María Martín López

Nicolas Jamey

Alexis Pinet

Bruno Figadère

Laurent Ferrié

Oxidative Ring Expansion of Cyclobutanols: Access to Functionalized 1,2-Dioxanes

Cyclobutanols undergo an oxidative ring expansion with Co(acac) 2 and triplet oxygen to give 1,2-dioxanols. The formation of an alkoxy radical drives the regioselective cleavage of the ring on the more substituted side before insertion of molecular oxygen. The reaction is particularly effective on secondary cyclobutanols but works also on certain tertiary alcohols. Further substitution with neutral nucleophiles under catalytic Lewis acid conditions led to original 1,2-dioxanes with a preferred 3,6-cisconfiguration.

 Figure 1. 1,2-Dioxane natural products involved in total synthesis studies (In blue, isolated from sponges; in purple, from other marine species, in green, from plants; in brown from fungi). 1,2-Dioxanes are a particular example of endoperoxides, which can be found in many natural products. They are mainly isolated from various sponges but also from other marine species, plants, and fungi. 1 Most of natural dioxanes display anti-parasitic, antifungal, or cytotoxic activities. Although hundreds of these natural substances were reported with more or less variety in their structures, relatively few works were driven towards their total synthesis.

Many of these synthetic studies were targeting natural products isolated from marine species, and more specifically marine sponges. Indeed, sponges are known to be a tremendous pool for endoperoxides, and 1,2-dioxanes represent a large part of them. Nevertheless, other natural products with a 1,2dioxane scaffold, produced by other marine species, fungi or plants, were studied for their total synthesis. Indeed, synthetic works toward mycaperoxyde B, [START_REF] Silva | Towards the Total Synthesis of Mycaperoxide B: Probing Biosynthetic Rationale[END_REF] 9,10-dihydro-plakortin, [START_REF] Gemma | Synthesis of Dihydroplakortin, 6-Epi-Dihydroplakortin, and Their C10-Desethyl Analogues[END_REF] peroxyplakoric acid A3, [START_REF] Xu | Asymmetric Synthesis of 1,2-Dioxanes: Approaches to the Peroxyplakoric Acids[END_REF] peroxyacarnoate A&D, [START_REF] Xu | Total Synthesis of Peroxyacarnoates A and D: Metal-Mediated Couplings as a Convergent Approach to Polyunsaturated Peroxides[END_REF] graciloether A, [START_REF] Li | Enantioselective Total Syntheses of (+)-Hippolachnin A, (+)-Gracilioether A, (-)-Gracilioether E, and (-)-Gracilioether F[END_REF] diacarnoxide C, [START_REF] Schneider | Towards the Total Synthesis of the Norsesterterpene Diacarnoxide C[END_REF] plakortolide E, [START_REF] Jung | First Total Synthesis of Natural 6-Epiplakortolide E[END_REF][START_REF] Barnych | Total Synthesis of Seco-Plakortolide E and (-)-Ent-Plakortolide I: Absolute Configurational Revision of Natural Plakortolide I[END_REF] stolenoxides, [START_REF] Hu | Catalytic Enantioselective Peroxidation of α,β-Unsaturated Aldehydes for the Asymmetric Synthesis of Biologically Important Chiral Endoperoxides[END_REF] talaperoxides and other derivatives of the chamigrane family, [START_REF] Chen | Expeditious Entry to the Chamigrane Endoperoxide Family of Natural Products[END_REF] isoacetylsaturejone, 12 yingzahosu A 13,14 &C, 15,[START_REF] Boukouvalas | Concise Synthesis of Yingzhaosu C and Epi-Yingzhaosu C by Peroxyl Radical Cyclization. Assignment of Relative Configuration[END_REF] and steenkrotin B [START_REF] Xuan | Diastereoselective Synthesis of the Hydroperoxide-Keto Form of (±)-Steenkrotin B[END_REF] were accomplished using different strategies to build the key 1,2-dioxane ring (Figure 1). [START_REF] Terent'ev | Synthesis of Five-and Six-Membered Cyclic Organic Peroxides: Key Transformations into Peroxide Ring-Retaining Products[END_REF] These last years, our group was involved in a scientific program towards the total synthesis of mycangimycin, a polyunsaturated fatty acid containing an uncommon disubstituted 1,2-dioxolane ring. [START_REF] Oh | a Polyene Peroxide from a Mutualist Streptomyces Sp[END_REF] Our strategy was to build the endoperoxide through an oxidative ring expansion of a cyclopropanol to a 1,2-dioxolan-3-ol. [START_REF] Kulinkovich | Synthesis of α,β-Epoxy Ketones from Alkyl-and Arylsubstituted Cyclopropanols[END_REF][START_REF] Nguyen | Synthesis of 3,5-Disubstituted-1,2-Dioxolanes: Access to Analogues of Mycangimycin and Some Rearrangement Products[END_REF] We discovered that the corresponding acetate can react with various silylated nucleophiles through either Sakurai or Mukaiyama reactions, catalyzed by strong Lewis acids such as TiCl 4 or SnCl 4 in quasi-stoichiometric amounts. [START_REF] Pinet | Synthesis of 3,5-Disubstituted 1,2-Dioxolanes through the Use of Acetoxy Peroxyacetals[END_REF] The process was further improved by the use of milder catalysts, such as Sc(OTf) 3 or InCl 3 /TMSCl in catalytic amount, which allows one to run the reactions at room temperature with an expanded reagent scope (Scheme 1). [START_REF] Pinet | Access to Functionalized 3,5-Disubstituted 1,2-Dioxolanes under Mild Conditions through Indium(III) Chloride/Trimethylsilyl Chloride or Scandium(III) Triflate Catalysis[END_REF] Scheme 1. Oxidative ring expansion of strained cycloalkyl alcohols and further functionalization of the endoperoxyacetals.

