H Porthault

C Calberg

J Amiran

S Martin

C Páez

N Job

B Heinrichs

D Liquet

R Salot

new gel polymer electrolyte operating at room temperature

Keywords: Gel polymer electrolyte, IoT, battery design, Lithium metal battery

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The 2019 Chemistry Nobel Prize was attributed to three researchers, J. Goodenough, S.

Whittingham and A. Yoshino, who contributed to the enhancement and the advent of the lithium ion batteries [START_REF]The Nobel Prize in Chemistry[END_REF][START_REF] Blomgren | [END_REF]. These developments modify our society since the 1990s and the first commercialization of a lithium ion battery by Sony Corporation [START_REF] Blomgren | [END_REF]. The development of lithium ion batteries then became exponential with its integration in numerous products, from the electric vehicles to the inevitable smartphones. More recently, the emerging of Internet of Things (IoT) provides a great easiness in everyday life fields such as smart homes, wearables, medical devices, data security, etc. The number of connected IoT devices was multiplied by 3 since the 2010s [3]. These new applications lead to toughen battery requirements like flexibility, limited thickness (< 500 µm), etc. The pouch cell configuration is the only current commercial one that could fit with these new requirements. However, despite a smaller dead volume than the cylindrical or prismatic geometries [4], if very low thickness are targeted (< 500 µm), the classical pouch cells still suffer from an important part of the total thickness dedicated to the packaging. Furthermore, IoT applications require an enhanced security (medical devices, battery-user proximity etc.) [START_REF] Zopf | CHAPTER 14 Wearable Energy Storage Based on Ionic Liquid Gels, in Polymerized Ionic Liquids[END_REF] and currently, the main safety hazard originates from the electrolyte leakage and its irreversible decomposition.

Hence, lithium polymer batteries are studied since the 1970s with the solid polymer electrolyte (SPE) described by Armand et al [6][7][START_REF] Armand | Polymeric solid electrolytes[END_REF] and composed of a solid polymer matrix of crystalline poly(ethylene) oxide (PEO) and a lithium salt. It could also enable the use of Li metal anode, considered as the ideal anode material regarding its high theoretical capacity (3860 mAh g -1 ) and low redox potential (-3.04 V vs NHE) [START_REF] Lopez | [END_REF]. Bolloré, with the BlueCar and Autolib car sharing development in Paris, brought lithium metal-polymer (LMP) batteries to a production level [10]. Nevertheless, the main drawback of these electrolytes remains its low ionic conductivity at room temperature (10 -4 -10 -7 S cm -1 ) [11,12]. These restrictions limit the C-rate and/or impose a working temperature around 60-80 °C. Indeed, the PEO matrix, despite a high dielectric constant (ε = 8) which enhances the salt dissolution, suffers from a limitation of Li mobility. The Li is crown solvated by oxygen of the polymer chains whose motion is restricted by the polymer crystalline domains [13]. Several studies are working on improving performances by limiting the host polymer crystallinity for example with the addition of a plasticizer [14,15], ceramic fillers [16,[START_REF] Armand | Chapter 1: Polymer Electrolytes[END_REF] or nano-clay [START_REF] Kim | [END_REF]19]. Among these nano-clays, the lithium montmorillonite (Li-MMT) presents various interests like its low cost, its ability to transfer Li + and its layered structure which can intercalate polymer chains [START_REF] Kim | [END_REF]20]. The added plasticizer can also be a liquid electrolyte which, trapped into the host polymer network, increases the ionic conductivity as initially proposed by Feuillade et al [12,21,22]. The Li salt dissolution is then not necessarily provided by the polymer host and new polymer matrix can be investigated. For example, the poly(vinylidene fluoridehexafluoropropylene) (PVDF-HFP), widely used as binder in electrode composition, is not involved in the Li solvation [23] and is studied as GPE host due to its amorphous domains able to trap large amounts of liquid phase without mobility restriction [14,22,23]. To enhance safety and thermal stability, many groups started to use ionic liquids as solvent instead of standard carbonates ones due to their low vapor pressure and high thermal stability [24][25][26]. Ionic conductivities around 1 mS cm -1 can be achieved with these ternary electrolytes. The added lithium salt also plays an important role on the electrochemical performances. Nowadays, the salt used in commercial Li batteries is predominantly the LiPF6 but its low thermal stability (~ 55 °C) and poor resistance against chemicals and moisture motivated the development of new lithium salts. The most studied are the lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and the adjoining lithium bis(fluorosulfonyl)imide (LiFSI) which shows a higher conductivity in solution [27,28] and a better compatibility with Al current collector in the high potential region (when high purity is achieved [29]). For many years, low salt concentrations, inducing higher conductivities due to lower viscosities, have been considered as favorable [30,31]. However, an increasing number of recent studies reports the positive effect of higher salt concentration, mainly on the Li transference number and molecular interactions [32][33][34].

In this work, we report on the preparation of a new gel polymer electrolyte performing at room temperature. The GPE material is characterized from a physico-chemical and electrochemical point of view. Simultaneously, we develop an innovative battery design with an improved ratio of packaging to active material thickness. The synthesized GPE is finally integrated in a full LiCoO2/Li battery using the new battery design.

Experimental

Materials and samples preparation

Lithium bis(fluorosulfonyl)imide (LiFSI, > 99.9 %) is purchased from Suzhou Fluolyte Co. Npropyl-N-methylpyrrolidinium bis(fluorosulfonyl)imide (PYR13FSI, 99.9 %) is purchased from Solvionic (Figure 1a). Cloisite Na + (Na-MMT) is purchased from BYK-Chemie. Poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP, SOLEF 21216) is kindly supplied by Solvay. The GPE electrolyte is composed of a binary liquid solution (PYR13FSI and LiFSI), a PVDF-HFP as host polymer and a modified phyllosilicate clay as reinforcing filler. Firstly, the liquid binary solution, consisting of LiFSI dissolved in PYR13FSI, with a LiFSI: Pyr13FSI molar ratio of The GPE membrane is then deposited by spray technique. The substrate is aligned on a plate heated at 80 °C. The flow rate through the spray nozzle is fixed at around 10 mL min -1 , the speed of the spray head at 40 cm s -1 and the atomization is obtained thanks to two lateral air jets with a pressure of 7 bar. The spray coating is realized by alternating deposition and drying steps (20 s) to allow the GPE deposit densification. These steps are repeated until a deposited mass of about 40 mg cm -2 is achieved which corresponds to about 80 to 100 deposition steps. To limit the clay decantation prior to spray, a fluid dispensing system with a reduced tank volume (10 mL) is used. Thus, this tank is refilled two times during the GPE deposition. At the end of the process, GPE films are dried under vacuum at 45 °C during one night. Solid membranes are obtained where the liquid phase (ensuring the electrochemical properties) is trapped in the PVDF-HFP polymer host that provides the mechanical properties with the support of the Li-MMT clay platelets scattered in the GPE.

