2017PA066331

Myocardial infarction and sudden death : a
population-based approach
Nicole Karam
To cite this version:

Nicole Karam. Myocardial infarction and sudden death : a population-based approach. Santé publique
et épidémiologie. Université Pierre et Marie Curie - Paris VI, 2017. English. �NNT : 2017PA066331�.
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THESE DE DOCTORAT DE
L’UNIVERSITE PIERRE ET MARIE CURIE
ECOLE DOCTORALE PIERRE LOUIS DE SANTE PUBLIQUE A PARIS
EPIDEMIOLOGIE ET SCIENCES DE L'INFORMATION BIOMEDICALE
EPIDÉMIOLOGIE CLINIQUE
Infarctus du Myocarde et Mort Subite:
Approche en Population
Présentée par
Mlle Nicole KARAM
Le 03 Novembre 2017
Pour obtenir le grade de
DOCTEUR de l’UNIVERSITÉ PIERRE ET MARIE CURIE
Membres du Jury :
Directeur et Co-directeur de Thèse : M. Xavier JOUVEN et M. Christian SPAULDING
Rapporteurs : M. Jean BOUYER et Mme Julinda MEHILLI
Examinateur : M. Jean-Philippe COLLET et Mme Vijay KUNADIAN
1
Acknowledgments
I would like to express my sincere gratitude Pr Xavier Jouven who supported me throughout
my career ever since I began working in Georges Pompidou, and who introduced me to
research and gave me the opportunity to join his amazing research team.
To Pr Christian Spaulding for his unfailing support, and for all his priceless help, advice and
encouragements whether in the research, technical, or career level.
To Pr Albert Hagege for giving me the opportunity to carry out my doctoral research in his
department and for pushing me forward in my career development
To Pr Eloi Marijon for the extended discussions and valuable suggestions which have
contributed greatly to the improvement of the thesis and of my research in general.
To Pr Jean-Philippe Empana, Muriel Tafflet, Marie-Cécile Périer and Lucile Offredo for their
valuable assistance, expert suggestions and reviews. This thesis could not have been
accomplished without your help.
To the members of the jury for the time they granted for the PhD defense, with a particular
thanks to Pr Julinda Mehilli for giving me the opportunity to regularly visit her catheterization
laboratory in Munich and for providing me a great example of success and modesty.
To the e-MUST team, especially Drs Sophie Bataille and Yves Lambert for granting me
access to their wonderful registry without which this work would not have been possible.
Last but not the least, I would like to thank my family and friends for their encouragement
and support throughout this thesis and in my life in general.
2
Publications Arising from the Thesis
Published:
Karam N, Marijon E, Dumas F, Offredo L, Beganton F, Bougouin W, Jost D, Lamhaut L,
Empana JP, Cariou A, Spaulding C, Jouven X, for the Paris Sudden Death Expertise Center.
Characteristics and Outcomes of Out-of-Hospital Sudden Cardiac Arrest According to the
Time of Occurrence. Resuscitation 2017;116:16-21
Karam N, Bataille S, Marijon E, Giovanetti O, Tafflet M, Savary D, Benamer H, Caussin C,

Garot P, Juliard JM, Pires V, Boche T, Dupas F, Lebail G, Lamhaut L, Laborne FX,
Lapostolle F, Spaulding C, Empana JP, Jouven X, Lambert Y; e-MUST study Investigators.
