MD, PhD Raphaël P Martins
email: raphael.martins@chu-rennes.fr

MD Vincent Galand

MD Edouard Colette

MD Nathalie Behar

MD Dominique Pavin

MD Christophe Leclercq

MD Jean-Claude Daubert

MD Philippe Mabo

Defining Non-Valvular Atrial Fibrillation: a Quest for Clarification

Non-vitamin K oral anticoagulants (NOACs) are currently recommended for patients with non-valvular atrial fibrillation (NVAF) since the publication of the four major pivotal trials evaluating the efficacy and safety of factor IIa and factor Xa inhibitors. The definition of NVAF is unclear, varying from one trial to another, and even between North-American and European guidelines, which is a source of uncertainties in clinical practice. However, many patients with atrial fibrillation (AF) present signs of valvular involvement, and clarification of this term is needed in order to not deny NOACs to patients based on the wrong perception that they may have valvular AF. The currently unique contraindications to NOACs are patients with mechanical heart valves and those with moderate-to-severe mitral stenosis, as stated by the recent 2015 position paper of the European Heart Rhythm Association. Patients with native heart valve involvement, regardless of their severity are suitable for NOAC therapy. Patients with bioprosthetic heart valves and mitral valve repair may be suitable for NOACs except for the first 3 and the first 3-6 months post-operatively, respectively. Patients with transaortic valve implantation (TAVI) or percutaneous transluminal aortic valvuloplasty are also considered as being eligible for NOACs, although the bleeding risk has to be carefully considered in this population often requiring a combination with antiplatelet therapy.

Future studies are warranted to increase the level of evidence of use of NOACs, particularly in patients with TAVI and valvular surgery, and to determine whether they could be used in the future in the only two remaining contraindications.

Introduction

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, with currently in Europe approximately 10 million patients with AF and 100,000-200,000 with new-onset AF. [START_REF] Zoni-Berisso | Epidemiology of atrial fibrillation: European perspective[END_REF] This arrhythmia has a high morbidity and mortality risk, mainly due to the elevated risk of ischemic stroke. The CHA 2 DS 2 VASc score is a validate tool to estimate the annual risk of stroke or systemic embolism, ranging from less than 1% to approximately 20% in the absence of oral anticoagulants. [START_REF] Hart | Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation[END_REF] Historically, vitamin-K antagonists (VKA) were the gold-standard treatment for the prevention of systemic embolism. However, this therapy has many downsides, like the interactions with food and other drugs, a narrow therapeutic window, the need for frequent coagulation monitoring and dosage adjustment, or its' particular pharmacokinetics (delayed onset and offset of anticoagulant effect) somehow complicating the management of patients.

Recently, non-VKA Oral Anticoagulants (NOAC) have been introduced. This therapeutic class facilitates the management of oral anticoagulation since the four currently available molecules do not have most of the downsides described above. Though, its use is contraindicated in patients with severe renal impairment and with so-called "valvular AF".

The definition of valvular and non-valvular AF (NVAF) are unclear, varying from one to the other NOAC study, [START_REF] Connolly | Apixaban in patients with atrial fibrillation[END_REF][START_REF] Connolly | Dabigatran versus warfarin in patients with atrial fibrillation[END_REF][START_REF] Giugliano | Edoxaban versus warfarin in patients with atrial fibrillation[END_REF][START_REF] Patel | Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[END_REF] and even between North-American and European guidelines, [START_REF] Camm | focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association[END_REF][START_REF] January | AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society[END_REF] which is a source of ambiguity in clinicians' minds. A clarification of the term NVAF is needed in order to not deny NOACs to patients based on the wrong perception that they may have NVAF.

In the present comprehensive review, we aimed at clarifying this point, by analyzing results of the main randomized trials in the area and recommendations in current guidelines and by describing the safety and efficacy of NOACs in patients with valvular abnormalities, based on the results of published studies.

The magnitude of the problem

A large proportion of the patients with AF have signs of valvular involvement. Among those included in the EURObservational Research Programme Atrial Fibrillation, a prospective survey in european countries, 63.5% had a valvular disease. [START_REF] Lip | A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry[END_REF] The presence of such anomalies increase the risk of AF by 1.8 and 3.4 in men and women, respectively. [START_REF] Benjamin | Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study[END_REF] On the other hand, animal studies have shown that AF, through atrial dilatation, results in a progressive mitral regurgitation, already present at the transition stage between paroxysmal and persistent AF, which becomes significant after one year of long-standing persistent AF. [START_REF] Martins | Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation[END_REF] Thus, the

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relationship between both anomalies is frequent and often unclear, particularly in the presence of atrial dilatation.

From NOAC trials to current guidelines

Factor IIa (dabigatran) and factor Xa (rivaroxaban, apixaban, and edoxaban) inhibitors have demonstrated their non-inferiority or superiority compared to VKA to reduce the risk of stroke and systemic thrombo-embolism. [START_REF] Connolly | Apixaban in patients with atrial fibrillation[END_REF][START_REF] Connolly | Dabigatran versus warfarin in patients with atrial fibrillation[END_REF][START_REF] Giugliano | Edoxaban versus warfarin in patients with atrial fibrillation[END_REF][START_REF] Patel | Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[END_REF] In the meta-analysis published in 2014 by Ruff et al [START_REF] Ruff | New oral anticoagulants in patients with atrial fibrillation -Authors'reply[END_REF] compelling the 4 major trials on stroke prevention for AF published so far, a significant reduction of 19% of this endpoint was observed. Importantly, major bleedings were significantly reduced by 14%. In these seminal trials, patients with contra-indications to NOACs were excluded, including those with chronic kidney disease or in case of treatment interactions. One of the major exclusion criteria was the presence of a "valvular" AF, but the definition varied widely between the pivotal trials. As shown in Table 1, the inclusion criteria of the RE-LY, [START_REF] Connolly | Dabigatran versus warfarin in patients with atrial fibrillation[END_REF] the ROCKET-AF, [START_REF] Patel | Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[END_REF] the ARISTOTLE, [START_REF] Connolly | Apixaban in patients with atrial fibrillation[END_REF] and the ENGAGE-AF TIMI 48 [START_REF] Molteni | The definition of valvular and non-valvular atrial fibrillation: results of a physicians' survey[END_REF] To the question "Do you think that the existing definitions of NVAF are sufficiently clear?", 57.1 and 67.9% of them answered "yes", respectively. Surprisingly, the answers of the following questions were not in accordance with this initial result. Indeed, for 28.2% of the cardiologists, the presence of a mitral regurgitation alone was sufficient to define AF as valvular AF, and 26.7% defined patients with biological aortic valve prosthesis as having NVAF. A clarification of the term NVAF is then urgently needed in order to homogenize current clinical practice and remove uncertainties regarding this common issue.

Valvular heart diseases, AF and thrombo-embolic risk

Mitral stenosis

Mitral stenosis has historically been considered a distinct disease in the area of AF. Indeed, it results in a low atrial flow, significantly increasing the risk of atrial thrombi, which, besides, are often located in various regions of the atria but the left atrial appendage (91% in NVAF and 57% in AF associated with mitral stenosis). [START_REF] Blackshear | Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation[END_REF] Since the thrombo-embolic risk is increased, and the efficacy of new anticoagulants uncertain, such patients were excluded from randomized controlled trials about NOACs, and to date, there are no data regarding the efficacy and safety of these molecules in patients with mitral stenosis. Whether pathophysiology of thrombi genesis in these patients is substantially different to contraindicate NOAC prescription is unknown and would probably require further studies.