For material characterizations (SEM images, Arrhenius plots, etc.), standalone membranes are formed by deposition on aluminum foil following by a GPE detachment. The obtained membranes are between 250 and 300 µm thick.

For battery integration, GPE is directly deposited on cathode material. The cathode consists of a LiCoO2 coating (96 wt% of LiCoO2, 2 wt% of carbon and 2 wt% of PVDF) deposited on aluminum foil by standard doctor blade method. The electrode loading is about 14 mg cm -2 which corresponds to a theoretical capacity is 1 mAh cm -2 . The GPE precursor solution being diluted with acetone, its viscosity is decreased and allows a good impregnation into the cathode pores. The GPE/LiCoO2/Al foil stack is then cut into 19×19 mm samples to be integrated in the new battery design.

New battery design description

The new battery design is mainly distinguished by the use of a copper foil acting both as current collector and as packaging allowing the overall battery thickness decrease. This new battery design is described in

Morphological, thermal and mechanical characterizations

The surface morphology and thickness of the GPE are observed using a Hitachi 4100 scanning electron microscope (SEM).

Thermogravimetric analyses (TGA) were carried out under air atmosphere using a Setaram SetSys equipment for GPE material or argon atmosphere using a Netzch STA449 F1 Jupiter equipment for the neat material. Thermal gradient is fixed at 5 °C min -1 . The degradation temperature (Td) is defined as the temperature of 1 wt% loss for the considering degradation. The onset temperature (Ton) is defined as the point of intersection of the slopes at the beginning and the end of the degradation as described in Figure S1 (supplementary file).

Conduction and Electrochemical measurements

Results and Discussion

GPE characterizations

The thermograms of the as synthesized GPE and neat materials, related degradation and onset temperatures (Td and Ton) are shown in Figure 2a. Considering that the GPE characterization is done under ambient atmosphere, the first loss below 100 °C is attributed to the water adsorbed during sample preparation and characterization and is not relevant.

The first significant loss occurs around 141 °C and is attributed to the beginning of the LiFSI decomposition. In the literature, the thermal behavior of the LiFSI salt is still deeply discussed. Its degradation temperature generally varies from 160 to 200 °C depending on the determination method (1 wt% or 5 wt% mass loss considering, static or dynamic thermal conditions, etc.) [29,[START_REF] Kerner | [END_REF]. Kubota et al [37] even reported a degradation temperature lower than 70 °C under static conditions. Beyond the determination methods, these variations are also attributed to composition and purity variations. The thermogram of our neat LiFSI (dash orange curve in Figure 2a) exhibits a two stages decomposition with a first loss at 179 °C and a second one around 308 °C (Ton), close to those observed by Kerner et al [START_REF] Kerner | [END_REF] and also evidenced in the liquid solution curve (dash dot green curve in Figure 2a). The LiFSI decomposition temperature in the GPE is slightly lower than the neat material one (179 °C) but close to the one observed in the liquid solution Pyr13FSI+LiFSI (140 °C). However, the decomposition kinetic seems to be increased since the mass loss occurred in a restricted temperature range. This could be explained by a confinement effect that leads to a liquid repartition in many little volumes split in the polymer matrix instead of a large unitary volume for the neat materials (LiFSI or liquid solution). The second major mass loss in the GPE thermogram at 266 °C is attributed to the second step of the LiFSI degradation and the Pyr13FSI decomposition. The degradation temperature is also slightly decreased compared with the neat Pyr13FSI one (291 °C). The last mass loss at 431 °C corresponds to the PVDF-HFP decomposition. This value is close to the one reported in the literature [38]. The exact mass loss value of each decomposition step is hardly readable due to the superposition of the degradation phenomenon. However, at 600°C, the remaining mass is about 14 wt%.

SEM cross section view of the GPE deposited on a LiCoO2 cathode coating is presented in Figure 2b. The GPE is 290 µm thick formed by three distinct layers of about 90-100 µm. Each layer corresponds to the three spray deposition stages required by the tank refill as explained in the experimental part. A higher magnification focused on the GPE material is presented in the Figure 2b inset. It shows the presence of small particles (500-800 nm) which may corresponds to Li-MMT clay aggregates. The material seems to be dense within the layers but exhibits some porosity at layer interfaces.

The ionic conductivity measured at 25°C is 0.48 mS cm -1 which is close to the values reported in the literature for this type of electrolyte (0.4-2 mS cm -1 ) [39]. The Arrhenius plot (Figure 2c, EIS spectra in supplementary file Figure S2) exhibits a linear shape (R² 0.997) corresponding to the Arrhenius behavior described by the following equation:

=

With A the pre-exponential factor, R the perfect gaz constant and Ea the activation energy (J mol -1 ). This behavior is quite different from the expected one as a GPE usually exhibits a Vogel-Tammann-Fulcher behavior based on the free volume theory [40,41]. It can be explained by the high liquid phase content of our GPE where the Li mobility is not directly 12 correlated to the segmental motion [39]. The addition of Li-MMT clay, which provides an additional diffusion path for lithium, can also contribute to this unexpected behavior.