Sudden Cardiac Arrest Complicating Myocardial Infarction in the Field: Incidence,
Characteristics and Outcomes. Circulation 2016.134(25):2074-2083
Under Review:
Karam N, Bataille S, Marijon E, Tafflet M, Savary D, Benamer H, Caussin C, Garot P,
Juliard JM, Pires V, Boche T, Dupas F, Lebail G, Lamhaut L, Laborne FX, Lefort H,
Mapouata MB, Lapostolle F, Spaulding C, Empana JP, Lambert Y, Jouven X. Prognosis and
Outcome Predictors of Sudden Cardiac Arrest Complicating Myocardial Infarction Prior to
Hospital Admission: The e-MUST Study. Submitted in August 2017
Upcoming submissions:
Karam N, Bataille S, Marijon E, Tafflet M, Savary D, Benamer H, Garot P, Juliard JM, Pires
V, Boche T, Dupas F, Le Bail G, Lamhaut L, Laborne FX, Lefort H, Lapostolle F, Empana
JP, Spaulding C, Lambert Y, Jouven X. Study of Incidence, Temporal Variations and
Associated Factors
Published articles, related but not in the strict framework of the PhD thesis
Karam N, Narayanan K, Bougouin W; Benameur N, Beganton F, Jost D, Lamhaut L, Perier
MC, Cariou A, Celermajer D, Marijon E, Jouven X. Major Regional Differences in
Automated External Defibrillator Placement and Basic Life Support Training Exposure in
France: Further Needs for Coordinated Implementation. Resuscitation 2017
3
Posters and Oral Presentations
Karam N, Pechmajou L, Dumas F, Bougouin W, Beganton F, Cariou A, Spaulding C,
Marijon E, Jouven X. Coronary Findings in Sports-Related Compared to Non Sports-Related
Sudden Cardiac Arrest. Advances in Science presentation, ESC 2017
Karam N, Spaulding C, Cariou A, Marijon E, Jouven X. Opening a new front in the fight
against sudden cardiac death: is it time for near-term prevention?. Rapid Fire Abstract
presentation, ESC 2017
Karam N, Pechmajou L, Bougouin W, Dumas F, Empana JP, Cariou A, Spaulding C, Jouven

X, Marijon E. Management and Outcomes of Sports-Related Cardiac Arrest in Young Adults.
Poster presentation, AHA 2016
Karam N, Bougouin W, Perier MC, Lamhaut L, Dumas F, Benameur N, Celermajer D,

Marijon E, Jouven X. Major Disparities in Public Access Defibrillation Programs
Implementation: a French Nationwide Study. Poster presentation, ESC 2016
Karam N, Tafflet M, Bataille S, Marijon E, Empana JP, Spaulding C, Lambert Y, Jouven X.

Risk of Sudden Cardiac Arrest According to the Month of STEMI Occurrence: the e-MUST
Study. Poster presentation, AHA 2015
Karam N, Bataille S, Tafflet M, Marijon E, Empana JP, Lambert Y, Spaulding C, Jouven X.

Risk of Sudden Cardiac Arrest According to the Time of STEMI Occurrence: the e-MUST
Study. Poster presentation, AHA 2015
Karam N, Marijon E, Offredo L, Beganton F, Lamhaut L, Dumas F, Spaulding C, Cariou A,

Jouven X. Management and outcomes of out of hospital cardiac arrest according to its time of
occurrence: results from the Paris SDEC study. Rapid Fire Abstract presentation, ESC 2015
Karam N, Marijon E, Beganton F, Lamhaut L, Dumas F, Cariou A, Spaulding C, Jouven X.

Initial prognosis and management of out-of-hospital cardiac arrest in women: the SDEC Paris
study. Poster presentation, ESC 2015
Karam N, Bataille S, Tafflet M, Marijon E, Lapostolle F, Spaulding C, Lambert Y, Jouven X.

Who presents sudden cardiac arrest before hospital admission at the acute phase of STEMI?
The e-MUST study. Poster presentation, ESC 2015
4
Abstract
Sudden cardiac arrest (SCA) is a major issue of public health with more than 40,000 cases
every year in France with a persistent poor prognosis. A great overlap exists between SCA
and coronary artery disease. On one hand, coronary artery disease accounts for the vast
majority (≥75%) of SCA. On the other hand, due to major in-hospital care improvement, out-
of-hospital SCA has become the main cause of death in the setting of ST-elevation
myocardial infarction (STEMI). Improving the prognosis of both entities starts with a better
understanding of the associations and the overlap between the two.
