MD, MSc Vincent Auffret
email: vincent.auffret@chu-rennes.fr

MD Clément Laurin

MD a , Guillaume Leurent

MD Romain Didier

MD c , Emmanuelle Filippi

MD d , Jean-Philippe Hacot

MD Amer Zabalawi

MD f , Gilles Rouault

MD g , Djamel Saouli

MD h , Philippe Druelles

MD Isabelle Coudert

MD j Bertrand Boulanger

MD k , Emilie Bot

MD Josiane Treuil

MD a , Marc Bedossa

MD a , Dominique Boulmier

MD a , Aurélie Loirat

MSc Sam Sharobeem

MSc Marielle Le Guellec

MD, PhD Martine Gilard

MD Hervé Le Breton

Pharmacoinvasive Strategy Versus Primary Percutaneous Coronary Intervention For ST-Segment Elevation Myocardial Infarction In Patients ≥ 70 Years of Age Running head: Pharmacoinvasive strategy in older STEMI patients

Keywords: STEMI, older patients, pharmacoinvasive strategy, primary percutaneous coronary intervention

The benefit-risk ratio of a pharmacoinvasive strategy (PI) among patients ≥70 years of age with ST-segment elevation myocardial infarction (STEMI) remains uncertain resulting in its limited use in this population. This study compared efficacy and safety of PI with primary percutaneous coronary intervention (pPCI). Data from 2841 patients (mean age: 78.1±5.6 years, female: 36.1%) included in a prospective multicenter registry, and who underwent either PI (n=269) or pPCI (n=2572), were analyzed. The primary endpoint was in-hospital major adverse cardiovascular events (MACE) defined as the composite of all-cause mortality, non-fatal MI, stroke and definite stent thrombosis. Secondary endpoints included all-cause death, major bleeding, net adverse clinical events and the development of in-hospital Killip class III or IV heart failure. Propensityscore matching and conditional logistic regression were used to adjust for confounders. Within the matched cohort, rates of MACE was not statistically different between the PI (n=247) and pPCI (n=958) groups, (11.3% vs. 9.0% respectively, OR: 1.25, 95% CI: 0.81-1.94; p=0.31). Secondary endpoints were comparable between groups at the exception of a lower rate of development of Killip class III or IV heart failure after PI. The rate of intracranial hemorrhage was significantly higher in the PI group (2.3% vs. 0.0%, p=0.03). In conclusion, the present study demonstrated no difference regarding in-hospital MACE following PI or pPCI in STEMI patients ≥ 70 years of age. An adequately-powered randomized trial is needed to precisely define the role of PI in this high-risk subgroup.

INTRODUCTION

Guidelines for patients with ST-segment elevation myocardial infarction (STEMI) recommend timely primary percutaneous coronary intervention (pPCI) as the preferred reperfusion strategy [START_REF] Keeley | Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials[END_REF]. If timely pPCI cannot be performed, a pharmacoinvasive strategy (PI) is recommended within 12 h of symptom onset in patients without contraindications [START_REF] Armstrong | Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction[END_REF][START_REF] Danchin | Impact of prehospital thrombolysis for acute myocardial infarction on 1-year outcome: results from the French Nationwide USIC 2000 Registry[END_REF][START_REF] Bonnefoy | Comparison of primary angioplasty and pre-hospital fibrinolysis in acute myocardial infarction (CAPTIM) trial: a 5-year follow-up[END_REF]. Largest benefits are seen among early presenters (<2-3h of symptom onset) with anterior STEMI [START_REF] Boersma | Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour[END_REF].

Older patients have a higher STEMI-related morbi-mortality [START_REF] Alexander | Acute coronary care in the elderly, part II: ST-segment-elevation myocardial infarction: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology[END_REF], and remain undertreated or subject to major delays to pPCI (7). To date, only few studies specifically reported the outcomes of PI among older patients with STEMI because they were often excluded from randomized trials therefore resulting in an uncertain benefit/risk ratio [START_REF] Koeth | Clinical benefit of early reperfusion therapy in patients with ST-elevation myocardial infarction usually excluded from randomized clinical trials (results from the Maximal Individual Therapy in Acute Myocardial Infarction Plus [MITRA Plus] registry)[END_REF]. Although age per se is not an absolute contraindication in guidelines [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF], this results in a lower use of PI in older patients in clinical practice mainly owing to the reluctance of physicians to use such a therapy in these patients usually at higher bleeding risk. The present study compares efficacy and safety of PI with pPCI in patients ≥70 years of age enrolled in a large prospective registry.

METHODS

This observational study used data from the Brittany Regional Infarction Observatory (Observatoire Régional Breton sur l'Infarctus, ORBI) that prospectively includes from 2006 all patients admitted to one of 9 participating pPCI-capable centers for STEMI, within 24h of symptom onset [START_REF] Auffret | Predicting the development of in-hospital cardiogenic shock in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention: the ORBI risk score[END_REF]. The centralized database used for the present study contains demographic and electrocardiographic data, treatments, time intervals and in-hospital events. This registry was approved by the Commission Nationale de l'Informatique et des Libertés and the study protocol was approved by the local ethics committee. Patients enrolled in ORBI between June 2006 and June 2016, aged ≥ 70 years old and treated by PI or pPCI were included in this analysis and compared. Patients aged ≥ 70 years old who received no reperfusion therapy at the acute phase 4 regardless of the performance of coronary angiography or secondary PCI during the index hospitalization were excluded from the analysis (Figure 1). STEMI was defined according to the universal definition of myocardial infarction [START_REF] Thygesen | Fourth universal definition of myocardial infarction[END_REF].

First medical contact (FMC) was defined as the time point when the patient was assessed by a physician able to obtain, and interpret an electrocardiogram, and deliver the appropriate initial interventions [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF]. FMC-to-pPCI delay was defined as the time from FMC to the first thromboaspiration or balloon inflation. Total ischemic time was defined as the time between symptom's onset and pPCI or fibrinolysis (i.e. start of the fibrinolytic infusion). FMC-totreatment delay was categorized according to the 2012 European STEMI guidelines [START_REF] Steg | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF] as beyond guidelines delay if > 30 min in patients treated by fibrinolysis, > 60 min in patients directly admitted to a pPCI-capable center, and > 120 min in the other patients treated by pPCI. Patients were managed according to participating centers' local protocols, which followed European guidelines at use at the time of patient's enrollment. Consequently, among patients who received PI, a full-dose of a fibrin-specific agent (tenecteplase: 96%; reteplase: 4%) was administered regardless of age as the study period predated the recent class IIaB recommendation of using a half-dose tenecteplase in patients ≥ 75 years of age [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF]. The choice of guidelinesrecommended co-therapies (antiplatelet and anticoagulant drugs) was left at the discretion of the attending physician.

Development of in-hospital

5

The primary endpoint of the study was in-hospital major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, non-fatal MI, stroke and definite stent thrombosis (ST) according to the Academic Research Consortium definition. Secondary endpoints included all-cause death, major bleeding recorded since the inclusion of the Bleeding Academic Research Consortium (BARC) definition in the ORBI database in 2011 and defined as BARC 3 or 5 bleeding, net adverse clinical events (NACE) defined as the composite of MACE and major bleeding, and calculated among patients with data regarding in-hospital BARC-defined bleeding events, and development of in-hospital Killip class III or IV heart failure.

Categorical variables were summarized as number (percentages) and compared using Chisquare or Fisher exact tests. Continuous variables were expressed as median (interquartile range, IQR) and compared using the Mann-Whitney test. The primary analysis was performed using propensity score-matching [START_REF] Heinze | An overview of the objectives of and the approaches to propensity score analyses[END_REF]. The propensity-score was developed using a non-parsimonious logistic regression model with the reperfusion strategy as the dependent variable and including all baseline characteristics listed in Table 1 at the exception of the GRACE and TIMI scores which include numerous characteristics already listed in Table 1. The c-statistic of the model of 0.81 (95% confidence interval [CI]: 0.78-0.84) showed good discrimination with adequate calibration (Hosmer-Lemeshow p=0.21). A 1-to-5 nearest neighbor matching without replacement with a caliper of 0.2 x SD (logit of the propensity score) was performed. The balance between matched groups was evaluated by the analysis of the standardized differences before and after matching.

