De novo atrial fibrillation : an independent prognostic marker after myocardial infarction: results from the ORBI and RIMA registries

Membres du jury

Monsieur le Professeur PRUNIER Fabrice | Président Monsieur le Professeur FURBER Alain | Directeur Monsieur le Docteur BIERE Loïc | Membre Monsieur le Docteur GALLET Jean | Membre

De novo atrial fibrillation: an independent prognostic marker after myocardial infarction:

results from the ORBI and RIMA registries

La fibrillation atriale de novo : un marqueur pronostique

indépendant après la survenue d’un infarctus du myocarde : résultats issus des registres ORBI et RIMA

MOINEREAU Thomas

Né le 21/05/1989 à Angers (49)

LE DOEUFF Camille

Née le 21/11/1991 à Morlaix (29)

Sous la direction du Pr. FURBER Alain

2019-2020

THÈSE

pour le

DIPLÔME D’ÉTAT DE DOCTEUR EN MÉDECINE

Qualification en CARDIOLOGIE ET MALADIES VASCULAIRES

ENGAGEMENT DE NON PLAGIAT

Je, soussignée Camille LE DOEUFF

déclare être pleinement consciente que le plagiat de documents ou d’une partie d’un document publiée sur toutes formes de support, y compris l’internet, constitue une violation des droits d’auteur ainsi qu’une fraude caractérisée.

En conséquence, je m’engage à citer toutes les sources que j’ai utilisées pour écrire ce rapport ou mémoire.

signé par l'étudiante le 12/10/2020

Je, soussigné Thomas MOINEREAU

déclare être pleinement conscient que le plagiat de documents ou d’une partie d’un document publiée sur toutes formes de support, y compris l’internet, constitue une violation des droits d’auteur ainsi qu’une fraude caractérisée.

En conséquence, je m’engage à citer toutes les sources que j’ai utilisées pour écrire ce rapport ou mémoire.

signé par l'étudiant le 12/10/2020

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RICHOMME Pascal Pharmacognosie Pharmacie

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maladies métaboliques Médecine ROQUELAURE Yves Médecine et santé au

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Clotilde Médecine légale et droit de

la santé Médecine

ROUSSEAU Audrey Anatomie et cytologie

pathologiques Médecine

ROUSSEAU Pascal Chirurgie plastique, reconstructrice et esthétique

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ROUSSELET Marie-

Christine Anatomie et cytologie

pathologiques Médecine

ROY Pierre-Marie Thérapeutique Médecine

SAULNIER Patrick Biophysique et

biostatistique Pharmacie

SERAPHIN Denis Chimie organique Pharmacie

TRZEPIZUR Wojciech Pneumologie Médecine

UGO Valérie Hématologie ; transfusion Médecine

URBAN Thierry Pneumologie Médecine

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Marie-Claire Pharmacotechnie Pharmacie

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ANGOULVANT Cécile Médecine Générale Médecine

BAGLIN Isabelle Chimie thérapeutique Pharmacie

BASTIAT Guillaume Biophysique et biostatistique Pharmacie

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Laurence Pharmacie Clinique et Education

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TANGUY-SCHMIDT Aline TESSIER-CAZENEUVE Christine

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Médecine

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RE MER C IE MENTS C OMM UNS

A Monsieur le Professeur Alain FURBER, pour nous avoir encadré dans ce travail, pour votre enseignement et vos conseils avisés tout au long de notre internat, soyez assuré de notre profond respect.

A Monsieur le Professeur Fabrice PRUNIER, pour nous faire l’honneur de présider ce jury, pour votre enseignement tout au long de notre internat, votre disponibilité et votre grande pédagogie, soyez assuré de notre profond respect.

A Monsieur le Docteur Loïc BIERE, nous te remercions sincèrement de tes précieux conseils dans la réalisation de ce travail ainsi que pour ton implication dans notre formation. Que ce soit par les séances de simulation, ta disponibilité pour répondre à nos nombreuses questions et tes encouragements pour que nous devenions les meilleurs cardiologues de l’hôpital (et pas que) le temps d’une garde.

A Monsieur le Docteur Jean GALLET, pour nous faire l’honneur d’être les premiers internes dont tu jugeras le travail de thèse. Que ce soit en tant que co-interne ou en tant que senior, merci de ta disponibilité, de ta constante gentillesse et de ton habileté à simplifier les cardiopathies les plus complexes. En espérant que nous continuerons longtemps à travailler ensemble.

RE MER C IE MENTS C A MI L L E

A Thomas, mon grand frère, pour tes encouragements, ta présence à chaque moment important et tes conseils toujours pertinents. Merci pour la relation que nous avons aujourd’hui qui m’est précieuse.

A Marion, ma grande sœur, toujours là pour m’éclairer et me conseiller. Avec toi, rien n’est impossible, tu as toujours le mot juste pour m’aider à retrouver la motivation nécessaire à l’accomplissement de mes projets. Merci pour ton implication, ta gentillesse et ton énergie.

A Céline, Raphaël, Léo, Manon, Jules et Mathis, merci pour tous ces moments privilégies en famille, ils me sont essentiels.

A Flore, merci pour ton soutien et tous ces bons moments passés au travail comme en dehors.

Vivement mon arrivée à Cholet, que nous puissions enfin reformer notre couple work qui fonctionne si bien !

A Antoine, un vrai chic type. Je n’aurais pas pu espérer trouver un meilleur co-interne pour partager nos débuts à la 370. Toujours présent, juste, droit, tu m’impressionnes par ton efficacité et ta rigueur ainsi que par ton sens de l’humour, ajusté en toutes circonstances.