GPE electrochemical ability

The voltage-time profiles of a Li symmetrical cell integrating the GPE are shown in Figure 3a and the maximum potential reached for each cycle in Figure 3b. For the lower current densities (0.04 and 0.08 mA cm -2 ), the maximum potential remains relatively stable upon cycling and a steady state is achieved at the end of each cycle. When the current density increases (0.4 mA cm -2 ), the steady state is no more achieved (no plateau at the end of each cycle) and the voltage-time curve shape is modified throughout cycling. An additional overpotential appears (inset in Figure 3a) indicating a dendritic lithium morphology as previously described by Best et al [42]. The dendrites formation increases the electrode surface area. This surface modification decreases the current density resulting in a maximum potential decrease evidenced in Figure 3b. The galvanostatic curve of the GPE integrated in a LiCoO2/Li cell is presented in Figure 3c. A slight polarization is visible at the beginning of the galvanostatic discharge. This polarization can be attributed to the relaxation after the 4.2 V constant voltage charge release and the GPE thickness (~ 290 µm). It does not allow the detection of the two LiCoO2 characteristic plateaus at high potential but the discharge curve shape remains close to the expected one for a LiCoO2 material [43,44]. The first discharge capacity is 1.06 mAh cm -2 , equal to the expected one. It drastically falls in the first cycles to stabilize around 0.5 mAh cm -2 and then slowly increases in the next cycles to reach 0.8 mAh cm -2 after 800 cycles. The discharge current of 0.35 mA is close to the current at which dendritic growth was observed during Li/Li cycling tests (Figure 3a). This dendritic growth phenomenon can be amplified by the coin cell geometry. Indeed, the GPE membrane is quite thick (~290 µm) and assumed to be highly pressed during the sealing of the coin cell. Its properties may be altered by this substantial compression. However, despite this unusual evolution, the system is able to achieve more than 800 cycles with a remaining capacity of more than 80 % of the initial one at room temperature that is quite promising. This high compression issue can be confirmed and solved by the integration in our new battery design.

GPE integration in new battery design

The GPE is integrated in the new Li metal battery with a LiCoO2 cathode material. The overall battery thickness is low, as shown in Figure 4a compared to a 2 centimes coin, 360 µm and 760 µm for the single side and double-sided architectures respectively. The association of the GPE and copper new battery packaging allows a high flexibility (bend radius up to 10 mm) and this new battery design still works under high bending constraint as seen in Figure 4b. Li-MMT (Figure 2b), are noticeable. After cycling, the GPE morphology is modified with the appearance of flakes not evidenced in the initial sample (before cycling) showing a modification of the GPE material upon cycling. Moreover, there is less load effects during the SEM observations meaning that electrons removal is easier and indicating a higher electronic conductivity of the observed sample. This result is consistent with the better cycling ability at higher current considering that the current increase hides the electronic conductivity rise.

However, this electronic conductivity rise is detrimental for the long term cycling and the coulombic efficiency and have to be solved. Further experiments are scheduled (XPS, deeper SEM observations, etc.) to elucidate this phenomenon.

The evolution of the impedance spectra is shown in Figure 5d. The spectra shape of singleside and double-sided architectures are close. The R0 value is attributed to the electrolyte resistance (contact resistance being neglected) and slowly decreases upon cycling. This decrease can be attributed to a surface increase resulting from a lithium dendritic growth as predicted by the Li symmetrical cell cycling. The first semi-circle in the middle high frequency domain is slightly flatten, mainly for the single-side architecture, and can comprise two contributions. In a first approach, we will consider it as a single one. For the single-side architecture, the characteristic frequency (fc) is 8.9 kHz, close to the 8 kHz reported in the literature for a polymer-Li interface [45]. For the double-sided architecture, the characteristic frequency (fc) largely decreases (1.9 kHz) indicating that the formed interface is quite different from the single-side architecture one, fc being independent of the surface and the thickness. The same observation is done for the second contribution in the medium frequency area with a decrease of the fc in the double-sided configuration (from 54 to 11

Hz). This loop represents the charge transfer of the LiCoO2 charge state. For both architectures, this second contribution tends to disappear with cycling progress but the fc remains quite constant. The first contribution corresponding to the Li/GPE interface increases upon cycling and a new contribution appears in the high frequency region. This contribution has been previously observed in a configuration without Li metal anode (''Lifree'') and is attributed to the LiCoO2/GPE interface (Supplementary file Figure S3). It means that the LiCoO2/GPE interface is formed and/or modified upon cycling and its resistance increases either by a thickness increase or by a composition modification. Post-mortem analyses by XPS are undergoing to confirm this hypothesis.

Conclusion

The studied GPE, composed of PVDF-HFP, LiFSI, Pyr13FSI and Li-MMT clay, exhibits a high thermal stability up to 140 °C and an ionic conductivity of 0.48 mS cm -1 at 25 °C, close to the state of the art for a GPE integrating ionic liquid based solvent. The discharge capacity of a LiCoO2/GPE/Li stack integrated in a coin cell system is 1 mAh cm -2 , equal to the theoretical one and remains high after more than 800 cycles (> 80 % of the initial capacity). However, the capacity evolution upon cycling is quite unusual with many disparities attributed to the high compression in the coin cell configuration, amplified by the important GPE thickness (290 µm). The new Li-ion metal battery design limits the compression phenomenon. The dual role of the copper foil, acting both as a current collector and a casing, allows to drastically decrease the part of the packaging in the overall cell volume compared to standard pouch cell architecture. Thus, the total thickness of these cells is 360 and 760 µm for single-side and double-sided architectures respectively, GPE representing a large part of this thickness. This design is flexible and exhibits a good functioning under high bending constraint (10 mm bend radius). The cycling ability is good with a capacity retention higher than 85 % after more than 200 cycles regardless of the architecture. SEM images and EIS show an evolution of the membrane upon cycling suggesting a detrimental evolution of the GPE electronic properties and GPE/electrode interfaces. Studies are then in progress to improve the system by optimizing the GPE composition to stabilize the interfaces and its electronic properties. The GPE thickness also needs to be minimized while preserving the GPE mechanical and electronic properties that allow it to act as a separator. Nevertheless, this new battery design integrating an original Cu packaging and flexible GPE exhibits promising properties to merge with the new IoT specifications.

