M Levillayer
email: maxime.levillayer@gmail.com

S Duzellier

I Massiot

A Arnoult

S Parola

R Rey

G Almuneau

L Artola

Impact of 1 MeV proton irradiation on InGaAsN solar cells

Keywords: Protons, irradiation, dilute nitrides, InGaAsN, solar cells, photovoltaics, PL, EQE, DLTS

The impact of 1 MeV proton irradiation on 1.12 eV bandgap InGaAsN solar cells was studied through device and material characterizations. After a 10 13 p + /cm 2 proton fluence, the photocurrent decreases by 28 %, due to the formation of defects in both the GaAs emitter and the InGaAsN absorber. Furthermore, photoluminescence measurements suggest that the proton radiation hardness of InGaAsN increases with the nitrogen.

Introduction

The current development of artificial satellites requires the conception of powerful and reliable electrical sources that can be used in a space environment. Today, on-board systems rely predominantly on photovoltaic conversion and more specifically on multijunction solar cells (MJSC).

The MJSCs offer the best conversion efficiencies because they are based on several subcells to harness the solar spectrum, which minimizes transmission and thermalization losses. The most common MJSC used for space applications is the GaInP/(In)GaAs/Ge 3J cell lattice-matched to its substrate, with 28-30 % efficiency under AM0 sunlight [1]. Research is now being carried out to increase further this efficiency to boost the power density (W/kg) of space solar arrays. One way of exceeding the 30 % efficiency barrier is to optimize the MJSC architecture in order to improve the near infrared light management. This can be achieved by changing or adding new subcells in the MJSC stack. Indeed, theoretical calculations of the optimal bandgap combination showed that higher efficiencies could be reached by replacing the Ge bottom cell with a 1 eV subcell [1]. Another possibility is to use a 4-junction solar cell by introducing a 1 eV subcell between the GaAs and Ge subcells.

The quaternary alloy InGaAsN is the most promising candidate to be used as a 1 eV absorber in a subcell grown latticematched to a Ge or GaAs substrate. Indeed, the bandgap energy and the lattice parameter of this alloy can be tuned with varying the indium and the nitrogen concentration [3][4].

In addition to lowering the bandgap energy, introducing nitrogen atoms in a GaAs matrix also leads to the creation of crystal defects, which shortens the minority carrier diffusion length [5]. InGaAsN solar cells with a p-i-n junction were then developed to take advantage of the drift collection in the space charge region and achieve higher photocurrents [6][7]. Doing so, high efficiency GaInP/GaAs/InGaAsN 3J cells were demonstrated for concentration [START_REF] Derkacs | [END_REF] (η=43.5 %, AM1.5D×500

) and space PV [START_REF] Campesato | Proceedings of the 11th European Space Power Conference[END_REF] (η=31 %, AM0). To be used for space applications, these dilute nitride-based MJSC need to fulfill a crucial requirement: radiation hardness. Indeed, space is a radiative and hostile environment where satellites and other spacecrafts are constantly bombarded by high energy particles such as electrons, protons and heavier ions. Through nuclear elastic interactions with the atoms of the solar cells, these particles generate displacement damage and crystal defects in the lattice. This in turn leads to a decrease in the minority carrier lifetime, which degrades the solar cell properties [START_REF] Yamaguchi | [END_REF].

Since the subcells in a MJSC are connected in series, the degradation of the photocurrent of a single cell can induce current limitation in the whole structure. Measuring the radiation sensitivity of InGaAsN towards space representative irradiation is then essential to evaluate the end of life (EOL) efficiency of the MJSC. While several studies reported on the effect of electron irradiation on InGaAsN solar cells [START_REF] Campesato | Proceedings of the 11th European Space Power Conference[END_REF][11] [START_REF] Khan | IEEE 4th World Conference on Photovoltaic Energy Conference[END_REF][13], the impact of protons was only investigated for latticemismatched dilute nitrides with very low nitrogen content (<0.5 %) [14] [15]. In order to fill this lack in the literature and quantify the radiation hardness of InGaAsN towards proton irradiation, we propose a study combining device characterization (I-V and external quantum efficiency (EQE) measurements) with material characterization (photoluminescence (PL) and deep-level transient spectroscopy (DLTS) measurements).

Experimental method

InGaAsN solar cells were grown with molecular beam epitaxy (MBE) on a n-GaAs substrate. The p-i-n solar cell structure consists in a 1 µm-thick non-intentionally doped (NID) InGaAsN absorber sandwiched between 200 nm-thick p-and n-doped GaAs layers. The InGaAsN alloy was grown at 465 °C under a As/III flux ratio of 12. The EQE and PL measurements performed on these solar cells indicate a bandgap of 1.12 eV, which corresponds to a 1.6 % and a 4.5 % nitrogen and indium contents, respectively.

Afterwards, the epitaxial stack was processed into 1 cm 2 devices with a AuGeNi/Au metallization at the rear and a Ti/Au front metal grid. The solar cells were then pasted onto AlN sample holders to facilitate handling during the irradiation and characterization steps. More information regarding the epitaxial procedure and the technological process can be found in [16].

In this study, four InGaAsN solar cells were irradiated under vacuum with 1 MeV protons using a Van de Graaff accelerator [START_REF] Duzellier | 17th European Conference on Radiation and Its Effects on Components and Systems[END_REF]. 900 nm-thick InGaAsN bulk layers were also irradiated for PL and DLTS measurements. The samples were cumulatively irradiated at 3.10 11 , 10 12 , 3.10 12 and 10 13 p + /cm 2 fluences with in-situ I-V measurements (under both dark and AM0) between each step. The samples were thermoregulated at 26 °C during the irradiation steps.

