgery was 105 min. Ten per cent of patients underwent a reoperation for bleeding with a mean OR time around 105 min. The average length of ICU stay for the analysed population was 8 days. Table 2 describes resource utilization according to the three groups' indications. Reoperation was significantly more frequent for the TXA group compared with the APR group (24% vs. 6%, p\0.0001) in indication 2.

There were some statistical differences regarding blood product transfusion and fibrinogen administration when comparing per indication:

-In indication 1, TXA patients were more likely to receive RBC than APR patients (26.8% vs. 16.2%, p\0.001). The reverse is observed for fibrinogen administration with a higher transfusion rate in the APR group (16.2%) than TXA group (9.8%) (p\0.001).

-In indication 2, TXA patients were more likely to receive RBC, FFP transfusion and fibrinogen administration than APR patients (68.3%, 51.2%, 41.5% vs. 55.9%, 47.1%, 29.4% respectively, p<0.001). The reverse is observed for platelet transfusion, which was statistically higher in the APR group compared to the TXA arm (55.9% vs. 39.0%, p<0.001).

-In indication 3, APR patients were more likely to receive RBC, FFP transfusion and platelets than TXA patients (60.6%, 49.7% and 42.4% vs, 56.7%, 42.6% and 37.6%, respectively, p<0.001). TXA patients received more fibrinogen administration than APR patients (39.7% vs. 32.8%, p<0.0001).

Cost Analysis

Independently of the indication, the mean cost per patient was estimated at €20,997 for the APR group compared to €24,133 in the TXA group. It included the following costs: antifibrinolytics, surgical procedure, transfusions and ICU stay (Supplementary materials, Table S2). The main resource use was driven by ICU stays.

When focusing on the three groups of indications (Table 3), the total mean cost was higher with TXA compared to APR except for indication 1. Total mean cost was always driven by ICU stays, independently of the indication, and increased substantially for indication 2 in TXA patients.

Budget Impact

The distribution of the 874 NAPaR patients (December 2018-December 2020) was 137 patients (15.7%) undergoing iCABG (indication 1), 126 patients (14.4%) with at least three risk factors undergoing high-risk cardiac surgery other than iCABG (indication 2) and 611 (69.9%) undergoing other high-risk surgical procedures (indication 3) (Supplementary materials, Table S3). The budget impact of APR reintroduction was calculated for this entire group of NAPaR patients (N = 874).

Base Case Analysis

Total costs of patients on APR undergoing cardiac surgery (scenario 2) according to NAPaR profiles were estimated to be approximately €18 million, whereas the costs for TXA patients (scenario 1) were estimated at €21 million. The budget impact of APR use, which was calculated as the difference in the total cost between the two scenarios (scenario 2 -scenario1), was estimated to a net saving of around €3 million over 2 years. Furthermore, over the same period, savings were achieved for surgical procedures, transfusions and ICU stay (Table 4). The total substitution of TXA for APR resulted in a net expenditure of approximately €433 K in antifibrinolytics. All other resources benefited from net savings: €54 K in costs associated with surgical procedures, €174 K in transfusions and €2984 K in ICU stay.

When considering the budget impact for each indication separately, the use of APR resulted in net savings for patients managed in indications 2 and 3, whereas in indication 1 a net saving was only observed for surgical procedure (Table 4).

Sensitivity Analysis

A one-way sensitivity analysis was performed by changing the base case values of several parameters of interest of the model; the results are presented using a tornado diagram in Fig. 3. The results showed that all input variables led to direct changes in the net budget impact. All conditions being equal, the analysis showed a greater sensitivity for the budget impact of the length of stay in ICU, the daily cost of stay in ICU and the distribution of patients in each indication group. Therefore, the reintroduction and use of APR result in net savings (ranging from €0.65 million to €4.9 million) compared to TXA for all the parameters variations simulated.

DISCUSSION

Comparing the costs associated with the patient journey in cardiac surgery departments according to the used prophylactic antifibrinolytics, we observed that APR reintroduction induced a reduction of the overall budget compared to the current use of TXA. Although there is an additional charge in the antifibrinolytics, the total savings from ICU stay and transfusion products compensated the initial additional costs. Central value: base case budget-impact cost saving of €2.78 million. One-way sensitivity analysis: difference in budget impact according to a variability of ± 20% for variable such as ICU length of stay, indication distribution, need for transfusion and surgery duration.