Figure 1 :

 1 Figure 1: a) Chemical Structures of Pyr13 + cation, FSI -anion and PDVF-HFP host polymer; b) Schematic exploded view of the new battery design (double-sided configuration); c) Image of the as-realized batteries.

  Figure 1b. The design can be realized in single side or doublesided architecture depending on the intended battery thickness and capacity. The battery is composed of Cu foils (12 µm, 25×25 mm out of connection tabs) and sealing rings (Tesa glue, 115 µm, 25×25 mm external size and 20×20 mm internal aperture) acting as airtight packaging. Sealing rings are fixed on Cu foils by thermal curing (120 °C). To improve the design reliability and avoid short circuits during the sealing process, a polypropylene (PP) ring (25 µm, 21.5×21.5 mm external size and 13×13 mm internal aperture) is added on the sealing ring. Li anode (Albemarle, 50 µm, 17×17 mm) is then pressed on the Cu foil in the center of the sealing ring. Two previously prepared GPE/LiCoO2/Al foil samples are aligned back to back and sandwiched between two Li anode/PP ring/sealing ring/Cu foil stacks. The assembly is then vacuum packed at 120 °C to ensure a good anode/cathode contact and achieve the airtight. The obtained batteries are shown in Figure 1c. The thickness is about 350-400 µm for the single side architecture and 600-750 µm for the double-sided ones. The overall size is 25×25 mm (out of connection tabs) with 2.89 cm² of active material surface.

  Ionic conductivity is determined by electrochemical impedance spectroscopy (Biologic VMP3 multichannel galvanostat/potentiostat, frequency range : 100 mHz-1 MHz, ∆V = 10 mV) on coin cells composed of two stainless steel disks separated by a 200 µm thick self-standing GPE membrane (16.5 mm diameter). Measurements are done in a temperature controlled climatic chamber between 25 and 80 °C (298-353 K). Due to the presence of the ionic liquid in the GPE, the ionic conductivity is increased and the Nyquist plot did not display any semicircle. The Nyquist plots are then adjusted with a simple equivalent circuit model composed of a resistance (R) and a constant phase element (CPE) in series representing the electrolyte resistance (Rel) (connection resistances being neglected) and the blocking electrodes respectively.Cycling ability is evaluated on Li symmetrical coin cells. Li electrodes (135 µm, Albemarle) and GPE membranes are cut into 12 mm and 14 mm disks respectively. Cells are cycled at various current densities from 0.04 to 0.4 mA cm -2 using a Biologic VMP3 multichannel galvanostat/potentiostat at room temperature, 100 cycles for each current density. The electrochemical performances of LiCoO2/GPE/Li stack are firstly evaluated on coin cell configuration. In this case, the diameter of Li anodes and LCO cathodes is 15.5 and 14 mm respectively. The electrodes are sandwiched between two stainless steel disks (15.8 x 0.5 mm) and the overall system is sealed into a coin cell (GELON, SS316) under a pressure of 500 psi.New battery design cycling ability is determined by long term cycling with potentiostatic charge (fitting with IoT application requirements), at 4.2 V during 2 h and galvanostatic discharge at various currents (from 1 to 4 mA) using a Biologic VMP3 multichannel galvanostat/potentiostat. Electrochemical impedance spectrum are recorded at 4.2 V for each cycle (100 mHz-1 MHz, ∆V = 10 mV). Characteristic frequency and resistance of each contribution are graphically determined.

Figure 2 :

 2 Figure 2: TGA of the neat materials and the as-synthesized GPE and related degradation and onset temperatures (a); cross section SEM view of a GPE/LiCoO2/Al stack (b); Arrhenius plot and fitting of the as-synthesized GPE (c).

Figure 3 :

 3 Figure 3: Voltage-time profiles of Li symmetric cell integrating GPE, 100 cycles at 0.04, 0.08 and 0.4 mA cm -2 (a) and associated maximum reached potential at each cycle for the various current densities (b); First cycle discharge curve of a LiCoO2/GPE/Li coin cell (c) and cycling ability upon potentiostatic charge 4.2 V 2 h and galvanostatic discharge 0.35 mA cm -2 (c, inset).

Figure 4 :

 4 Figure 4: Single-side new battery design beside a 2 centimes coin (a); Double-sided battery working under high bending constraint (10 mm bend radius) (b).

Figure 5 :

 5 Figure 5: Galvanostatic discharge curves of a double-sided architecture for various currents (25 °C) (a); Cross section SEM images of a GPE before and after cycling (b); Cycling ability of LiCoO2/GPE/Li new design batteries in single-side (orange curves) or double-sided (green curves) architectures (charge at 4.2 V 2 h, galvanostatic discharge at 1 mA, 25 °C) (c) and charge state (4.2 V) batteries impedance spectra at various cycles (d).

Acknowledgements

Authors thank Florence Rouillon and Benjamin Amestoy (CEA/LITEN/DEHT) for their technical expertise on electrode fabrication process and access to their facilities.

Financial support for this work was provided through the EnSO project. EnSO has been accepted for funding within the Electronic Components and Systems For European Leadership Joint Undertaking in collaboration with the European Union's H2020 Framework Program (H2020/2014-2020) and National Authorities, under grant agreement n° 692482.


MD Romain Chopard
email: chopardromain@yahoo.fr

PhD Marc Badoz

MD Charly Eveno

MD Fiona Ecarnot

PhD Nicolas Falvo

MD Elsa Kalbacher

MD Gilles Capellier

PhD Benoit Guillon

MD François Schiele

PhD Nicolas Meneveau

Early prescription of direct oral anticoagulant for the treatment of intermediate-high risk pulmonary embolism: a multi-center, observational cohort study

Keywords: pulmonary embolism, direct oral anticoagulant, right ventricular dysfunction, cardiac biomarkers pulmonary embolism, direct oral anticoagulant, outcomes

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Highlights:

-One third of intermediate-high risk PE patients treated with DOAC receive them early -The rate of outcomes in patient receiving a DOAC early after admission was low -Early DOAC pts were discharged earlier -Adverse outcome rates were similar between groups.