Other valvular diseases

The other valvular diseases (mitral or tricuspid regurgitations, aortic stenosis) were not considered to increase per-se the risk of thrombo-embolic event. However, Philippart et al recently demonstrated that patients with left-sided valvular disease had a 1.39-fold increase risk of stroke/thrombo-embolic events, probably explained by a higher CHA 2 DS 2 -VASc score and significantly more comorbidities in these patients, compared to those with no valvular diseases. [START_REF] Philippart | Prognostic value of CHA2DS2-VASc score in patients with 'non-valvular atrial fibrillation' and valvular heart disease: the Loire Valley Atrial Fibrillation Project[END_REF] Indeed, older age and higher CHA 2 DS 2 -VASc scores were the only independent predictors of ischemic events, but not the presence of a valvular disease.

Many studies have shown that mitral regurgitation might reduce the risk of stroke since atrial flow is increased and atrium and left atrial appendage are "washed" by the regurgitant flow.

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This phenomenon has been described especially in case of severe regurgitation, and not demonstrated for mild or moderate regurgitations. [START_REF] Fukuda | Relation of the severity of mitral regurgitation to thromboembolic risk in patients with atrial fibrillation[END_REF][START_REF] Nakagami | Mitral regurgitation reduces the risk of stroke in patients with nonrheumatic atrial fibrillation[END_REF] Regarding aortic stenosis, one have to keep in mind that calcic microemboli may occur, and that stroke in the presence of AF may have a different pathophysiologic origin.

Data regarding the use of rivaroxaban and apixaban in patients with valvular involvement have recently been published. Among the 14 171 patients included in the ROCKET-AF trial, 2003 (14.1%) had a valvular disease, mainly mitral or aortic regurgitations (respectively 89.6% and 24.8% of the patients) or aortic stenosis (11.0%), half of them from degenerative origin. The severity of those valvular diseases was not reported. [START_REF] Breithardt | Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial[END_REF] To note, 5.3% had prior cardiac valvular surgeries. Baseline characteristics of patients with or without valvular involvement significantly differed, since the former were older and had more comorbidities like congestive heart failure, prior myocardial infarction, chronic obstructive pulmonary disease or smoking. Although rivaroxaban had a similar efficacy in patients with or without valvular disease, a significant lower bleeding rate was observed in the latter group, probably explained by the differences in terms of baseline characteristics. The interaction of valvular disease in patients randomized to rivaroxaban and warfarin was not significant in intention-totreat in terms of efficacy outcomes. However, a significant higher bleeding rate was observed in patients with valvular involvement randomized to rivaroxaban compared to warfarin.

A similar analysis was performed among patients included in the ARISTOTLE trial comparing efficacy and safety outcomes in patients randomized to apixaban or warfarin. [START_REF] Avezum | Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial[END_REF] Among However, no differential effect of apixaban over warfarin in patients with and without valvular diseases in reducing stroke and systemic embolism was observed. Similarly, bleeding and mortality were similar among patients randomized to apixaban or warfarin, whether valvular involvement was present or not.

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As previously stated, the NOAC trial with the most restrictive inclusion criteria was the RE-LY trial. Results about the outcomes of patients with valvular heart diseases included in this trial (21.0% of the population) have not been published yet but presented as preliminary form. 20 Similarly to the results of the subanalysis of the ROCKET-AF and the ARISTOTLE trials, the benefit of dabigatran in reducing stroke and systemic embolism, major bleeding and life-threatening or intracranial bleeds, were similar in patients with valvular diseases compared to those without. Similar data for patients included in the ENGAGE-AF TIMI 48 trial and receiving edoxaban have not been published or presented so far. In summary, patients with valvular diseases are not at higher risk of stroke per-se, but are often older, with several comorbidities, and consequently have a higher thrombo-embolic (CHA 2 DS 2 -VASc) score, putting them at risk for stroke and embolic complications of AF independently of the type of anticoagulant. NOACs appear to have similar efficacy and safety profiles irrespective to the presence of a valvular disease. In parallel to the CHA 2 DS 2 -VASc score, hemorrhagic scores (HAS-BLED or HEMORRAGE scores) are also often increased, and one have to keep in mind that a careful attention is required when NOACs are prescribed in such patients.

Mechanical valves

Patients with mechanical valves are at a high risk of thrombo-embolic complications and require permanent anticoagulation after valve implantation. Warfarin has been shown to decrease this risk to an annual rate of 0.7-1%. [START_REF] Cannegieter | Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses[END_REF][START_REF] Cannegieter | Optimal oral anticoagulant therapy in patients with mechanical heart valves[END_REF] Thrombi may form directly in the surface of the valve or in the left atrial appendage as a consequence of the low-flow induced by the presence of the valve. During the post-operative time or later during follow-up, AF may appear, further increasing thrombo-embolic risk. The phase-2 RE-ALIGN study was designed to test the safety and efficacy profile of dabigatran in patients with aortic and/or mitral mechanical prosthesis. [START_REF] Eikelboom | Dabigatran in patients with mechanical heart valves[END_REF] Drug doses varied from 150 mg x 2 to 300 mg x 2 depending on kidney function and blood concentrations of the molecule. Two populations of patients were studied, i.e. those with early (< 7 days) or late (> 3 months) initiation of dabigatran after the surgery. The trial was terminated prematurely since the use of dabigatran in patients with mechanical prosthesis was associated with an increased risk of thromboembolic and major bleeding complications (5% vs. 0%, and 4% vs 2%, respectively) compared to warfarin. Most thrombo-embolic events occurred in patients from the early-initiation group, while bleeding events occurred similarly in both groups. However, major bleeding occurred only in patients for whom dabigatran was initiated early after the valve implantation, all being pericardial bleeding. Thus, authors conclude that dabigatran is not a safe alternative for patients requiring

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anticoagulation after the implantation of a mechanical heart valve, and VKAs remain the gold-standard treatment in such patients.

Bioprosthesis

The antithrombic strategy after bioprosthesis valve implantation is currently controversial, but most of the times, aspirin may be a safe option in such patients in sinus rhythm. [START_REF] Bonow | Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons[END_REF][START_REF] Nishimura | AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease (version 2012)[END_REF][START_REF] Whitlock | Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines[END_REF] Whenever AF occurs, an oral anticoagulation has to be prescribed. [START_REF] Vahanian | Guidelines on the management of valvular heart disease (version 2012)[END_REF] As recently demonstrated, the presence of a bioprosthesis is associated with a non-significant increase in stroke/thromboembolic events but is not independently associated with their occurrence. [START_REF] Philippart | Oral anticoagulation, stroke and thromboembolism in patients with atrial fibrillation and valve bioprosthesis. The Loire Valley Atrial Fibrillation Project[END_REF] Whether pathophysiology of thrombi formation is sufficiently different in these patients to contraindicate NOAC prescription is unknown.