An absolute value of < 0.1 after matching was considered an adequate reduction of baseline imbalance. In the matched population, multivariable conditional logistic regression was used to calculate adjusted odds-ratio (OR) with their corresponding 95% CI for reperfusion strategies regarding the occurrence of the endpoints while adjusting for admission to a non-PCI capable hospital, which despite adequate reduction of baseline imbalance as assessed by standardized differences demonstrated a significant absolute numerical difference between matched groups. As 6 a sensitivity analysis, a propensity score-adjusted logistic regression was performed in the entire population to confirm the results of the primary analysis. In this analysis, missing data were assumed to be missing at random and handled by chained equations multiple imputations. Overall, 1.6% of data were missing and a total of 23.3% of patients had at least 1 missing value. Ten complete datasets were generated and the propensity score was calculated within each dataset using the above described methodology. Multivariable logistic regression adjusted on the propensity score was then performed. Results were expressed as adjusted OR (95% CI) and pooled using Rubin's rule. Statistical analysis was performed with the use of Statistical Package for Social Sciences version 22 (SPSS, Chicago, IL, USA). All tests were 2-sided at the 0.05 significance level.

RESULTS

A total of 2841 patients (mean age: 78.1±5.6 years; female: 36.1%) aged ≥ 70 years old were included, among them 269 patients underwent PI and 2572 were treated by pPCI (Figure 1).

Patients ≥90 years of age represented 1.1% and 3.2% of the PI and pPCI group, respectively (p=0.06). Baseline characteristics and in-hospital outcomes of patients who received no reperfusion therapy are compared with those of patients who received reperfusion therapy (either PCI or fibrinolysis) in supplementary Tables 1 and2. The management strategy evolved over time with an increasing rate of pPCI from 78% in 2006-2007 to 95% in 2014-2016. During the study period, a non-significant trend towards a lower symptom's onset-to-FMC delay was observed (Jonckheere-Terpstra test p=0.085). However, no such trend was apparent for the FMCto-pPCI delay (p=0.93). There was no significant difference in rates of patients treated within guidelines-recommended delays over time (p=0.84). Patients with a symptom's onset-to-FMC delay >12h represented only 2.9% and 0.8% of pPCI and PI patients, respectively (p=0.06). Total ischemic time was significantly lower among PI patients: 180 (115-280) min vs. 227 (165-335) min (p<0.001). Baseline characteristics of patients are listed in table 1. Procedural and in-hospital 7 management of the study population are described in table 2. The median delays from failed fibrinolysis to angiography, and PCI were 115 min (98.5-162.5), and 138 min (110-185), respectively. The median delays between successful fibrinolysis and angiography, and PCI were 260 min (115-1500), and 1185 (152-2785), respectively. MACE occurred in 31 patients (11.5%) in the PI group compared with 270 patients (10.5%) in the pPCI group (p=0.68) (Table 3). There was no significant interaction between the reperfusion strategy and age group or total ischemic time regarding the occurrence of MACE (Figure 2). Patients requiring rescue PCI had numerically higher rates of in-hospital adverse events than patients with successful fibrinolysis or Ppci (Supplementary Table 3).

Supplementary Table 4 provides a comparison of baseline characteristics of patients with and without data regarding BARC-defined bleeding events. BARC-defined major bleeding and NACE were numerically higher in PI recipients (7.0% vs. 4.5%, p=0.28 and 17.4% vs. 13.8%, p=0.44, respectively). Of note, rates of intracranial hemorrhage were significantly higher in the fibrinolysis group (2.3% vs. 0.3%, p=0.04). Supplementary Table 5 summarizes bleeding sites according to treatment group. As an exploratory analysis, we compared the characteristics of PI patients with and without MACE (supplementary table 6). Patients who experienced MACE tended to have more diabetes mellitus, more often presented with a history of myocardial infarction, and with severe heart failure on admission. They also had higher levels of serum creatinine, and glycemia on admission, and higher GRACE, and TIMI STEMI risk scores.

Among pPCI patients, the rate of development of Killip class III or IV heart failure was higher (8.6%) than in PI patients (3.4%,p=0.004). This trend was more pronounced among patients with anterior STEMI (12.0% vs. 4.2%, p=0.013) compared with their non-anterior STEMI counterparts (6.1% vs. 2.7%, p=0.098). Moreover, the FMC-to-pPCI delay was longer among pPCI patients who developed (median 114 min, IQR: 85-150 min) compared with those who did not developed severe heart failure (median 102 min, IQR: 80-139 min, p=0.018), whereas symptom's onset-to-FMC delays were comparable (median:118 min, IQR: 60-235 min vs. median:105 min, IQR:60-199 min, respectively; p=0.42).

A total 247 patients from the PI group and 958 from the pPCI group whose baseline and procedural characteristics are listed in supplementary tables 7 and 8 were included in the matched cohort. The rate of MACE was not statistically different between the PI and pPCI groups, (11.3% vs. 9.0% respectively, OR:1.25, 95% CI: 0.81-1.94; p=0.31) (table4, Figure 3).

Secondary endpoints were comparable between groups at the exception of a significant difference for the development of Killip class III or IV heart failure favoring the PI group (3.3% vs 9.3%, OR: 0.38, 95% CI : 0.18-0.79 ; p =0.01). There was no significant interaction between treatment effect and total ischemic time (supplementary table 9). Two intracranial hemorrhages occurred, both in the PI group (2.3% vs. 0.0%, p=0.03). Propensity score-adjusted logistic regression was performed in the entire cohort and confirmed the primary analysis results for the primary endpoint (OR = 1.23, 95% CI: 0.78-1.91; p = 0.37) and for secondary endpoints (supplementary Table 10).

DISCUSSION

This analysis of data from a large prospective registry provides valuable insights regarding the use of PI in a STEMI population ≥ 70 years of age which constitutes a large and growing proportion of STEMI patients. The main findings can be summarized as follows: first, PI use was infrequent in older patients, performed in only 9.4% of patients aged ≥ 70 years old. Second, PI use dramatically decreased over the decade studied from 22% to 5%. Third, no difference was observed in MACE and all-cause death between reperfusion strategies. Fourth, in an analysis limited to half of the population, no significant difference was demonstrated in major bleeding between pPCI and PI recipients, although intracranial hemorrhage was more frequent following PI. Fifth, pPCI associated with an increase rate of in-hospital development of severe heart failure.

9

A significant heterogeneity in reperfusion strategies across countries has been reported in a recent European survey with rates of fibrinolysis ranging from 0 to 55% [START_REF] Widimsky | Reperfusion therapy for ST elevation acute myocardial infarction in Europe: description of the current situation in 30 countries[END_REF]. Therefore, providing contemporary data regarding outcomes of PI remains crucial, especially for countries that do not have the pPCI infrastructure or are not able to use it sufficiently to treat the majority of their STEMI patients. Within the French national registry, FAST-MI (15), a gradual decrease in the use of fibrinolysis was observed over time from 37.5% of STEMI patients in 1995 to 6% in 2015. This trend likely reflects improvements in emergency care networks with a higher availability of pPCI. However, it may also translate a certain reluctance of clinicians to perform PI owing to its potentially life-threatening side effects, especially in older patients.

Establishing the efficacy and safety of PI among older patients may be of paramount importance to reduce the proportion of patients who do not benefit from any reperfusion therapy.

The TRIANA trial attempted to address this unmet need but was terminated early after enrollment of approximately half (n=266 patients ≥75 years old with STEMI <6h) of the estimated population. pPCI resulted in a non-significant 30% reduction in the 30-day primary composite endpoint of all-cause mortality, re-infarction, or disabling stroke, compared with fibrinolysis, which is comparable to the present study. Nonetheless, a pooled analysis with two previous reperfusion trials performed in older patients showed the superiority of pPCI over fibrinolysis (without widespread use of coronary angiography and secondary PCI) in reducing death, reinfarction, or stroke at 30 days, suggesting that a lack of statistical power likely impeded the demonstration of significant differences in individual studies [START_REF] Bueno | Primary angioplasty vs. fibrinolysis in very old patients with acute myocardial infarction: TRIANA (TRatamiento del Infarto Agudo de miocardio eN Ancianos) randomized trial and pooled analysis with previous studies[END_REF].