Merci pour tous ces bons moments, je compte sur toi pour que nous en vivions encore beaucoup d’autres.

A Ali, qui m’a accueilli avec beaucoup de bienveillance dès mon arrivée à Angers. Toujours prêt à rendre service, présent dans les bons moments et aussi dans les plus délicats, notre semestre aux soins intensifs a été riche en apprentissage et en émotions et je suis très heureuse de l’avoir vécu avec toi.

A Adrien, Youna, Jean, Céleste, Gabriel, Yohan, Camille, Claire et Floriane, les « vieux » internes qui nous ont montré la voie, merci pour votre aide et vos conseils.

A Alban, Eloi, Lise, Thanh-Hien ainsi qu’aux plus jeunes internes : merci pour les moments partagés et bon courage pour la suite !

A Vianney, mon premier chef de garde, merci pour ton enseignement, ta patience et ta bienveillance. Ton soutien et tes encouragements ont beaucoup comptés.

Aux Docteurs Le Page, Niro, Camarzana, Laporte, Benard, Tassin, Rouleau, Delépine, Abi Khalil, Dupuis et Grall pour leur enseignement.

A l’ensemble des équipes paramédicales des services de cardiologie du CHU d’Angers : merci pour votre bonne humeur, votre aide au quotidien, c’était un plaisir de travailler à vos côtés.

Une mention toute particulière à l’équipe du 370 qui a veillé sur moi aussi bien que sur leurs patients durant les premiers mois d’internat, votre soutien a été précieux.

Un grand merci également aux équipes de nuit, toujours présentes et soutenantes.

A l’équipe de cardiologie du centre hospitalier de Cholet : Laurent, Prosper, Romain, Youna, Maxime, Houssem ainsi que l’ensemble de l’équipe paramédicale. C’est avec plaisir que je reviens continuer l’aventure avec vous !

A toute l’équipe du service de Réanimation du Mans et notamment à Juliette, Clémence et Delphine.

RE MER C IE MENTS C A MI L L E

A mes amis de Brest, en particulier Louise, Quentin et Maxime. Malgré la distance je n’oublie pas que c’est avec vous que tout a commencé et j’espère bien que vous ferez partie de la suite de l’histoire.

A Angèle, collègue puis colocataire, puis amie, je suis heureuse de poursuivre l’aventure nantaise à tes côtés.

A Virginie et Laura, que de chemin parcouru depuis nos débuts à Brest…peu importe le temps et la distance, rien ne change.

A Thomas, notre collaboration dans ce travail n’a fait que renforcer l’estime que j’ai pour toi.

D’une gentillesse à toute épreuve et impressionnant par l’étendue de tes connaissances, je compte sur nous pour entretenir encore longtemps cette belle amitié.

A Julien, mon plus grand soutien. Tu m’as accompagnée dans chaque grande étape de cette aventure. Tu as partagé les joies et les peines avec une patience infinie et un dévouement incroyable. C’est grâce à toi si j’arrive au bout de ce projet aujourd’hui.

RE MER C IE MENTS THOM A S

A Victor, qui est venu apporter beaucoup de bonheur à cette aventure.

A mes parents, qui ont su éveiller ma curiosité, la nourrir. Vous êtes exemplaires par votre soutien indéfectible.

A mes sœurs, leurs conjoints et mon neveu, toujours disponibles et bienveillants à mon égard.

A ma belle-famille, toujours un grand plaisir de vous retrouver; l’assurance de moments heureux.

A ma famille, mes grands-parents, ma grand-mère, oncles, tantes, cousins, cousines d’une gentillesse et d’une bonne humeur constantes.

A Camille, brillante et sincère, qui a su mener conjointement ce travail à son terme. Que notre amitié se poursuive !

Evidemment à mes co-internes de promo, mais avant tout amis, Antoine et Ali toujours de bons conseils.

Aux anciens co-internes devenus chefs : Adrien, Audrey, Camille, Claire, Flore, Floriane, Gabriel, Jean, Yohan, Youna, pour vos conseils avisés et votre disponibilité remarquable.

Aux plus jeunes co-internes, c’est un vrai plaisir de travailler ensemble.

Aux Docteurs Abi Khalil, Benard, Behaghel, Delepine, Dupuis, Grall, Laporte, Le Page, Mezdad, Niro, Rouleau, Tassin pour le partage de vos savoirs et de vos expériences.

Aux équipes soignantes de cardiologie du CHU, de Saumur et de Cholet : votre soutien et votre savoir-faire furent précieux.

Aux équipes de chirurgie cardiaque et de réanimation médicale pour l’accueil, la bienveillance et l’enseignement de grande qualité.

A tous mes amis d’enfance, de Centrale, d’externat, d’internat, à mes proches, mes collègues qui m’ont soutenu dans cette belle aventure.

A Jérémy et Thiébaud pour leur implication et l’aide indispensable à l’exploitation des données.

Pour ce travail, qui n’est pas un aboutissement mais le commencement d’une belle histoire, merci à chacun qui y a pris part.