The only dedicated trial was the DAWA study (Dabigatran versus warfarin after mitral and/or aortic bioprosthesis replacement and atrial fibrillation postoperatively) was designed to compare dabigatran (at a dose of 110 mg x 2) with warfarin in patients with bioprostheses, 29 but results cannot be interpreted due to the very limited number of patients enrolled. 30 To date, the only data available on the efficacy and safety profiles of NOACs in patients with bioprosthesis come from subgroup analyses. The ARISTOTLE trial brings us some insights about this specific group of patients, with data recently presented at the 2015 AHA meeting. 31 As stated above, 251 patients (1.7%) included in the ARISTOTLE trial had a history of valve surgery. Details on the valve surgery were not collected at the time of the trial but gathered retrospectively after the completion of the study, and were completely available for 165 patients. Baseline clinical characteristics of patients with bioprothetic aortic and/or mitral valves receiving apixaban (N=56) or warfarin (N=52) were similar. Efficacy (stroke and systemic embolism) and safety outcomes (major bleeding, intracranial hemorrhage, cardiovascular and all-cause death) were similar among both groups. Data about patients with bioprosthetic heart valves included in the ENGAGE-AF TIMI 48 trial (the only trial having clearly stated this inclusion criterion) have not been presented so far.

Trans-aortic valve implantation

Trans-aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement for patients with aortic stenosis. Antithrombic management after implantation remains empiric, often based on a dual antiplatelet therapy, associating aspirin and clopidogrel for 3 to 6 months, followed by long-term aspirin or a thienopyridine alone. [START_REF] Nishimura | AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease (version 2012)[END_REF][START_REF] Whitlock | Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines[END_REF] The optimal management of TAVI recipients experiencing AF is currently unknown. The

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ESC and the European Association for CardioThoracic Surgery recommend a combination of VKA and aspirin or thienopyridine, weighed against increased risk of bleeding. [START_REF] Vahanian | Guidelines on the management of valvular heart disease (version 2012)[END_REF] Similarly to what was stated for bioprosthetic valves, whether pathophysiology of thrombi formation is sufficiently different in TAVI patients to contraindicate them to NOACs would require further studies, and to the best of our knowledge, there are no data published so far in the literature in this topic.

Moving towards new recommendations?

In 2015, the European Heart Rhythm Association (EHRA) published a practical guide on the use of NOACs in patients with AF. [START_REF] Heidbuchel | Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation[END_REF] In this position paper, authors state that NVAF refers to "AF that occurs in the absence of mechanical prosthetic heart valves and in the absence of moderate-to-severe mitral stenosis", and add that patients with biological valves or valve repair are in a "grey area" and may be suitable for NOAC prescription. Indeed, it is stated that patients with bioprosthetic heart valves and mitral valve repair are suitable for NOAC therapy except for the first 3 and the first 3-6 months post-operatively, respectively. Patients with TAVI or percutaneous transluminal aortic valvuloplasty are also considered as being eligible for NOACs, although the bleeding risk has to be carefully considered in this population often requiring a combination with antiplatelet therapy. The only remaining contraindications of NOAC remain mechanical prosthetic valves and moderate-to-severe mitral stenosis, while patients with other native valvular diseases are not considered as having valvular AF, regardless of severity. A flow chart to guide decision making is depicted in the Figure.

Future perspectives

Elderly patients are at risk of AF and may at some point present with a degenerative calcific aortic stenosis, requiring surgery or percutaneous therapy. To date and as stated above, there is a clear lack of evidence of NOAC suitability in such patients. Thus, studies analyzing the safety and efficacy profile of NOACs in patients with bioprosthetic heart valves and TAVI are urgently warranted.

Lifelong oral anticoagulation with VKAs is mandatory for patients with mechanical heart valves to prevent thromboembolic complications although lability of INRs is a major drawback in this situation, requiring strict coagulation monitoring and drug-adjustments.

Initial promising results of in-vitro and animal studies showing the efficacy of dabigatran in preventing valve thrombosis raised hope about use of NOACs in patients with mechanical prosthetic heart valves, [START_REF] Mckellar | Effectiveness of dabigatran etexilate for thromboprophylaxis of mechanical heart valves[END_REF][START_REF] Schomburg | Dabigatran versus warfarin after mechanical mitral valve replacement in the swine model[END_REF] unfortunately deceived by the results of the RE-ALIGN trial. [START_REF] Eikelboom | Dabigatran in patients with mechanical heart valves[END_REF] In-

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10 vitro coagulation studies later demonstrated that mechanical heart valves induce a local generation of thrombin via the intrinsic pathway in concentrations that overwhelm the inhibitory effect of dabigatran at clinical doses, [START_REF] Jaffer | Dabigatran is Less Effective Than Warfarin at Attenuating Mechanical Heart Valve-Induced Thrombin Generation[END_REF] probably explaining the negative results of the trial. Whether a similar effect occurs with factor Xa inhibitors would require further studies. Preliminary in-vitro [START_REF] Kaeberich | Comparison of unfractionated heparin, lowmolecular-weight heparin, low-dose and high-dose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study[END_REF] and animal [START_REF] Greiten | Effectiveness of rivaroxaban for thromboprophylaxis of prosthetic heart valves in a porcine heterotopic valve model[END_REF] studies demonstrated that high-dosed rivaroxaban might be effective in preventing thromboembolic events after mechanical heart valve replacement. However, in the light of the results of the RE-ALIGN trial, [START_REF] Eikelboom | Dabigatran in patients with mechanical heart valves[END_REF] further studies would be needed to provide additional data to support clinical trials evaluating factor Xa inhibitors as an alternative to warfarin in patients with prosthetic heart valves.

Patients with moderate-to-severe mitral stenosis (usually of rheumatic origin) have not been included in NOAC trials on the basis of a potential higher risk and different pathophysiologic mechanism of thrombi formation. The prevalence of rheumatic heart disease, the most common cause of mitral stenosis, is widely variable, remaining a major problem in developing areas of the world. Irrespective to atrial rhythm, thrombo-embolic strokes are frequent, estimated to reach around 4 million events per year. Oral anticoagulation using VKAs is recommended in patients with mitral stenosis and AF, and may be proposed to patients with mitral stenosis in the absence of AF. [START_REF] Bonow | Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons[END_REF][START_REF] Nishimura | AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease (version 2012)[END_REF][START_REF] Whitlock | Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines[END_REF] However, times in therapeutic range, already suboptimal in developed countries, are even worst in developing parts of the world with high incidence of rheumatic fever. [START_REF] Connolly | Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range[END_REF] Alternative therapeutic strategies, such as aspirin, are sometimes offered to such patients, despite the well-known inferiority to VKAs. [START_REF] Hart | Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation[END_REF] Based on these assumptions, De Caterina and Camm recently wrote "the concept for a trial"

comparing NOACs to the standards of care for thromboembolic prophylaxis (antiplatelet agents or VKA) in patients with mitral stenosis. [START_REF] Caterina | Non-vitamin K antagonist oral anticoagulants in atrial fibrillation accompanying mitral stenosis: the concept for a trial[END_REF] They claim that a randomized, open-label, superiority trial should be conducted in specific countries with a high prevalence of mitral stenosis using a NOAC available for once daily use (rivaroxaban or edoxaban) to facilitate patients' compliance, at the same dosage used in pivotal trials in AF. The overall sample size would vary depending on the expected stroke rate, the study duration and the expected hazard ratio of stroke reduction, from around 600 to 7000. Such study appears to be feasible, at least by academic centers, if not by pharmaceutical companies, and is warranted to improve the suboptimal current standard antithrombotic treatment of patients with mitral stenosis.