Results and Discussion

The current-voltage characteristics of the four solar cells were measured in-situ at beginning of life (BOL) and after each irradiation step. The solar cells exhibited virtually identical J-V characteristics at BOL. Fig. 1 presents the average light J-V characteristics of the cells obtained under AM0 illumination at different fluences. Two J-V curves corresponding to the lowest and the highest degradation are plotted for the final fluence 10 13 p + /cm 2 . The small dispersion exhibited here arises likely from a moderate proton flux inhomogeneity and from measurement uncertainties.

Under 1 MeV proton irradiation, the photovoltaic parameters (J sc , V oc and FF) are all degraded. The J sc decrease results from the degradation of the collection efficiency caused by the creation of crystal defects reducing the minority carrier lifetime. The V oc reduction arises both from the photocurrent decrease and from the increase in the dark saturation current density shown in Fig. 2. This latter parameter increased from 6.6×10 -7 A/cm 2 to 9.5×10 -6 A/cm 2 after irradiation. The average degradation of the J sc , V oc and FF after 10 13 p + /cm 2 , is equal to 28 %, 18 % and 14 %, respectively. Although these degradations are quite significant, they remain much lower than the degradation rates exhibited by GaAs solar cells irradiated with 1 MeV protons [START_REF] Pellegrino | [END_REF] [19].

We investigated the effect of post-irradiation annealing by exposing the InGaAsN solar cells to AM0 sunlight for 60 minutes, under thermoregulation. The dark and light J-V characteristics did not show any change after this annealing step, which highlights the stability of the defects introduced throughout proton irradiation.

One of the limitations of the light J-V characterization performed here that it does not give specific information regarding the degradation of the InGaAsN layer. Under AM0, the carrier collection in the p-i-n subcell arises both from the diffusion in the p-GaAs emitter and from the drift/diffusion regime in the NID-InGaAsN absorber. The global degradation of the cell arises then from the introduction of defects in both InGaAsN and GaAs materials. Yet, only the deterioration of the dilute nitride absorber would be detrimental to a p-i-n subcell integrated within a MJSC structure, as photons with a wavelength shorter than 870 nm would be absorbed in the GaAs middle cell.

As presented in Fig. 3, EQE measurements were performed on the irradiated solar cells in order to discriminate the degradations of the InGaAsN and GaAs compounds. The quantum efficiency of the InGaAsN subcells shows an overall deterioration, consistent with the photocurrent drop observed in Fig. 1 and with the dark current increase shown in Fig. 2. However, the EQE decrease is more important in the [400-870 nm] spectral window, which indicates that part of the J-V degradation arises from the introduction of defects in the GaAs emitter. Using the Beer-Lambert relation and the absorption coefficient of GaAs [START_REF] Palik | Handbook of optical constants of solids[END_REF], we calculate that approximately 40 % of the 700 nm-photons are absorbed in the 200 nm emitter. The inhomogeneity in the EQE degradation goes in line with the lower radiation hardness of GaAs compared to InGaAsN, as mentioned earlier.

To further investigate the degradation of InGaAsN under proton irradiation, we performed PL measurements on NID-InGaAsN bulk layers of different nitrogen content (1.2 and 2.3 %). These samples were excited with a 15 mW 488 nm laser source at room temperature. The photoluminescence intensity of the InGaAsN layers is an insightful parameter because it indicates the magnitude of non-radiative recombination and therefore highlights the introduction of defects throughout irradiation. As represented in Fig. 4, the PL signal shows a 30 % decrease after irradiation in the 1.2 % nitrogen layer whereas the other sample remains virtually unaffected by the 1 MeV protons. This radiation hardness discrepancy arises from the difference in the BOL optoelectronic properties of the samples, which can be observed by a PL signal tenfold lower in the 2.3 % nitrogen sample. Indeed, the crystal defect concentration tends to increase with the nitrogen content in InGaAsN [START_REF] Kurtz | Conference Record of the Thirty-first IEEE Photovoltaic Specialists Conference[END_REF]. In the high N content sample, the irradiation-induced defects concentration is then negligible compared to the density of growth defects. Overall, the PL reduction in the InGaAsN 0.012 bulk layer sample concurs with the J-V and EQE degradations of the InGaAsN 0.016 solar cells.

Current-based DLTS measurements were conducted on reference and irradiated bulk layers to investigate the introduction of defects throughout irradiation. We used a current-based rather than a capacitance DLTS mode to avoid parasitic capacitances present in the devices. The residual doping of the NID samples is n-type, meaning that the majority carriers probed here are electrons. The reverse voltage was set to -3 V and we used a 1 ms filling pulse of 1 V. All measurements were performed in the dark condition.

The impact of 1 MeV protons on the DLTS response can be observed in Fig. 5. It can first be noticed that the DLTS signal b1 (first sine term of the Fourier transform) of the high nitrogen content sample increases after irradiation. This signal can be deconvoluted into two peaks at 265 and 340 K corresponding to two electron traps E1 and E2. This increase in the DLTS signal indicates then defect introduction which is in line with our previous observations. Additionally, the activation energy and the cross-section capture were calculated to be 0.43 eV and 2.7×10 -16 cm² for E1, and 0.63 eV and 4.2×10 -15 cm² for E2. Those two traps lie in the middle of the InGaAsN bandgap and are likely to act as strong non-radiative recombination centers. The E2 defect is conjectured to be a nitrogen split interstitial as its activation energy was theoretically calculated to be 0.66 eV below the conduction band [START_REF] Zhang | [END_REF].