Liste des abréviations

ACE Angiotensin Converting Enzym AF Atrial Fibrillation

CABG Coronary Artery Bypass Graft CPK Creatine Phosphokinase ECG Electrocardiogram

Hb Hemoglobin

HF Heart Failure

HR Hazard Ratio

LAD Left Anterior Descending LMWH Low Molecular Weight Heparin LVEF Left Ventricular Ejection Fraction NOAF New Onset Atrial Fibrillation

OR Odd Ratio

ORBI Observatoire Régional Breton sur l’Infarctus PAD Peripheral arterial disease

RIMA Registre des Infarctus en Maine Anjou SBP Systolic Blood Pressure

STEMI ST Elevation Myocardial Infarction VKA Vitamin K Antagonist

De novo atrial fibrillation: an independent prognostic marker after myocardial infarction:

results from the ORBI and RIMA registries

MOINEREAU Thomas et LE DOEUFF Camille Répartition du travail

Thomas MOINEREAU : Analyse des bases de données, recueil des données, réalisation des analyses statistiques, recherche bibliographique, rédaction

Camille LE DOEUFF: Analyse des bases de données, recueil des données, réalisation des analyses statistiques, recherche bibliographique, rédaction

Table of contents

ABSTRACT

INTRODUCTION

METHODS

1. Diagnosis of atrial fibrillation and myocardial infarction 2. Data Collection

3. Statistical Anayses

4. Outcomes

RESULTS

1. Population characteristics

2. Events

3. Sub-group analysis according to the time of new onset atrial fibrillation 4. Analysis of events at one year on the population of the RIMA registry DISCUSSION

1. Limits

CONCLUSION

BIBLIOGRAPHY

FIGURES

TABLES

TABLE OF CONTENTS

ABSTRACT

Aims : New onset atrial fibrillation after a STEMI is at greater risk of complications. We focus on determining the incidence of new onset AF, analysing the prevalence of prior AF for patients hospitalized for STEMI, identifying predictive factors of AF and assessing the impact of AF on morbidity and mortality during hospitalization and at one year.

Methods : 3357 patients with STEMI were enrolled in the RIMA and ORBI registries. They were divided into 3 groups according to the timing of AF occurrence: 1) patients free of AF; 2) patients with prior AF; 3) patients with New Onset AF. We defined 3 primary outcomes during hospitalization and at 1-year post-discharge: mortality, heart failure (HF) and stroke. One-year events were only assessed on RIMA registry.

Results : During hospitalization, cardiovascular mortality was higher in prior AF (10.7%) and new onset AF (7.5%) compared to AF-free (3.2%). Results were similar for heart failure with respectively 25.9%, 27.0% and 8.6%. Strokes were more frequent in new onset AF versus AF-free patients (3,2%

versus 0,4%, p < 0.001). In multivariate analysis, NOAF was an independent factor in development of heart failure during hospitalization (p 0.001, OR 1.897 [1.303-2.763]) and also in development of stroke (p 0.006, OR 4.304 [1.522-12.168]). At one year, from RIMA registry, we observed a significant difference in mortality, stroke and hospitalization for heart failure between AF-free and new onset AF patients. Mortality was 28.9% for NOAF group versus 8.2% in AF-free group (p <

0.001) and stroke rate was 5.9% versus 1.12% (p 0.007). In NOAF, 9.6% of patients were hospitalized within one year for heart failure versus 3% in AF-free group (p<0.001).

In multivariate analysis, absence of AF appears to be a protective factor for the occurrence of stroke (p 0.033 OR 0.267; CI [0.080-0.898]) and heart failure (p 0.030 OR 0.398; CI [0.173-0.915]).

Conclusion : NOAF occurring after STEMI is a marker of severity that should not be overlooked. AF is an independent marker for stroke and heart failure during hospitalization and a marker for mortality, readmission for heart failure and stroke at one year.

INTRODUCTION

Atrial fibrillation (AF) is the most common supraventricular rhythm disorder, with an incidence ranging from 5% to 18% for patients with myocardial infarction, although there has been an improvement these last years with an incidence of 4.8% to 7.7% ⁽¹⁾ since early revascularization became widespread.

The occurrence of AF in STEMI is due to different mechanisms. Ischemia reduces atrial perfusion, increases the telediastolic pressure of the left ventricle as well as the pressure in the left atrium, leads to diastolic dysfunction and autonomic nervous system abnormalities promoting this arrhythmia. The inflammation induced by ischemia also causes rhythm disturbance ⁽²⁾.

It has already been shown that patients who present AF after STEMI have more co- morbidities and are at greater risk of complications ⁽³⁾⁽⁴⁾, including increased mortality, suggesting that atrial fibrillation should be considered as a true marker of severity ⁽⁵⁾.

Furthermore, it has also been shown that depending on the time of onset of AF in the post- infarction period, the impact on morbidity and mortality was different. Indeed, some studies have demonstrated a higher morbidity and mortality for AF occurring more than 30 days after STEMI ⁽⁶⁾.

In this study, we focus on evaluating the incidence of New Onset Atrial Fibrillation (NOAF), the prevalence of prior AF for patients hospitalized for STEMI, identifying predictive factors of AF and the impact of AF on morbidity and mortality during hospitalization and at one year.

We also analyzed intra-hospital morbidity and mortality according to the time of AF occurrence: early (< 24h), intermediate (24-72h) or late (>72h).

METHODS

This is a retrospective study based on the prospective registries RIMA (Registre des Infarctus en Maine-Anjou) and ORBI (Observatoire Régional Breton sur l'Infarctus).

The RIMA Registry prospectively included all patients presenting for STEMI and treated at the Angers University Hospital and who could also come from three peripheral centers that do not perform angioplasty (Cholet, Saumur and Château-Gontier Hospital Centers).