Lastly, it may be now time to stop using the confusing term "non-valvular" to define a type of AF. As stated by De Caterina and Camm, a novel terminology should be used in order to clarify this confusion situation. [START_REF] Caterina | What is 'valvular' atrial fibrillation? A reappraisal[END_REF] Authors proposed the term "MARM-AF", acronym standing for "Mechanical And Rheumatic Mitral-AF", since it clearly describes the currently real contraindications to NOACs. The future will tell us whether this term will be life-standing and used by futures researchers.

Conclusion

The term "NVAF" and the inclusion and exclusion criteria in NOACs pivotal trials have created some confusion in physicians' minds about patients who are eligible or not to this therapy. Evidences are progressively coming and showing that NOACs can be safely used in patients with native valvular diseases, regardless of their severity, and probably in bioprosthetic heart valve recipients. The only contraindications remain the presence of a mechanical heart valve and moderate-to-severe mitral stenosis. Future studies are warranted to increase the level of evidence of the safety and efficacy of NOACs in specific populations, particularly in patients with TAVI and bioprosthetic valve, and to determine whether they could be used in the future in the two remaining contraindications.

Disclosures

No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents

Figure legend

Flow chart to guide decision making in patients with atrial fibrillation.

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A

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Fig. 1

 1 Fig. 1

  As previously described in the subanalysis of the ROCKET-AF trial, patients with valvular heart diseases were older and had more comorbidities; CHADS2 score was also significantly higher in this group. Patients with valvular heart disease had higher rates of stroke or systemic embolism

	(3.2% versus 2.4%; HR, 1.34; 95% CI, 1.10-1.62; p=0.003) and bleeding (4.6% versus 4.3%;
	HR, 1.11; 95% CI, 0.95-1.29; p=0.21) compared to patients without valvular heart diseases.

the 18 201 patients included, 4808 had valvular heart diseases (26.4%), including mitral, tricuspid and aortic regurgitations, or aortic stenosis, with various grades of severity (from mild to severe). To note, a total of 465 patients with mild mitral stenosis were included, as were 251 patients with prior valve surgeries (see below for details).

Table 1 .Inclusion criteria in NOACs pivotal trials.

 1

	Tables
	Trial	Molecule	Exclusion criteria
	RE-LY	Dabigatran	History of heart valve disorder (i.e., prosthetic valve or hemodynamically relevant valve disease)
			Hemodynamically significant mitral valve stenosis, prosthetic
	ROCKET-AF	Rivaroxaban	heart valves (annuloplasty with or without prosthetic ring,
			commisurotomy and/or valvuloplasty are permitted)
	ARISTOTLE	Apixaban	Conditions other than AF that require anticoagulation (i.e. prosthetic heart valves)
			Moderate-to-severe mitral stenosis, other indication for
	ENGAGE AF	Edoxaban	anticoagulation (subjects with bioprosthetic heart valves and/or
			valve repair could be included)

AF = Atrial fibrillation.

ACCEPTED MANUSCRIPT

fees/speaker honoraria for Daiichi Sankyo, Boehringer, Pfizer, Bristol Myers Squibb and Bayer; PM: consulting fees from Daiichi; speaker honoraria from Boehringer, Pzifer, Bristol Myers Squibb; consulting fees/ speaker honoraria from , Pfizer, Bristol Myers Squibb.


"Acteurs et stratégies du développement local en Europe centrale"

Séance proposée par Marie-Claude Maurel (section Sciences de l'homme et de la société) en partenariat avec Maria Halamska (section Économie et politique agricoles et rurales)

Date : 18 janvier 2012

Présentation du thème par Marie-Claude MAUREL Les transformations intervenues dans les nouveaux Etats membres d"Europe centrale, au lendemain de leur entrée dans l"Union européenne (UE), invitent à renouveler les cadres d"analyse du développement rural. Pendant plus de quarante ans, les sociétés rurales de l"Est européen ont été le champ d"application du modèle collectiviste, encadré par le pouvoir central. Elles ont fait l"objet d"une planification du développement économique et social leur déniant toute autonomie d"action. A présent, l"introduction d"un modèle de développement local qui repose sur des principes et une démarche radicalement opposés, fait figure d"expérience inédite et novatrice. Le modèle de développement endogène, fondé sur une démarche ascendante et partenariale, et la mobilisation des initiatives locales, est la source d"inspiration de l"approche LEADER1 qui a été expérimentée dès les années 1990 par les anciens Etats membres. Dans les nouveaux Etats membres, le transfert de l"approche LEADER prend place dans le contexte spécifique de sociétés rurales qui ont renoué il y a deux décennies avec la démocratie et l"autonomie locale. Or, la mise en oeuvre de l"approche LEADER implique l"apprentissage d"un nouveau mode d"action publique fondé sur la valorisation des atouts propres à chaque territoire et la mobilisation des initiatives portées par des partenariats publics /privés (élus, animateurs de projets, entrepreneurs, associations). En soi, un tel apprentissage constitue une forme de mise à l"épreuve des acteurs locaux. De quelle manière ces derniers se sont-ils approprié les nouveaux dispositifs d"action publique proposés par le modèle LEADER ? Pour quels usages ? Quels peuvent être les effets du transfert de modèle de développement local sur des systèmes politiques dont l"ancrage démocratique est récent et fragile ? Ces questions invitent à examiner les conditions de réception de l"approche LEADER.

Dans une perspective d"analyse de transfert dans le cadre de la Politique Européenne de Développement Rural (PEDR) pour la période 2007-2013, une recherche comparative portant sur la transcription et la mise en oeuvre de l"axe LEADER dans quatre pays : Hongrie, Lituanie, Pologne, République tchèque, a été engagée. Communs à tous les Etats membres de l"UE, les objectifs de la Politique Européenne de Développement Rural peuvent être déclinés de manière flexible (selon un « menu » de mesures) afin de tenir compte de la spécificité des contextes économiques et sociaux nationaux. Chaque Etat membre est responsable de la transposition des priorités de la PEDR, sous forme de programmes intégrés à sa stratégie nationale de développement rural. Dés lors, la question est de savoir comment s"opère le processus de transcription et quels effets politiques, économiques et sociaux on peut en attendre. De manière à fonder l"étude comparative en toute rigueur, notre groupe de recherche a élaboré une méthodologie commune (protocole d"enquête auprès des acteurs, analyse des systèmes d"action et des territoires de projet, examen des stratégies et des projets)2 . L"attention se porte sur les modalités de transposition de l"axe LEADER dans les nouveaux Etats membres, les canaux de diffusion et les « opérateurs » de transfert, ainsi que sur les conditions de réception du nouveau mode d"action publique locale.

Maria HALAMSKA (Professeur de sociologie, Université de Varsovie et Académie polonaise des Sciences, membre correspondant de l"Académie d"agriculture de France) : Le nouveau modèle de développement rural et la PAC : LEADER en Pologne En 2004, l"année de la grande ouverture de l"Union européenne aux nouveaux Etats membres de l"Europe centrale, la Politique agricole commune (PAC) dans sa version « classique » avait déjà épuisé, pour diverses raisons, ses possibilités d"intervention. En raison de ses coûts élevés et des négociations de l"OMC, la PAC était en train de subir une reconstruction substantielle, en intégrant un second pilier de la Politique Européenne de Développement Rural (PEDR) à son action. Ce changement consistait en un passage d"un « développement agricole élargi » à « un développement local intégré » avec des éléments de développement durable. Etant donné la généralisation de la critique du paradigme de la modernisation, la nouvelle PAC proposait un changement de la méthode même de développement, aussi le programme LEADER intégrait-il les ressources et les acteurs locaux dans le processus de développement.