On the other side, the DLTS response of the 1.2 % content sample is found to drop after the irradiation. This is inconsistent with our PL findings and probably arises from the nature of the irradiation-induced defects. These latter ones are likely to act as hole traps rather than electron traps, making them invisible to DLTS characterization.

Conclusion

InGaAsN solar cells and InGaAsN bulk layers were irradiated with 1 MeV protons. The dark and light J-V characteristics of the cells show a monotonic degradation with the proton fluence. The heterogeneous EQE decrease after irradiation indicates that the deterioration of the photovoltaic properties is caused by the introduction of crystal defects in both the GaAs emitter and the InGaAsN absorber.

Moreover, the InGaAsN solar cells studied here are found to be more resistant towards 1 MeV protons than their GaAs counterpart. It can be explained by their higher growth defect concentration, making them less sensitive to irradiation induced defects. This behavior is also supported by the difference in PL degradation exhibited by InGaAsN samples with different nitrogen content. Finally, DLTS results suggest that some of the defects introduced by 1 MeV protons acts as hole traps.

Fig. 1 .

 1 Fig. 1. Light J-V characteristics of the InGaAsN solar cells for various fluences (in p + /cm 2 ) obtained under AM0. The colored area between the two 1e13 p + /cm 2 fluence curves represent the dispersion in the J-V degradation within the four cells.

Fig. 2 .

 2 Fig. 2. Dark J-V characteristics of the InGaAsN solar cells for various fluences (in p + /cm 2 ).

Fig. 3 .

 3 Fig. 3. External quantum efficiency spectra of a non-irradiated InGaAsN solar cell (BOL) and of the four irradiated samples

Fig. 4 .

 4 Fig. 4. Photoluminescence spectra of reference (BOL) and irradiated (EOL) InGaAsN bulk layers. The 15 % error bars correspond to the measurement uncertainty. The PL intensity of the 2.3 % N sample was multiplied by 5 for the sake of clarity.

Fig. 5 .

 5 Fig. 5. DLTS spectra of reference (BOL) and irradiated (EOL) InGaAsN bulk layers. The DLTS signal intensity of the 1.2 % N sample was multiplied by 100 for the sake of clarity.

Acknowledgements

We acknowledge the technical support from the LAAS-CNRS micro and nanotechnologies platform, a member of the French RENATECH network and the CNES for its support through R-S19/MT-9999-245 project. We also acknowledge the technical support from ONERA for its radiation facilities and characterization platform AXEL. This work was also partly supported by the LAAS-CNRS PROOF platform funded by the Occitanie Region and by the program « Investments for the future » managed by the National Agency for Research under contracts ANR-10-LABX-22-01-SOLSTICE. The authors have no conflict of interest to declare.


Dr Karin Martin-Latry
email: karin.martin-latry@u-bordeaux.fr

PhD Philippe Latry

PhD, MD Camille Berges

Pierre Coste

PhD Hervé Douard

PhD Yann Pucheu

MD Thierry Couffinhal

Parcours

MS ; Pierre Coste

First one-year care pathway after Myocardial Infarction in 2018: prescription, medical care and medication adherence using a French health insurance reimbursement database

Keywords: myocardial infarction/Medication adherence/ Databases, Factual/ Insurance, Health, Reimbursement/health care/France, Care pathway

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

Résumé

Contexte : L'infarctus du myocarde (IDM) reste une cause majeure de morbi/mortalité. Objectifs : Décrire le parcours de soins de l'IDM en 2018 pendant l'année suivant la sortie de l'hôpital et l'utilisation et l'adhésion des médicaments de prévention secondaire.

Méthodes : Les patients hospitalisés pour un IDM en 2018 ont été identifiés. Leurs soins médicaux et leurs médicaments au cours des 12 mois suivants ont été analysés à partie de la base de données de remboursement de l'assurance maladie française de la région ex-Aquitaine. L'adhésion au traitement a été évaluée en utilisant la proportion de jours couverts par le traitement et la persistance.

Résultats : 3015 patients ont été inclus avec un âge moyen de 66 ans. Près de 76% des patients ont eu un remboursement pour un traitement BAS, BASI ou AS. La persistance à un an était de 83 % pour l'aspirine et 75 % pour les hypolipémiants, mais la proportion de jours couverts était sous-optimale. Près de 45 % des patients sont allés en centre de réadaptation et 23 % a eu au moins une réhospitalisation. 4% des patients sont décédés après retour à domicile. Les patients ont consulté en moyenne 11 fois un médecin généraliste dans l'année. Près de 41 % des patients n'ont pas eu de remboursement de consultation chez le cardiologue de ville et 38,5 % ont eu au moins deux consultations. La réadaptation et les consultations de médecine générale sont associés à l'adhésion médicamenteuse.

Conclusions :

Ces nouveaux résultats pourraient nous aider à améliorer la transition des soins, et la collaboration entre les professionnels de santé impliqués dans un suivi ambulatoire.