The ORBI registry prospectively included all patients presenting for STEMI within 24 hours of the onset of symptoms in the 9 Breton interventional cardiology centers (Rennes University Hospital; Clinique Saint-Laurent, Rennes; Saint-Malo Hospital; Saint-Brieuc Hospital; Lorient Hospital; Vannes Hospital; Brest University Hospital; Quimper Hospital; Clinique du Grand Large, Brest).

We study here the period from January 2017 to December 2018 for the ORBI registry and from January 2016 to July 2019 for the RIMA registry.

1. Diagnosis of atrial fibrillation and myocardial infarction

Atrial fibrillation is defined by the absence of distinct P waves and an irregular R-R interval on the ECG.

All patients were monitored during the intensive care hospitalization. A 12-lead ECG was performed whenever an atrial fibrillation was suspected on the monitoring.

Patients were classified into three groups: 1) No AF; 2) Patients with a history of AF (permanent, paroxysmal, or persistent); 3) Patients with New Onset AF between the first medical contact for STEMI and discharge.

For this last group, subgroups were carried out according to the time of onset of AF:

early AF occurring within the first 24 hours of hospitalization, intermediate AF occurring

between 24 and 72 hours of hospitalization and late AF occurring more than 72 hours after STEMI.

STEMI was defined by the following characteristics: ST segment elevation ≥0.1 mV in two contiguous peripheral leads, and V5 V6, or > 0.2mV in two contiguous leads from V1 to V4 associated with troponin elevation.

2. Data Collection

About the characteristics of populations and intra-hospital events, data were collected prospectively upon patient admission. The main antecedents, cardiovascular risk factors, treatments on admission and at discharge, characteristics of the infarction and its management (size, location, treatment) as well as complications (death, heart failure, bleeding, etc.) were collected.

One-year events were collected retrospectively on the basis of computerized records at the Angers University Hospital and the Cholet Hospital Center.

The study was carried out in accordance with the Declaration of Helsinki and the protocol was approved by the Ethics Committee of the Angers University Hospital.

3. Statistical Anayses

All calculations were performed using SPSS^® Version 27.0 for Windows^® (SPSS Inc., Chicago. Illinois. USA). Quantitative variables were expressed as a mean associated with the standard deviation. Qualitative variables were expressed as absolute values and as a percentage of the total data available for the study population. The comparison of quantitative variables was carried out using a Student t-test, supplemented by an analysis of variance test. The comparison of qualitative variables was performed by a chi-2 test, and for theoretical numbers of less than 5 patients a Fisher test. At one year, the survival curves

associations at one year by the Hazard Ratio (HR) was carried out by the Cox model. The statistical significance was set at p<0.05.

4. Outcomes

In this study, we focus on demonstrating the impact of atrial fibrillation on cardiovascular mortality and the occurrence of heart failure or ischemic stroke at one year of hospitalization for myocardial infarction for patients in the RIMA Registry and at the hospital phase for all patients in both registries.

RESULTS

5. Population characteristics

3357 patients were included for myocardial infarction, 2875 were AF-free (85.6%), 139 had a history of AF (4.1%) and 343 had new onset AF (10.2%) (see Figure 1 and Table I).

The mean age was 63 years and 79% of patients were male.

Patients in prior AF group were significantly older, had more hypertension, a greater history of coronary artery disease, renal insufficiency, a history of stroke, and higher CHA2DS2-VASc compared to the AF-free population and the new onset AF population.

At baseline, only 62% of patients with prior AF had curative anticoagulation, evenly distributed between VKA and direct oral anticoagulant.

Patients with new onset AF were older, had more hypertension, more frequent renal failure, had higher CHA2DS2-VASc compared to the population without AF.

About the characteristics of myocardial infarction,

The location of myocardial infarction was different between the groups, with more left anterior descending artery lesions guilty in the AF-free group (55.2%) compared to prior AF (41.9%) and new onset AF (36.4%) groups.

There was also a higher rate of angioplasty failure of the guilty lesions in new onset AF group (8.4%) compared to population without AF (3.8%), (p < 0.001).

There was more multivessel disease in new onset AF group (59%) compared to AF- free (50.3%) and prior AF (47.6%) groups (p 0.009).

Left ventricular function was significantly more impaired in the groups with AF (45.8%) compared to AF-free group (50.3%) (p<0.001).

Finally, populations with AF had significantly longer hospital stays in intensive care (5 days) and total hospital stays (9 days) compared to AF-free population (respectively 4 days and 6 days) (p<0.001).

Concerning the treatments at discharge,

Patients in new onset AF and prior AF groups were less often treated with ACEI/ARB compared to AF-free group, p<0.001.

Beta-blockers and statins were less prescribed in AF groups (new onset and prior AF) compared to AF-free group, but were more prescribed in new onset AF group compared to prior AF group, p<0.001.

About antithrombotic therapy at discharge (see Figure 2), in group with prior AF, the same proportion of patients had curative anticoagulation between admission and discharge (62% and 63.5%), with more frequent use of direct oral anticoagulants (30.9% at admission versus 37.4% at discharge). The preferred combination of antithrombotic with anticoagulant was aspirin and clopidogrel.

In new onset AF group, only 38.9% of patients received curative anticoagulation at discharge.

Finally, for AF-free group, the majority of patients benefited from a double anti- aggregation, mainly by aspirin and prasugrel (45%) then aspirin and ticagrelor (40%).

6. Events

During hospitalization, cardiovascular mortality was found to be significantly higher in prior AF (10.7%) and new onset AF (7.5%) groups compared to the AF-free population (3.2%) (p<0.001) (see Table II).

However, there was no significant difference between prior AF and new onset AF groups.