Several studies have been performed on the economic impact of APR before its withdrawal [START_REF] Ray | Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass[END_REF][START_REF] Smith | Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials[END_REF][START_REF] Meyerson | Medical and economic impact of aprotinin use in adult cardiac surgery[END_REF][START_REF] Robinson | A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit[END_REF][START_REF] Karkouti | The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery[END_REF]. These studies were based on cost analyses similar to our study since all included at least the drug cost, blood product costs, length of stay and utilization of resources of operating room (including reoperation) and ICU stay. However, these studies varied on other associated factors like staff grades, staff availability, long-term complications after ICU and surgery cases with a majority of low-risk surgery [START_REF] Ray | Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass[END_REF][START_REF] Smith | Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials[END_REF][START_REF] Meyerson | Medical and economic impact of aprotinin use in adult cardiac surgery[END_REF][START_REF] Robinson | A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit[END_REF][START_REF] Karkouti | The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery[END_REF]. Nevertheless, they demonstrated that, though APR increased costs due to drug acquisition as well as the cost of administration, its use led to the utilization of fewer resources than with placebo. Our study tends to actualize the economic impact of APR on the following key points: first, expenses were updated with current resource costs; second, the study compared APR to another antifibrinolytic drug, TXA; third, various conditions of bleeding risk were studied with three distinct indications.

Owing to the updated resource costs, we observed that APR introduction was associated with a lower budget impact compared to TXA provided administration followed specific indications. Resource costs were mainly driven by ICU stays, then by surgical procedures and transfusions (66%, 17% and 14% versus 72%, 15% and 13%, respectively, for APR versus TXA), far above antifibrinolytics' weight in average hospital expenditure per patients (2% versus 0.02% for APR versus TXA).

However, the budget impact varied drastically with the indication.

For indication 1, 17% of patients included in the study underwent iCABG surgery. In our model, APR use compared to TXA had only a moderate reduction in surgical procedure costs (-2.3%), which did not compensate for the increased costs on other resource utilization (+ 50%). The results seem at odds with former studies on CABG surgery [START_REF] Smith | Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials[END_REF][START_REF] Meyerson | Medical and economic impact of aprotinin use in adult cardiac surgery[END_REF][START_REF] Robinson | A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit[END_REF][START_REF] Karkouti | The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery[END_REF]. However, perioperative cost had been shown not to be significantly different between full-dose or halfdose APR and placebo for primary CABG surgery [START_REF] Smith | Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials[END_REF]; cost savings were previously described in cases of repeated CABG surgery due to reduced complication costs, particularly with the full-dose regimen [START_REF] Smith | Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials[END_REF]. We cannot exclude that the use of half-dose APR had limited cost savings in our series. Robinson et al. [START_REF] Robinson | A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit[END_REF], who have developed an operational model to evaluate the influence of APR use on waiting lists and time, demonstrated that APR indirectly decreased costs by reducing waiting lists as well as by reducing morbidity and mortality associated with waiting time. We observed longer reoperation times for TXA patients than for APR patients, for which the consequences on the waiting list were not evaluated. However, the incidence of reoperation (around 5%) was small, and the cost saving was probably very limited [START_REF] Robinson | A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit[END_REF].

Practitioners have purposefully decided to administer APR in high-bleeding-risk patients, due to either patients' conditions (indication 2) or complex surgery cases (indication 3). The low proportion of patients in the on-label group (indication 1) might appear unconventional but it was following practitioners' empirical experience of a favourable risk-benefit ratio beyond CABG surgery. Repeated data had suggested that APR might have clinical advantages over TXA in high-risk patients [START_REF] Karkouti | The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery[END_REF][START_REF] Sander | Mortality associated with administration of highdose tranexamic acid and aprotinin in primary openheart procedures: a retrospective analysis[END_REF][START_REF] Walkden | Increased perioperativemortality following aprotinin withdrawal: a real-world analysis of blood management strategies in adult cardiac surgery[END_REF]. These studies, along with clinical experience, helped to forge a strong opinion in the cardiac anaesthesiologist community in favour of APR use in cases at higher risk than iCABG. The common feeling was quite well represented in the consensus statement issued by the European Society of Anaesthesiologists task force in 2015 [START_REF]The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesia. Aprotinin: is it time to reconsider?[END_REF]. In the NAPaR, which reports real-life data from 83 European centres, APR was used mostly in surgical procedures other than iCABG (74.3% of surgery cases) [START_REF] Hert | Use and safety of aprotinin in routine clinical practice. A European postauthorisation safety study conducted in patients undergoing cardiac surgery[END_REF].