Cette méthode novatrice de développement rural, fondée sur une approche territoriale, les initiatives proposées par les acteurs et les organisations concernées (ou initiatives par le bas), un développement intégré, le rôle important de l"innovation, le partenariat, l"autogestion et la coopération, avait été testée par les anciens Etats membres, sous la forme de l"Initiative communautaire LEADER. Pour la période 2007-2013, elle est devenue le quatrième axe du deuxième pilier de la PAC, financé par le Fonds européen agricole pour le développement rural (FEADER). Cela a modifié les principes de fonctionnement du programme au point que certaines de ses caractéristiques initiales ont subi une épreuve majeure. Cela concerne en particulier les nouveaux Etats membres (NEM).

La Pologne, comme les autres NEM, a eu l"occasion d"expérimenter le modèle LEADER, entre 2004 et 2006, sous la forme du Programme Pilote LEADER+ qui faisait partie du programme sectoriel opérationnel « Restructuration et modernisation du secteur alimentaire et développement des territoires ruraux » avec un budget de 30 440 000 EUR, soit 1,7% du budget du programme sectoriel opérationnel. Il a été réalisé en deux phases, auxquelles ont pris part respectivement 167 et 150 groupes d"action locaux (GAL). 35% des communes, occupant plus du tiers de la superficie de la Pologne et représentant plus de la moitié de la population rurale nationale, ont participé à ces partenariats. Du point de vue du sociologue, il s"agissait d"une expérience intéressante de mise en oeuvre centralisée d"une méthode endogène de développement rural.

Lors de la période de financement 2007-2013, LEADER fonctionne en Pologne en tant que quatrième axe du deuxième pilier du Plan de développement des Territoires ruraux, (Program Rozwoju Obszarów Wiejskich ou PROW) doté d"un budget de 787 000 000 EUR, soit 4,7% du budget total du Programme. En tant qu"axe transversal, LEADER peut mettre en oeuvre les objectifs des trois autres axes, et en particulier ceux du troisième : l"amélioration de la qualité de vie en milieu rural et l"encouragement à la diversification de l"économie rurale. L"administration de cet axe est déconcentrée et sa mise en oeuvre confiée aux organes d"autogestion des voïvodies (collectivités territoriales de niveau NUTS 2). Ces derniers n"ont toutefois qu"une influence limitée sur la forme des projets réalisés parce que des critères stricts d"évaluation ont été fixés par le Ministre de l"Agriculture. Le financement du programme reste, lui, centralisé.

Partout en Pologne, la phase initiale de la mise en oeuvre du programme a été considérée comme un succès. Les collectivités locales ont mobilisé leurs services pour créer un réseau dense de GAL : ils sont au nombre d"environ 350 et couvrent presque 90% de la surface du pays. Leur création et la préparation des stratégies du développement local ont reçu des aides multiples, y compris financières. Le but principal de cette opération a consisté à attirer le maximum de moyens de développement vers une région donnée, parfois selon le principe : « il y a des moyens, il faut donc créer les structures requises pour en profiter ». C"est une des raisons pour lesquelles la réalisation du programme s"avère difficile : à la fin de l"année 2010, les contrats n"étaient signés que pour 17% du budget du quatrième axe.

Le programme qui a représenté en Pologne une source d"espoirs multiples, apporte à présent de nombreuses déceptions à ses participants et partisans. Les recherches conduites dans le cadre du projet ALDETEC montrent les difficultés liées au transfert de ce modèle de développement rural en Europe centrale. Du point de vue du sociologue, ces difficultés se situent principalement à deux niveaux : d"abord, à celui des structures très complexes de mise en oeuvre du programme ; ensuite, en raison de certaines caractéristiques propres aux sociétés locales (la passivité des citoyens correspondant à une attitude des leaders locaux digne des « démocrates de l"âge des Lumières », le niveau faible du capital humain et social des participants) qui éclairent la « municipalisation » du programme LEADER.

En Pologne, le processus de décentralisation n"est qu"apparent, la bureaucratie est plus importante encore que celle qui règne à Bruxelles (un fait qui se rencontre aussi dans les anciens Etats membres).

Pascal CHEVALIER (Maître de Conférences en géographie, Université Montpellier 3), Marie-Claude MAUREL (Directrice d"études à l"Ecole des hautes études en sciences sociales) : Le développement local en Hongrie et en République tchèque : une entreprise de « leadership » politique ?

En Hongrie comme en République tchèque, la PEDR s"applique à des espaces ruraux qui émergent d"une période de recomposition des activités (diversification socio-économique) et de transformation du mode de gouvernance (autonomie des collectivités locales). Le modèle européen de développement local qui leur est proposé dans le cadre de l"axe IV de la PEDR est transcrit par chacun de ces Etats afin d"être mis en oeuvre à l"échelle des territoires ruraux. Cadre de la vie démocratique au niveau local, les communes rurales sont en charge de la gestion des équipements et des services publics de proximité mais en raison de la fragmentation de la trame communale (intervenue au début des années 1990), elles ne disposent ni des compétences ni des ressources nécessaires pour impulser des stratégies de développement local. Celles-ci doivent être conçues et mises en oeuvre à l"échelle d"un territoire d"action regroupant plusieurs collectivités locales et impliquant des partenariats élargis à diverses catégories d"acteurs sociaux.

A partir des recherches empiriques conduites à l"échelle des Groupes d"action locaux (GAL) constitués pour mettre en oeuvre l"axe LEADER de la PEDR dans chacun de ces pays, la communication a analysé le rôle des élus locaux dans la structuration des scènes de concertation locales et la manière dont ils coordonnent l"action publique en termes d"orientation des stratégies et de sélection des projets de développement local. A partir de l"examen de la configuration des partenariats locaux, du rôle des diverses catégories d"acteurs (élus, entrepreneurs, responsables associatifs), de la nature des intérêts qui sous-tendent stratégies et projets, la recherche interroge la transformation du mode d"action publique locale.

Définie et formulée au niveau européen, la PEDR est transcrite de manière différente par les acteurs étatiques et incorporée dans leur système de gouvernance territoriale selon des logiques politiques qui leur sont propres. A une logique démocratique faisant sa place à une construction ascendante de l"action publique (bottom-up) qui l"emporte en République tchèque, s"oppose une logique bureaucratique imposant des contraintes normatives fortes aux initiatives locales et un pilotage par le haut (top-down) des procédures, en Hongrie. Ces logiques se traduisent par la mise en place de territoires d"action de conception radicalement différente en termes de couverture du territoire et d"articulation avec les espaces institutionnels. La structuration des systèmes d"action au niveau local est abordée à travers la composition des partenariats des GAL et l"analyse de leurs réseaux d"acteurs. Les élus locaux, qui sont le plus souvent à l"initiative de la constitution des GAL, occupent une place centrale tant par leur implication dans l"activité du GAL que par la notoriété dont ils jouissent auprès des autres acteurs locaux. Le positionnement d"un petit nombre de maires révèle l"établissement d"un véritable leadership politique sur la scène de concertation locale.