Mots clés : infarctus du myocarde/ Adhésion médicamenteuse/ Bases de données/ Assurance maladie/ France, Parcours de soins.

Background

Prognosis for patients with myocardial Infarction (MI) has improved over the past decade due to the use of guideline-recommended therapies, such as early revascularization, antithrombotic therapies and other secondary prevention measures [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF][START_REF] Puymirat | Determinants of improved one-year survival in non-ST-segment elevation myocardial infarction patients: insights from the French FAST-MI program over 15 years[END_REF][START_REF] Fox | Underestimated and under-recognized: the late consequences of acute coronary syndrome (GRACE UK-Belgian Study)[END_REF]. However, few but regular studies convincingly and repeatedly showed the low short-and long-term adherence to treatment in the post-MI setting [START_REF] Jackevicius | Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction[END_REF][START_REF] Latry | Adherence with statins in a real-life setting is better when associated cardiovascular risk factors increase: a cohort study[END_REF][START_REF] Latry | Dual antiplatelet therapy after myocardial infarction and percutaneous coronary intervention: analysis of patient adherence using a French health insurance reimbursement database[END_REF][START_REF] Tuppin | Evidence-based pharmacotherapy after myocardial infarction in France: adherence-associated factors and relationship with 30-month mortality and rehospitalization[END_REF].

Non-adherence medication is a complex and multidimensional phenomenon precluding the achievement of therapeutic targets [START_REF] Sabaté | Adherence to long-term therapies: evidence for action[END_REF]. The discontinuation of the recommended post-MI therapy predisposes patients to serious thrombotic events, particularly myocardial infarction, and disease progression and destabilization [START_REF] Hamood | Effect of adherence to evidence-based therapy after acute myocardial infarction on all-cause mortality[END_REF][START_REF] Tea | Appropriate secondary prevention and clinical outcomes after acute myocardial infarction according to atherothrombotic risk stratification: The FAST-MI 2010 registry[END_REF][START_REF] Neumann | Clinical Events After Discontinuation of β-Blockers in Patients Without Heart Failure Optimally Treated After Acute Myocardial Infarction: A Cohort Study on the French Healthcare Databases[END_REF][START_REF] Bezin | Comparative effectiveness of recommended versus less intensive drug combinations in secondary prevention of acute coronary syndrome[END_REF].

Often, the studies on medication adherence only described a single aspect of this phenomenon, providing analyses of either its prevalence or consequences or its determinants and not the full aspect that is needed to have a more complete vision. Moreover, most of these studies have used data from 10 to 15 years ago [START_REF] Tuppin | Evidence-based pharmacotherapy after myocardial infarction in France: adherence-associated factors and relationship with 30-month mortality and rehospitalization[END_REF][START_REF] Blin | Outcomes following acute hospitalised myocardial infarction in France: An insurance claims database analysis[END_REF][START_REF] Bezin | Use of the recommended drug combination for secondary prevention after a first occurrence of acute coronary syndrome in France[END_REF] and there is a need to update it especially since the management of MI has constantly evolved and these previous studies do not reflect current practices.

The French health and reimbursement organizations recommend that strategy in preventing cardiovascular recurrence after hospitalization for myocardial infarction should be based on an optimal cardiovascular prescription at discharge, a cardiac rehabilitation in the weeks after hospital discharge, a regular follow-up every three months with the general practitioner and at least one consultation per year with a cardiologist [START_REF]HAS : PROGRAMME INFARCTUS 2007 -2010[END_REF][START_REF]Améli -Juin 2021 -Vivre après un infarctus du myocarde[END_REF].

Cardiac rehabilitation (CR) program was associated with improved patient survival and a better long-term adherence. As the latest studies published data between seven to fifteen years ago showed that approximately 25% to 40% of the patients went to CR [START_REF] Cottin | Specific profile and referral bias of rehabilitated patients after an acute coronary syndrome[END_REF][START_REF] Pouche | Cardiac rehabilitation and 5-year mortality after acute coronary syndromes: The 2005 French FAST-MI study[END_REF][START_REF] Gabet | National trends in admission for cardiac rehabilitation after a myocardial infarction in France from 2010 to 2014[END_REF], it is also interesting to update the data and to see if the access to cardiac rehabilitation is better and definitely improve cardiovascular disorders.

During the first year after discharge, cardiovascular evolution and treatment are often reassessed and therapeutical education program may be proposed to patients. Thus, one may consider that patients are thoroughly followed during the first year after the cardiovascular event, a great part in hospital.

Few authors have reported on global care trajectory outhospital including adherence focus for the first year [START_REF] Jackevicius | Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction[END_REF][START_REF] Tuppin | Evidence-based pharmacotherapy after myocardial infarction in France: adherence-associated factors and relationship with 30-month mortality and rehospitalization[END_REF][START_REF] Ho | Impact of medication therapy discontinuation on mortality after myocardial infarction[END_REF][START_REF] Gislason | Long-term compliance with betablockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial infarction[END_REF][START_REF] Tuppin | Combined secondary prevention after hospitalization for myocardial infarction in France: analysis from a large administrative database[END_REF]. The aim of this study was to describe the whole and the most recent available patient' acute myocardial infarction care pathway during the one year after hospital discharge and to describe their use and adherence to secondary prevention drugs.