On the basis of this work, we were wondering if we could apply this strategy to the synthesis of functionalized 1,2dioxanes. Indeed, Dussault earlier reported the nucleophilic substitution on 6-membered endoperoxyketal rings on 1,2dioxene derivatives in some pioneering studies. 24 In contrast, oxidative ring expansion of cyclobutanols under radical conditions was relatively unknown, and there was concerns that the difference of kinetics between cyclopropoxyl and cyclobutoxyl radicals, by analogy with the cyclopropylmethyl radicals [START_REF] Beckwith | Kinetics of Reactions of Cyclopropylcarbinyl Radicals and Alkoxycarbonyl Radicals Containing Stabilizing Substituents: Implications for Their Use as Radical Clocks[END_REF] and cyclobutylmethyl radicals, 26 might not allow the expected transformation in our favor. Nevertheless, a few examples of ring opening of cyclobutyloxyl radicals were reported in the literature, driving to the formation of 1,4diketones under oxidative conditions, [START_REF] Che | Intermolecular Oxidative Radical Addition to Aromatic Aldehydes: Direct Access to 1,4-and 1,5-Diketones via Silver-Catalyzed Ring-Opening Acylation of Cyclopropanols and Cyclobutanols[END_REF] or to 4-substituted ketone derivatives when the radical is trapped with some good radical acceptors. 28 It is also important to note that during the total synthesis of graciloether A, the last key step included a radical transformation of a particularly strained cyclobutane ring into a 1,2-dioxane (Scheme 1). [START_REF] Li | Enantioselective Total Syntheses of (+)-Hippolachnin A, (+)-Gracilioether A, (-)-Gracilioether E, and (-)-Gracilioether F[END_REF] To study the oxidative ring expansion of cyclobutanols into 1,2-dioxolan-3-ols, the desired starting materials were first prepared. For this purpose, we found that the most general route was based on a Wittig olefination of ketones or aldehydes 1a-f with a cyclopropyl ylide. Further epoxidation with m-CPBA provided unstable spiro-epoxycyclopropanes 3a-f, which were converted into cyclobutanones 4a-f through a pinacol rearrangement promoted by acid catalysis. 29 On one hand, further reduction with NaBH 4 gave cyclobutanols 5a-f as a mixture of diastereoisomers. Tertiary alcohols 6a-e were also synthesized, on the other hand, by addition of an organolithium or organomagnesium reagent onto cyclobutanones 4a-e (Scheme 2).

Scheme 2. Preparation of 2-substituted cyclobutanols 5a-f and 6a-e. Final yields over 4 steps.

A first investigation of the oxidative ring expansion of cyclobutanols was conducted on cyclobutanol 5a. This substrate was an excellent choice to start the study with, as a driving force of the C-C bond cleavage would be the stabilization of the new radical 29 into the intermediate opened product, and a benzene substituent could play perfectly this role. By using reported conditions for the oxidative ring expansion of cyclopropanols, [START_REF] Kulinkovich | Synthesis of α,β-Epoxy Ketones from Alkyl-and Arylsubstituted Cyclopropanols[END_REF][START_REF] Nguyen | Synthesis of 3,5-Disubstituted-1,2-Dioxolanes: Access to Analogues of Mycangimycin and Some Rearrangement Products[END_REF][START_REF] Pinet | Synthesis of 3,5-Disubstituted 1,2-Dioxolanes through the Use of Acetoxy Peroxyacetals[END_REF][START_REF] Pinet | Access to Functionalized 3,5-Disubstituted 1,2-Dioxolanes under Mild Conditions through Indium(III) Chloride/Trimethylsilyl Chloride or Scandium(III) Triflate Catalysis[END_REF] it was observed that cyclobutanol 5a did not react in presence of Mn(acac) 2 (Table 1, entries 1 and 2). Gratifyingly, Co(acac) 2 proved to promote strained cycle cleavage and be able to deliver a small amount of desired product over 48 h (Table 1, entry 3). Almost full conversion was attained with more cobalt salt (Table 1, entry 4), but yield was overestimated because of a large production of THF peroxide byproducts, which contaminated the desired product. These side-products were not observed, in contrast, on the ring expansion of cyclopropanols because of the fast scission process. To overcome this problem we switched THF for MeCN, which seemed inert to oxidation and allowed the transformation to occur, providing dioxane 7a in 61% yield after 48 h at room temperature (Table 1, entry 5). Increasing the temperature to 40 °C could decrease significantly the reaction time to 8 h improving the overall process (Table 1, entry 6). Using stoichiometric amount of cobalt(II) salt did not improve significantly the kinetic of the reaction, but lowered the yield due to the appearance of some degradations (Table 1, entry 7). Co(II) salt was essential to this reaction since starting directly from a source of Co(III) proved to be unproductive (Table 1, entry 8).

Oxidative ring expansion was then applied to other cyclobutanols 5b-f and 6a-e. Secondary alcohols 5b-f are, in general, best substrates for such a transformation. Indeed, the reaction works well, with 2,2-disubstituted cyclobutanols 5b-d and 5f, affording isolated yields above 60%. Mono-substituted cyclobutanol 7e were also able to undergo an oxidative ring extension but required a longer reaction time (up to 48 h). We also observed no reaction at room temperature with this last substrate, so heating was necessary in this case. Tertiary alcohols 6a-e were also examined, and first trials did not lead to good results. Mono-substituted cyclobutanols 6a and 6e gave unsatisfactory results: no conversion into dioxane 8e was observed from 6e. Isolation of diketone 9a and hydroxyketone 10a in 36% and 24% yield, respectively, from cyclobutanol 6a was experienced in place of dioxanol 8a. Isolation of these two unexpected products means the reaction was probably working but compound 8a might undergo a Kornblum-DeLamare rearrangement to form 9a in one hand, because the benzylic position facilitates an elimination process. In the other hand, hydroxyketone 10a might have been produced from 1,2-dioxane 8a by homolytic cleavage of the peroxide bond, but the exact pathway is for the while unclear. In contrast, it was found that 2,2-disubstituted cyclobutanols 5b-d and 5f were better substrates for an oxidative ring expansion. However, the rate of the reaction was slower compared to secondary alcohols derivatives 6b-d, affording the desired products in lower yields with sometimes recovery of unreacted starting materials. This observation was unexpected and might be attributed to steric hindrance for the formation of the cyclobutyloxy radical rather than a decrease of the kinetic of the radical scission. (Scheme 3). Scheme 3. Diverse attempts towards the synthesis of 1,2dioxan-6-ols 7b-g and 8a-e.

Although similar oxidation was reported in the literature, the exact mechanism has never been determined on how are formed peroxy radical species. [START_REF] Che | Intermolecular Oxidative Radical Addition to Aromatic Aldehydes: Direct Access to 1,4-and 1,5-Diketones via Silver-Catalyzed Ring-Opening Acylation of Cyclopropanols and Cyclobutanols[END_REF] It seems plausible that Co(II)(acac) 2 is reacting with oxygen to form a superoxocobalt(III) radical and a µ-peroxocobalt (III) species. [START_REF] Yoshino | Catalytic Oxidation of Alkylbenzenes with Molecular Oxygen under Normal Pressure and Temperature by N-Hydroxyphthalimide Combined with Co(OAc)2[END_REF] Indeed the reaction mixture, in presence of oxygen, turns rapidly from light brown color to intense green, which is a characteristic of Co(III) ions. As well, the inability of Co(III)(acac) 3 to promote the reaction, (Table 1, entry 8) indicates the crucial role of these oxocobalt(III) species. Alkoxy radicals are less stable than peroxy radicals by about 4 kJ/mol, [START_REF] Møller | Side-by-Side Comparison of Hydroperoxide and Corresponding Alcohol as Hydrogen-Bond Donors[END_REF] and by consequence makes hydrogen abstraction of a hydroxyl group from A an endothermic process. However the strain ring scission which follows, with stabilization of the radical at position 4, is highly exothermic, making the overall process highly favorable [about -71 KJ/mol for scission of trans-2-methylthylcyclobutyloxyl radical (determined by calculation at B3LYP/6-31+G(d,p) 32 level of theory]. Coordination of hydroxyl group to Co(III) species is also very plausible during the hydrogen abstraction step, facilitated by a directed process such as represented in B. Moreover, the observed difficulty applying the reaction to tertiary cyclobutanols is consistent with higher steric hindrance of these substrates, which strengthens the hypothesis of a coordination. Regioselectivity in the carbon-carbon bond cleavage to C is dependent of the ability of the new site to stabilize the new radical species. Therefore, this driving force explains some differences of reactivity between mono-and disubstituted cyclobutanols. A molecule of 3 O 2 is then trapped by the radical, making new peroxyradical D, which can evolve between the opened form E and the closed one F. One or the other form might abstract a hydrogen atom from a new cyclobutanol to propagate the reaction such as in path a or a cobalt(III)hydroperoxide species could reinitialize the process from the beginning such as in path b (Scheme 4). Scheme 4. Plausible mechanism of the cyclobutanol oxidative ring-expansion.