The results were similar for the occurrence of heart failure (Killip >2) with 25.9% in prior group, 27.0% in new onset AF group and 8.6% in AF-free population (p<0.001).

The number of strokes was also significantly increased in the inpatient phase among AF-free patients versus new onset AF (0.4% versus 3.2%, p<0.001).

Multivariate analysis (see Table VI) showed that new onset AF appears to be an independent marker for the occurrence of heart failure in the inpatient phase of myocardial infarction (p 0.001, OR 1.897 [1.303-2.763]) and an independent marker for the occurrence of ischemic stroke (p 0.006, OR 4.304 [1.522-12.168]).

7. Sub-group analysis according to the time of new onset atrial fibrillation

In patients considered to have early AF, in the absence of a known history of AF, 36.5% had an ECG showing AF at admission. Only 3.7% of patients considered as new onset AF had both entry and discharge ECGs in AF.

Patients with early AF (< 24h) were younger than patients with intermediate AF (24- 72h) or late AF (> 72h) (see Table III).

The early AF group had fewer prior infarctions; the left arteries were less often guilty compared to the late AF group.

There were significantly more angioplasty failures in the late and intermediate AF groups compared to early AF group.

About treatments at discharge, patients with early AF were less often treated with direct oral anticoagulant than those in intermediate and late AF groups. There was no

The populations between early and late atrial fibrillation are therefore different.

However, we do not observe any significant difference in terms of intra-hospital events between these populations (see Table IV).

8. Analysis of events at one year on the population of the RIMA registry

Univariate analysis at one year, in the population limited to the RIMA registry followed at the Angers or Cholet Hospitals, showed a significant difference in mortality, stroke occurrence and hospitalization for heart failure between AF-free and new onset AF patients.

New onset AF group had a 28.9% mortality rate versus 8.2% in AF-free group (p<0.001), and a stroke rate of 5.9% versus 1.1% (p 0.007). In new onset AF group, 9.6% of patients were hospitalized within one year for heart failure versus 3.0% in AF-free group (p<0.001) (see Table V).

In multivariate analysis, the absence of AF appears to be a protective factor in the occurrence of stroke (OR 0.267; CI [0.080-0.898] p=0.033) and heart failure (OR 0.398; CI [0.173-0.915] p=0.030) (see Table VI).

A more detailed look at the conditions in which ischemic stroke occurred at the one- year follow-up:

- Only 1 out of 8 patients with stroke in AF-free group was on VKA for left intraventricular thrombus on discharge for STEMI and still treated at the moment of stroke.

- In prior AF group, the only patient with stroke was on anticoagulant but at an inappropriate dose (Rivaroxaban 15mg).

- In new onset AF group: 5 patients had a stroke at one year, with only one of these patients being treated with LMWH at discharge and at the moment of stroke for left intraventricular thrombus. Another patient was discharged from hospital on VKA but the

DISCUSSION

We therefore confirm that the occurrence of atrial fibrillation is a marker of poor prognosis in myocardial infarction. In our study, new onset AF appears to be an independent predictor of in-hospital heart failure and stroke. However, this association is not significant for in-hospital mortality.

We also show that new onset AF appears to be a prognostic marker for mortality, ischemic stroke, and hospitalization for heart failure in the year following myocardial infarction.

A Chinese study ⁽⁸⁾ of 25,000 patients showed that AF is an independent risk factor for in-hospital mortality after acute coronary syndrome. As in our study, patients had more co- morbidities and revascularization was more often incomplete compared to AF-free population.

Our study therefore probably lacks power to confirm the independent nature of this factor on mortality.

The occurrence of AF highlights the need to be particularly vigilant in optimizing therapy for these patients. However, in our population, only 43% and 33.3% of patients in prior AF and new onset AF groups were treated with ACE inhibitors or ARB, 75.9% and 88.7% with statins, 72.9% and 83.8% with beta-blockers, compared to 74.7%, 90.1% and 93.3% respectively in AF-free group.

Some studies have shown the efficiency of ACE inhibitors in the prevention of new onset AF after myocardial infarction ⁽⁹⁾. Other studies clearly showed that ACE inhibitors reduced mortality without being a protective factor against the development of AF ⁽¹⁰⁾. Other studies have also shown the protective effect of statins on the development of new onset AF

Moreover, a study published in 2018 recommended the use of a risk score for the development of new onset AF during hospitalization for STEMI and took into account age (>

80 years), BNP (80ng/L), obesity and leukocyte count (> 9.68 x 10³/µL). Patients with a score > 4 points were at increased risk of developing AF ⁽¹²⁾.

The time to onset of AF also appears to be an important factor for determining the prognosis for this event and the appropriate therapies to be introduced. In our study, there were significant differences in age, infarct territory and angioplasty failure between the early versus intermediate and late AF groups. Another study showed already in 1995 that early- onset AF was more often related to inferior infarction and late-onset AF patients with anterior infarction. The latter group also suffered significantly more of heart failure during their hospitalization ⁽¹³⁾.

Our study focused on looking for intra-hospital complications, but further studies seem to confirm the notion that late atrial fibrillation has a poorer prognosis than early atrial fibrillation. For example, a study published in 2011 showed a significant increase in mortality for AF occurring more than 30 days after infarction (OR 2.58 [2.21-3]) ⁽⁶⁾.

Concerning the territory of the infarction, our study found a significant difference in the anterior territory, less often involved in the groups with AF. These results are consistent with a Portuguese study of more than 6,000 patients, with a majority of inferior infarctions in patients with new onset AF after STEMI ⁽¹⁴⁾. Another study published in 2019 confirmed this notion by demonstrating a significant association between proximal right coronary occlusion including an atrial branch and the occurrence of new onset atrial fibrillation in myocardial infarction ⁽¹⁵⁾.