The STrategic Reperfusion Early After Myocardial infarction (STREAM) trial specifically compared a contemporary pharmacoinvasive strategy with pPCI (2) in 1892 patients with STEMI presenting within 3 hours of symptom onset, and in whom pPCI was not feasible within 60min of FMC. This trial established clinical equipoise between PI with a weight-adjusted dose of tenecteplase and pPCI. The 30-day primary endpoint of death, cardiogenic shock, congestive heart 10 failure, or reinfarction occurred in 12.4% of the PI recipients and 14.3% of their pPCI counterparts (p=0.21). Among patients ≥75 years old, the primary endpoint occurred in 26.9% of patients in the PI group and in 29.2% of patients in the pPCI group (p=0.68). Importantly, the original trial protocol was amended after 21% of the intended enrollment to allow halving the bolus of tenecteplase for patients aged ≥75 years because of a high intracranial hemorrhage rate (7.1%). This strategy resulted in a 0% intracranial hemorrhage rate post-amendment, whereas indices of reperfusion and rates of rescue pPCI were comparable to that achieved with full-dose tenecteplase. These data contributed to the recent class IIaB recommendation of using a half-dose tenecteplase in patients ≥75 years of age in the latest European Society of Cardiology Guidelines [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF]. The inclusion period of the present study predating this recommendation, patients received a standard lytic dose, which may explain the crucial finding of a higher rate of intracranial hemorrhage. However, confirmation in a dedicated randomized clinical trial in older adults is required, and will be the purpose of the STrategic Reperfusion in Elderly Patients Early After Myocardial Infarction trial (STREAM-2, NCT 02777580).

A lower risk of development of severe acute heart failure associated with the fibrinolysis strategy was observed in the present analysis. Acute heart failure should be taken under consideration when discussing the reperfusion strategy, especially when the predictable pPCIinduced delay is prolonged [START_REF] Steg | Impact of time to treatment on mortality after prehospital fibrinolysis or primary 16 angioplasty: data from the CAPTIM randomized clinical trial[END_REF][START_REF] Auffret | Incidence, timing, predictors and impact of acute heart failure complicating ST-segment elevation myocardial infarction in patients treated by primary percutaneous coronary intervention[END_REF] . Indeed, the main advantage of PI is its rapid initiation, while pPCI may expose to major delays [START_REF] Pinto | Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy[END_REF][START_REF] Gusto | The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction[END_REF]. The impact of such a pPCI-related delay has been wellevaluated in randomized trials in which this time is relatively limited, yet, in clinical practice it seems to be more prolonged [START_REF] Nallamothu | Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis[END_REF]. A recent meta-analysis of 33 studies reported a 4% to 12% increased risk of new-onset heart failure and a 4% relative increase of incident heart failure during follow-up with every 1-hour delay in time to reperfusion [START_REF] Goel | Association of time to reperfusion with left ventricular function and heart failure in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: a systematic review[END_REF]. Moreover, a meaningful association between longer pPCI-related delays and increased mortality, the survival advantage of pPCI over PI declining in parallel, has been demonstrated [START_REF] Pinto | Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy[END_REF]. Therefore, pPCI may be overused (or misused) in the contemporary era, especially in transferred patients. Indeed, a recent meta-11 analysis of 17 studies demonstrated a 48% increased risk of cardiogenic shock associated with the use of pPCI compared with PI among patients transferred from non-pPCI capable hospitals [START_REF] Siddiqi | Meta-Analysis Comparing Primary Percutaneous Coronary 17 Intervention Versus Pharmacoinvasive Therapy in Transfer Patients with ST-Elevation Myocardial Infarction[END_REF].

Nonetheless, it should be stressed that, regardless of the reperfusion strategy used, a majority of patients included in the present analysis did not meet the ESC guidelines FMC-to-treatment goals. This prolonged delay, previously observed with both reperfusion strategies among older patients [START_REF] Armstrong | Reduced dose tenecteplase and outcomes in elderly ST-segment elevation myocardial infarction patients: Insights from the STrategic Reperfusion Early After Myocardial infarction trial[END_REF], likely highlights clinicians' apprehension of reperfusion therapies despite their welldemonstrated absolute benefit in these high-risk individuals. Continuous efforts are needed to further improve the performance of timely reperfusion in older patients. Some limitations should be acknowledged. Given the retrospective non-randomized design of this analysis, patients included in the PI group likely represent selected "low-risk" patients deemed suitable for PI following physicians' assessment. Propensity score matching does not balance unmeasured confounders, which likely contributed to the reperfusion strategy's selection, between treatment groups. The present study may not be generalizable to all older patients and should not be regarded as supportive of the widespread use of PI in this population.

Loading doses of anti-thrombotic treatments were not systematically reported in the database.

Given the inclusion period, the proportion of drug-eluting stents was low, which may have impacted the results. Major bleeding were recorded since the inclusion of the BARC definition in the ORBI database in 2011, allowing us to analyze the safety of PI in a limited number of patients.

Therefore, a lack of statistical power regarding certain endpoints (e.g. stroke, major bleeding) cannot be ruled out. On the contrary, p-values were not adjusted for multiple comparisons, which implies a risk of type I error regarding other findings (e.g. in-hospital heart failure). We observed a higher rate of intracranial hemorrhage among patients receiving PI, which may reflect the use of full-dose lytics. Nonetheless, important baseline differences between patients treated in routine practice and those included in randomized trials may also explain this detrimental association, which would suggest that we need more stringent selection criteria when considering PI among older patients.

FIGURES LEGEND

  Killip class III or IV heart failure was defined as a maximum Killip class III or IV at any time during the index hospitalization among patients with Killip class I or II at admission. Killip class was determined by local investigators in charge of the patients. Mechanical circulatory assistances included intra-aortic balloon pump, extra-corporeal membrane oxygenation and the Impella left ventricular assist device (Abiomed, Danvers, MA). Mechanical complication was defined as the occurrence of either ischemic mitral regurgitation or ventricular septal rupture. High-degree atrioventricular block was defined as third or second-degree type 2 atrioventricular blocks.

Figure 1 -Figure 2 -

 12 Figure 1-Flow-chart of the study population

Figure 3 -

 3 Figure 3-Results of the primary analysis regarding the primary and secondary endpoints.

Table 1 -Baseline characteristics of the study population

 1

	Variables	Pharmacoinvasive group (n=269)	pPCI group (n=2572)	p-value
	Baseline characteristics
	Age (years)	76.0 (72.0-79.0)	78.0 (74.0-82.0)	<0.001
	70-74	117 (43.5%)	780 (30.3%)
	75-79	92 (34.2%)	794 (30.9%)
	≥80	60 (22.3%)	998 (38.8%)
	Female sex	91/269 (33.8%)	935/2572 (36.4%)	0.45

Table 1 .Table 3 -In-hospital outcomes of the study population

 13

	Outcomes	Pharmacoinvasive group (n=269)	pPCI group (n=2572)	p-value
	Major adverse cardiovascular events	31/269 (11.5%)	270/2572 (10.5%)	0.68
	All-cause death	25/269 (9.3%)	232/2572 (9.0%)	0.97
	Cardiovascular death	22/269 (8.2%)	222/2572 (8.6%)	0.89
	Non-fatal myocardial infarction	4/269 (1.5%)	22/2572 (0.9%)	0.30
	Stent thrombosis	1/269 (0.4%)	27/2572 (1.0%)	0.51
	Stroke	4/269 (1.5%)	12/2572 (0.5%)	0.06
	BARC 3 or 5 major bleeding	6/86 (7.0%)	64/1438 (4.5%)	0.28
	Intracranial hemorrhage	2/86 (2.3%)	4/1438 (0.3%)	0.04
	Net adverse clinical events*	15/86 (17.4%)	199/1438 (13.8%)	0.44
	Development of Killip class III or IV HF	9/267 (3.4%)	220/2546 (8.6%)	0.004
	Sustained ventricular arrhythmias	14/269 (5.2%)	180/2572 (7.0%)	0.33
	New-onset atrial fibrillation	18/269 (6.7%)	278/2572 (10.8%)	0.046
	High-degree atrioventricular block	9/269 (3.3%)	147/2572 (5.7%)	0.14

ACKNOWLEDGMENTS

The authors are indebted to all physicians and clinical research assistants that ensured data collection and monitoring of the ORBI registry.