In order to prepare different 1,2-dioxanes, the so obtained 1,2-dioxanols 7a-g were then acylated using Yb(OTf) 3 as a Lewis acid catalyst to produce different acetate derivatives 11a-g. [START_REF] Pinet | Synthesis of 3,5-Disubstituted 1,2-Dioxolanes through the Use of Acetoxy Peroxyacetals[END_REF][START_REF] Pinet | Access to Functionalized 3,5-Disubstituted 1,2-Dioxolanes under Mild Conditions through Indium(III) Chloride/Trimethylsilyl Chloride or Scandium(III) Triflate Catalysis[END_REF] Further functionalization of these compounds was initiated with different silylated nucleophiles. The catalytic version of the nucleophilic substitution using Sc(OTf) 3 [START_REF] Pinet | Access to Functionalized 3,5-Disubstituted 1,2-Dioxolanes under Mild Conditions through Indium(III) Chloride/Trimethylsilyl Chloride or Scandium(III) Triflate Catalysis[END_REF] was chosen for this screening for a better convenience. The reac-tion of acetate 11e with allylTMS drove to compound 12 as a sole cis-product in 65% yield. In contrast, reaction of acetate 11e with TMS cyanide was less selective and gave product 13 with only a 65:35 cis:trans ratio, 33 while Mukayama aldol reaction with a ketene TMS-thioethylacetal furnished 1,2dioxane 14 with a quite good diastereoselectivity. The synthesis of allyl 1,2-dioxane 15 from 11a was achieved in poor yield due to an elimination process, which might take place more easily at the benzylic position, and produced many degradation products. [START_REF] Pinet | Synthesis of 3,5-Disubstituted 1,2-Dioxolanes through the Use of Acetoxy Peroxyacetals[END_REF] Sakurai reactions on acetate 11b produced compounds 16 and 17 with pretty good yields. Mukaiyama reaction on acetate 11b with silyl enol ether of acetophenone gave dioxane 18 in good yield, and a vinylogous process was also possible to produce 19 from TMS-siloxyfuran as a 2:1 mixture of diastereomers. 34 Reduction of acetal 11d with triethylsilane furnished compound 20 in moderate yield. With unsymmetrical dialkylated dioxanes 11c and 11d, the diasteroselectivity is not as good as with mono-substituted compounds, but generally a major isomer is observed such as in the synthesis of 1,2-dioxanes 21-24. Carbamate 7f proved to be unreactive under our used Lewis acid catalysis, due to Lewis base properties of the nitrogen function (Scheme 5).

The diastereoselectivity in this nucleophilic substitution leads to the 3,6-cis diastereomer as a major product, in an analogous manner to 4-substituted tetrahydropyranyl acetals. 35,[START_REF] Romero | Stereochemical Reversal of Nucleophilic Substitution Reactions Depending upon Substituent: Reactions of Heteroatom-Substituted Six-Membered-Ring Oxocarbenium Ions through Pseudoaxial Conformers[END_REF] If we consider dioxanyl acetate 11e for example, reaction with a Lewis acid drives to the formation of peroxycarbenium species, which adopt a half-chair like conformation (Scheme 6). [START_REF] Woods | Molecular Mechanical Investigations of the Properties of Oxocarbenium Ions. 2. Application to Glycoside Hydrolysis[END_REF] This species can evolve between conformations 27-eq and 27-ax, depending if the substituent is placed in axial or equatorial position. Because alkyl substituents prefer to adopt an equatorial position, the major reactive conformer must be 27-eq. A nucleophilic substitution takes then place preferentially to the axial position of the peroxycarbenium species, which lead 27-eq to compound 28cis. In contrast, diastereoselectivity is poorer from 6,6disubstituted-1,2-dioxannyl acetates where no high selective conformation of 27 could be adopted, excepted for 11c, which gave decent selectivities due to the bulky t-butyl group (75:25 and 85:15 selectivity for 23 and 24 respectively, Scheme 5) Scheme 5. Functionalization of 1,2-dioxanyl acetates 11a-g. Scheme 6. Rationalization of the observed selectivity towards the 3,6 cis-diasteroisomer in the nucleophilic substitution of 1,2-dioxanyl acetates.

In conclusion, we developed a new access to 1,2-dioxanes, by using an original approach involving an oxidative ring expansion of cyclobutanols under radical conditions. [START_REF] Martín López | Oxidative Ring Expansion of Cyclobutanols: Access to Functionalized 1,2-Dioxanes[END_REF] The oxidation is regioselective and its kinetic seems dependent of the ability of the substituents to stabilize an intermediate alkyl radical. The process seems to work particularly well with secondary alcohols even if specific examples of tertiary alcohols can also moderately work sometimes. Further functionalization was then achieved. For instance, the corresponding acetates 11a-g, by generating reactive peroxycarbenium species, react with neutral nucleophiles to afford expected 1,2dioxanes, preferentially as the 3,6-cis diastereoisomers. This new method is able to provide quickly functionalized 1,2dioxanes, which would be difficult to prepare by another method. Indeed, this approach would be very valuable for the synthesis of new endoperoxides, but in particular for the total synthesis of natural marine products containing a 1,2-dioxane moiety such as mycaperoxides, stolonoxides, dihydroxyplakortides, diacarnoxide C and many others, whose structures seem to correspond to potential targets for its use.

Table 1 . Screening of conditions for oxidative ring expan- sion of cyclobutanol 5a into 1,2-dioxane 7a.