L"examen des projets sélectionnés et réalisés par les GAL montre que les porteurs sont majoritairement des municipalités tandis que la nature des projets atteste de la priorité donnée aux équipements publics et aux infrastructures. Enfin la répartition géographique des projets (concentration versus dispersion) éclaire le type de rapports de force existant sur la scène intercommunale entre les municipalités et leurs édiles. Le leadership politique local s"est emparé d"un modèle de développement dans lequel il voit un instrument de rattrapage des équipements publics et une source de légitimation de son action.

Jurgita MAČIULYTĖ (Maître de Conférences en géographie, Université de Vilnius), Marc DEDEIRE (Maître de Conférences en aménagement, Université Montpellier 3) : Communautés rurales et initiatives locales en Lituanie Pour comprendre le développement local en Lituanie, il faut avant toute chose apprécier le rôle des héritages sociaux, économiques et spatiaux dans le fonctionnement des territoires. Pendant l"époque soviétique, l"exploitation agricole collective constituait le cadre territorial et institutionnel de la vie des communautés rurales. Regroupant plusieurs localités villageoises qui avaient progressivement perdu leurs fonctions économiques et sociales, les exploitations agricoles (kolkhozes et sovkhozes) constituaient les territoires concrets dans lesquels s"inscrivaient la vie et les activités des populations rurales. Au lendemain de la décollectivisation, la situation de faillite de nombreuses « associations agricoles » ayant pris le relai des structures collectives et le processus de dégradation des équipements collectifs socioculturels ont provoqué une profonde mutation du fonctionnement des sociétés locales, susceptible de menacer leur survie. Le vide institutionnel, laissé par la disparition de la grande exploitation collective, n"a pas été comblé par la reconnaissance de l"autonomie des collectivités locales comme cela a été le cas dans d"autres pays d"Europe centrale.

Dès le milieu des années 1990, un mouvement social original, d"auto organisation des citoyens, a émergé qui a pris le nom de « communautés rurales ». Ces communautés rurales apportent une réponse au vide institutionnel. Renouant avec un maillage villageois pré-soviétique, elles signent le retour d"un maillage concret et opérationnel mais qui ne bénéficie d"aucune reconnaissance institutionnelle officielle. Ces communautés rurales ont le statut d"organisations non gouvernementales, souvent créées à l"initiative des femmes les plus instruites résidant à la campagne (institutrices, responsables de centres culturels).

Quelle place ces communautés rurales prennent-elles à présent dans le développement local en Lituanie ? Si pendant la première décennie de leur existence, leurs activités étaient principalement orientées vers un renforcement des liens sociaux entre les habitants des communautés locales, depuis l"arrivée du programme LEADER, source principale du financement du développement rural en Lituanie, ces communautés rurales souhaitent territorialiser leur présence en misant sur des stratégies et des projets plus concrets. Par l"aménagement de lieux de rencontre et de convivialité, par la création d"espaces publics pour le sport et les loisirs, les projets matérialisent l"existence des communautés rurales bien au-delà de l"institutionnalisation de réseaux d"acteurs sociaux sous la forme de groupes d"action locaux.

Le financement des projets, sur les fonds du programme LEADER, ne pouvant être que partiel, le travail bénévole des habitants permet d"apporter les ressources complémentaires nécessaires à leur réalisation. A travers une logique d"organisation « par le bas », c"est l"autonomie d"action de la communauté locale qui s"exerce, les relations entre individus qui se tissent, le capital social qui se renforce. Le nouveau mode d"action locale peut être décrit à partir de l"analyse de quelques projets issus de l"initiative des communautés rurales participant au Groupement d"Action Locale du district de Joniškis (au nord de la Lituanie). Ce GAL repose sur l"existence de réseaux communautaires denses qui assurent une bonne mise en oeuvre du programme LEADER ainsi qu"une forte adéquation des projets aux besoins des populations locales ainsi qu"aux potentialités et ressources du territoire local.

Conclusion

Les débats qui ont suivi ont permis de mettre en évidence les premiers enseignements que l"on peut tirer du transfert de l"approche LEADER dans les NEM d"Europe centrale. Sa mise en oeuvre politique est-elle fidèle aux principes qui fondent le modèle de développement local ? Quel est l"impact de son introduction sur le fonctionnement de la démocratie locale ? Telles sont les questions qui suscitent le plus d"interrogations.

Parce qu"elle met en relation divers niveaux de gouvernement (européen, national et local), l"approche LEADER permet d"appréhender de quelle manière le processus d"européanisation pénètre de nouveaux espaces d"action publique, à un niveau pertinent pour coordonner les initiatives des acteurs dans une perspective de développement local de type endogène. L"approche LEADER se définit par la cohérence d"ensemble des principes qui la spécifie. Or, les modalités de transposition du modèle LEADER dans les divers contextes nationaux peuvent venir modifier certaines de ses caractéristiques spécifiques. Dans son rôle d"opérateur de transfert, l"acteur étatique peut encadrer et réglementer l"application de la politique européenne de développement rural au point d"en réduire la portée novatrice. Le respect du caractère décentralisé du nouveau mode d"action publique s"accommode mal des contraintes réglementaires qu"il s"agisse de l"imposition d"un agenda et de procédures, des critères de délimitation des périmètres d"intervention ou des prescriptions concernant la présentation des stratégies de développement. Encadrée par un Ministère de l"Agriculture interventionniste, comme c"est le cas en Hongrie, l"approche LEADER peut être déviée de son but pour devenir un instrument au service d"une politique visant à assujettir les territoires ruraux à une programmation normative. En Pologne, le Ministère de l"Agriculture n"intervient pas moins dans la réglementation qui encadre la formation des GAL et l"élaboration de leurs stratégies même si la mise en application de cette politique publique est confiée aux collectivités territoriales de niveau régional. Le Ministère de l"Agriculture tchèque se montre plus fidèle à l"esprit animant le modèle LEADER puisqu"il laisse les groupes d"action locale s"organiser librement dans le cadre de regroupements volontaires sur une base intercommunale. Les choix politiques opérés par l"acteur étatique pèsent sur les conditions de réception du modèle par les acteurs locaux. Une forte instrumentalisation de l"axe LEADER peut venir limiter la marge de manoeuvre des communautés locales tandis qu"une liberté plus grande accordée aux acteurs locaux pour former les partenariats leur permet de s"approprier le dispositif et de mieux l"adapter au contexte local. de l"axe LEADER peut être vue comme un processus d"apprentissage collectif d"un nouveau mode de gouvernance coordonnée d"un territoire. Fondée sur une logique ascendante (bottom-up), l"approche LEADER devient le vecteur de diffusion d"un nouveau modèle d"action collective de nature à contribuer à la transformation de sociétés rurales qui portent l"empreinte de l"ancien système politique et social. Une telle approche est vue comme le moyen approprié pour stimuler l"implication des acteurs locaux, développer le capital social, renforcer la démocratie participative. Pour autant, comme le montrent les recherches présentées, la gouvernance locale n"en sort pas radicalement transformée. Par leur position au sein des réseaux d"acteurs et leur rôle, les maires exercent un véritable leadership. Ils sont les seuls en mesure de mobiliser l"énergie des autres membres des GAL, les compétences des professionnels de l"action publique (les managers), ainsi que les cofinancements indispensables à la réalisation des projets. L"exercice d"un leadership politique, fût-il « bienveillant », n"est pas sans danger pour la consolidation de la participation citoyenne à l"échelon local. L"engagement des membres des GAL, en termes de contribution à l"élaboration des stratégies et au montage des projets, est pour beaucoup d"entre eux réduit à une simple figuration. L"entreprise de « municipalisation » du programme LEADER, observable en Hongrie, Pologne, République tchèque (bien que sous des versions différentes), ne contribue pas à favoriser l"avancée vers une démocratie participative. Un mode d"exercice « paternaliste » du leadership politique peut ralentir l"apprentissage de l"engagement civique à l"échelon local. De manière paradoxale, le vide institutionnel créé par l"absence de collectivités locales en Lituanie permet aux communautés rurales de se mobiliser sur un mode participatif plus spontané. HIGH C., NEMES G., 2007, Social Learning in LEADER: Exogenous, Endogenous and Hybrid Evaluation in Rural Development, Sociologia Ruralis, 47, 2, 103-119.