Indication 2 concerned a small group of patients (16.3%) but a substantial reduction (37%) in costs associated with resource utilization was observed with APR compared to TXA, mainly due to transfusions and ICU stays (reduction by 39% and 43%, respectively). The results suggested that indication 2 defined by patient's risk was quite appropriate for APR administration as it contributed to the biggest reduction in our budget impact model (Table 4).

These financial benefits answered, at least partly, the ESA task force's question about the place that APR might hold nowadays [START_REF]The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesia. Aprotinin: is it time to reconsider?[END_REF].

The biggest group of patients was included in indication 3 (66.7%). Overall reduction in cost resources was rather modest (11%) mainly because of reduction in resource costs for ICU stay (18%). Considering the larger number of patients, the results on the budget impact model were nevertheless quite important with overall savings estimated around the same as for indication 2 (€1.626 K versus €1.789 K).

The more significant change in the budget impact model in indication 2 and 3 compared to TXA is related to ICU stays. The ICU stays were influenced by incidence of complications like low cardiac output syndrome, acute renal failure, stroke or other thrombo-embolic events. Details on postoperative outcomes were not collected in the study because extra costs related to the treatment of complications were supposedly covered by daily ICU costs. It was assumed that prolonged stay in ICU was related to complicated postoperative follow-up. The reduction in ICU stay with APR is puzzling considering the small reduction in bleeding and small differences in transfusion or fibrinogen administration compared to TXA, which can hardly explain the prolonged stay. The reduction of ICU stay has been barely described in previous studies [START_REF] Deloge | Aprotinin vs tranexamic acid in isolated coronary artery bypass surgery. A multicentre observational study[END_REF] and might be related to other mechanisms than preventing bleeding and transfusion [START_REF] Mcevoy | Aprotinin in cardiac surgery: a review of conventional and novel mechanisms of action[END_REF]. Interestingly, the higher ICU costs for TXA patients were mainly due to those patients who stayed [2 weeks in the ICU (data not shown). Further studies are required to confirm this observation and eventually to establish the causality of APR effect on ICU stay.

Strengths and Limitations

Our study had several limitations. First, the results observed reflect the practice in France and may not apply to other healthcare systems. Second, our cohort was retrospective and heterogeneous with recruitment of various indications, and we used a non-standardised protocol for TXA administration, with the inherent limitation of a before-and-after design.

Third, the matching process based on APR indication definition might not fully exclude residual confounding. However, since all consecutive potential participants were screened over the study period, the cohort reflected real world antifibrinolytic exposure. Moreover, the sensitivity analysis seemed to confirm the primary result. Fourth, costs were calculated with official prices (fixed by the national health regulatory authorities), which could be slightly different in each institution after negotiation with the manufacturer. However, the negotiated prices concerned only blood products with a limited impact on the overall costs. Finally, the small recruitment for indications 1 and 2 may preclude definitive conclusions.

Strengths of our study included its careful design that limited missing data. In addition, patients' recruitment was based on consecutive cases, which reflected real-life activity. Lastly, it involved a comparison of APR to the current antifibrinolytic competitor.

Fig. 2

 2 Fig. 2 Flow chart illustrating the assessed population.

Fig. 3

 3 Fig. 3 One-way sensitivity analysis: difference in the budget-impact between APR and TXA settings.

ACKNOWLEDGEMENTS

The authors thank the contract research organisation CEMKA France for performing the statistical analysis.

Funding.

Sponsorship for this study and the journal's Rapid Service Fee and Open Access fees were funded by Nordic Pharma.

CONCLUSION

The present budget impact analysis projected that the re-introduction and use of APR tend to reduce the requirement for transfusion and ICU stay in patients undergoing high-risk cardiac surgery and therefore leads to substantial cost savings from the hospital's perspective compared with exclusive use of TXA.

Authorship.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.

Author Contributions.

Pascal Colson, Jean-Luc Fellahi, Philippe Gaudard, Sophie Provenchère, Bertrand Rozec: concept and planning of the work described; acquisition, analysis and interpretation of the data; Pascal Colson, Jean-Luc Fellahi, Philippe Gaudard, Sophie Provenchère, Bertrand Rozec: drafting and/or critical revision of the manuscript and approved the final submitted version of the manuscript.

Disclosures.