 1

	Entry	Metal salt		(mol%)	Conditions	Solvant	Yield a (%)
	1	Mn(acac)	2	1	rt, 48h	THF	No reaction
	2	Mn(acac)	2	5	rt, 48h	THF	No reaction
	3	Co(acac) 2	1	rt, 24h	THF	23 b
	4	Co(acac) 2	5	rt, 48h	THF	84 b
	5	Co(acac) 2	5	rt, 48h	MeCN	61
	6	Co(acac) 2	5	40 °C, 8 h	MeCN	76
	7	Co(acac)2	100	rt	MeCN	56
	8	Co(acac) 3	5	rt, 48h	MeCN	traces

a Isolated yield as a 60:40 mixture of diastereomers.

b

Yield was overestimated because of THF peroxides byproducts contamination.

ACKNOWLEDGMENT

N. Jamey and A. Pinet thank the Ministère de l'Enseignement Superieur, de la Recherche et de l'Innovation (MESRI) for a PhD fellowship. M. Martín López thank the European Union for an Erasmus fellowship. We thank Nina Cooper (Université Paris-Saclay) for exploratory studies, Karine Leblanc for HRMS analysis (BioCIS, Châtenay-Malabry) and Jean-Christophe Jullian (BioCIS, Châtenay-Malabry) for NMR services.

ASSOCIATED CONTENT Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI. Experimental Procedures, characterization data, cartesian coordinates and energy diagram of trans-2-methylcyclobutoxyl radical, pentanal-4-yl radical and their transition state, and copies of 1 H and 13 C NMR spectra of all compounds. (PDF).

AUTHOR INFORMATION Corresponding Author

* E-mail: laurent.ferrie@universite-paris-saclay.fr ORCID Laurent Ferrié: 0000-0002-1171-205X Bruno Figadère: 0000-0003-4226-8489 Alexis Pinet: 0000-0003-1263-9824

Notes

The authors declare no competing financial interest.


MD MSc Patrick Blin
email: patrick.blin@u-bordeaux.fr

Charles-Marc M Samama

Alain Sautet

Jacques Benichou

S Lignot-Maleyran

Séverine Lignot- Maleyran

Stéphanie Lamarque

Simon Lorrain

Régis Lassalle

Cécile Droz-Perroteau

Patrick Mismetti

Nicholas Moore

replacement: A nationwide database cohort study

Keywords: Total hip replacement, total knee replacement, venous thromboembolism prevention, effectiveness, risk CI: confidence interval DOAC: Direct-acting oral anticoagulants DVT: deep vein thrombosis

published or not. The documents may come

Comparative effectiveness of direct oral anticoagulants versus low-molecular weight heparins for the prevention of venous thromboembolism after total hip or knee

Introduction

Thromboprophylaxis is recommended after major orthopedic surgery to prevent the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) (1)[START_REF] Geerts | Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)[END_REF][START_REF] Hill | Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance[END_REF]. Three direct oral anticoagulants (DOAC), apixaban 2.5 mg (bid), dabigatran 110 mg (bid), and rivaroxaban 10 mg (od), were granted an European market authorization for the prevention of venous thromboembolic events (VTE) in adults after elective total hip or knee replacement (THR, TKR). In randomized controlled trials, they showed non-inferiority or superiority to 40 mg of enoxaparin, a low-molecular weight heparin (LMWH) (4-9), without increasing major bleeding.

However, these clinical trials included a limited number of patients with too few symptomatic VTE to reach statistical power for comparisons. To overcome this limit, the primary efficacy outcome was defined as the composite of asymptomatic and symptomatic DVT, non-fatal PE and death from any cause, the clinical relevance of which is disputable in the face of a high ratio of asymptomatic DVT to symptomatic VTE [START_REF] Chan | Lack of consistency in the relationship between asymptomatic DVT detected by venography and symptomatic VTE in thromboprophylaxis trials[END_REF] and high rate of false positives from imaging performed for another reason. [START_REF] Kearon | Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines[END_REF] A meta-analysis of 16 trials of DOAC versus enoxaparin to assess symptomatic VTE after THR or TKR still had few events and wide 95% confidence intervals (95%CI) for each drug comparison [START_REF] Gomez-Outes | Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons[END_REF]. Furthermore, the impact of anticoagulant thromboprophylaxis in real-life is probably not the same when physician practice, patient characteristics, drug use and prescription, and care management are not standardized as they are in clinical trials [START_REF] Rothwell | External validity of randomised controlled trials: "to whom do the results of this trial apply?[END_REF][START_REF] Steg | External validity of clinical trials in acute myocardial infarction[END_REF]. Several real-world cohort studies using claims databases were published for other indications of DOAC, such as stroke prevention in atrial fibrillation [START_REF] Graham | Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation[END_REF][START_REF] Larsen | Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study[END_REF][START_REF] Maura | Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensity-matched cohort study[END_REF][START_REF] Yao | Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation[END_REF][START_REF] Blin | Comparative effectiveness and safety of standard or reduced dose dabigatran versus rivaroxaban in non-valvular atrial fibrillation[END_REF] or treatment of VTE [START_REF] Jun | Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study[END_REF], but only one was found for thromboprophylaxis after major orthopedic surgeries [START_REF] Rosencher | Dabigatran etexilate for thromboprophylaxis in over 5000 hip or knee replacement patients in a real-world clinical setting[END_REF]. The present study was designed to compare the risk of VTE, bleeding and death in clinical practice between all

Materials and methods

Research question and objectives

To compare the 3-months event rates of VTE, bleeding or death in patients treated with a DOAC or LMWH after total knee of hips replacements;

Design:

This was a high-dimensional propensity-score (hdPS) matched cohort study of all out-patients dispensed DOAC or LMWH during 3 months, after THR or TKR, in France from January 1, 2013 to September 30, 2014.

Study Setting

SNDS is the national healthcare data system in France. It links the nationwide mandatory public health insurance system claims database SNIIRAM, to the national hospital discharge database PMSI and to the national death registry CépiDC. It includes more than 99% of the French population (66 Million persons in 2013) from birth (or immigration) to death (or emigration), even if a subject changes occupation or retires, and irrespective of socioeconomic status. The SNDS contains individual pseudonymized information on all medical and paramedical encounters, drugs claims, hospital admissions and procedures, and date of death, that are linked to create a longitudinal record of outpatient health encounters, hospital diagnoses and drug dispensing. [START_REF] Bezin | The national healthcare system claims databases in France, SNIIRAM and EGB: Powerful tools for pharmacoepidemiology[END_REF] SNDS includes the hospital discharge summaries database, which includes all hospital discharge summaries from all private or public hospitals with main, associated and secondary diagnoses. Procedures are also recorded, as are the more expensive drugs or implantable devices.

Diagnoses may be identified from:

-Registration for long-term diseases (LTD, over 4000 ICD-10 codes) that warrant full healthcare coverage with no co-payment. This registration is requested by the patient's physicians (outpatient or hospital), and diagnoses are verified by the healthcare insurance system. Registration is not mandatory. It may be missing for instance if the medical expenses are already covered by another chronic disease or the treatment is not expensive. LTD concern background diseases and are not directly related to any individual medical encounter. They are therefore not used for outcomes, only for baseline patient description parameters.