Sylvain Le Tonquesse

Zelia Verastegui

Helene Huynh

Vincent Dorcet

Quansheng Guo

Valérie Demange

Carmelo Prestipino

David Berthebaud

Takao Mori

Mathieu Pasturel
email: mathieu.pasturel@univ-rennes1.fr

Hélène Huynh

Magnesioreduction Synthesis of Co-Doped beta-FeSi2: Mechanism, Microstructure, and Improved Thermoelectric Properties

Keywords: Iron silicide, Thermoelectrics, Magnesiothermy, Mesostructuration, Stacking faults, Thermal conductivity

come   L'archive ouverte pluridisciplinaire

Introduction

Thermoelectric (TE) materials are being extensively investigated because they enable the direct conversion of (wasted) heat into electricity, and vice versa, through highly reliable solid state devices. [START_REF] Bell | Heating, Generating Power, and Recovering Waste Heat with Thermoelectric Systems[END_REF][START_REF] Petsagkourakis | Thermoelectric materials and applications for energy harvesting power generation[END_REF] The material performances are directly related to the TE gure-of-merit ZT dened as:

ZT = α 2 ρ(κ L + κ e ) T ( 1
)
where α is the Seebeck coecient, ρ the electrical resistivity, κ L and κ e the lattice and electronic contributions to the total thermal conductivity κ and T the absolute temperature.

Large enhancement of ZT and subsequent conversion yield is however challenging due to interrelated physical components. Common strategies consist on the one hand in the opti-2 mization of the power factor, PF = α 2 /ρ, essentially via doping and band engineering, [START_REF] Pei | Band Engineering of Thermoelectric Materials[END_REF] and on the other hand in the reduction of κ L via nanostructuration, porosity/defects engineering and complex alloying. [START_REF] Toraya | Estimation of statistical uncertainties in quantitative phase analysis using the Rietveld method and the whole-powder-pattern decomposition method[END_REF] In the past twenty years, these strategies successfully resulted in TE materials with ZT much higher than 1. 79 Most of these materials, including clathrates, 10 Pd/Te-based alloys [START_REF] Pei | Convergence of electronic bands for high performance bulk thermoelectrics[END_REF] or Hf-containing Heusler phases, [START_REF] Shutoh | Thermoelectric properties of the Ti x (Zr 0.5 Hf 0.5 ) 1-x NiSn half-Heusler compounds[END_REF] are however hardly industrializable candidates because of time and energy consuming syntheses, poor mechanical properties and most importantly chemical compositions including toxic and/or expensive constituents. [START_REF] Leblanc | Materials and manufacturing cost considerations for thermoelectrics[END_REF] From these points of view, β-FeSi 2 is considered as a reasonable candidate for large scale application due to its extremely abundant and ecofriendly constituting elements, and good oxidation resistance. However, the intrinsic TE properties of pristine FeSi 2 are poor, especially due to its high thermal conductivity (16 -17 W m -1 K -1 at 273 K) and electrical resistivity (5 -10 mΩ m at 370 K). [START_REF] Kim | High temperature thermoelectric properties of p-and n-type β-FeSi 2 with some dopants[END_REF] Doping with Co, [START_REF] Kim | High temperature thermoelectric properties of p-and n-type β-FeSi 2 with some dopants[END_REF]15 Al, 15 Mn [START_REF] Gayner | Inuence of secondary phases dispersants and porosity on thermoelectric properties of β-Fe 0.91 Mn 0.09 Si 2[END_REF] or Cr [START_REF] Kim | High temperature thermoelectric properties of p-and n-type β-FeSi 2 with some dopants[END_REF] eciently improves the maximum ZT to about 0.15. Moreover, the synthesis of β-FeSi 2 (space group Cmce ) by conventional metallurgical routes is facing the peritectoid decomposition in -FeSi (s.g. P 2 1 3) and α-Fe 1-δ Si 2 (s.g. P 4/mmm) above 1255 K, [START_REF] Massalski | Binary Alloy Phase Diagrams[END_REF] implying long annealing at high-temperature to recover the β-phase. For such reasons, extensive research has been devoted to the development of alternative synthesis routes for nanostructured silicides with reduced thermal conductivity adapted to large scale production. For example, mechanical alloying [START_REF] Kim | High temperature thermoelectric properties of p-and n-type β-FeSi 2 with some dopants[END_REF]1820 or melt spinning [START_REF] Han | Quick preparation and thermal transport properties of nanostructured β-FeSi 2 bulk material[END_REF] followed by reactive sintering were used for the fabrication of mesostructured and highly substituted β-FeSi 2 . Recently, several studies reported the synthesis of β-FeSi 2 /Si(Ge) nanocomposites by the eutectoid decomposition of α-Fe 1-δ Si 2 . 2225 The resulting microstructure consists in 10 to 200 nm Si(Ge) well-dispersed inclusions inside a β-FeSi 2 matrix allowing a κ reduction up to 50 %. Controlled doping remains however dicult by this approach resulting in materials with peak ZT rarely exceeding 0.1, 2629 but reaching values as high as 0.4 -0.6 when the doping is successful. [START_REF] Mohebali | Thermoelectric gure of merit of bulk FeSi 2 -Si 0.8 Ge 0.2 nanocomposite and a comparison with β-FeSi 2[END_REF][START_REF] Liu | Improved thermoelectric performance of eco-friendly β-FeSi 2 -SiGe nanocomposite via synergistic hierarchical structuring, phase percolation, and selective doping[END_REF] More exploratory synthesis routes such as laser sintering [START_REF] Wu | Preparation of β-FeSi 2 thermoelectric material by laser sintering[END_REF][START_REF] Kinemuchi | Rapid synthesis of thermoelectric compounds by laser melting[END_REF] or gas-phase reaction 32 were successful to obtain β-FeSi 2 but they still remain more adapted to laboratory scale production.

3

Sen et al. reported an innovative synthesis of (doped) β-FeSi 2 nanopowders by magnesioreduction of mixed oxide mixtures prepared by sol-gel method from tetraethylorthosilicate (Si(OC 2 H 5 ) 3 ) and ferric nitrate (Fe(NO 3 ) 3 •9H 2 O). [START_REF] Sen | Synthesis and characterization of β-phase iron silicide nano-particles by chemical reduction[END_REF][START_REF] Sen | Mn and As doping of β-FeSi 2 via a chemical method[END_REF] The high reducing power of Mg allows the reaction to be carried out in short reaction time (6 h) and at relatively low temperature (1073 K) thus avoiding the post-synthesis annealing step. In addition, the powder obtained by this process has grain sizes as small as 50 nm, which might be suitable for the preparation of nanostructured thermoelectrics. However, the as-reported synthesis procedure remains hardly compatible with industrial scale production, mainly due to the numerous steps involved (up to 6) including a time-consuming preparation of the oxide mixture (2 steps totaling 18 h) from highly hygroscopic reactants.

In the present article, a modied magnesioreduction synthesis for thermoelectric β-FeSi 2 and β-Co 0.07 Fe 0.93 Si 2 powders with 30 -400 nm grain sizes is described. The preparation of the oxide precursor mixture is realized in a single step by ball-milling (Co-doped) Fe 2 O 3 and Si. This oers many advantages such as a higher scalability perspective, the use of cheap, air stable and non-hazardous precursors and a nal yield greater than 98 %. The chemical reactivity has been followed by powder X-ray diraction during the whole process to optimize the temperature/duration of the thermal treatment. The crystal structure, rened for the rst time using a dedicated software to analyze the impact of stacking faults on Bragg reections, and the microstructure, characterized by scanning and transmission electron microscopies, are presented on as-synthesized powders and spark plasma sintered pellets. Finally the improved TE properties are discussed toward the inuence of the microstructure and compared to similar materials synthesized by conventional arc-melting/sintering/annealing route.