Graphical Abstract 34

Introduction

The European Society of Cardiology (ESC) guidelines stratify a sub-group of hemodynamically stable pulmonary embolism (PE) patients with right ventricular (RV) dysfunction and elevation of troponin stratified as intermediate-high risk [START_REF] Konstantinides | ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)[END_REF]. This PE category has 30-day mortality of 3.0% and most adverse events occur within the first 72 hours [START_REF] Meyer | Fibrinolysis for patients with intermediate-risk pulmonary embolism[END_REF]. Direct oral anticoagulants (DOACs) have demonstrated a better safety profile than the standard low molecular weight heparin (LMWH)/warfarin regimen [START_REF] Gomez-Outes | Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis[END_REF]. The factor X-inhibitors rivaroxaban and apixaban were tested with a single-drug approach, do not require parenteral anticoagulation, and were associated with shorter hospital stay [START_REF] Agnelli | Oral apixaban for the treatment of acute venous thromboembolism[END_REF][START_REF] Investigators | Oral rivaroxaban for symptomatic venous thromboembolism[END_REF][START_REF] Badreldin | Hospital length of stay in patients initiated on direct oral anticoagulants versus warfarin for venous thromboembolism: a real-world single-center study[END_REF].

The utility of initial high dose rivaroxaban and apixaban to prevent early venous thromboembolism (VTE) recurrence in intermediate-high risk PE was not evaluated in randomized trials [START_REF] Agnelli | Oral apixaban for the treatment of acute venous thromboembolism[END_REF][START_REF] Investigators | Oral rivaroxaban for symptomatic venous thromboembolism[END_REF]. Accordingly, and given the potential need for thrombolysis if hemodynamic failure occurs, practice guidelines recommend initial parenteral anticoagulation for at least 3 days in intermediate-high risk PE [START_REF] Konstantinides | ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)[END_REF].

The aim of this pilot study was to describe 30-day outcomes of intermediate-high risk patients receiving rivaroxaban or apixaban within the first 72 hours. We also compared these patients to those treated with the guidelines-defined delayed DOAC approach.

Material and methods

This cohort study is a non-interventional retrospective post-hoc analysis based on prospectively collected data from 7 French centers, including two tertiary care facilities and five general hospitals, and recorded in the BFC-FRANCE registry [START_REF] Meneveau | Long-term prognostic value of residual pulmonary vascular obstruction at discharge in patients with intermediate-to high-risk pulmonary embolism[END_REF]. We report the study methods and results in accordance with the STrengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines [START_REF] Elm | The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies[END_REF]. In accordance with current French legislation, informed consent was not required for the analysis of patient data, because the study did not modify diagnostic or therapeutic strategies. The study received approval from the National the national commission for data privacy and protection (CNIL) (under the number 917 149).

Patients, setting, and participants

We screened patients who were admitted between September 2012 and November 2019 at 7 cooperating centers. Inclusion criteria were: (1) consecutive patients aged 18 years or older with a diagnosis of PE confirmed by computed tomography pulmonary angiography or ventilation-perfusion scan. For confirmation of the diagnosis of PE, we required an intraluminal filling defect on CTPA [START_REF] Remy-Jardin | Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the single-breath-hold technique--comparison with pulmonary angiography[END_REF]; or a high probability V-Q scan according to the criteria of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) [START_REF] Investigators | Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED)[END_REF]; (2) PE stratified as intermediate-high risk according to the 2019 ESC guidelines including hemodynamic stability (systolic blood pressure > 90 mmHg and no sign of end-organ hypoperfusion), simplified Pulmonary Embolism Severity Index (sPESI) score ≥1, elevation of troponin and RV dysfunction on transthoracic echocardiography (TTE) performed at admission [START_REF] Konstantinides | ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)[END_REF]; and (3) patients had to have received treatment with apixaban or rivaroxaban during the in-hospital course. sPESI score was assessed as previously described (1 point for each of the following: age >80 years, systolic blood <100 mmHg, heart rate ≥110 beats per minute (bpm), oxygen saturation <90%, history of cancer, congestive heart failure or pulmonary diseases) [START_REF] Jimenez | Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism[END_REF]. Different assays for troponin I measurement were used over time (ACS:180 before 2014, and Elecsys thereafter, ROCHE, Basel, Switzerland). Cardiac troponin elevation was defined as a value above the 99th percentile of healthy subjects with a coefficient of variation of 10% for the test used. Transthoracic echography was performed in routine practice at least at admission and at 48 hours.

Right ventricle dysfunction was defined by the presence of at least one of the following on echography: increased end-diastolic RV/left ventricle (LV) diameter ≥ 1.0 in the apical fourchamber view, Flattened intraventricular septum, decrease tricuspid annular plane systolic (TAPSE) excursion < 16 mm, or right heart thrombus detected in right heart cavities [START_REF] Konstantinides | ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)[END_REF].

Data collection

All sites followed a standardized protocol, as previously described [START_REF] Meneveau | Long-term prognostic value of residual pulmonary vascular obstruction at discharge in patients with intermediate-to high-risk pulmonary embolism[END_REF]. Baseline characteristics, in-hospital therapies and adverse events were prospectively recorded by research physicians.

One month after diagnosis, patients returned to the hospital for a follow-up visit. If the patient failed to attend (12.0%), the following sequential procedure was followed: telephone interview with the patient (or family), consultation of hospitalization records since discharge, telephone contact with the patient's physicians, consultation of the national death registry.

Vascular disease included coronary artery disease, stroke, or peripheral arterial disease.

Active cancer was defined by a cancer being treated, symptomatic, or palliated within the last 6 months. Bleeding risk was estimated with the modified HAS-BLED score [START_REF] Bassand | Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF[END_REF]. .

Early versus delayed DOAC prescription

Early DOAC prescription with apixaban (Bristol-Myers Squibb/Pfizer, New-York, USA) or rivaroxaban (Bayer HealthCare AG, Leverkusen, Germany) was defined as prescription <72 hours after admission, either without heparin or after a short lead-in period with heparin (early DOAC group). Delayed DOAC was defined as prescription at 72 hours or beyond (delayed DOAC group). Participation to the study was not supposed to change the therapeutic approach in any way, and management of acute PE was at the discretion of the physicians in charge.