  -C. , 2003, « Les élus ruraux face à la territorialisation de l'action publique », Revue française de science politique (Vol. 53) /4, 583-606. CHEVALIER P., MAUREL M.-C., 2010, « LEADER w krajach Europy Środkowej. Mechanizmy transferu modelu rozwoju lokalnego» (Policy Transfer of the Local Development Model. The Leader Program Implementation in Central European countries), n°4/2010, Wieś i Rolnictwo, 26-41. HALAMSKA M., MAUREL M.-C., 2010, Les acteurs locaux à l'épreuve du modèle européen LEADER. France-Hongrie-Pologne, IRWIR PAN & CEFRES, Prague, 205 p.

LEADER est l"acronyme de « Liaisons entre actions pour le développement de l"économie rurale ».

Tous les intervenants participent à un projet de recherche financé par l"Agence nationale de la recherche, intitulé « Action locale et développement territorial » (ALDETEC) n°ANR-08-BLAN-0270-01. http://recherche.univ-montp3.fr/artdev/aldetec


Eric Serris
email: serris@emse.fr

Ana Cameirao

Frédéric Gruy

Monitoring industrial crystallization using Acoustic emission

Keywords: particle size, crystallisation, monitoring, industrial processes

Acoustic emission (AE), which has been successfully applied for monitoring a rather wide variety of solids elaboration processes, was almost never evaluated in the field of industrial crystallization for pharmaceutical or chemical products. Few papers reported that crystallization processes give rise to acoustic emission signals that could be related to the development of the basic crystallization phenomena. This study is intended to demonstrate new perspectives opened up by the possible use of acoustic emission (AE) as a non-intrusive and non destructive sensor for monitoring crystallization with a particular focus being put on real industrial processes. The preliminary results of the study will be reported in this work namely concerning the ability of the EA to follow the crystallization processes under different operating conditions and different types of crystallisation, and the obtained crystals in terms of particle size distribution and agglomeration degree.

Introduction

We show that acoustic emission (AE) is a very attractive non-intrusive technique for monitoring crystallization processes. AE has been successfully applied in many fields of material sciences [START_REF] Marec | Damage characterization of polymerbased composite materials: Multivariable analysis and wavelet transform for clustering acoustic emission data[END_REF] and it was also used in the pharmaceutical industry for monitoring various chemical engineering processes [START_REF] Boyd | The uses of passive measurement of acoustic emissions from chemical engineering processes[END_REF] including fluidized bed granulation [START_REF] Hansuld | Audible acoustics in highshear wet granulation: Application of frequency filtering[END_REF], fluidized bed coating [START_REF] Naelapää | Acoustic monitoring of a fluidized bed coating process[END_REF], powder compaction [START_REF] Salonen | Monitoring the acoustic activity of a pharmaceutical powder during roller compaction[END_REF][START_REF] Serris | Acoustic emission of pharmaceutical powders during compaction[END_REF], etc. However, few studies deal with the use of AE to monitoring crystallization processes [START_REF] Lube | In-process monitoring of crystal perfection during melt growth[END_REF][START_REF] Sawada | Acoutics Emission from Phase Transition of Some Chemicals[END_REF][START_REF] Chotard | Effect of malic and citric acid on the crystallisation of gypsum investigated by coupled acoustic emission and electrical conductivity techniques[END_REF][START_REF] Betteridge | Acoustic Emissions from Chemical Reactions[END_REF]. The objective of this work is to evaluate the potential for using acoustic emission to monitor batch crystallization. The basic concept behind AE monitoring of crystallization processes is that the phase transitions occurring during crystallization in solution induce physicochemical changes in the suspension. Such changes release energy and therefore generate acoustic elastic waves propagating in the liquid medium [START_REF] Head | Crystalloluminescence[END_REF]. Furthermore, as crystal particles are generated, the elastic properties of the dispersed phase also change. The latter changes affect the acoustic emission caused by the particle collision impacts and inter-particles and/or particles-wall frictions. In this present work, -we will only consider particles impacts and the influence of several parameters on it.

Materials and Method

Acoustic emission on crystallisation vessel

As displayed in Fig. 1, a 3 L glass vessel equipped with a jacket was used for the experiments. The jacket is baffled and a centrifugal pump forces the circulation. Stainless -steel baffles and a high efficiency propeller (Mixel TT TM) are used to maintain a good homogeneity of particles in the slurry. The temperature is set at 20°C and the rotating speed of the impeller is 300 rpm. The energy of reference (600 atto Joules) and a threshold of acquisition (30 dB) were given starting from measurements taking of account the electromagnetic environment, the agitation and the flow of coolant on the level of dual envelope.

Powders

Two powders we used in this study, adipic acid and also citric acid. Sigma Aldrich provided both powders and the purity is above 99%. In the table 1 The solubility is given by the work done by Apelblat et al [START_REF] Apelblat | Solubility of oxalic, malonic, succinic, adipic, maleic, malic, citric, and tartaric acids in water from 278[END_REF]. The density is obtained by helium pycnometer (accupyc from micrometrics) and the D50 by laser granulometry using the sirocco device of the Mastersizer 2000 (Malvern).

Experimental procedure

We only want to study the influence of several parameters of crystallisation on acoustic emission, that's why the solutions must be at a saturation state. The first step of experiments is the dissolution of the two products in order to achieve the saturation stage. Sufficient amount of powder is dropped into the water in order to dissolve all particles. We consider that this stage is achieved when no particles are observed in the vessel. This stage is at least three hour for citric acid and two hours for adipic acid. The next step of experiment is to drop a certain amount of powder inside the solution and then change the volume fraction, the rotating speed or the particle size and records the associated acoustic emission.

Results and discussion

This work on acoustic emission on monitoring industrial crystallization will only consider the impacts of particles and the sensibility of the AE to several parameters such as volume fraction, rotating speed and also particle size. Previous work [START_REF] Gherras | Monitoring Industrial Pharmaceutical Crystallisation Processes Using Acoustic Emission[END_REF] shows that crystallization processes like nucleation and growth is also responsible for AE, but this will not be included in this work.

Acoustic emission during dissolution

First we discuss on some acoustic event that occur during the dissolution stage of citric acid and then of adipic acid.