Experimental methods

The experimental set-up for the magnesioreduction synthesis (MR) is described in more details in our previous articles. [START_REF] Le Tonquesse | Innovative One-step Synthesis of Mesostructured CoSb 3based Skutterudites by Magnesioreduction[END_REF][START_REF] Le Tonquesse | Mesostructure -thermoelectric properties relationships in V x MnSi 1.74 (x = 0, 0.04) Higher Manganese Silicides prepared by magnesiothermy[END_REF] [START_REF] Casas-Cabanas | FAULTS: a program for renement of structures with extended defects[END_REF][START_REF] Treacy | A general recursion method for calculating diracted intensities from crystals containing olanar faults[END_REF] included in the FullProf Suite package. 40 Interestingly, Fe 3+ (Fe 2 O 3 ) is entirely reduced in Fe 2+ (FeO, Fe 2 SiO 4 ) or metallic Fe (Fe, FeSi, α-Fe 1-δ Si 2 ) during the milling process. Solid state redox reactions occur with Si playing the role of reducing agent most probably according to:

2 Fe 2 O 3 + Si --→ 4 FeO + SiO 2 ∆G • r (300 K) = -353.3 kJ 42 2 FeO + Si --→ 2 Fe + SiO 2 ∆G • r (300 K) = -444.4 kJ 42
Both reductions are thermodynamically possible at room temperature in view of their large negative Gibbs free energies. The activation energies are overcome by the highly energetic shocks occurring in the milling vial. Analogous reactions are reported for higher manganese silicides where MnO is reduced by Si in similar milling conditions. [START_REF] Le Tonquesse | Mesostructure -thermoelectric properties relationships in V x MnSi 1.74 (x = 0, 0.04) Higher Manganese Silicides prepared by magnesiothermy[END_REF] As a result, SiO 2 has to be present in the precursor mixture. Its amorphous nature is suggested by the broad deviation of the background of XRD patterns around 22 • associated to silica glass. 43 The Si/Fe atomic ratio of 1.5 determined from Rietveld renement is much smaller than the value of about 2 expected from the reactant quantities and conrmed by SEM-EDS analyses. A SiO 2 concentration of about 23 mol.% in the precursor mixture can thus be estimated. Moreover, freshly reduced metallic Fe is expected to react with Si by mechanical alloying forming FeSi and α-Fe 1-δ Si 2 as already reported in the literature. 18,[START_REF] Dézsi | Mechanical alloying of Fe-Si and milling of α-and β-FeSi 2 bulk phases[END_REF][START_REF] Nagai | Eect of mechanical alloying and grinding on the preparation and thermoelectric properties of β-FeSi 2[END_REF] The formation of the high temperature allotrope of the disilicide upon milling highlights the 8 energetic conditions in the vial during the milling. Fe 2 SiO 4 is probably formed in a similar manner from FeO and SiO 2 . SiO 2 , FeO and Fe 2 SiO 4 are the remaining oxide phases to be reduced by Mg during the magnesioreduction process. The thermal cycle used for the magnesiothermic reaction consists in a heating ramp up to 1173 K in 9 h followed by a 10 h isothermal plateau. To better understand the reaction mechanism, the reactor was quenched in cold water at dierent times of the process and the phases in presence were quantied by Rietveld renement of XRD patterns. The evolution of phase concentrations (excluding MgO) as a function of the reaction time is presented in g. 2 with lines+symbols while the overall content in MgO in the reaction media is displayed with a red line. The tted XRD pattern and rened structural parameters and details about the renement procedure can be found in g. S2a-h and tables S1-S9.

During the rst 6 hours of the reaction, no signicant changes can be observed indicating that Mg is quite unreactive below 873 K toward the species in presence. Only α-Fe ) is expected to intensify the reactivity of Mg and to enhance the reaction rate, in a scenario close to a combustion synthesis. 48,[START_REF] Nersisyan | Direct magnesiothermic reduction of titanium dioxide to titanium powder through combustion synthesis[END_REF] The β-FeSi 2 concentration strongly increases (+23 %) between 873 K and 1173 K which is mostly attributed to the solid-state reaction between Fe (-17 %) and Si (-30 %).

At 1173 K, the reaction media is composed of β-FeSi 2 , FeSi, Mg 2 Si and some unreacted Si and Fe giving an overall Si/Fe metal ratio of 1.8. This is higher than the 1.5 ratio determined for the precursor mixture but still lower than the expected value of 2. This suggests that the reduction of amorphous SiO 2 is not yet completed at the end of the heating ramp.

As indicated by the decrease of Mg 2 Si content and the increase of Si/Fe ratio during the isothermal plateau, amorphous SiO 2 is slowly reduced by highly reactive Mg 2 Si 50,51 according to the reaction:

SiO 2 + Mg 2 Si 1173 K ---→ 2 Si + 2 MgO ∆G r (1200 K) = -252.0 kJ 42
Finally, after 10 h at 1173 K, XRD pattern shows that MgO and β-FeSi 2 are the main phases in the reduced pellets with only small amounts of residual Si and FeSi.

Weighing the pellets before the reaction and the powders after HCl-washing indicates reaction yields typically higher than 98 % using this process. to MgO (s.g. Fm 3m, a = 4.21 Å) [START_REF] Wechsler | Thermodynamics and structural chemistry of compounds in the system MgO-TiO 2[END_REF] while sharp spots are ascribed to β-FeSi 2 . [START_REF] Dusausoy | Crystal structure of iron disilicide, FeSi 2 β[END_REF] In light of these observations, the aggregate irregular shape of as-synthesized powder derives from the association of well-crystallized β-FeSi 2 particles (darker areas) being embedded inside a nanocrystalline MgO matrix (bright area). We hypothesize here that the MgO layer surrounding the β-FeSi 2 grains plays a signicant role during the heat treatment to limit the grain growth and stabilize the submicronic size of the silicide.

After diluted hydrochloric acid washing, the diraction peaks of MgO disappear on the XRD patterns, indicating its elimination at least below the detection level of the technique (g. 1). The almost entire dissolution of MgO, as well as the homogeneous insertion of cobalt in the doped samples, are conrmed by SEM/TEM-EDS analyses.

Removal of the MgO layer reveals the morphology of the β-FeSi 2 particles (g. 3b,d)

having sizes spanning from 30 nm to about 400 nm, suggesting that the present magnesioreduction process produces powders with a slightly larger average size than the process described by Sen et al. [START_REF] Sen | Synthesis and characterization of β-phase iron silicide nano-particles by chemical reduction[END_REF] We attribute it to the smaller size of the oxide particles, lower reaction temperature (-100 K) and presence of MgO diluent in their precursor mixture. In our case, adding MgO diluent was found to considerably reduce the reaction kinetics.

Crystal structure

As reported by Dusausoy et al., [START_REF] Dusausoy | Crystal structure of iron disilicide, FeSi 2 β[END_REF] [START_REF] Zheng | Planar defects in β-iron disilicide (β-FeSi 2 ) analyzed by transmission electron-microscopy and modeling[END_REF] and conrmed by Yamane et al. [START_REF] Yamane | Eect of stacking fault on the diraction intensities of β-FeSi 2[END_REF] In other words, the expected AB stacking is randomly replaced by an AB* one where the B* layer is obtained by a x+1/2, y, z+1/2 translation of the A-layer (g. 4c).

A consequence of these stacking faults is the formation of a third type of Fe@[Si 8 ] network (layer 3 in g. 4b) at the interface of the stacking fault, which can be considered as a twinned version of the layer 2, [START_REF] Zheng | Planar defects in β-iron disilicide (β-FeSi 2 ) analyzed by transmission electron-microscopy and modeling[END_REF] with minor dierences in the Fe-atom coordination sphere.

In the case of the magnesioreduced powders, the presence of the stacking faults (SF) is highlighted by an important XRD peak shape broadening of the hkl reections with k+l = 2n (g. 1) corresponding to diuse streaks observed in the electron diraction pattern along the a* -direction for this condition (g. 5a). Dark-eld images obtained from the diuse streaks of a crystal oriented along the [0 12] zone axis (g. 5b) clearly reveal a high density of planar defects. High resolution TEM image of this defective crystal (g. 5c) shows 4.9 Å (i.e. a /2) thick layers perpendicular to the [100] direction and AB or AB* stacking.