STEMIs occurring during off-hours (nights, weekends, and holidays) have a worse
prognosis compared to those occurring during working hours. Whether the same impact is
observed on SCA has not been documented yet. The first part of the thesis therefore assessed
the impact of time of occurrence on the prognosis of SCA. Using data from the Sudden Death
Expertise Centre that includes all SCA occurring in Paris and its suburbs, we compared SCA
outcome according to the time of occurrence. We observed a 30% higher mortality rate during
off-hours, mainly due to differences in the very early initial management provided by
witnesses (cardiopulmonary resuscitation and automated external defibrillation), while EMS
and in-hospital management was not influenced by the time of occurrence. Accordingly, it
becomes clear that efforts should focus on improving this early SCA management.
The second part of the thesis therefore aimed on identifying, among STEMI patients,
those at high risk of pre-hospital SCA, in order to plan SCA management immediately before
it occurs, allowing a better initial resuscitation. Using data from the e-MUST registry that
includes all STEMI managed by the EMS in the Greater Paris area, we identified 5 simple
predictors of pre-hospital SCA that are systematically assessed by dispatchers on the phone
when called for a chest pain: younger age, absence of obesity, absence of diabetes mellitus,
5
shortness of breath, and a short delay between pain onset and call to emergency medical
services. Using those variables, we built an SCA prediction score that we than validated
internally on one third of the population, and externally on a STEMI population from another
French region.
The first minutes of SCA management are the main determinants of its prognosis and
should ideally be planned before SCA occurrence. Prediction of imminent SCA in STEMI,
the main cause of SCA, is feasible with a simple phone-obtainable score, which would allow
anticipation of SCA occurrence by the EMS services and adjusting STEMI management
accordingly. Even though the generalizability of this strategy to other causes of SCA remains
to be demonstrated, a promising path for decreasing SCA burden can be foreseen with the
development of a new strategy based on SCA near-term prevention to ensure optimal initial
resuscitation, planned before SCA occurrence.
6
Résumé
La mort subite constitue un problème majeur de santé publique avec plus de 40 000 cas par an
en France et un pronostic qui reste sombre. La mort subite et la maladie coronaire sont
étroitement liées. D'une part, la vaste majorité des morts subites sont d'origine coronaire
(≥75% des cas). D'autre part, avec les progrès dans la prise en charge hospitalière de
l'infarctus du myocarde (IDM), la mort subite est devenue le principal mode de décès des
IDM. L’amélioration du pronostic de ces deux entités doit donc passer par une meilleure
analyse des points communs et des relations existant entre mort subite et IDM.
Les IDM survenant durant les heures non ouvrables (fin de semaine, jours fériés,
nuits) ont une mortalité accrue. Cette relation n’a pas été étudiée en détail dans la mort subite.
La première partie de la thèse s'est donc focalisée sur le pronostic des morts subites selon
leurs horaires de survenue. Dans le registre francilien du Centre d'Expertise Mort Subite qui
collecte l'ensemble des morts subites survenant à Paris et Petite Couronne, nous avons
comparé les caractéristiques et le pronostic des morts subites selon leur horaire de survenue.
Nous avons constaté que les morts subites en dehors des heures ouvrables ont une mortalité
plus élevée (jusqu’à 30%), en raison essentiellement d'une prise en charge initiale moins
optimale par le témoin en termes de massage cardiaque et de défibrillation externe, alors que
les prises en charge spécialisées pré- et intra-hospitalière ne semblent pas être influencées par
l'horaire de survenue. Ainsi, il devient clair que dans l'avenir, les efforts devraient se focaliser
sur l'amélioration de la prise en charge très précoce de la mort subite afin d'obtenir
l'amélioration manquante du pronostic de la mort subite.
La deuxième partie de la thèse a donc eu pour objectif d'identifier, parmi les victimes
d'IDM, celles à risque de présenter une mort subite pré-hospitalière, afin de planifier la prise
en charge de l'arrêt cardiaque juste avant sa survenue en vue d'une meilleure réanimation
initiale. A partir du registre e-MUST qui inclue tous les IDM pris en charge par le SAMU en
7
Ile-de-France, nous avons identifié 5 facteurs associés à un risque accru de mort subite pré-
hospitalière (âge jeune, absence de diabète et d'obésité, dyspnée, délai court entre le début de
douleur et l'appel des secours). Nous avons ainsi créé un score de risque de mort subite que
nous avons validé en interne (tiers de la population) et en externe (population similaire en
Haute-Savoie).