Methods

Study design and source of data

A historical cohort study was conducted using data from the main French health insurance reimbursement database of the ex-Aquitaine region (southwest France) [START_REF] Martin-Latry | Pharmacoepidemiological research using French reimbursement databases: yes we can![END_REF] in 2018. In this region, which includes approximately 5 % of the French population, 2.5 million patients are covered by this insurance.

Inclusion criteria

Patients hospitalized for MI between January 1 st and December 31 st 2018, and followed-up after hospital discharge were selected whatever their medical becoming for one year, therefore until December 31 st , 2019 maximum.

Assessment of medical conditions and drug reimbursed

Identification of MI in the database was based on ICD-10 which allowed selection of patients hospitalized for MI and vascular endoprothesis. These codes are identical in all French hospitals and are disease specific. The ICD-10 codes considered was I21: acute myocardial infarction [24,[START_REF] Tuppin | Chaînage des données du PMSI avec les données de remboursement de l'assurance-maladie : exemple de l'analyse de la prévention secondaire après un infarctus du myocarde[END_REF].

Records for all patients included were reviewed for the 12 months-period following their event/hospitalization. Sociodemographic characteristics including age and gender were retrieved.

We also retrieved data to assess patients care pathway across the year: length of hospital stay, medication at discharge, medical care and medical events after discharge for a year and medication adherence during the study period for lipid lowering agents and aspirin.

The medical care for a year after discharge included: rehabilitation center stay, onset' delay for the first medical consultation in primary care, the number of medical consultations for general practitioners (Gps) and cardiologists, the number of reimbursement of drug prescription and onset' delay for the first reimbursement (in France the date of reimbursement is similar to the date of purchase).

The medical events for a year after discharge included hospitalization whatever the reason and/or death after hospital discharge regardless of the cause.

We described in Figure 1 the optimal care pathway after MI as published by the French health and reimbursement organizations as a common thread to present the results.

Drugs of interest were identified in the database according to their "Club Inter Pharmaceutique" (CIP) code which is a unique product identifier [26].

Classes were beta-blockers (Anatomical Therapeutic Chemical classification code: C07), antiplatelet agents (B01AC), lipid lowering agents (statins and ezetimibe or anti-PCSK9) (C10), angiotensin-converting-enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) with the ATC code C09.

Statistical analysis

We described the care pathway including all the variables presented above. Continuous variables were described with mean and 95% confidence intervals or median if the latter was different from the mean. Discontinuous variables were described with percentage.

The medication adherence was assessed for lipid-lowering agents and aspirin. Those are the two pharmacological classes of drugs that are most expected to be stable for one year regardless of the medical diagnosis. Indeed, the other classes of drugs included in the BASI treatment may vary according to diagnosis, prognosis, or tolerance thus medication adherence may be more difficult to interpret.

For lipid-lowering agents, we analyzed statins and/or ezetimibe adherence to consider the medical desire to treat hypercholesterolemia independently of statin tolerance.

Medication adherence was assessed by using two parameters: medication availability and persistence.

The medication availability is defined as the proportion of days covered during the period in which patients could have been on therapy. The medication availability (also termed proportion of days covered) was estimated using the "Continuous Multiple-interval measures of medication Availability" (CMA) definition [START_REF] Steiner | A general method of compliance assessment using centralized pharmacy records. Description and validation[END_REF][START_REF] Steiner | The assessment of refill compliance using pharmacy records: methods, validity, and applications[END_REF][START_REF] Grymonpre | Validity of a prescription claims database to estimate medication adherence in older persons[END_REF][START_REF] Hess | Measurement of adherence in pharmacy administrative databases: a proposal for standard definitions and preferred measures[END_REF][START_REF] Bourgault | Persistence and discontinuation patterns of antihypertensive therapy among newly treated patients: a population-based study[END_REF][START_REF] Caetano | Toward a standard definition and measurement of persistence with drug therapy: Examples from research on statin and antihypertensive utilization[END_REF]. The CMA is defined as the sum of the days of medication supplied divided by the number of days between the first fill and the last refill and assesses the number of days covered by treatment due to the purchase of medications. The theoretical days' supply is calculated by dividing the number of units dispensed by the daily dose for the drug considered. The daily dose is the recommended dose per day for its main indication in adults. The CMA was assessed using a consensual cut-off at 80 %, i.e. 80% of the time covered by the medication-intake. A CMA lower than 80% was considered as unsatisfactory in several previous studies for treatment of cardiovascular diseases).

Persistence was measured as the duration of uninterrupted therapy on the patient's index product using the anniversary Model. The patient is deemed persistent for 1 year if she/he refills a prescription within a specific interval surrounding the anniversary of her/his first prescription [START_REF] Bourgault | Persistence and discontinuation patterns of antihypertensive therapy among newly treated patients: a population-based study[END_REF][START_REF] Caetano | Toward a standard definition and measurement of persistence with drug therapy: Examples from research on statin and antihypertensive utilization[END_REF].

The analysis of both persistence and medication availability allows to assess if patients continue their treatment for a long period (persistence) and to assess if the gap is not big enough to induce recurrences or worsening (medication availability) whatever the duration of the treatment.

Analysis was performed using SAS software version 9.1 for PC; the Student t and Chi tests were used.

At last, we assessed factors associated with medication adherence (CMA upper than 80%) (independent variable) and each explicative factor was firstly measured by an odds ratio (OR) using conditional univariate logistic regression. The level of statistical significance was set at 0.05 and the statistical uncertainty of the estimates was assessed by 95% confidence intervals (95% CI). Then variables with a level of statistical significance <0.05 or p<0.20 and those clinically relevant were included in a matched multivariate logistic regression model. The final model was determined using a backward stepwise procedure, with 0.1 as the threshold for eviction from the model.