The study period encompassed September 2012 through November 2019. We chose September 2012 as the starting point of this study as it corresponded to the launch date of the direct inhibitor of activated factor X rivaroxaban, the first DOAC to be approved on our national market for the dedicated indication of acute PE treatment. The direct inhibitor of activated factor X, apixaban, was authorized in this indication from April 2015 onwards (edoxaban (Daiichi Sankyo, Tokyo, Japan) and the direct inhibitor of activated factor II, dabigatran (Boehringer Ingelheim, Ingelheim am Rhein, Germany) were not approved for the treatment of acute PE in the market during the study period).

Outcomes and definitions

The primary efficacy outcome was a composite of all-cause death or hemodynamic decompensation at 30 days. Secondary efficacy outcomes at 30 days included a composite of PE-related death or hemodynamic decompensation, as well as recurrent VTE, length of hospital stay, and in-hospital recovery of RV function. The primary safety outcome was 30-day major bleeding. The secondary safety outcome at 30 days was clinically relevant non-major (CRNM) bleeding and Intra-cranial hemorrhage.

Hemodynamic decompensation was defined as presence of cardiogenic shock or sustained hypotension justifying advanced therapies including systemic thrombolysis, surgical embolectomy or extra-corporeal membrane oxygenation (ECMO). RV function recovery included absolute change in RV/left ventricle (LV) diastolic diameter ratio, systolic pulmonary artery pressure, (sPAP), and tricuspid annulus plane systolic excursion (TAPSE) assessed by trans-thoracic echocardiography (TTE) performed at admission and at 48 hours. Bleeding events were classified according to the International Society of Thrombosis and Haemostasis criteria [START_REF] Schulman | Subcommittee on Control of Anticoagulation of the, T. Standardization Committee of the International Society on, Haemostasis, Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients[END_REF]. All suspected outcome events were classified by a central adjudication committee (CE and FS) whose members were unaware of the DOAC strategy (i.e. early vs delayed). An independent data safety monitoring board periodically reviewed outcome. Disagreement was solved by a third author (RC).

Statistical analysis

Statistical analyses were performed according the SAMPL guidelines. Continuous variables are expressed as mean ± standard deviation (SD) when normally distributed, or median ± interquartile range if not normally distributed, and were analysed with the Student t test or Wilcoxon rank sum test as appropriate. Categorical variables are described as number (percentage) and were compared with the chi-square test or Fisher's exact test. The multivariable models included a missing indicator if a variable had more than 10% of missing values and the variable sites of care. To investigate the independent associations of various characteristics with the prescription or non-prescription of DOACs in the acute phase of intermediate-high risk PE, as well as the association with early and delayed DOAC prescription, we constructed a hierarchical modified Poisson regression models with robust error variance, adjusted for patient and practice-level characteristics. Covariates entered into the model were all baseline characteristics including socio-demographic, clinical and biological data and imaging findings. Because the rate of DOAC prescription exceeded 10%, we used modified Poisson regression at all steps to estimate relative prescription rates (relative risk, RR) with 95% confidence intervals (CI) directly (instead of odds ratios (OR) obtained from logistic regression, which may overestimate effect differences) [START_REF] Zou | A modified poisson regression approach to prospective studies with binary data[END_REF]. We compared 30-day primary clinical outcomes from patients treated with early versus those treated with guidelines-defined delayed DOAC prescription by using a logistic regression. Results are reported as OR with associated 95% CI. A p-value <0.05 was considered significant for the primary endpoint; all other analyses are exploratory [START_REF] Li | An introduction to multiplicity issues in clinical trials: the what, why, when and how[END_REF]. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Study sample

Among 2,411 patients admitted to participating centers with a confirmed diagnosis of PE during the study period, 653 (27.0%) were stratified as intermediate-high risk for early mortality according to the ESC guidelines. Among them, 351 (53.7%) did not receive a DOAC during the hospital stay, (249 patients (70.9%) received LMWH of whom 122 switched to vitamin K antagonist (VKA); and 102 patients (29.1%) received intra-venous unfractionated heparin followed by VKA) (mean age, 76.2 ± 13.9; 57.1% were women) (Table S1 in the supplementary material). Poisson regression adjustment identified active cancer (OR, 0.02; 95% CI, 0.007-0.08), renal function impairment (OR, 0.42, 95% CI 0.20-0.89) and prior vascular disease treated with an antiplatelet therapy (OR, 0.73, 95% CI 0.45-0.88) as being associated with the nonprescription of a DOAC during the hospital course. The rate of the primary end-point was higher in patients not treated with a DOAC as compared to those who received a DOAC during the hospital course, mainly driven by cancer-related death (Table S2, in the supplementary material).

The remaining 302 patients (46.2%) were treated with a DOAC between admission and discharge and composed the study population (mean age, 76.5 ± 13.6 years in average; 62.2% were women) (Figure 1). All the 302 patients included in the study population underwent a TTE at admission and at 48 hours.

Overall, 103 patients (34.2%; 95% CI, 28.8-39.8) were in the early group and 199 patients (65.8%; 95% CI, 60.1-71.1) were in the delayed group (Table 1 (all had heparin lead-in).

Patients in the early group were aged 75.8 ± 16.0 years in average; 63.1% were women (Table 1). The most frequent co-morbidities were coronary disease (20.4%) and prior VTE (26.2%). The primary outcome occurred in 5 out of 103 patients (4.8%; 95% CI, 1.6-10.9), including 1 death and 4 hemodynamic decompensations. The cause of death of the patient who died during the follow-up was infection. All 4 patients who developed hemodynamic decompensation in the early group received low dose systemic thrombolysis (50 mg of rt-PA), and did not experience any adverse events at 30 days. None of the 15 patients who received a DOAC without heparin lead-in experienced an adverse event during follow-up. The rate of secondary outcomes in the early group were: 1.0% (95% CI, 0.03-5.34) for recurrent VTE and 2.9% (95% CI, 0.6-8.3) for the composite of PE-related death or hemodynamic decompensation (Table 2). The length of hospital stay in this group was 6.0 ± 3.6 days (Figure 2). Normalization of RV function was observed by TTE for 95/103 patients (92.2%). Changes in RV function parameters in the early group are displayed in Figure 3. The rate of major bleeding was 2.9% (95% CI, 0.6-8.3) including no intra-cranial hemorrhage, and 3 patients experienced CRNM (Table 2).