Pascal Colson is a consultant for Nordic Pharma. Jean-Luc Fellahi is a consultant for Nordic Pharma. Philippe Gaudard is a consultant for Nordic Pharma. Sophie Provenchère is a consultant for Nordic Pharma. Bertrand Rozec is a consultant for Nordic Pharma. Compliance with Ethics Guidelines. As required by French regulations, the real-life data from the NAPaR study were approved by the French data protection authority (CNIL) and the French ethics committee on January 16, 2018. Due to the use of a pooled anonymized data set, no ethics approval for this study was needed.

Data Availability.

The data are available from CEMKA, Bourg-la-Reine, France.


Fabien Brette1

Pierre Dos Santos1

Jean-Sebastien Hulot5

Fabien Brette
email: fabien.brette@inserm.fr

Editorial: Heart failure with preserved ejection fraction: Basic, translational, and clinical research

Keywords: heart failure, disease model, diastolic dysfunction, basic mechanisms, diagnosis, therapeutic target

Editorial on the Research Topic

Heart failure with preserved ejection fraction: Basic, translational, and clinical research

Heart failure (HF) is a complex clinical syndrome that occurs as a consequence of structural or functional impairment of ventricular filling and/or ejection [START_REF] Heidenreich | AHA/ACC/HFSA guideline for the management of heart failure: A report of the American college of cardiology/American heart association joint committee on clinical practice guidelines[END_REF]. It is a worldwide condition with a high prevalence and mortality and is a frequent cause of recurrent hospitalizations. As per the most recent guidelines, HF is classified into three categories according to left ventricular (LV) ejection fraction (EF): HF with reduced ejection fraction (HFrEF) when EF is less than 40%, HF with preserved ejection fraction (HFpEF) when EF is greater than 50%, and the newly renamed HF with mildly reduced ejection fraction (HFmrEF) when EF is between 40 and 49%. Recent studies have reported a continuous increase in the proportion of patients with HFpEF, representing approximately 50% of all HF cases [START_REF] Fayol | Aetiological classification and prognosis in patients with heart failure with preserved ejection fraction[END_REF]. However, the mechanisms leading to HFpEF remain poorly understood.

Over the last 30 years, a plethora of data from animal models have improved our understanding of the pathophysiology of HFrEF at the molecular and cellular levels. Meanwhile, clinicians have developed and used different therapeutic strategies for treating HFrEF. Disappointingly, effective therapies for patients with HFrEF are not adequate, with the notable exception of sodium-glucose cotransporter two inhibitors (SGLT2i); their benefit for these patients was recently demonstrated [START_REF] Anker | Empagliflozin in heart failure with a preserved ejection fraction[END_REF][START_REF] Solomon | Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction[END_REF]. Although the exact mechanism by which SGLT2i affect cardiac cells remains unclear and debatable [START_REF] Dyck | Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects[END_REF], recent evidence suggests a direct inhibition of sodium-hydrogen exchanger 1 (NHE-1). At the clinical level, impaired LV relaxation and filling is characterized by a decreased ventricular relaxation rate and an increased left ventricular chamber stiffness. More specifically, patients with HFpEF present an impaired diastolic reserve, characterized by an inadequate increase in myocardial relaxation and filling in response to situations requiring increased energy demand, such as exercise [START_REF] Phan | Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency[END_REF][START_REF] Borlaug | Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction[END_REF].

The mechanisms leading to impaired LV relaxation and filling remain obscure. They involve the consequences of multiple comorbidities and other contributing factors such as aging or lifestyle habits. Recent studies have shown that HFpEF is a heterogeneous syndrome, with dissimilar abnormalities observed at the cellular level in patients. For instance, recent studies have shown that disruption of the t-tubules in HFpEF is not involved, unlike in HFrEF [START_REF] Frisk | Etiologydependent impairment of diastolic cardiomyocyte calcium homeostasis in heart failure with preserved ejection fraction[END_REF]; the consequences also depend on the diabetes status as diabetic patients with HFpEF display impaired calcium handling, whereas patients with HFrEF do not [START_REF] Hulot | HFpEF: Should we consider diabetic patients separately? The cardiomyocytes say yesp[END_REF]. This not only highlights the divergent pathophysiology between patients with HFrEF and HFpEF, but also within patients with HFpEF (Figure 1).More mechanistic studies are thus needed in animal, patient, or innovative models of cardiac relaxation [START_REF] Kilfoil | Distinct features of calcium handling and β-adrenergic sensitivity in heart failure with preserved versus reduced ejection fraction[END_REF].