The one-year indicators were given excluding patients who died during the year.

Ethical considerations

We performed an observational study on anonymous data. Thus, based on the French legislation, it did not need to be approved by an ethic committee, although this study did conform to the principles of the Helsinki Declaration.

Results

Baseline characteristics of the study population

The study included 3,015 patients hospitalized between January 1 st and December 31 st 2018, in the Aquitaine region, with the diagnosis of myocardial infarction (MI) (ICD-10). The sex ratio was 2.1 with 32% of female and a mean age of 66 (median: 66, CI95% [65.4;66.4]).

37.6% (n=834) of the population was over 75 years old (Table 1).

We detailed the results below, following the patient care pathway described in the Figure 1 as a common thread.

Time course of Myocardial infarction care pathway

Hospitalization

The mean duration of hospitalization was 6 days (median: 6, CI95% [6.0;6.3]) (Table 1).

Medication at Discharge

At discharge, 53.7% of the patients asked for a reimbursement (ask the pharmacist) of a combined prescription including betablockers, antiaggregant, lipid-lowering agents and ACE inhibitors (name as BASI treatment).

The Figure 2 details the percentage of prescription of the different pharmacological classes and the main combination found. Almost 78% had a betablocker prescription, 83.7% had a lipid-lowering agent prescription and 69% had an ACEi prescription. Almost all the patients had at least one antiaggregant or anticoagulant therapy (Table 2).

The median delay between discharge and drugs delivery was 0 day (Table 1) with 62% of the patients who buy their medication the day of hospital discharge and 83% in the week after hospital discharge.

Medical care after discharge

During the study period, 45.2% of the patients went to a cardiac rehabilitation center of whom 98.2% during the first three months. As compared to patients not referred to rehabilitation, patients that went to a cardiac rehabilitation were statistically younger (mean=63 vs. 66, p˂10 - 6 ), and the percentage of male patients was higher (71% vs. 65.5%, p=10 -3 ).

For a one-year period, the mean number of general physician consultation was 11, i.e. one a month and only 4% had less than 3 general physician consultations during the year.

The median delay between discharge and the first outhospital GP medical consultation was 6 days, (mean=26, CI95% [24. 8-28.4]). Most of the patients had a GP consultation in the first week after discharge and another group of patients had a GP consultation about a month (see

Supplementary files).

The median number of cardiologist consultation per patient was 2 per year. However, almost 41% % had no cardiological consultation in clinical setting during the year and 38.4% had two or more consultations (Table 1).

Medical events after discharge

During the study period, 22.7% of the patients were admitted to hospital whatever the reason with a median delay of 100 days (approximately three months). The percentage of death during the year after the initial hospital discharged for MI was 3.7% (mean and median delay = 4.6 months, CI95% [START_REF] Jackevicius | Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction[END_REF][START_REF] Latry | Adherence with statins in a real-life setting is better when associated cardiovascular risk factors increase: a cohort study[END_REF]).

Assessment of medication adherence

For the study period, patients also went to the pharmacy once a month to buy their medications.

At the end of the year, 83.1% of patients still use low dosage of aspirin (rate of persistence= duration of uninterrupted therapy) and for the remaining 16.9%, the treatment's purchase was not found in the database. During the same period 64.2% of the patients have taken at least 80% of their dose of aspirin (proportion of days covered ≥80%) with a mean delay between two refills of 37 days although size of medication'packagings is scheduled to last 28 to 30 days.

At the end of the year, 75% of patients still used lipid-lowering agents (statin or ezetimibe) and for the remained 25%, the treatment' purchase was not found in the database. During the same period 69.4% of the patients have taken at least 80% of their dose of medication (proportion of days covered ≥80%) with a mean delay between two refills of 48 days but this data is not interpretable due to the existence of both boxes of 30 and 90 units of this class of drugs.

There was a statistically positive association between non-adherence to lipid-lowering drugs and non-adherence to aspirin with correlation for 67% of the patient (p<10 -6 ).

During the year, almost 14.5% (n=438) of the patients had a reimbursed prescription for oral anticoagulant and 92.2% of the 14.5% had a refill. In this population, 63.4% (CI95% [58.6-68.1]) still used oral anticoagulant at the end of the study period.

Factors of medication adherence for aspirin and statins

In univariate analysis, 86% of the adherent patients to low-dosage aspirin (LDA) had at least 6 GPs consultations that year vs 69.4% for non-adherent LDA patients (p<10 -5 ) and 48% went to cardiac rehabilitation center vs 38% for non-adherent LDA patient (p<10 -6 ).

Considering adherence to lipid-lowering agents, in univariate analysis, 87% of the adherent patients had at least 6 GPs consultations that year vs 75.5% for non-adherent patients (p<10 - 14 ) and 50% went to cardiac rehabilitation center vs 38% for non-adherent patient (p<10 -8 ).

Seven variables were included in the multivariate logistic regression model as the result of univariate analysis: age, gender, rehabilitation center, number of general practitioner consultation during the year, number of cardiologist consultation during the year, delay of first medication delivery and delay of first medical consultation.