Overall, patients in the early group and those in the delayed group did not differ significantly in terms of demographic data, pre-existing medical conditions, and in terms of relevant hospital parameters. The HAS-BLED and the sPESI scores, as well as the Charlson comorbidities index were similar between groups (Table 1). Site of care, outpatient vs inpatient, and conventional ward vs intensive care unit were similar between groups.

In total, 23/302 patients (7.6%; 95% CI, 4.8-11.2%) died or suffer from a hemodynamic decompensation during the first month of follow-up (i.e., primary efficacy outcome). The rate of 30-day all-cause mortality was 2.6% (95% CI, 1.1-5.1) (8/302 patients)). Pulmonary embolism (definite (n=5) or possible (n=1)) was the primary cause of death (75.0%) followed by infection (12.5%), and bleeding (12.5%). All the 15 hemodynamic decompensations (4.9%, 95% CI 2.8-8.0%) were treated with systemic thrombolysis without used of surgical embolectomy or ECMO. Recurrent VTE was observed for 1.3% of patients (95% CI, 0.3-3.3%) (4/302 patients) (Table 2). The mean length of hospital stay was 7.2 ± 1.3 days (Figure 2). The average changes in RV/LV diameter ratio, in sPAP, and in TAPSE between two TTE performed at admission and at 48 hours were -0.29 ± 0.12 mm, -18.3 ± 4.4 mmHg, and +2.9 ± 1.1 mm, respectively (Figure 3). The rates of safety outcomes were 3.0% (95% CI, 1.4-5.6%) (9/302 patients) for major bleeding at 30 days (i.e., primary safety outcome), and 2.0% (95% CI, 0.7-4.3) (6/302 patients) for CRNM bleeding at 30 days. One intra-cranial hemorrhage (0.3%; 95% CI, 0.01-1.8) occurred within the first month of follow-up (Table 2).

In univariate analysis, male sex, age (per quartile), saddle PE, and systolic blood pressure at admission were significantly associated with the primary composite outcome all-cause death or hemodynamic decompensation (Table 3). The relative risk for early DOAC prescription regarding the occurrence of the primary outcome in univariate analysis was 0.38 (95% CI, 0.11-1.38) (Table 3). The rate of the primary efficacy outcome was numerically higher in the delayed group as compared to the early group but without reaching statistical significance after multivariable adjustment (4.8% vs 9.0%; absolute difference, 4.2%; OR, 0.44 (95% CI 0.15-1.30)). Secondary clinical efficacy outcomes, including the composite of PE-related death and hemodynamic decompensation, as well as recurrent VTE, were numerically similar between both groups (Table 2). The adjusted length of stay was numerically lower in the early group (Figure 2). In total, 180/199 patients had RV function recovery in the delayed group (90.4%, p = 0.65 vs early DOAC group). Overall, no patient had clinical signs of pre-existing chronic thromboembolic pulmonary hypertension on TTE at admission. We did not observe any difference in RV function recovery between groups (Figure 3). There was no significant difference in primary safety outcome (OR, 0.99; 95% CI 0.45-2.18) or secondary safety outcome between both groups (Table 2).

Discussion

In the present cohort study, we observed that a DOAC strategy using apixaban or rivaroxaban is prescribed earlier than the guidelines-defined 3 days starting points in a third of patients with acute intermediate-risk PE treated with a DOAC. The rate of outcomes in patients receiving a DOAC earlier after admission was low. Patients in the early group were discharged earlier, with similarly low rates of death and bleeding, and similar RV function recovery compared to the delayed strategy. These results suggest that, if a DOAC is selected by the physician in charge (mainly due to the absence of associated cancer, renal dysfunction, or concomitant antiplatelet therapy), it may be prescribed within the first 72 hours after admission without incurring an excess risk of adverse events. Nevertheless, our results should be interpreted as a pilot study, and deserve confirmation in randomized trials.

To the best of our knowledge, our cohort study is the first to describe prescription practices and outcomes in patients with acute intermediate-high risk PE receiving early apixaban or rivaroxaban. The post hoc analysis of the HOKUSAI-VTE was currently the only study reporting the effectiveness of the LMWH followed by edoxaban in intermediate-high risk PE as compared to the warfarin regimen [START_REF] Brekelmans | Recurrent venous thromboembolism in patients with pulmonary embolism and right ventricular dysfunction: a post-hoc analysis of the Hokusai-VTE study[END_REF]. However, most of the information needed to classify the intermediate-high risk PE patients was not available, weakening the interpretation of this study.

Thrombolysis is often administered with LMWH [START_REF] Jerjes-Sanchez | Improving adjunctive treatment in pulmonary embolism and fibrinolytic therapy. The role of enoxaparin and weight-adjusted unfractionated heparin[END_REF], and there are some arguments to support the hypothesis that rt-PA could also be used with DOACs. Indeed, apixaban and rivaroxaban share several characteristics with parenteral anticoagulants, such as factor Xa activity, lower risk of major bleeding versus heparin [START_REF] Cossette | Evaluation of bleeding risk in patients exposed to therapeutic unfractionated or low-molecular-weight heparin: a cohort study in the context of a quality improvement initiative[END_REF], and the lack of a reversal agent [START_REF] Connolly | Investigators, Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors[END_REF].

Nevertheless, Sharifi et al reported no bleeding in a retrospective study of 159 PE patients treated with low dose rt-PA followed by a DOAC [START_REF] Sharifi | Safe-dose thrombolysis plus rivaroxaban for moderate and severe pulmonary embolism: drip, drug, and discharge[END_REF]. The ongoing PEITHO-2 trial is investigating whether treatment of intermediate-high risk PE with parenteral heparin over the first 72 hours, followed by dabigatran is effective, but this trial is not designed to evaluate the safety of thrombolysis in PE patients treated with DOAC [START_REF] Klok | Dabigatran after Short Heparin Anticoagulation for Acute Intermediate-Risk Pulmonary Embolism: Rationale and Design of the Single-Arm PEITHO-2 Study[END_REF].