-Hospital discharge diagnoses (main, associated, secondary), which will inform on the reason for admission (main), and on background risk modifiers (e.g., diabetes, renal failure, coronary heart disease) that modify the hospital costs. Associate diagnoses inform on reasons for procedures as main diagnosis. They also include disease related group (DRG) cost coding system, and most expensive drugs out of DRG cost. Diagnostic codes are input by the hospital physician in charge of the patient, assisted by professional coders. The quality of the coding is the object of regular internal and external audits, from within the Hospital information systems and fro the national healthcare system within the national accreditation process. When verified, the positive predictive values of the codes in the cardiovascular field were 85% or higher, improving over time. [START_REF] Bezin | Choice of ICD-10 codes for the identification of acute coronary syndrome in the French hospitalization database[END_REF][START_REF] Bosco-Lévy | Diagnostic accuracy of the international classification of disease 10th revision codes of heart failure in administrative database[END_REF][START_REF] Giroud | Positive Predictive Value of French Hospitalization Discharge Codes for Stroke and Transient Ischemic Attack[END_REF][START_REF] Gouverneur | Agreement between hospital discharge diagnosis codes and medical records to identify metastatic colorectal cancer and associated comorbidities in elderly patients[END_REF][START_REF] Prat | Positive predictive values of peripheral arterial and venous thrombosis codes in French hospital database[END_REF] -Drug, laboratory, imaging or other procedures, as outpatient or inpatient, whose combinations may be diagnostic. [START_REF] Bernard | Use of health insurance claim patterns to identify patients using nonsteroidal anti-inflammatory drugs for rheumatoid arthritis[END_REF] THR studies using SNDS have been published [START_REF] Beziz | Association between Exposure to Benzodiazepines and Related Drugs and Survivorship of Total Hip Replacement in Arthritis: A Population-Based Cohort Study of 246,940 Patients[END_REF][START_REF] Colas | Association Between Total Hip Replacement Characteristics and 3-Year Prosthetic Survivorship: A Population-Based Study[END_REF], as well as several studies with our major outcomes of interest [START_REF] Blin | Comparative effectiveness and safety of standard or reduced dose dabigatran versus rivaroxaban in non-valvular atrial fibrillation[END_REF][START_REF] Blin | Parkinson's disease incidence and prevalence assessment in France using the national healthcare insurance database[END_REF][START_REF] Blin | A population database study of outcomes associated with vitamin K antagonists in atrial fibrillation before DOAC[END_REF][START_REF] Blin | Insulin glargine and risk of cancer: a cohort study in the French National Healthcare Insurance Database[END_REF][START_REF] Weill | Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study[END_REF].

Study Subjects

All adult (age ≥ 18) patients who underwent THR or TKR in France between 1 st January 2013 and 30 th September 2014 were identified in SNDS, [START_REF] Bezin | The national healthcare system claims databases in France, SNIIRAM and EGB: Powerful tools for pharmacoepidemiology[END_REF] using diagnostic related groups (DRG) from hospitalization discharge summaries. Patients who were discharged to home with a dispensing of a DOAC (apixaban, dabigatran, rivaroxaban) or LMWH within a week after discharge, a 3-year look-back period before THR or TKR and a follow-up of three months were included in the cohorts. Patients admitted to a rehabilitation facility were not included because their drug prescriptions are not available in the database.

Chronic medical conditions, cardiovascular risk factors, previous and concomitant drug dispensings, and hospital admission diagnoses were collected over the three years previous to the index date. These baseline covariates were included in the propensity score.

Follow-up

Follow-up began at discharge, (index date) and continued until patient death, treatment switch to another anticoagulant, occurrence of an outcome of interest (for that outcome only), or the end of the study period (three months), whichever came first. There was no loss to follow-up.

Outcomes:

The primary effectiveness outcome was defined as a hospitalization with a main diagnosis of VTE (I801-9, I81, I82 ICD-10 codes for VTE, and I26 for PE). The primary safety outcome was hospitalization with a main diagnosis of bleeding (ICD-10 codes detailed in supplementary materials). For sensitivity analyses, broader definitions were used for both outcomes. For VTE, it took into account all hospitalizations with VTE as main or associated diagnosis, and non-hospitalized VTE defined as an anticoagulant switch (to DOAC, LMWH, Vitamin-K antagonist (VKA), fondaparinux) or dispensing of a higher dosage of DOAC, along (± 1 day) with medical imaging for DVT or PE (compression ultrasonography, venography, thoracic CT angiogram, lung scintigraphy). For bleeding, sensitivity analysis included all hospitalizations with main or associated diagnosis of bleeding.

Statistical analysis

The conditional probability to be treated by DOAC or LMWH was estimated using propensity scores for each type of surgery (THR and TKR) according to the following patient and disease characteristics at inclusion: age, gender, hospitalization duration, hospital category (university, public, private), bleeding diagnosis during hospitalization, hip, pelvis or leg fracture at index hospitalization, history of atrial fibrillation, other risk factors concerning at least 1% of patients in each group: history of cancer, active cancer (treatment ongoing within the year before THR or TKR), rheumatic disease, recent antithrombotic treatment (≤ 3 month before THR or TKR), oral contraception or hormone replacement therapy, antiplatelet agents (acetylsalicylic acid, clopidogrel, prasugrel or ticagrelor) in the week after discharge, acetylsalicylic acid during follow-up, as well as individual VTE and bleeding risk factors identified by the IMPROVE research group for hospitalized medical patients [START_REF] Decousus | Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators[END_REF][START_REF] Spyropoulos | Predictive and associative models to identify hospitalized medical patients at risk for VTE[END_REF]; VTE and bleeding IMPROVE risk score are presented in table 1 for descriptive purpose.

Propensity score distributions were examined to check the overlap between two groups before and after matching (see supplementary materials). DOAC patients were 1:1 matched to LMWH patients separately for THR and TKR, on gender, age and propensity scores using the Greedy method (without replacement) with a caliper of 0.2 of the standard deviation of the logit of the propensity scores [START_REF] Austin | Goodness-of-fit diagnostics for the propensity score model when estimating treatment effects using covariate adjustment with the propensity score[END_REF]. For each DOAC, apixaban, dabigatran and rivaroxaban, versus LMWH, patients were individually matched to LMWH patients with the same method and a ratio of 1:6, 1:3 and 1:1, respectively, to have approximately the same number of LMWH patients in each of the three comparisons.