In multivariate analysis, a rehabilitation program, a low delay of first consultation and the mean number of medical consultations per year were associated with aspirin adherence. For statin adherence the delay of first medication's delivery was also associated (Tables 3 and4).

Discussion

The originality of this study was to describe the recent (2018) patient's care pathway in primary care after discharge from hospital for myocardial infarction. We described the recent patient' MI medical and pharmaceutical care pathway for a year and described their use and persistence of secondary prevention drugs. To our knowledge, no study has recently investigated such a global outcome.

There are 6 important findings: i. Most patients purchased cardiovascular therapy with 75.8% of the patients with a reimbursement for a BAS, a BASI or a AS treatment. However, 16.3% have not purchased a lipid-lowering agents. Almost all the patients had at least one antiaggregant or anticoagulant therapy ii. Most of the patients collect their medication immediately after discharge.

iii. 45.2% of the patients went to a rehabilitation center.

iv.

Patients consult their GP early and extensively as soon as they leave hospital (mean of one per month), almost 41% of the patients did not have a consultation with a cardiologist during the year and 38.4% had at least two consultation per year.

v. The medication adherence is suboptimal during the first year, with 17% of the days where the aspirin treatment is not taken and 25% of the days without taking lipidlowering drugs.

vi.

Optimal medication adherence was statistically associated with a stay in a rehabilitation center and well associated with the number of medical consultations.

Depending on the drug, the delay between the 1 st GP consultation and the hospital discharge can be positively or negatively associated and is well associated with delay of first medication delivery. There were no association with age and gender.

Our results for medication at discharge are similar to previous published studies even if the temporality of the studies carried out and methods to analyze medication adherence are not fully comparable. Their percentages of betablockers and statins prescription were around 82 to 85% [START_REF] Bezin | Comparative effectiveness of recommended versus less intensive drug combinations in secondary prevention of acute coronary syndrome[END_REF][START_REF] Tuppin | Combined secondary prevention after hospitalization for myocardial infarction in France: analysis from a large administrative database[END_REF] except for Blin et al [START_REF] Blin | Outcomes following acute hospitalised myocardial infarction in France: An insurance claims database analysis[END_REF] with 92% and almost 99% with one or two antiaggregant or anticoagulants. In their recent article, Dibao-Dina et al [START_REF] Dibao-Dina | Patients' adherence to optimal therapeutic, lifestyle and risk factors recommendations after myocardial infarction: Six years follow-up in primary care[END_REF] found that the reason for non-prescription of betablockers is due to medical contraindications (bradycardia, COPD…). For statins, the reason is well known, patients are afraid of side effects and perceived side effects, and sometimes, do not purchase it even if it has been prescribed [START_REF] Bradley | Patient-Reported Reasons for Declining or Discontinuing Statin Therapy: Insights From the PALM Registry[END_REF].

Non-prescription may also result from a concerted choice between doctor and patient.

Considering medication adherence, our results with 81% of aspirin persistence and 75% of statin persistence are slightly higher than previous studies assessing persistence where results varied from 45 to 65%. The proportion of days covered ≥80% ranged around 65% is similar to previous studies that went from 56% to 72% depending on the duration of the study [START_REF] Latry | Adherence with statins in a real-life setting is better when associated cardiovascular risk factors increase: a cohort study[END_REF][START_REF] Tuppin | Evidence-based pharmacotherapy after myocardial infarction in France: adherence-associated factors and relationship with 30-month mortality and rehospitalization[END_REF][START_REF] Hamood | Effect of adherence to evidence-based therapy after acute myocardial infarction on all-cause mortality[END_REF].

However, it is difficult to compare as methods used to define persistence or study periods are different. One may conclude that medication adherence remains suboptimal across time.

The delay between MI hospital discharge and purchase of medication was very optimal. We did not find previous published studies to compare this parameter.

The percentage of cardiac rehabilitation program (CR) of 45% in our study is known to have a beneficial effect on patient survival [START_REF] Cottin | Specific profile and referral bias of rehabilitated patients after an acute coronary syndrome[END_REF] and is similar to other recent studies with a percentage of 41% who attended at least half of the sessions in the EUROASPIRE IV survey [START_REF] Kotseva | Determinants of participation and risk factor control according to attendance in cardiac rehabilitation programmes in coronary patients in Europe: EUROASPIRE IV survey[END_REF][START_REF] Vynckier | Medical Treatment in Coronary Patients: Is there Still a Gender Gap? Results from European Society of Cardiology EUROASPIRE V Registry[END_REF], and almost 37% for Gabet et al [START_REF] Gabet | National trends in admission for cardiac rehabilitation after a myocardial infarction in France from 2010 to 2014[END_REF] 44% for Dibao-Dina et al [START_REF] Dibao-Dina | Patients' adherence to optimal therapeutic, lifestyle and risk factors recommendations after myocardial infarction: Six years follow-up in primary care[END_REF] and Puymirat E et al [START_REF] Puymirat | Outcome associated with prescription of cardiac rehabilitation according to predicted risk after acute myocardial infarction: Insights from the FAST-MI registries[END_REF]. This percentage was higher than most older studies such as FAST-MI 2005 and the French nationwide PREVENIR in 1998 with 22 % to 24 % [START_REF] Cottin | Specific profile and referral bias of rehabilitated patients after an acute coronary syndrome[END_REF][START_REF] Pouche | Cardiac rehabilitation and 5-year mortality after acute coronary syndromes: The 2005 French FAST-MI study[END_REF] suggesting an improved access to cardiac rehabilitation for the last ten years. Our recent results confirm the impact of CR on medication adherence.