In this Research Topic, we present a series of articles from experts in various areas of HF.

The Research Topic starts with two articles on cardiorespiratory dysfunction and HFpEF. In conclusion, this Research Topic covers a broad range of HFpEF at different levels. Cleary, more basic, translational, and clinical research is needed to delineate the complexity of the mechanisms involved in HFpEF and their interactions. Given the multidimensionality of the HFpEF syndrome, new experimental models, which represent clinical situations, are required.

In terms of patients, in depth imaging as well as genomic, proteomic, and metabolomic analyses will help for a better characterization. Both human and animal models will contribute to identifying potential therapeutic targets. We hope that this Research Topic encourages further investigation of these exciting areas.

FIGURE 1 :

 1 FIGURE 1 :Schematic representation of excitation contraction coupling in control, HFrEF, and HFpEF cardiomyocytes

  In a review article, Toledo et al. discuss the possible effect of the activation of central chemoreflex pathways on autonomic function and its potential role in breathing disorders during HFpEF. By comparing to HFrEF, where most studies have been done (in patients and animal models), the authors highlight that enhanced central chemoreflex sensitivity, cardiac autonomic imbalance, and breathing disorders are all observed in experimental animal models based on non-ischemic HFpEF. However, the precise mechanism(s) responsible for central chemoreflex sensitization, autonomic imbalance, and respiratory disorders in HFpEF are not yet clearly established.As Toledo et al. ask for further studies on cardiorespiratory dysfunction, Jones et al. investigate the relation between obstructive sleep apnea and obesity in animal models. They show that caloric restriction can prevent obesity-induced LV hypertrophy. This protects against intermittent hypoxia induced remodeling, independent of leptin signaling. Clinical relevance of these observations needs additional investigations.A second review article focuses on endothelial dysfunction as a critical player of HFpEF development. The review by Cornuault et al. aims to present and discuss evidence supporting a causal role of endothelial dysfunction in the pathophysiology of HFpEF in patients and animal models. Endothelial cells dysfunction can alter cardiomyocytes functions such as survival, contractility and metabolism. The authors conclude that at molecular and cellular levels, endothelial to cardiomyocyte crosstalk is still poorly understood and new animal models of HFpEF should bring some clues regarding pathophysiology.In this Research Topic, an article by Lamonzie et al. provides a new aspect on imaging diagnosis. Cardiac magnetic resonance imaging (MRI) is the gold standard for evaluating myocardial function, volumes, and scarring. Currently, gadolinium-based contrast agents are widely used to improve the sensitivity and specificity of imaging. As an extracellular agent, gadolinium is a powerful tool for imaging scarring and highlighting intravascular and extracellular spaces. Manganese-enhanced MRI (MEMRI) has emerged as a complementary approach, enabling intracellular myocardial contrast imaging that can identify functional myocardium through its ability to act as a calcium analog. An important issue is the possible cardiac toxicity of manganese. Lamonzie et al. provide a comprehensive evaluation of its toxicity. At the whole heart level, micromolar concentrations of manganese, up to 25 μM, have no impact on cardiac function. At the cellular level, a small decrease in the calcium transient amplitude and action potential duration are observed, mainly due to a block of Ltype Ca2+ channels. MnCl2 at a concentration of 25 μM decreases T1 in MRI experiments, demonstrating that this concentration is sufficient for using manganese as a contrast agent. The authors conclude that as MEMRI has the potential to monitor changes in intracellular Ca2+ homeostasis at the whole heart level, it should optimize patient diagnosis and therapeutic decision-making by providing visualization of potentially arrhythmic locations.The last research article uses numerical modelling to investigate the role of the Purkinje fiberventricle junction on pro-arrhythmic events. Jian et al. demonstrate that HF-induced ionic remodeling reduced conduction safety and increased tissue vulnerability to the genesis of unidirectional conduction blocks. The Purkinje fiber-ventricle junction can form a potential substrate for the genesis of conduction failure that leads to reentry. The study by Jian et al. highlights the utility of single cell and multiscale modeling of cardiac electrophysiology as an important tool to widen the understanding of underlying mechanisms at cellular and tissue levels.

Acknowledgments

We thank all contributors and reviewers for their work and impact on this Research Topic. We also thank Matthieu Douard for a draft version of the Figure.

Funding

FB is financially supported by the French National Funding Agency for Research (ANR) (ANR-10-IAHU04-LIRYC; ANR-20-CE17-0010).

Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and have approved it for publication.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.