Medical costs were calculated using total cost of the claims and mean cost from the national private and public hospital annual study of cost according to hospital stay group and diagnostic related group (collective perspective). Initial characteristics are presented for the matched DOAC and LMWH patients with standardized differences (expressed as a percentage). A standardized mean difference of 10% or less indicates a negligible difference between groups [START_REF] Austin | Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples[END_REF]. Absolute risk of each outcome was also calculated for all patients (supplementary material) and matched patients. The relative risk (RR) of each outcome and its 95% confidence interval (95%CI) was estimated using quasi-Poisson models for DOAC compared to LMWH. Statistical analysis was conducted using SAS ® software (Version 9.4, SAS Institute, North Carolina, USA).

Ethics

The protocol was reviewed and approved by the French health authorities (HAS), and received all legal authorizations from the National data-protection commission (CNIL). The study was registered with the EUPAS registry as 11521, conducted according to ENCePP guidance endorsed by the European Medicines Agency on best practices for conducting and reporting Post-authorization safety studies (PASS) using electronic healthcare data sets, and follow the STROBE guidelines.

Results

During the 21-month inclusion period, 227,034 THR and 161,724 TKR were identified in the SNDS database, and 97,646 and 49,235, respectively, were included in the THR and TKR cohorts (figure 1). The main reason for non-inclusion was transfer to a rehabilitation facility.

Other reasons included no anticoagulation or presence of other anticoagulants (unfractionated heparin, fondaparinux, vitamin K antagonists, or two or more anticoagulants) dispensed within a week after initial hospital discharge. A few patients died during index hospitalization or had probable DRG or main diagnosis miscoding (figure 1). For both surgical procedures, around one third of the patients received a DOAC, mostly rivaroxaban, followed by dabigatran and apixaban (66.7%, 22.5% and 10.8%, respectively), and two thirds were treated with LMWH, enoxaparin being the most commonly used, followed by tinzaparin, dalteparin and nadroparin (63.7%, 33.4%, 2.8% and 0.1%, respectively) (figure 1). For most patients (> 95%), DOAC and LMWH were dispensed on the day of discharge or the day after, with a an average of 30 days of Table 1). Almost all DOAC patients (≥ 99.8%) were individually matched to a LMWH patient, 31 619 for THR and 15 720 for TKR (figure 1).

The mean age of THR and TKR patients was 68.5 and 68.2 years, 50.6% and 53.0% were women, with a mean duration of hospital stay of 7.6 and 7.9 days, respectively. The median IMPROVE VTE risk score was 2 and bleeding risk score was 3.5 for both surgical procedures. For THR, patients in the DOAC group were younger than LMWH patients, more often male, with a slightly lower VTE and bleeding risk scores, mainly because of age difference, with one day more for the mean hospital stay duration, more often from private hospitals, while the differences between DOAC and LMWH were less marked for TKR patients (supplementary material). All these characteristics were very similar for the three DOAC (apixaban, dabigatran and rivaroxaban), except for more use of apixaban from public hospitalizations (supplementary material). After matching, DOAC and LMWH patients were well balanced for both THR and TKR populations with standardized differences below 5% for all variables (table 1) and good overlap of propensity scores distributions (supplementary material).

The absolute risk of VTE (hospitalization main diagnosis) for matched patients during the 3month follow-up after THR hospitalization discharge was significantly lower with DOAC than LMWH for THR (0.9‰ and 2.5‰, respectively), but not significantly for TKR (1.6‰ and 2.3‰, respectively) (table 2). Using hospitalized and non-hospitalized VTE criteria, results remained significant for THR and became significant for TKR (table 2). Absolute risk of individual events showed that PE represented about two thirds of VTE hospitalizations, and less than one third when hospitalized and non-hospitalized VTE were considered (supplementary material).

The absolute risk of hospitalized bleeding (hospitalization main diagnosis) during the 3month follow-up after TKR hospitalization discharge was also lower with DOAC than LMWH, not significantly for THR (1.8‰ and 2.1‰, respectively, HR 0.88 [0.62 to 1.25]) and significantly for TKR (2.4‰ and 3.8‰, respectively, HR 0.56 [0.43 to 0.73]) (table 2).

Major bleeding, using the ISTH definition [START_REF] Schulman | Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients[END_REF], represented more than half of bleeding hospitalizations for both treatment groups and both surgery procedures (supplementary material).

The risk of death was not significantly different between DOAC and LMWH for THR or TKR (table 2). For each individual DOAC, relative risks point estimates for VTE, hospitalized bleeding and death were similar to all DOAC pooled, but with wider 95%CI in relation with lower number of event and patients exposed, especially for apixaban (Table 2).

Mean medical cost was 28% lower with DOAC than LMWH for the 3 months after THR discharge (€1374 versus €1906), and 21% lower for TKR (€1808 and €2276), respectively.

The mean difference for THR was mainly from nursing (-€199, €82 versus €281), drugs (-€122, €283 versus €405), hospitalizations (-€89, €312 versus €401), lab tests (-€55, €29 versus €84), and transports to visit for medical or paramedical care (-€40, €91 versus €132); 70% of the total mean difference between DOAC and LMWH came from nursing, drugs and lab tests (37%, 23% and 10%, respectively), 17% from hospitalizations and 8% from medical transports (Figure 2). For TKR, the difference was mainly from nursing (-€183 €, €81 versus €264), drugs (-€109, €330 versus €439), medical transports (-€72, €281 versus €353), lab tests (-€49, €33 versus €82), and hospitalizations (-€27, €316 versus €443): 73% of the total mean difference between DOAC and LMWH came from nursing, drugs and lab tests (39%, 23% and 11%, respectively), 6% from hospitalizations and 15% from medical transports (Figure 2). On the other side, DOAC and LMWH average costs were similar for medical visits, physiotherapy, and other costs for both THR and TKR.

Discussion

This nationwide cohort study of about 100 000 THR and 50 000 TKR who returned home after discharge is the first large study comparing DOAC and LMWH for post-surgical thromboprophylaxis in a real-life setting. In patients sharing the same characteristics, it shows that the risk of hospitalized VTE within 3 months after hospital discharge for THR was 65% lower with DOAC than LMWH, without any increase of hospitalized bleeding risk or death, associated with a 28% medical cost saving. For TKR, the lower risk of VTE with DOAC was not significant, but associated with a 36% lower risk of hospitalized bleeding, no death increase, and 21% medical cost saving. Moreover, since the study included all patients in the country, one might consider the point estimates as sufficient to conclude that the risk of VTE, hospitalized bleeding and death for 3 months after discharge was lower with DOAC than with LMWH for THR (by 65%, 12% and 32%, respectively), and TKR (by 31%, 36% and 31%, respectively). These results are consistent with a recent network meta-analysis that concluded to a superiority of DOAC over LMWH. [START_REF] Kapoor | Comparative effectiveness of venous thromboembolism prophylaxis options for the patient undergoing total hip and knee replacement: a network meta-analysis[END_REF] SNDS is the nationwide healthcare claims and hospitalization database that covers 99% of the French population. It is fully representative of the French population. It provided the opportunity to identify all THR and TKR performed in France during the inclusion period with exhaustive information about public and private hospitalizations with high specificity of diagnosis for THR, TKR and outcomes, as well as reimbursed outpatient healthcare resources including reimbursed drugs. The main limit is that the database was built for administrative and reimbursement purposes with little clinical information that could be useful to validate diagnoses, to assess disease severity and some behavioural risk factors. However, for THR and TKR, the procedure is well identified through DRG, and furthermore the information was checked with discharge diagnoses leading to exclude very few patients with probable DRG or main diagnosis miscoding (figure 1).