Citric acid

The first experiment on citric acid is recorded after dissolving a large amount of powder (2kg) in 1L of pure water. We show the evolution of AE amplitude during three hours after the introduction of 500 g of citric acid in order to reach a supersaturated state. This evolution is plotted in figure 3. Two periods (from 0 to 1000s and from 5000s to 6000s) of acoustic activity is observed. The first one is the dissolution and the particles impacts of the powders. The other one is not obvious. Normally nothing changes during this period of dissolution. In order to have an idea of what may happen during this period, let's have a look on the evolution of centroid frequency versus time. The centroid frequency of dissolution phenomena is generally under 200 khz but for the second part of ÀE activity the frequency is above 200 khz. In oxalate ammonium crystallisation in Gherras work [START_REF] Gherras | Monitoring Industrial Pharmaceutical Crystallisation Processes Using Acoustic Emission[END_REF] is generally near 250 khz for nucleation and/or growth of particles. We can consider that, thanking into account the fact that we are above the supersaturation stage, we have a crystallisation of citric acid during this period.

For this reason and also for the strong viscosity of the solution due to the high concentration of citric acid, we change to adipic acid system for the following results.

Adipic acid

The first experiment on adipic acid is recorded after dissolving 16g of powder in 2L of pure water. We show the evolution of AE amplitude during three hours after the introduction of 8 g of adipic acid in order to reach a supersaturated state. This evolution is plotted in figure 5. In this case, we observe in the vessel that the powder is on the surface of the water; the wettability of the adipic acid is not good. That's why a large number of AE counts are recorded by 2000s and 3000s when the powder sink into the water and the dissolution occur. The dissolution and particles impacts are responsible of this AE. In order to have a better idea of this AE, the evolution of centroid frequency versus time is plotted in figure 6. At the beginning the AE frequency is centred around 175 kHz, and then the frequency dropped and is between 100 and 175 kHz. This may be the related frequency of dissolution of adipic acid that is different to the frequency of particle impact. So we can characterize both AE. In the following results we change the experimental procedure by adding surfactant to overcome the poor wettability of adipic acid.

Influence of volume fraction

We want now know the sensibility of AE to the volume fraction  of particles inside the vessel. After dissolving 16g of adipic acid with surfactants in 2L of pure water and waiting for total dissolution, we introduce different quantity of powder by adding it with a funnel. After several tests, we decide to introduce from 0,001 up to 0,02 of volume fraction. In table 2, we have the experimental procedure of the different stages of volume fraction, introduced mass of adipic acid versus time.

Time (s) Volume fraction

Total introduced mass (g) 0-1800s 0,001 2,72 1800-3600s 0,005 13 3600-5000s 0,01 27,5 In figure 7, cumulative counts versus time of this experiment are plotted. First, we notice that around 100000 counts are recorded when we introduce the particle inside the vessel. This is the AE of the sliding particles in the funnel. We only want the AE between those two very emissive events. That's why we will analyse the AE amplitude versus time of figure 8. We have also the AE of the introduction of particles with amplitude up to 80dB. For the first volume fraction, AE is recorded in the beginning then weak AE is detected (may be the background noise).

Influence of rotating speed

We want now know the sensibility of AE to the rotating speed of the impeller. After dissolving 16g of adipic acid with surfactants in 2L of pure water and waiting for total In figure 9, cumulative counts versus time of this experiment are plotted. We easily notice that the number of counts increases with increasing rotating speed. With higher rotating speed, the velocity inside the vessel is higher and the particle impacts are more numerous and more energetics. The stability of AE is quite good because we can draught straight line of number of counts versus time. The slope of the line may be in relation with the number of particles and the size of particles. This will be discussed in the last part of this work.

Influence of particle size

In this part, we sieve the adipic acid powder into two different granulometrics classes, big particles (250-500 µm) and small particles (50-125µm). After dissolving 16g of adipic acid with surfactants in 2L of pure water and waiting for total dissolution, we change rotating speed from 300 rpm to 500 rpm with the sieved particles .In figure 10 cumulative counts versus time is shown of the experimental part of 500 rpm in order to have the better differences between the AE of particles. The big particles are represented by the cluster in green dots 2 and the small one by the purples ones 3. We have more counts for big particles and we have also a linear slope for AE counts versus time like in figure 9. The AE is related to the particle size, and we try to assign one AE characteristic by looking at the variation of centroid frequency versus time plotted in figure 11. In this figure, the big particles are represented by the cluster in green dots 2 and the small one by the purples ones 3. We notice that the centroid frequency is lower for big particle and the range is broader (175 to 300 kHz) than those for smaller particles. So we can use AE to estimate particle size distribution by using may be several sensors and filters in order to have specific response to precise particle size. In this case, we can monitor crystallisation in order to stop the process when a certain size is reached.

Conclusions

In this study of monitoring industrial crystallization using acoustic emission, several interesting results are obtained. We can notice that we can distinguish different phenomena with different centroid frequencies. The crystallisation can be characterized with frequencies above 200 kHz (figure 4), the dissolution with frequencies down to 100 kHz and for all the particles impacts (figure6). We can detect particles (with this sensor and this experimental procedure) when the volume fraction inside the vessel is above 0,05. Further work must be done in this field to try to detect particle with lower volume fraction. One way can be by increasing rotating speed because the AE is far higher with a speed of 50 rpm for example. To conclude we can distinguish the particle size with AE because the AE signature is changing with particle size.

Figure 1 :

 1 Figure 1 : Experimental apparatus

Figure 2 :

 2 Figure 2 : Main characteristics of acoustic emission

Figure 3 :

 3 Figure 3 : Amplitude of AE (dB) versus time(s).

Figure 4 :

 4 Figure 4 : Centroid frequency (kHz) versus time (s)

Figure 5 :

 5 Figure 5: Cumulative counts versus time (s)

Figure 6 :

 6 Figure 6: Frequency centroid (khz) versus time (s)

Figure 7 :

 7 Figure 7: Cumulative counts versus time (s)

Figure 8 :

 8 Figure 8: Amplitude of AE (dB) versus time(s).

Figure 9 :

 9 Figure 9: Cumulative counts versus time (s)

Figure 10 :

 10 Figure 10: Cumulative counts versus time (s)

Figure 11 :

 11 Figure 11: Frequency centroid (kHz) versus time (s)

table 1 : physic-chemical properties of powders

 1 , the list of the physical properties is given:

		Density	Solubility	D50
	Adipic acid	1,36 g.cm3	8 g .L -1	250 m
	Citric acid	1,66 g.cm3	2000 g .L -1	500 m

table 2 : experimental procedure

 2

table 3 : experimental procedure with evolving rotating speed

 3 32nd European Conference on Acoustic Emission Testing (EWGAE 2016), Czech Republic, Prague, September 07-09, 2016 dissolution, we change rotating speed from 300 rpm to 500 rpm. In table3, we have the experimental procedure of the different steps of rotating speed versus time.

	Time (s)	Rotating speed
	2500-5200 s	300 rpm
	5500-7200 s	400 rpm
	7200-9000 s	500 rpm
	9000-10800 s	400 rpm
	10800-12600 s	300 rpm

32nd European Conference on Acoustic Emission Testing (EWGAE 2016), Czech Republic, Prague, September 07-09, 2016

32nd European Conference on Acoustic Emission Testing (EWGAE 2016), Czech Republic, Prague, September 07-09, 2016

This work must be proceed by further investigation with other products, other sensors and also vessel to better understand all the AE sources and the AE signature.