Les premières minutes de la prise en charge d'une mort subite sont les principaux
déterminants de son pronostic et devraient idéalement être planifiées avant sa survenue. La
prédiction de la mort subite parmi les victimes d'IDM, la cause principale de mort subite, est
faisable grâce à un score facile à obtenir au téléphone, permettant aux services de secours
d'anticiper la survenue de la mort subite et de planifier la prise en charge en fonction. Quoique
la possibilité de généralisation de cette stratégie à d'autres causes de mort subite reste à
démontrer ; cependant, elle semble être intéressante pour diminuer la mortalité de la mort
subite grâce au développement de la prévention à court terme avec organisation de la prise en
charge des morts subites avant leur survenue.
8
Table of Contents
Acknowledgments……………………………………………………………………...……2
Publications arising from this Thesis…………………………………………………...….3
Posters and Oral Presentations……………………………………….………………….…4
Abstract in English………………………………………………………………………..…5
Abstract in French……………………………………………….……………………..……7
Table of Contents……………………………………………….……………………………9
List of Abbreviations and Acronyms……………….………….………………...………..11
List of Figures………………..………………………………….………………………..…12
1. Introduction……………………………………………………………………………....13
1.1. Definitions of SCA………………………………………………………………...…14
1.2. Incidence and Demographics of SCA…….………………...……………………….14
1.3. Cardiovascular Conditions Associated to SCA Occurrence.....…………………...15
1.3.1. Coronary Artery Disease………………………….……………………………..17
1.3.1.1. Acute Coronary Events……………………………………………………...18
1.3.1.2. Chronic Coronary Artery Disease………………………………………..…21
1.3.2. Non-Ischemic Cardiac Etiologies………………………………………………..22
1.3.2.1. Non-ischemic Cardiomyopathies……………………………………………22
1.3.2.2. Other Structural Cardiac Causes of SCA………………………………….23
1.3.2.3. Non-Structural Cardiomyopathies………………………………………….24
1.4. Prognosis of SCA………..………………………………………………………...…25
2. Chapter 1………..……………………………...……………………………………...…28
2.1. Introduction…………………………………………………………………………..28
2.2. Article………………………………………………...……….………………………29
3. Chapter 2……………………………………………………….………………………...35
9
3.1. Introduction………………………………………………………………………….35
3.2. Article………………………………………………………….……………………..36
4. Discussion………………………………………………………………………………...52
4.1. Strategies to Reduce SCA Burden…………………………………..……………...52
4.1.1. Resuscitation Strategy……………………………..…………………...………..52
4.1.1. Prevention Strategy……………………………..………………….......………..55
4.2. Burden of STEMI-Related SCA……………………………………..…….………..56
4.3. Predictors of Pre-Hospital STEMI-Related SCA…...…………………….………..57
4.4. Strength and Limitations…………………….…..…...…………………….………..58
5. Conclusion………………………..…...……………………...………………….………..61
6. Perspectives…………………………………………………………………….……….…62
7. References…………………………………………………………………………..……..64
8. Appendix (French summary) …………………………………………………………....82
10
List of Abbreviations and Acronyms
AED: Automated External Defibrillator
APEX-AMI: Assessment of Pexelizumab in Acute Myocardial Infarction
CAD: Coronary Artery Disease
CPR: CardioPlumonary Resuscitation
EKG: Electrocardiogram
EMS: Emergency Medical Service
GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded
Coronary Arteries
e-MUST: Evaluation en Médecine d’Urgence des Stratégies Thérapeutiques des infarctus du
myocarde
MVP: Mitral Valve Prolapse
PAMI: Primary Angioplasty in Myocardial Infarction
SCA: Sudden Cardiac Arrest
SCD: Sudden Cardiac Arrest
SDEC: Sudden Death Expertise Center
STEMI: ST-segment elevation myocardial infarction
VF: Ventricular Fibrillation
11
List of Figures
Figure 1: Structural Heart Disease in SCA Survivors
Figure 2: Pathogenesis of Coronary Artery Disease
Figure 3: Trends in Out-of-Hospital and In-Hospital Mortality Within 28 Days of Acute Coronary