Another difficulty of such administrative databases is the diagnostic validity of outcomes. In this study, the main analysis used main hospitalization diagnoses to have a very specific definition that minimized the risk of false positives, but concerned more severe cases, i.e. PE and major bleeding. Broader definitions take into account less severe cases (associated diagnosis from hospitalization, non hospitalized VTE) to minimize the risk of false negatives, which provides relative risks that strengthen the robustness of study results. Coding in the hospital database is done by the physician in charge of the patient, assisted by professional medical information technicians. These codes are subject to quality assurance processes to obtain accreditation and certification, and to regular audits from the insurance payer system to ensure the quality of the coding. ( 41) Major cardiovascular outcomes have been validated, with positive predictive values around 90%, improving over time. [START_REF] Bezin | Choice of ICD-10 codes for the identification of acute coronary syndrome in the French hospitalization database[END_REF][START_REF] Bosco-Lévy | Diagnostic accuracy of the international classification of disease 10th revision codes of heart failure in administrative database[END_REF][START_REF] Giroud | Positive Predictive Value of French Hospitalization Discharge Codes for Stroke and Transient Ischemic Attack[END_REF][START_REF] Gouverneur | Agreement between hospital discharge diagnosis codes and medical records to identify metastatic colorectal cancer and associated comorbidities in elderly patients[END_REF][START_REF] Prat | Positive predictive values of peripheral arterial and venous thrombosis codes in French hospital database[END_REF] Residual confounding cannot be excluded for comparisons in observational studies. In this study, the matched groups were very well balanced with the 1:1 propensity score matching for main characteristics and known VTE and bleeding risk factors. Furthermore, the few small residual differences between DOAC and LMWH were most of the time not in favor of DOAC, limiting the risk of residual confounding that could explain the lower risk found with DOAC compared to LMWH.

Another limit is that results apply only to patients who returned home after discharge. Those who did not represented a large part of the THR and TKR populations (figure 1), and were excluded because their drug information including anticoagulant use was not available in the database. Most of them went to a rehabilitation facility. Although their characteristics, VTE and bleeding risk factors were not the same, the risk of VTE during the follow-up was quite the same (supplementary materials), while rates of hospitalized bleeding and death were higher due to older age. This population will have to be specifically studied.

Our results do not apply also to events occurring during index hospitalization for which a global estimation of VTE, bleeding and death risks has been done, but could not be attributed to DOAC or LMWH, because their use was not registered in the database. For those without event, it is highly probable that the same drug was prescribed before and after discharge, but for those with a VTE event, the drug and dosage initially prescribed in hospital would most probably be changed after the occurrence of an event. The presence of in-hospital bleeding was however included in the determination of the propensity score. Patients with a VTE event during hospitalization should be treated by VKA, high-dose DOAC or fondaparinux and were consequently not included in this analysis.

Apixaban and rivaroxaban trials for registration demonstrated a better efficacy compared with 40 mg enoxaparin, and non-inferiority for dabigatran, without increasing the haemorrhagic and death risks [START_REF] Lassen | Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial[END_REF][START_REF] Lassen | Apixaban versus enoxaparin for thromboprophylaxis after hip replacement[END_REF][START_REF] Eriksson | Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty[END_REF][START_REF] Lassen | Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty[END_REF][START_REF] Eriksson | Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial[END_REF][START_REF] Eriksson | Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial[END_REF]. Randomized controlled trials are the gold standard to assess treatment efficacy, but may have limited external validity [START_REF] Rothwell | External validity of randomised controlled trials: "to whom do the results of this trial apply?[END_REF][START_REF] Steg | External validity of clinical trials in acute myocardial infarction[END_REF]. Furthermore, these trials had also several limitations with a composite criterion including symptomatic and non-symptomatic VTE and deaths, and only between 64 % and 76 % of the randomized patients in the modified intent to treat analysis. For symptomatic VTE, as for major bleedings and deaths, the number of events was very low in 6 studies, with insufficient statistical power for the comparison of anticoagulants, except for symptomatic VTE with rivaroxaban versus enoxaparin in TKR [START_REF] Lassen | Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty[END_REF].

Although our study was not randomized, its real-life results go in the same direction as those from clinical trials (4-9), as well as the meta-analysis of orthopedic surgery trials [START_REF] Gomez-Outes | Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons[END_REF], but with a better bleeding risk profile. Death was not analyzed in those trials. A recent metaanalysis of all DOAC versus enoxaparin trials did not reach the same conclusions, but it mixed orthopedic and medical patients, different dosages and treatment durations [START_REF] Cimminiello | Thromboprophylaxis with enoxaparin and direct oral anticoagulants in major orthopedic surgery and acutely ill medical patients: a meta-analysis[END_REF].

However, despite the inclusion of almost 100,000 matched THR and TKR over 21 months in one of the largest European countries, there were very few actual outcome events. This resulted in limited study power, precluding meaningful direct comparisons of symptomatic events or death with individual anticoagulants.

Another result of this study is a very low risk of VTE after discharge in real life, between 3 and 10 per 1 000 patients using main hospitalization discharge diagnoses, according to surgical procedures and treatment groups, far from historical background risks (2), and also lower than but close to the last estimation of the American College of Chest Physicians for LMWH (1). The prevention with anticoagulant reduces VTE risk, but a large part of this low risk is due to the development of enhanced rehabilitation after surgery (ERAS) including minimally invasive surgery, improvement of post-surgical care with early mobilization, as well as shorter and shorter hospitalization durations [START_REF] Ibrahim | Peri-operative interventions producing better functional outcomes and enhanced recovery following total hip and knee arthroplasty: an evidence-based review[END_REF]. It might be worthwhile to better characterize in the future patients and situations with weak VTE risk for whom the risk of severe bleeding could overcome the benefit of anticoagulants [START_REF] Lieberman | American College of Chest Physicians evidence-based guidelines for venous thromboembolic prophylaxis: the guideline wars are over[END_REF], and for whom aspirin might be more suitable. [START_REF] Mistry | A Systematic Review on the Use of Aspirin in the Prevention of Deep Vein Thrombosis in Major Elective Lower Limb Orthopedic Surgery: An Update from the Past 3 Years[END_REF] The cost analysis applied to the French healthcare system and is not directly generalizable. However, at least 70% of the difference between two groups was related to the price of the drug, to nurse care linked with LMWH injections (daily or twice daily), and to lab tests for surveillance. These could be easily extrapolated to other settings.