For stroke, we therefore showed a significant difference between the AF-free and new onset AF groups for intra-hospital events. Moreover, we noted a lower use of anticoagulants in new onset AF group (38.9%). An Israeli study of 7,000 patients found a higher number of strokes in late-onset atrial fibrillation (> 24 hours) compared to no atrial fibrillation, which is not the case for atrial fibrillation occurring within the first 24 hours ⁽¹⁶⁾. In addition, a population-based on OPTIMAAL study showed a higher incidence of stroke at 30 days in patients with new onset AF (HR=14.6 [5.87-36.3], p<0.001) ⁽¹⁷⁾.

However, the use of anticoagulation to prevent stroke after infarction is still debated.

A study published in the JACC⁽¹⁸⁾ investigated the occurrence of stroke at 3 years in 2300 patients with AF in post-infarction, post-sepsis and post-lung disease: no reduction in the number of strokes was noted in patients treated with anticoagulants, subject to a probable lack of potency with low numbers.

Also, as early and late-onset AF do not appear to occur in the same population, it may be useful to consider the time to onset and duration of AF and of course the CHA2DS2VASC score when deciding whether to initiate long-term anticoagulation.

1. Limits

This is a retrospective analysis with 3.4% missing data (mean 3240^±373 available data/event) for the initial hospital analysis on both registries and 24.3% missing data (mean 769^±22 available data/event) on the one-year follow-up through the RIMA registry alone.

The one-year analysis was limited by the lack of follow-up in the ORBI registry and by the data collection of patients followed up only at the Angers and Cholet hospitals for the RIMA registry. The initial population may differ from the one followed at one year.

In addition, we considered patients with AF on the first ECG recorded in new onset AF

were in AF at management and included in new onset AF group. This may have falsely increased the number of patients in new onset AF group due to lack of knowledge of a previous arrhythmia. However, only 13 patients (3.7%) in new onset AF group were still in AF on the ECG performed at discharge, so the vast majority of patients included were not in permanent AF.

Conversely, we may have underestimated the true incidence of short episodes of AF:

although all patients were monitored, if the episodes were short with no therapeutic involvement at discharge, they may not have been reported on the medical record. As the study was retrospective, the monitors were not reviewed for AF.

Similarly, we included patients treated by coronary artery bypass graft who were over-represented in the late AF subgroup (10% versus 1% early AF, p<0.001), but the pathophysiology of this AF is different from the one of ischemic AF.

In addition, the duration of the first episode of new onset AF was available in the ORBI registry but not in the RIMA registry.

About discharge treatments, we found a significant difference between our populations on the prescription of ACE renin blocker treatments. It would be possible to nuance this with the prescription of associated anti-aldosterone, but unfortunately this was not reported in the ORBI registry. In the RIMA registry alone, patients with new onset AF was the group that appeared to benefit the most from this treatment (19.3% versus 13.1% in patients without AF, p=0.06).

Finally, we were unable to work on all the biological markers of the infarction and in particular troponins because of different kits between each center, without any possible equivalence. For CPKs, few data were available (only information for 50.2% of patients).

Only the RIMA registry was completed exhaustively. In this population, there was a non-

CONCLUSION

New onset atrial fibrillation occurring in the immediate aftermath of a myocardial infarction is therefore a frequent event and a marker of particular severity that should not be overlooked.

Although it has not been shown to be an independent risk factor for intra-hospital mortality, atrial fibrillation is an independent marker for ischemic stroke and heart failure in the inpatient phase and a marker for mortality and hospitalization for heart failure and stroke at one year.

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LIST OF FIGURES

FIGURE 1 – FLOW CHART FOR CHARACTERISTICS AND HOSPITALISATION EVENTS 18

FIGURE 2 – DISCHARGE ANTITHROMBOTIC TREATMENT COMBINATION DEPENDING ON PRESENCE OR ABSENCE OF AF 19

FIGURE 3 - FLOW CHART OF THE POPULATION ACCORDING TO PRESENCE OF AF AND TIME TO ONSET 20

FIGURE 4 - DISTRIBUTION OF THE NEW ONSET AF POPULATION ACCORDING TO TIME OF ONSET, IN DAYS, OF AF 21

FIGURE 5 – SURVIVAL CURVES ACCORDING TO THE KAPLAN-MEIER METHOD AND THE LOG-RANK TEST 21

FIGURE 1 – FLOW CHART FOR CHARACTERISTICS AND HOSPITALISATION EVENTS

3357 patients included with STEMI

from january 2017 to december 2018 for ORBI registry and from january 2016 to july 2019 for RIMA registry

2875 Free AF (85,6%)

139 Prior AF (4,1%)

343 NOAF

(10,2%)

FIGURE 2 – DISCHARGE ANTITHROMBOTIC TREATMENT COMBINATION DEPENDING ON PRESENCE OR ABSENCE OF AF

A aspirin, C Clopidogrel, LMWH low-molecular-weight heparin, NOAC non-vitamin K antagonist oral anti-coagulant, P prasugrel, T ticagrelor, VKA vitamin K antagonist

3357 patients included for STEMI

139 prior AF (4%) 343 new

onset AF(10%)