Event per 100 000 Population Aged 35 to 84 Years Between 1991 and 2006
Figure 4: ESC Guidelines for the Management of Acute Myocardial Infarction in Patients Presenting
with ST-segment Elevation
Figure 5: The Chain of Survival
Figure 6: Revised Chain of Survival
12
1. Introduction
Sudden cardiac arrest (SCA) is a major issue of public health with more than 350.000 deaths
per year in the United States, accounting for almost half of cardiovascular mortality.(1)
Despite huge investments that have allowed some increase in survival rates,(2)(3) outcomes
remain poor with an overall survival to hospital discharge of less than 10%.(4)
A major overlap exists between Coronary Artery Disease (CAD) and SCA. On one
hand, CAD, and in particular ST-elevation myocardial infarction (STEMI), accounts for most
cases of SCA. On the other hand, overall mortality related to STEMI has decreased drastically
during the last decades, mainly due to a major reduction in in-hospital mortality.(5) Pre-
hospital death by SCA has therefore become the main cause of death from STEMI. This close
association between SCA and STEMI leads to a close interaction between their prognosis, and
therefore, improving the prognosis of both entities has to start with a better understanding of
the overlap and the associations between the two.
Using data from two prospective registries, the SDEC (Sudden Death Expertise
Center) registry that includes all SCAs occurring in Paris and its suburbs since 2011, and the
e-MUST (Evaluation en Médecine d’Urgence des Stratégies Thérapeutiques des infarctus du
myocarde) registry that includes all STEMIs occurring in the Greater Paris Area since 2003,
we assessed in the first part of the thesis, the major determinants of the prognosis of SCA
through an analysis of the impact of the time of occurrence on the mortality rate. In the
second part of the thesis, we identified the characteristics associated with a higher risk of pre-
hospital SCA during STEMI and created a risk score for SCA that could help emergency
medical services anticipate the occurrence of SCA and plan the patients’ management
accordingly.
13
1.1. Definitions of SCA
Sudden cardiac death (SCD) refers to an unexpected death from a cardiovascular cause in a
person with or without preexisting heart disease.(6) Therefore, extracardiac conditions need to
be excluded before the diagnosis of SCD can be confirmed, and death should not have
occurred in the setting of a prior terminal condition, such as a malignancy that is not in
remission or end-stage chronic obstructive lung disease. An “established SCD” is an
unexpected death without obvious extracardiac cause, occurring with a rapid witnessed
collapse, or if unwitnessed, occurring within 1 hour after the onset of symptoms. A “probable
SCD” is an unexpected death without obvious extracardiac cause that occurred within the
previous 24 hours.
The term Sudden Cardiac Arrest (SCA) should be used to describe SCD cases in
which specific resuscitation records are available or the individual has survived the cardiac
arrest event.(7) Since most of the studies are rather based on SCA cases, the term SCA will be
used in the thesis for homogeneity reasons.
1.2. Incidence and Demographics of SCA
Estimates regarding the annual incidence of SCA vary widely depending on the
employed definitions, the data sources for case ascertainment, and the methods used to assess
the rates. The majority of global comparisons are based upon rates of emergency medical
service (EMS) attended out of hospital SCA, which appear to be much lower in Asia (52.5 per
100,000 person-years) as compared to Europe (86.4 per 100,000 person-years), North
America (98.1 per 100,000 person-years), and Australia (111.9 per 100,000 person-years).