The event rates may also be applied to other contexts, taking into account the relevant cost structures.

In conclusion, this nationwide cohort study shows a globally low risk of VTE, hospitalized bleeding and death after discharge, for patients given an anticoagulant for the prevention of VTE following THR or TKR in a real-life setting, with a better benefit-risk ratio of DOAC compared to LMWH, associated with cost savings. -Antiplatelet agent (4) in the week after discharge, % 1.9 -Rehabilitation centre, (%) (a) -Other institutionalization, (%) (a) -No or other anticoagulant, (1) (%) (a) -Not eligible, (2) (%) (a) -Died before discharge, (%) (a) -Probable DRG error, (3) (%) (a) TKR (a) (46.6) (6.5) (7.

Figure 1 :

 1 Figure 1: Study flow chart

Figure 2 :

 2 Figure 2: THR and TKR medical costs according to the societal perspective for DOAC and

Figure 1 :THR 1 : 1

 111 Figure 1: Study flow chart

Figure 2 :

 2 Figure 2: THR and TKR medical costs according to the collective perspective for DOAC and LMWH matched patients DOAC = Direct Oral AntiCoagulant; LMWH = Low Molecular Weight Heparin.

Table 1 :

 1 Characteristics of matched THR and TKR patients according to DOAC and LMWH treatment groups

		matched THR patients		matched TKR patients
	DOAC	LMWH	Standardized	DOAC	LMWH	Standardized
	n = 31 619	n = 31 619	difference	n = 15 720	n = 15 720	difference

  Total Knee Replacement; DOAC: Direct Oral AntiCoagulant; LMWH: Low Molecular Weight Heparin; n: number of events; ‰: Absolute risk per 1000 persons; VTE: Venous Thromboembolic Event; (1) Hospitalization with main or associated diagnosis

	All DOAC (1:1)	31 619 / 31 619 58 (1.8)	66 (2.1)	0.88 [0.62 -1.25]	15 720 / 15 720 38 (2.4)	59 (3.8) 0.64 [0.43 -0.97]
	Apixaban (1:6)	3 380 / 20 265	4 (1.2)	38 (1.9)	0.63 [0.23 -1.77]	1 759 / 10 503	5 (2.8)	32 (3.0) 0.93 [0.36 -2.39]
	Dabigatran (1:3)	7 098 / 21 286	12 (1.7)	49 (2.3)	0.73 [0.39 -1.38]	3 554 / 10 648	3 (0.8)	45 (4.2) 0.20 [0.06 -0.64]
	Rivaroxaban (1:1)	21 191 / 21 191 42 (2.0)	45 (2.1)	0.93 [0.61 -1.42]	10 412 / 10 412 30 (2.9)	38 (3.6) 0.79 [0.49 -1.27]
	Hospitalized (1) bleeding
	All DOAC (1:1)	31 619 / 31 619 138 (4.4) 159 (5.0) 0.87 [0.69 -1.09]	15 720 / 15 720 81 (5.2)	95 (6.0) 0.85 [0.63 -1.15]
	Apixaban (1:6)	3 380 / 20 265	10 (3.0)	84 (4.1)	0.71 [0.37 -1.37]	1 759 / 10 503	7 (4.0)	55 (5.2) 0.76 [0.35 -1.67]
	Dabigatran (1:3)	7 098 / 21 286	31 (4.4)	1.8 101 (4.7) 0.92 [0.62 -1.38] -1.1	2.0 3 554 / 10 648 13 (3.7)	1.9 70 (6.6) 0.56 [0.31 -1.00] -0.5
	-ASA during follow-up, % Rivaroxaban (1:1)	0.9 21 191 / 21 191 97 (4.6)	0.7 114 (5.4) 0.85 [0.65 -1.11] -2.5	1.2 10 412 / 10 412 62 (6.0)	0.8 59 (5.7) 1.05 [0.74 -1.50] -4.2
	Index hospitalization Death
	-Category of hospital, % All DOAC (1:1)	31 619 / 31 619 23 (0.7)	34 (1.1)	0.68 [0.40 -1.15]	15 720 / 15 720 9 (0.6)	13 (0.8) 0.69 [0.30 -1.62]
	Teaching hospital Apixaban (1:6)	3 380 / 20 265	11.3 2 (0.6)	10.1 18 (0.9)	-3.9 0.67 [0.15 -2.87]	8.1 1 759 / 10 503	2 (1.1)	6.9 6 (0.6)	-4.6 1.99 [0.40 -9.86]
	Other public hospital Dabigatran (1:3)	7 098 / 21 286	12.4 8 (1.1)	12.8 32 (1.5)	1.4 0.75 [0.35 -1.63]	10.5 3 554 / 10 648	2 (0.6)	11.0 11 (1.0) 0.54 [0.12 -2.46] 1.8
	Private hospital Rivaroxaban (1:1)	76.3 21 191 / 21 191 13 (0.6)	77.0 19 (0.9)	1.7 0.68 [0.34 -1.39]	81.5 10 412 / 10 412		82.1 9 (0.9)	1.7 0.56 [0.19 -1.66]
	-Duration, mean (SD) THR: Total Hip Replacement; TKR:		7.0 (2.1)	7.0 (2.2)	0.9	7.7 (2.3)		7.7 (2.4)	1.5
	-Hip, pelvis or leg fracture, %		1.9	2.0		0.8	0.3		0.2	-
	-Bleeding diagnosis during hospitalization, %		1.3	1.1		-1.7	1.8		1.6	-1.3
	Drug dispensing duration (5) (days), mean (SD)		30.2 (5.9)	27.2 (7.6)	-	29.1 (6.9)	25.6 (8.3)	-

THR and TKR hospitalisations from 1 Jan. 2013 to 30 Sept. 2014

	ALL	THR	TKR
	388 758	227 034	161 724
	ALL	THR	TKR
	99 463	65 966	33 497
	63 333 (63.7)	42 284 (64.1)	21 049 (62.8)
	32 245 (33.4)	21 714 (32.9)	11 531 (34.4)
	2 812 (2.8)	1 919 (2.9)	893 (2.7)
	73 (0.1)	49 (0.1)	24 (0.1)
	47 418	31 680	15 738
	31 621 (66.7)	21 200 (66.9)	10 421 (66.2)
	10 657 (22.5)	7 099 (22.4)	3 558 (22.6)
	5 140 (10.8)	3 381 (10.7)	1 759 (11.2)
	ALL	THR	TKR
	47 339 (47.6)	31 619 (47.9)	15 720 (46.9)
	47 339 (99.8)	31 619 (99.9)	15 720 (99.8)