77 patients AF between> 24h and

<72h after admission 202 patients AF<24h after

admission

63 patients AF>72h after 1 patient unknown delay

FIGURE 3 - FLOW CHART OF THE POPULATION ACCORDING TO PRESENCE OF AF AND TIME TO ONSET

Sinusal rhythm at admission AF rythm at admission

FIGURE 4 - DISTRIBUTION OF THE NEW ONSET AF POPULATION ACCORDING TO TIME OF ONSET, IN DAYS, OF AF

FIGURE 5 – SURVIVAL CURVES ACCORDING TO THE KAPLAN-MEIER METHOD AND THE LOG-RANK TEST

# p<0.05 AF Free vs Prior AF / ¤ p<0.05 AF Free vs New Onset AF / $ p<0.05 Prior AF vs New Onset AF

LIST OF TABLES

TABLE I. CHARASTERISTICS OF PATIENTS WITH MYOCARDIAL INFARCTION ACCORDING TO THE PRESENCE

OF ATRIAL FIBRILLATION... .24

TABLE II. IN HOSPITAL EVENTS ACCORDING TO THE PRESENCE OF ATRIAL FIBRILLATION ... 25

TABLE III. CHARASTERISTICS OF PATIENTS WITH MYOCARDIAL INFARCTION ACCORDING TO THE TIME OF NEW ONSET ATRIAL FIBRILLATION ... .26

TABLE IV. IN HOSPITAL EVENTS ACCORDING TO THE TIME OF NEW ONSET ATRIAL FIBRILLATION ... 27

TABLE V. ONE YEAR EVENTS AT HOSPITAL ADMISSION FOR RIMA REGISTRY ONLY ………27

TABLE VI. MULTIVARIATE ANALYSIS OF INTRA-HOSPITAL EVENTS……….……….28

TABLE VII. ANALYSIS ACCORDING TO THE COX MODEL OF ONE YEAR-EVENTS, RIMA REGISTRY ONLY………29

Table I. Charasteristics of patients with myocardial infarction according to the presence of atrial fibrillation

Total AF Free Prior AF NOAF p

Number of patients 3357 2875 139 343

Baseline charasteristics

Age (years) 63 ± 14 62 ± 14 77 ± 11 71 ± 13 <0,001^#¤$

Weight (kg) 77± 15 77 ± 15 77 ± 16 75 ± 16 0,025^¤

Tall (cm) 170±9 170±8 168±9 168±9 <0,001^#¤

Male gender 2646 (78,8%) 2292 (79,7%) 100 (71,9%) 254 (74%) 0,007^#¤

History of hypertension 1448 (43,1%) 1145 (39,8%) 101 (72,6%) 202 (58,8%) <0,001^#¤$

History of diabetes mellitus 324 (9,9%) 270 (9,3%) 20 (14,3%) 34 (9,9%) 0,148

History of dyslipidemia 1507 (45,2%) 1279 (44,7%) 73 (52,8%) 155 (45,5%) 0,167

Current smoker 1381 (41,3%) 1274 (44,4%) 11 (8,2%) 96 (27,9%) <0,001^#¤$

History of coronary disease 734 (21,8%) 606 (21%) 52 (37,4%) 76 (22,2%) <0,001^#$

History of stroke 155 (4,6%) 104 (3,6%) 33 (23,7%) 18 (5,2%) <0,001^#$

History of PAD 147 (4,3%) 114 (3,9%) 15 (10,7%) 18 (5,2%) <0,001^#$

History of renal failure 97 (2,8%) 59 (2%) 23 (16,5%) 15 (4,3%) <0,001^#$

CHA2DS2-VASc 3 ± 1,9 2,8 ± 1,8 4,6 ± 1,9 3,8 ± 1,9 <0,001^#¤$

Medical therapy at admission

Antiarrythmics (except beta-blockers) 47 (1,4%) 21 (0,7%) 22 (15,8%) 4 (1,1%) <0,001^#$

ACEI or ARB 709 (21,1%) 589 (20,4%) 48 (34,5%) 72 (20,9%) <0,001^#$

Beta-blockers 586 (17,4%) 409 (14,2%) 82 (58,9%) 95 (27,7%) <0,001^#¤$

Statins 637 (18,9%) 511 (17,7%) 54 (38,8%) 72 (20,9%) <0,001^#$

Aspirin 501 (14,9%) 398 (13,8%) 34 (24,4%) 69 (20,1%) <0,001^#¤

Clopidogrel 100 (2,9%) 73 (2,5%) 7 (5%) 20 (5,8%) 0,001^¤

Prasugrel 5 (0,1%) 5 (0,1%) 0 (0%) 0 (0%) 0,657

Ticagrelor 17 (0,5%) 14 (0,4%) 1 (0,7%) 2 (0,5%) 0,911

VKA 69 (2%) 21 (0,7%) 43 (30,9%) 5 (1,4%) <0,001^#$

NOAC 56 (1,6%) 13 (0,4%) 43 (30,9%) 0 (0%) <0,001^#$

LMWH 10 (0,2%) 9 (0,3%) 1 (0,7%) 0 (0%) 0,391

Charasteristics of qualifying myocardial infarction

SBP at baseline (mmhg) 136 ± 28 137 ± 27 127 ± 32 130 ± 31 <0,001^#¤

Heart rate at baseline (bpm) 77 ± 19 77 ± 18 78 ± 25 81 ± 26 0,001^¤

Killip admission 1,2 ± 0,6 1 +/ 0,6 1,5 ± 1 1,5 ± 1 <0,001^#¤

HF at baseline (killip > ii) 459 (13,6%) 328 (11,4%) 43 (30,9%) 88 (25,6%) <0,001^#¤