As pointed out by Yamane et al., [START_REF] Yamane | Eect of stacking fault on the diraction intensities of β-FeSi 2[END_REF] the density of SF in β-FeSi 2 is strongly dependent on the synthesis method. Indeed, pulverized crystals grown in relatively mild conditions, e.g. metal ux or chemical transport methods, are found to be relatively free of SF while polycrystalline samples prepared for example by conventional fusion/solidication or powder metallurgical methods are more aected. In order to quantify the probability of SF in our samples, the general recursion method for crystals containing planar faults developped by Treacy et al. [START_REF] Treacy | A general recursion method for calculating diracted intensities from crystals containing olanar faults[END_REF] has been applied to both pristine and Co-doped β-FeSi 2 prepared by magnesioreduction.

The SF have been taken into account in the modeling of the X-ray diraction data using the dedicated FAULTS software. [START_REF] Casas-Cabanas | FAULTS: a program for renement of structures with extended defects[END_REF] For this, half a unit cell along the a -axis, corresponding to a single layer A (g. 4), was considered along with two possible displacement vectors,

x + 1, y + 1/2, z and x + 1, y, z + 1/2 corresponding to the normal and faulty stacking, respectively. Using this approach, the patterns were rened by optimizing the stacking fault probability, the lattice and atomic parameters and the peak prole function. Rened The SF probabilities were found to be close to 15 % for both compositions. This value is similar to the ratios reported by Yamane et al. for β-FeSi 2 samples synthesized by powder metallurgy methods. [START_REF] Yamane | Eect of stacking fault on the diraction intensities of β-FeSi 2[END_REF] As pointed out by Zheng et al., [START_REF] Zheng | Planar defects in β-iron disilicide (β-FeSi 2 ) analyzed by transmission electron-microscopy and modeling[END_REF] the layer 3 exhibits a twin-like structure, as if the b and c axes were exchanged in the defect layer. Thus with increasing the SF concentration, one expects the b and c lattice parameters to converge to an average value between those in the regular lattice. Accordingly, the b and c lattice parameters in the MR powders are rather close from each other. Interestingly, the lattice constant a of the Co-doped sample increasing from 9.88240(2) Å to 9.89838(8) Å seems to be the only structural parameter aected by the insertion of Co in the structure. This is consistent with Hesse's work [START_REF] Hesse | Solid Solubility of CoSi 2 in β-FeSi 2[END_REF] Secondary electrons SEM images of the broken cross-section of undoped β-FeSi 2 densied pellets are shown in g. 8 for MR and AM samples. The microstructure of the AM sample is relatively common for sintered iron silicides prepared by fusion-solidication techniques 15,18 and the particle sizes span from 1 µm to tens of µm. Porosity is hardly visible and only a few submicronic pores can be detected at high magnication in agreement with the high density (97 %) measured by the Archimede method. In the case of the MR samples, the microstructure is signicantly dierent with less well-faceted particles and smaller average grain size (mainly from 500 nm to 1 µm range). By analogy with our previous report on higher manganese silicides and TEM analysis (g. 3d) prior to SPS, we assume here that 18 XRD realized on crushed pellets are presented in g. 9a for undoped and in g. S3 for

Co-doped samples. Lattice and structural parameters extracted by renements are presented in table 2 and table S10. The lattice constants and atomic coordinates are comparable for the corresponding compositions. More particularly, the similar a parameters for the doped samples suggest equivalent Co substitution in agreement with SEM-EDS results. The SF probability is however systematically higher for MR (≈ 10 %) than for AM samples (≈ 3 %).

19

The density of SF in the samples can be directly appreciated by comparison of the (312)

Bragg reections (g. 9b) which become signicantly less intense and broader with increasing SF probability. This result conrms that the synthesis route has a strong inuence on the SF density in β-FeSi 2 even after high-temperature sintering/annealing steps. and back to β-form after annealing, the microstructures of the densied materials remain signicantly dierent for the two synthesis routes. The MR samples are characterized by smaller average particle sizes and higher density of grain boundaries, of porosities and higher concentration of SF. All these defects acting at dierent scales in the materials are expected to scatter eciently the phonons over a broad energy spectrum and thus to reduce the thermal conductivity of FeSi 2 . The inuence of this microstructure on the thermoelectric properties of this material is thus presented in the following.

Thermoelectric properties

The TE properties of β-FeSi 2 and β-Co 0.07 Fe 0.93 Si 2 synthesized by magnesioreduction and arc-melting were investigated from room temperature up to 773 K. Measurements of the electronic properties were cycled twice and showed good reversibility. Undoped MR β-FeSi 2 samples have elevated electrical resistivity (14 mΩ m) (g. 10a) and Seebeck coecient (550 µV K -1 ) (g. 10b) at room temperature which is in agreement with the relatively low charge carrier concentration (10 17 -10 18 cm -3 ) reported for this semiconductor. [START_REF] Arushanov | Transport properties of β-FeSi 2[END_REF][START_REF] Arushanov | Hole Mobility in p-Type β-FeSi 2 Single Crystals[END_REF] Interestingly, the Seebeck coecients are positive for MR and negative for AM samples indicating n-type and p-type conductions, respectively. Experimental data from the literature report ptype [START_REF] Tani | Thermoelectric Properties of β-Fe 1-x Co x Si 2 Semiconductors[END_REF] as well as n-type [START_REF] Kim | High temperature thermoelectric properties of p-and n-type β-FeSi 2 with some dopants[END_REF][START_REF] Rajasekar | Eect of Al-doping on suppression of thermal conductivity in Si dispersed β-FeSi 2[END_REF] bulk materials. The conduction type change is often attributed to the presence of impurities or defects (e.g. Fe or Si vacancies), which strongly depends on the synthesis route. [START_REF] Tani | First-principle study of native point defects in β-FeSi 2[END_REF] For instance Chu et al. also reported a change from p-to n-type conduction on a β-FeSi 2 thin lm after prolonged annealing at 1163 K. 60 These results suggest that the synthesis routes, as well as the high-temperature treatment, can strongly inuence the transport properties of β-FeSi 2 materials and possibly explain the dierent conduction types measured in the present work. Due to its smaller electrical resistivity and despite its smaller Seebeck coecient, the PF of the MR β-FeSi 2 sample is found far superior to that of the AM sample on the whole temperature range, reaching a maximum value of 0.2 mW m -1 K -2 at 650 K (g. 10c). Upon Co doping, the electrical resistivities of both MR and AM samples signicantly drop while the Seebeck coecient stabilizes around -180 µV K -1 . This can be explained by the creation of donor levels in the band gap [START_REF] Ware | Iron disilicide as a thermoelectric generator material[END_REF] increasing the estimated charge carriers concentration up to 10 20 -10 21 cm -3 according to literature data. [START_REF] Tani | Thermoelectric Properties of β-Fe 1-x Co x Si 2 Semiconductors[END_REF][START_REF] Brehme | Electrical properties of Co-doped β-FeSi 2 crystals[END_REF][START_REF] Tani | Electrical properties of Co-doped and Ni-doped β-FeSi 2[END_REF] The electrical resistivity of the MR sample is however systematically 35 % higher than the AM sample on the whole temperature range which can be partially explained by the lower density of the MR material. [START_REF] Gayner | Inuence of secondary phases dispersants and porosity on thermoelectric properties of β-Fe 0.91 Mn 0.09 Si 2[END_REF] The resulting PF are increased to values as high as 0.9 and 1.0 mW m -1 K -2 at 773 K for the MR and AM β-Co 0.07 Fe 0.93 Si 2 , respectively. The thermal conductivities of AM β-FeSi 2 and β-Co 0.07 Fe 0.93 Si 2 (g. 10d) equal 17.5 and 4.7 W m -1 K -1 at room temperature, which is in good agreement with most literature data. [START_REF] Kim | High temperature thermoelectric properties of p-and n-type β-FeSi 2 with some dopants[END_REF]15,[START_REF] Hesse | Solid Solubility of CoSi 2 in β-FeSi 2[END_REF][START_REF] Tani | Thermoelectric Properties of β-Fe 1-x Co x Si 2 Semiconductors[END_REF] The lower thermal conductivity of the doped sample can be attributed to the mass uctuation phenomenon at the mixed Fe/Co sites or to the scattering of phonons by polarons in these silicides. [START_REF] Tani | Thermoelectric Properties of β-Fe 1-x Co x Si 2 Semiconductors[END_REF] The thermal conductivities of the respective MR synthesized 22 samples are comparatively lower by 32 % and 15 % at 320 K. At the highest temperature, the thermal conductivity reduction reaches 23 % for both compositions. The lattice thermal conductivity of all the samples were estimated by subtraction of κ E calculated with the Wiedermann-Franz law κ e (T) = L•T/ρ(T) with the commonly used L = 2.4.10 -8 W Ω K -2 to the total thermal conductivity. The lower κ measured for MR samples can thus be mostly attributed to κ L reduction reaching 24 % and 17 % at 773 K for the undoped and Co-doped sample, respectively. The MR and AM samples have similar compositions, so the reduction of κ L is attributed to enhanced scattering at pores, grain boundaries and stacking faults, [START_REF] Lefévre | Layered tellurides: stacking faults induce low thermal conductivity in the new In 2 Ge 2 Te 6 and thermoelectric properties of related compounds[END_REF] all of which occur in higher densities in the MR materials. Eventually, maximum gure-of-merit ZT of 0.015 at 673 K and 0.18 at 773 K could be calculated for the undoped and doped MR samples, respectively (g. 10e). In the case of MR β-FeSi 2 , ZT has been improved compared to the AM sample mostly because of the reduced thermal conductivity, but it remains low due to the exceedingly large electrical resistivity. On the other hand, MR β-Co 0.07 Fe 0.93 Si 2 has a much higher maximum ZT, which corresponds to a 12 % improvement compared to the conventionally synthesized sample thanks to the mesostructuration. This value is to the best of our knowledge among the highest ZT value reported at this temperature for Co-doped