There is a high number of general practitioners (GPs) medical consultations over the first year after MI with a mean of one a month. There are several possible explanations. The social health insurance system allows patients to regularly visit their GPs without most of the time paying and advancing the costs of the consultation and French people are used to seeing their GPs regularly. Moreover GPs may want to be able to follow their patients frequently during their first year after MI. However as cardiovascular risks have been assessed and treated in hospital after their MI and that mostly half of the patients went to rehabilitation center in the first three months, one may consider that there is no need for GPs' consultation in the first three months. Moreover, our results showed that the impact of medical consultation on medication adherence is extremely low while this induces reimbursement costs for health insurance. The patients return every month to the pharmacy for the medication which may be due in part to every month GPs consultation and the prescription of a month period treatment.

However, the packaging is changing and last up to three months in France and we may hope that the number of medical consultations will be reduced.

In our study, mortality after discharge is comparable with previous studies that published a six-month mortality of approximately 5% [START_REF] Tuppin | Evidence-based pharmacotherapy after myocardial infarction in France: adherence-associated factors and relationship with 30-month mortality and rehospitalization[END_REF][START_REF] Dibao-Dina | Patients' adherence to optimal therapeutic, lifestyle and risk factors recommendations after myocardial infarction: Six years follow-up in primary care[END_REF]. It remains lower than another study with 10% for a year for Blin et al [START_REF] Blin | Outcomes following acute hospitalised myocardial infarction in France: An insurance claims database analysis[END_REF]. It may be explained by different inclusion criteria.

Strengths and limitations

Due to the use of a reimbursement database, this historical study has the advantage of not altering the behavior of either prescribers or patients. As adherence is a multifaceted question, two standardized parameters were used. These have been extensively discussed in the literature [START_REF] Andrade | Methods for evaluation of medication adherence and persistence using automated databases[END_REF]. One factor that may be debated is the use of 80% treatment coverage as the cut-off for assessing adherence. This is commonly used in literature, yet it may not be appropriate for all types of drugs [START_REF] Stephenson | The rational clinical examination. Is this patient taking the treatment as prescribed?[END_REF]. However, this cut-off of 80% is commonly used for cardiovascular studies. We can easily consider than below this threshold, there is a problem with pill taking and medicament efficacy.

A study conducted using a reimbursement database suffers from some limitations. The results presented are likely to be an overestimation of adherence since some patients who buy their treatment, may not take it. Patients may have been classified as having discontinued if they moved outside the administrative region (Aquitaine) but this can be considered as only marginal as the population over 50 years old is geographically quite stable. Discontinuation for financial reasons is also improbable owing to the extent of the national health insurance system, which offers full coverage for underprivileged and unemployed people. Conversely, the cost of cardiovascular drugs is high enough to practically preclude claims for reimbursement not to be made and the electronic system used in France for reimbursement (SESAM-ViTALE) [START_REF] Martin-Latry | Pharmacoepidemiological research using French reimbursement databases: yes we can![END_REF] guarantees the exhaustive capture of deliveries in the database in real-time. Moreover, MI belongs to the French list of chronic diseases ("Affections de longue durée" or ALD) for which the national health insurance funds reimbursement at 100% of expenses. Patients may ask to be registered as a patients with MI on this list in order to not pay [START_REF]Définition de l'ALD[END_REF].

Conclusions

The new results provide clear information on the medical care environment of patients and help us improve care transition. A close collaboration between healthcare practitioners is very important in the early stages of outpatient follow up. Moreover these results concerning adherence and higher medical care plead for the development of therapeutical patient

Figure 1 :

 1 Figure 1: Care pathway after MI according to the French health and reimbursement organizations and possible medical outcome

4 -Figure 2 :

 42 Figure 2: Percentage of prescription reimbursed at discharge

Table 1 : Characteristics of patients hospitalized for myocardial infarction and included in the study and main medical follow-up outcome results

 1

	Total	CI 95%
	n=3,015

Table 2 : Antiagregants and anticoagulants treatments characteristics at discharge n %

 2

	Aspirin alone	255	8.5
	Others antiaggregants (AAG) than aspirin	173	5.7
	Anticoagulant (OAC) alone	44	1.5
	At least one AAG or OAC	2,886	98.6
	At least one antiaggregant (AAG)	2,842	95.7
	Biantiaggregant therapy	2,214	73.4
	Single antiagregant+OAC	62	2.1
	Biantiaggregant+OAC	137	4.5

Table 3 : Multivariate regression analysis for aspirin adherence

 3

	Attribute	OR	Low	High	p
	Medical readaptation	1.30	1.07	1.59	0.008
	Number of general practitioner consultation	1.17	1.14	1.18	< 10 -6
	Delay for first consultation	1.004	1.002	1.006	10 -4

Table 4 : Multivariate regression analysis for lipid-lowering drug adherence

 4

	Attribute	OR	Low	High	p
	Medical readaptation	1.53	1.27	1.84	10 -5
	Number of general practitioner consultation	1.16	1.13	1.19	10 -6
	Delay of first medical consultation	0.97	0.96	0.98	< 10 -6
	Delay of first medication delivery	1.04	1.03	1.05	< 10 -6

education in order to optimize the patients' implication in their chronic disease. This will help limit medical costs, which aren't always completely effective.