Our study suffers from several limitations. First, the sample size is relatively small (n = 302), and consequently, may be underpowered to demonstrate a statistical difference in terms of outcomes between the early and delayed DOAC groups. Second, the study design could introduce some selection bias as we focused on intermediate-high risk PE patients treated with a DOAC during the in-hospital course. Indeed, we observed a higher rate of adverse events, especially cancer-related death, in patients who were not treated with a DOAC for intermediate-high risk PE. Patients not treated with a DOAC during the hospital stay were more likely to have active cancer, renal dysfunction and to be treated with concomitant antiplatelet therapy. In this context, prior studies have shown that: (1) cancer-associated VTE patients treated with anticoagulants are at 3-fold higher risk of VTE recurrence, and at 2-to 6-fold higher risk of bleeding [START_REF] Klok | Dabigatran after Short Heparin Anticoagulation for Acute Intermediate-Risk Pulmonary Embolism: Rationale and Design of the Single-Arm PEITHO-2 Study[END_REF]; (2) renal dysfunction was an independent predictor of 30-day mortality in PE patients (hazard ratio, 1.6, 95% CI, 1.2-2.1) [START_REF] Mahe | Long-Term Anticoagulant Therapy of Patients with Venous Thromboembolism. What Are the Practices?[END_REF]; and (3) concomitant antiplatelet therapy increased the risk of bleeding in patients treated with an oral anticoagulant [23]. Third, assessment of RV dysfunction on TTE was not centralized in a core laboratory, leading to some potential for misinterpretation of TTE data. Finally, we were unable to identify factors associated with early DOAC prescription despite investigating many confounders in a multivariable model. However, this does not exclude the possibility of hidden confounding. It is likely that the main cause of delay in DOAC prescription was the physician's concern about hemodynamic decompensation or bleeding risk. A previous study showed that a delay in the initiation of oral anticoagulant therapy may be associated with a poor prognosis [START_REF] Mahe | Long-Term Anticoagulant Therapy of Patients with Venous Thromboembolism. What Are the Practices?[END_REF]. Further studies are warranted to better define the profile of patients who may benefit from early DOAC prescription, likely by developing a specific scoring system.

Conclusions

In conclusion, the rate of outcomes at 30 days was low in patients receiving a DOAC within 72 hours after admission Patients in the early DOAC group had a shorter length of stay, with similarly low rates of death and bleeding, and similar RV function recovery compared to the delayed strategy. Our results should be interpreted as a pilot study, and deserve confirmation in randomized trials.

Figure 1 :

 1 Figure 1: Patient flow diagram. PE: pulmonary embolism; DOAC: direct oral anticoagulant;

Figure 2 :Figure 3 :

 23 Figure 2: Bar-diagram of the length of hospital stay according to the anticoagulation regimen at

  ). Patients who received early DOAC prescription were treated with rivaroxaban in 83.8% and apixaban in 16.2%, vs 85.1% and 14.9% respectively in the delayed DOAC group. Median time to DOAC introduction was 36 hours [24-48] in the early group including 15 patients who received a DOAC first without heparin lead-in. Median time to DOAC introduction in the delayed group was 96 hours [72-120]

Table 1 :

 1 Baseline characteristics of the study population according to the prescription of direct oral anticoagulants (i.e., rivaroxaban, or, apixaban) < 72 hours after admission (either without heparin or after a short lead-in period with heparin) (early DOAC group), or at 72 hours or beyond after admission for the treatment of acute intermediate-high risk pulmonary embolism. Tricuspid annular plane systolic excursion; sPESI: simplified Pulmonary Embolism Severity Index; HAS-BLED: Hypertension-Abnormal renal and liver function-Stroke-Bleeding-Labile INR-Elderly-Drugs or alcohol.

		Early DOAC group	Delayed DOAC group
	Variables			P-value
		(n=103)	(n=199)
	Age, years	75.8 ± 16.0	77.3 ± 11.3	0.31
	Male (%)	38 (36.9)	77 (38.7)	0.73
	BMI	28.1 ± 6.1	27.0 ± 6.3	0. 43
	Sites of care			0.73
	University hospital #1	33 (32.0)	69 (34.7)
	University Hospital #2	25 (24.2)	49 (24.6)
	General hospital #1	12 (11.6)	20 (10.0)
	General hospital #2	10 (9.7)	14 (7.0)
	General hospital #3	10 (9.7)	23 (11.5)
	General hospital #4	7 (6.8)	15 (7.5)
	General hospital #5	6 (5.8)	9 (4.5)
	Co-morbidities (%)
	Diabetes	11 (10.7)	32 (16.1)	0.22
	Coronary disease	21 (20.4)	39 (19.6)	0.91
	Chronic pulmonary disease	13 (12.6)	32 (16.1)	0.52
	Prior vascular disease	30 (29.4)	47 (23.5)	0.10
	Active Cancer	1 (1.0)	3 (1.6)	0.88
	Neurocognitive disorder	7 (6.8)	5 (2.5)	0.13
	Prior VTE	27 (26.2)	40 (20.1)	0.33
	Prior bleeding	3 (2.9)	7 (3.5)	0.10
	Provoked PE	23 (22.3)	48 (24.1)	0.52
	Associated DVT (%)	39 (37.9)	104 (52.3)	0.051

DOAC: direct oral anticoagulant; BMI: body mass index; VTE: venous thromboembolic; DVT: deep vein thrombosis; PE: pulmonary embolism; HR: heart rate; SBP: systolic blood pressure; RV: right ventricle; LV: left ventricle; sPAP: systolic pulmonary arterial pressure; TAPSE:

This registry-based study was funded, in part, by research grants from Bristol-Myers Squibb-Pfizer, Bayer, Boehringer-Ingelheim, and Daiichi Sankyo.