Creatinin value at baseline (µmol/l) 82 ± 45 79 ± 30 112 ± 116 98 ± 77 <0,001^#¤

Anterior myocardial infarction 944 (40,4%) 834 (41,2%) 41 (41,8%) 69 (32,7%) 0,055

Coronarography 3283 (97,7%) 2830 (98,4%) 132 (94,9%) 321 (93,5%) <0,001^#¤

LAD guilty lesion 1726 (52,8%) 1556 (55,2%) 54 (41,9%) 116 (36,4%) <0,001^#¤

Left coronary guilty lesion 1983 (60,4%) 1734 (61,3%) 75 (57,6%) 174 (54,2%) 0,037^¤

TIMI flow at baseline = 0 1974 (60,5%) 1673 (59,5%) 89 (68,9%) 212 (65,8%) 0,012^#¤

Medical therapy 262 (7,8%) 209 (7,3%) 12 (9%) 41 (12,3%) 0,005^¤

Fibrinolysis 110 (3,2%) 96 (3,3%) 4 (2,8%) 10 (2,9%) 0,884

Initial angioplasty of other lesion 225 (7,3%) 183 (6,9%) 11 (8,9%) 31 (10,5%) 0,060

CABG 41 (1,2%) 32 (1,1%) 1 (0,7%) 8 (2,4%) 0,116

Multivessel disease 1662 (51%) 1411 (50,3%) 61 (47,6%) 190 (59%) 0,009^¤$

Complete revascularization 1428 (45,3%) 1259 (46,6%) 52 (40,3%) 117 (36,7%) 0,002^¤

LVEF (%) 50 ± 10 50 ± 10 46 ± 12 46 ± 11 <0,001^#¤

Usic duration (d) 4 ± 3 4 ± 3 4 ± 3 5 ± 5 <0,001^¤$

Hospital duration (d) 6,6 ± 6,5 6 ± 5 9 ± 10 10 ± 10 <0,001^#¤

Medical therapy at discharge

Antiarrythmics (except beta-blockers) 125 (3,7%) 36 (1,2%) 22 (16%) 67 (20,8%) <0,001^#¤

ACEI or ARB 2292 (69,4%) 2126 (74,7%) 59 (43%) 107 (33,3%) <0,001^#¤$

Beta-blockers 2931 (88,8%) 2562 (90,1%) 100 (72,9%) 269 (83,8%) <0,001^#¤$

Statins 3043 (92,2%) 2654 (93,3%) 104 (75,9%) 285 (88,7%) <0,001^#¤$

Aspirin 3156 (95,6%) 2745 (96,5%) 114 (83,2%) 297 (92,5%) <0,001^#¤$

Clopidogrel 623 (18,8%) 404 (14,2%) 93 (67,8%) 126 (39,2%) <0,001^#¤$

Prasugrel 1263 (38,2%) 1191 (41,9%) 3 (2,1%) 69 (21,4%) <0,001^#¤$

Ticagrelor 1175 (35,6%) 1075 (37,8%) 11 (8%) 89 (27,7%) <0,001^#¤$

VKA 120 (3,6%) 53 (1,8%) 30 (21,8%) 37 (11,5%) <0,001^#¤$

NOAC 135 (4%) 25 (0,8%) 52 (37,4%) 58 (16,9%) <0,001^#¤$

LMWH 126 (3,8%) 93 (3,2%) 5 (3,6%) 28 (8,7%) <0,001^#¤$

# p<0.05 AF Free vs Prior AF

¤ p<0.05 AF Free vs New Onset AF

$ p<0.05 Prior AF vs New Onset AF

Table II. In hospital events according to the presence of atrial fibrillation

Total AF Free Prior AF NOAF p

In hospitals events

All-cause mortality, n(%) 148 (4,4%) 100 (3,4%) 15 (10,7%) 33 (9,6%) <0,001^#¤

CV mortality, n(%) 135 (4,0%) 94 (3,2%) 15 (10,7%) 26 (7,5%) <0,001^#¤

Reinfarction, n(%) 117 (3,4%) 92 (3,2%) 4 (2,8%) 21 (6,1%) 0,019^¤

Stroke, n(%) 26 (0,7%) 13 (0,4%) 2 (1,4%) 11 (3,2%) <0,001^¤

Hb loss between 3 and 5 points 104 (3,1%) 77 (2,6%) 3 (2,1%) 24 (6,9%) <0,001^¤$

Hb loss superior to > 5 points 49 (1,4%) 23 (0,8%) 4 (2,8%) 22 (6,4%) <0,001^#¤

Blood transfusion need 69 (2%) 45 (1,5%) 4 (2,8%) 20 (5,8%) <0,001^¤

Intracranial bleeding 4 (0,1%) 4 (0,1%) 0 (0%) 0 (0%) 0,735

HF (Killip ≥3) during initial hospitalisation, n(%) 373 (11,1%) 245 (8,6%) 36 (25,9%) 92 (27,0%) <0.001^#¤

Severe Ventricular Arrythmias, n(%) 218 (6,4%) 162 (5,6%) 18 (12,9%) 38 (11%) <0,001^#¤

Severe atrioventricular block, n(%) 152 (4,5%) 100 (3,4%) 12 (8,6%) 40 (11,6%) <0,001^#¤

Left ventricular thrombus 59 (1,7%) 45 (1,5%) 2 (1,4%) 12 (3,4%) 0,035^¤

Acute septal or wall defect 22 (0,6%) 11 (0,3%) 3 (2,1%) 8 (2,3%) <0,001^#¤