6 Page 6 of 33 ACSFigure 1 : 7 Page 7 of 33 ACSFe

 6331733 Figure 1: XRD patterns of the precursor mixture (green), as-synthesized (red) and HClwashed (blue) MR β-FeSi 2 powders, as well as simulated pattern for β-FeSi 2 41 (black). Intensity discrepancies between some peaks in the experimental and theoretical β-FeSi 2 patterns are linked to the presence of (100)[011]/2 stacking faults in the crystals (see text for details).

Figure 2 :

 2 Figure 2: (left) Evolution of the sample composition during the magnesioreduction synthesis of β-FeSi 2 determined by Rietveld renements. The relative deviation on the concentrations is estimated to be well below 5 % according to measurement conditions, quality of the ts and Ref. 46 (right) Schemes of the crucible at three important stages of the reaction: heating-up (top), melting of Mg and reduction of the precursor mixture (middle), completed reaction after 19 h (right) (s: solid, l: liquid, g: gas).

10 Page 10 of 33 ACS

 1033

Figure 3 :

 3 Figure 3: (a-b) Secondary electron SEM and (c-d) brighteld TEM images of the assynthesized (left) and HCl-washed (right) MR β-FeSi 2 powder. The electron diraction pattern shown in inset was taken at the green circle in (c).

  β-FeSi 2 crystallizes in the orthorhombic Cmce space group with lattice parameters a = 9.8774(3) Å, b = 7.8128(3) Å and c = 7.8272(3) Å. This structure type derives from the uorite-type structure by strongly distorting the [Si 8 ] cubes into irregular prisms where Fe-atoms occupy alternatively one half of the central sites (g. 4a,b).In this initial description of the crystal structure, two independent Fe-sites are distributed over two kind of layers stacked along the a -axis (g. 4a): the layer 1 contains the Fe1 atoms in 8d Wycko site surrounded by [Si 8 ] trapezoid-based prisms, the layer 2 contains the Fe2 atoms in 8f Wycko site coordinated by similar [Si 8 ] trapezoid-based prisms with additional torsion angle between the rectangular faces. This structure of β-FeSi 2 can also 12 be alternatively described as another layered one with ABAB stacking mode along the [100] direction, as shown in g. 4a. While the individual layers are structurally identical, the layer A transforms into the layer B by the translation vector x + 1/2, y + 1/2, z, as represented in the projections along the a -axis of the layers in g. 4c. In this description, each layer is composed of the layer 1 (g. 4b) sandwiched between two half of the layer 2, and the pseudo-cubic layer 2 is build from the interaction of the A and B layers.

Figure 4 : 13 Page 13 of 33 ACS

 41333 Figure 4: (a) c-axis projection of the crystal structure of β-FeSi 2 reported by Dusausoy et al. 41 showing the Fe@[Si 8 ] networks and the ABAB stacking mode; (b) a -axis projections of the pseudo-cubic networks 1, 2 and 3; (c) a -axis projections of the normal stacking A and B layers and alternative stacking layer B* along with related displacement vectors.

14

 14

Figure 5 :

 5 Figure 5: (a) Electron diraction pattern of MR β-FeSi 2 taken along the [0 12] zone axis showing diuse streaks for hkl reections with k+l = 2n. (b) Dark-eld image using the diuse streak (white circle) revealing high density of planar defects in MR FeSi 2 (c) HRTEM image showing the stacking faults indicated with white arrows.

Figure 6 :

 6 Figure 6: Rietveld renement of the washed MR β-FeSi 2 (left) and MR β-Co 0.07 Fe 0.93 Si 2 (right) powder XRD. The experimental data are plotted in colored symbols, the calculated one with a black line and the dierence with a blue line. The vertical ticks indicate the Bragg peak positions for β-FeSi 2 (black), FeSi (red) and Si (green).

3. 3

 3 Densied pellet microstructureAny attempts to obtain densied pellets by spark plasma sintering below the decomposition temperature of β-FeSi 2 resulted in materials with low relative density (< 85 %) and were consequently abandoned. Pellets with 94 % and 97 % relative density were prepared from magnesioreduced (MR) and arc-melted (AM), respectively, β-FeSi 2 and β-Co 0.07 Fe 0.93 Si 2 powders by SPS at 1323 K followed by 24 h annealing at 1100 K to recover the expected β-phase. Backscattered electron SEM images and EDS mappings of polished pellet surfaces obtained from the MR process reveal relatively homogeneous chemical composition (g. 7) with the exception of small amount of FeSi impurity as well as a few WSi 2 particles certainly coming from WC contamination during the early precursor milling. SEM-EDS elementary analyses realized on the Co-doped samples synthesized by MR or conventional AM routes give a similar global Co concentration of about 2 at.% in good agreement with the targeted composition. None of EDS spectra measured inside the grains show the presence of magnesium, indicating the absence of signicant contamination of the silicides by this element.

Figure 7 :

 7 Figure 7: Backscattered electron SEM images and corresponding EDS mappings of the polished surface of undoped MR β-FeSi 2 (top) and MR β-Co 0.07 Fe 0.93 Si 2 (bottom) densied pellets.

Page 18 of 33 ACS

 33

Figure 8 :

 8 Figure 8: Secondary electron SEM images of broken cross-sections of MR (left side) and AM FeSi 2 (right side) at two dierent magnications.

Figure 9 :

 9 Figure 9: (a) FAULTS rened powder XRD patterns of sintered MR β-FeSi 2 (red) and AM β-FeSi 2 (green). The experimental data are plotted in colored symbols, the calculated one with a black line and the dierence with a blue line. The vertical ticks indicate the Bragg peak positions for β-FeSi 2 (black), FeSi (red) and Si (green). (b) Inuence of the stacking fault density on the (312) diraction peak prole and intensity.

21 Page

 21

Figure 10 :

 10 Figure 10: High temperature thermoelectric properties of β-FeSi 2 (black symbols) and β-Co 0.07 Fe 0.93 Si 2 (red symbols) synthesized by magnesioreduction (MR, circles) and conventional arc-melting (AM, squares). Thermal dependence of (a) the electrical resistivity, (b) the thermopower, (c) the power factor (PF ), (d) the total (lled symbols) and lattice (empty symbols) thermal conductivity and (e) resulting gure-of-merit ZT.

  synthesis of β-FeSi 2 and β-Co 0.07 Fe 0.93 Si 2 powders from (Co-doped) Fe 2 O 3 and Si has been developed. It oers many advantages over more conventional synthesis routes such as the use of air-stable and inexpensive precursors, short heat treatment below the decomposition temperature of β-FeSi 2 , very high yield (> 98 %) and a satisfying control of the chemical composition including dopant concentration. Detailed study of the reaction mechanism by means of XRD pattern Rietveld renements enabled to determine the reduction starting temperature between 923 K and 973 K, the formation 23

  -milling stoichiometric amounts of Fe 2 O 3 (Merck, > 99 %) and Si powder (Ventron, 99.9 %) using WC vial and balls (ball-to-powder ratio of 5 : 1) with rotation speed of 650 rpm for 4 h under air atmosphere. Good control of milling conditions of precursors was Co 0.07 Fe 0.93 Si 2 , the addition of Co 3 O 4 to Fe 2 O 3 and Si during the ball-milling preparation of the precursor mixture leads to the formation of CoSi 2 during

	ACS Applied Energy Materials
	X-ray diraction (XRD), the obtained red powder is single phase α-Co x Fe 2-x O 3 (s.g. R 3c)
	with a = 5.0327(1) Å and c = 13.7413(4) Å as determined by Le Bail renement of the
	diraction patterns (g. S1). The lattice parameters are signicantly dierent from those
	found essential to prevent contamination by WC during the milling and formation of side-reported for pure α-Fe 2 O 3 (a = 5.0368(1) Å and c = 13.7601(3) Å 37 ) and energy disper-
	products (FeSi, Fe 3 Si, unreacted Si) during the magnesioreduction process. The precursor sive spectroscopy (EDS) elementary analyses indicate a Co concentration of approximately
	mixture is cold pressed (100 MPa) in Ø 10 mm pellets with 2 mm height and placed with 2 at.% in agreement with the targeted composition.
	adequate amount of Mg turnings according to: The conventional synthesis of β-FeSi 2 and β-Co 0.07 Fe 0.93 Si 2 consisted in arc-melting (AM)
	stoichiometric amounts of the metallic elements three times to ensure homogenization. The
	Fe 2 O 3 + 4 Si + 3 Mg (+25%) resulting ingots are milled, SPS sintered at 1223 K and 90 MPa for 5 min and nally annealed --→ 2 β-FeSi 2 + 3 MgO
	for 60 h at 1123 K in evacuated silica tubes.
	in a clamped Mo crucible. The latter is heated under Ar protective atmosphere at a rate of The crystal structure and purity of the samples are checked by powder XRD using a
	100 K h -1 up to 1173 K, maintained at this temperature for 10 h and cooled down to room Bruker D8 Advance diractometer working in the modied Bragg-Brentano geometry with
	temperature by switching o the furnace. The reaction product is recovered by opening a monochromatized Cu Kα 1 radiation (λ = 1.54059 Å) and equipped with a LynxEye fast
	the crucible and MgO by-product is removed by soaking the as-synthesized powder twice in detector. Structural parameters are determined by Rietveld renements of the XRD patterns
	diluted hydrochloric acid (2 wt.%) and washing three times with distilled water and once using the FullProf or FAULTS softwares
	more with ethanol before being dried at 353 K overnight. Densied β-FeSi 2 pellets are
	obtained by spark plasma sintering (SPS, FCT HP-D-10 apparatus) the `washed' powders in
	Ø 10 mm graphite dies at 1323 K -80 MPa for 30 min followed by 24 h annealing at 1100 K
	in an evacuated silica tube.
	For the synthesis of β-the magnesioreduction process, attributed to an uneven distribution of Co in the mix-
	ture. Starting from a properly doped Co 0.14 Fe 1.86 O 3 precursor allows Fe and Co to be
	homogeneously distributed at the atomic scale and the probability to form side-products
	is greatly reduced. Co 0.14 Fe 1.86 O 3 is synthesized by dissolving stoichiometric proportions
	of Co(NO 3 ) 2 •6H 2 O (Fluka, ≥ 98 %) and Fe(NO 3 ) 2 •9H 2 O (Fluka, ≥ 98 %) in a minimum
	amount of distilled water and by calcinating the mixture at 773 K for 6 h in air. According to
	5
	ACS Paragon Plus Environment

For undoped β-FeSi 2 , a precursors mixture is rst prepared 4 by dry ball

  1-δ Si 2 9 slowly transforms in β-FeSi 2 which is the thermodynamically stable allotrope in this temperature range. Between 873 and 973 K, the reduction process starts as indicated by the formation of MgO (1 mol.%). Interestingly, it corresponds well to the melting temperature of Mg (melting point T m = 922 K) and suggests that liquid Mg with high vapor pressure (383 Pa at T m ) is required to initiate the reduction.[START_REF] Haynes | CRC Handbook of Chemistry and Physics[END_REF] At 1073 K, MgO and newly formed Mg 2 Si intermetallic represent as much as 33 and 16 mol.% of the whole reaction media, respectively. The heat produced locally by the highly exothermic reduction of SiO 2 by Mg (∆H r (1200 K) = -344 kJ mol -1[START_REF] Knacke | Thermo-chemical Properties of Inorganic Substances[END_REF]

Table 1 :

 1 reporting a linear increase of a with increasing Co substitution and an expected value of about a = 9.905 Å for β-Co 0.07 Fe 0.93 Si 2 . 15 Lattice parameters, atomic coordinates, isotropic thermal displacement parameters and stacking fault propability (SF) extracted from the Rietveld renement of the HCl-washed MR β-FeSi 2 and MR β-Co 0.07 Fe 0.93 Si 2 XRD patterns MR β-FeSi 2 MR β-Co 0.07 Fe 0.93 Si 2

	a (Å)	9.88240(2)	9.89838(8)
	b (Å)	7.81651(2)	7.81778(

Table 2 :

 2 Lattice parameters, stacking fault probability and impurity content for spark plasma sintered MR FeSi 2 , AM FeSi 2 , MR Co 0.07 Fe 0.93 Si 2 , and AM Co 0.07 Fe 0.93 Si 2 obtained by renements, together with their relative density obtained by the Archimede method. MR FeSi 2 AM FeSi 2 MR Co 0.07 Fe 0.93 Si 2 AM Co 0.07 Fe 0.93 Si 2 Despite the phase transition from β-FeSi 2 to α-Fe 1-δ Si 2 during the sintering process 20

	a (Å)	9.89104(6) 9.87518(4)	9.91176(8)	9.91200(4)
	b (Å)	7.81612(3) 7.79980(3)	7.81410(4)	7.81500(4)
	c (Å)	7.84209(3) 7.83727(2)	7.84084(5)	7.84060(3)
	SF (%)	10.7(2)	3.7(1)	10.4(1)	3.2(1)
	Rel. density (%)	94	97	94	97
	Impurities (wt.%)	1 (FeSi)	1 (FeSi)	2 (FeSi)	5 (FeSi)
			2.5 (Si)

ACS Paragon Plus Environment

Acknowledgement

The authors thank Loic Joanny and Francis Gouttefangeas for SEM images, and EDS analyses performed on the CMEBA platform. The TEM analyses were performed at THEMIS platform. Both platforms belong to the ScanMAT unit (UMS 2001, University of Rennes 1) which received a nancial support from the European Union (CPER-FEDER 2007-2014). The authors acknowledge support from CREST JPMJCR15Q6 and JSPS KAKENHI JP17H02749, JP16H06441.

of Mg 2 Si intermediate during the process, and a total duration of the thermal treatment of 19 h to achieve a total reaction. After removal of MgO by-product by diluted HCl washing, the as-synthesized silicide powders are composed of well-crystallized grains with sizes ranging between 30 and 400 nm. TEM observations reveal high concentration of stacking faults evaluated at 15 -18 % by renement of the XRD pattern using a dedicated software.

The high temperature TE properties of MR/SPS/annealed densied pellets were measured up to 773 K and compared to conventionally AM/SPS/annealed samples with similar compositions. The higher densities of grain boundaries, stacking faults and porosities in the magnesioreduced materials lead to strongly reduced lattice thermal conductivities. As a result, the TE gures-of-merit ZT of the two compositions are improved, even reaching 0.18 at 773 K in the case of β-Co 0.07 Fe 0.93 Si 2 .

Conicts of interest

There are no conicts to declare.

Supporting Information Available