There also appear to be regional variations within geographic regions. For instance, among 10
regions in North America, rates of EMS attended cardiac arrest range from 159 per 100,000
person-years in Dallas, Texas to 71.8 per 100,000 person-years in Ottawa, Ontario.(8)
14
Overall, the global rate of SCA seems to range from 50 to 100 per 100 000 in the general
population.(6)
Regardless of the method used for the rate estimation, it is well documented that the
incidence of SCA increases markedly with age, mainly due to an increase in the rate of CAD
in older age. For example, the annual incidence for 50-year-old men is 100 per 100 000
population compared with 800 per 100 000 for 75-year-old men.(9) Median age of SCA
occurrence is higher among women than among men (71 years vs. 66 years, respectively).
SCA is much less frequent among women group in any age group, and even after adjustment
for CAD risk factors and other predisposing conditions.(10) Accordingly, the SCA rate is
estimated to range from 1.40 per 100 000 person-years [95% confidence interval (CI) 0.95,
1.98] in women to 6.68 per 100 000 person-years (95% CI 6.24, 7.14) in men.(11) However,
this difference seems to be decreasing over the last three decades, mainly due to a greater
reduction in the incidence of SCA among men than among women (10% vs. 43%,
respectively), particularly in the younger population.(12) (13)(14) This evolution might be
explained by the increasing prevalence of CAD among women while it has been decreasing
among men.(15)
1.3. Cardiovascular Conditions Associated to SCA Occurrence
Approximately 50% of cardiac arrests occur in individuals without a known heart disease, but
most suffer from concealed ischemic heart disease.(16) Epidemiologic data indicate that CAD
is the most common cause of SCA in adults over age 35, particularly among men where it is
responsible for approximately 75–80% of SCAs. In women, the percentage of SCA due to
CAD is lower, but still accounts for around 45% of SCAs (Figure 1).(17)(6)(18)(19)
15
Figure 1: Structural Heart Disease in SCA Survivors. These pie charts depict the
proportions of underlying cardiac disease among men and women who survive SCA.
CAD was the main diagnosis in the majority of men. In contrast, women had more
nonischemic heart disease than men, including dilated cardiomyopathy (19%) and
valvular heart disease (13%). CAD indicates coronary artery disease; DCM, dilated
cardiomyopathy; VHD, valvular heart disease; Spasm, coronary vasospasm; and RV,
right ventricular (Adapted from Albert et al, Circulation 1996)
Dilated and hypertrophic cardiomyopathies account for the second largest number of
sudden deaths from cardiac causes. Other cardiac disorders, such as valvular or congenital
heart diseases, acquired infiltrative disorders, primary electrophysiological disorders, and the
known genetically determined ion channel abnormalities, account for only a small proportion
of SCA in the general population.(20) Finally, unexplained SD, also called sudden
arrhythmic death syndrome, in which a significant cardiac abnormality is not found after
clinical evaluation in SCA survivors or at autopsy in SCA victims, accounts for less than 5%
of cases.(21)(22) This percentage appears to be higher in women, where structurally normal
hearts are more commonly encountered.(23)(17) In Asians, the primary ion channelopathies
are estimated to be responsible for 10% of SCA.(24) In young adults and children less than
age 35, CAD accounts for a much smaller proportion of deaths, with hypertrophic
16
cardiomyopathy, coronary artery anomalies, myocarditis, arrhythmogenic right ventricular
cardiomyopathy, and primary ion channelopathies accounting for significant proportions.(25)
1.3.1. Coronary Artery Disease
CAD accounts for most cases of SCA. In survivors of SCA, CAD with vessels exhibiting
more than 75% cross-sectional stenosis are found in 40% to 86% of patients, depending on
the age and sex of the studied population.(26) (20)
There are three general settings where SCD occurs in patients with CAD: (1) during an
acute coronary event, particularly STEMI, (2) provoked by coronary ischemia due to
significant coronary stenosis but in the absence of acute coronary event, (Figure 2) and (3) in
the presence of myocardial structural alterations (fibrosis, scar, left ventricular dilatation) due
to prior myocardial infarction or chronic ischemia.
Figure 2: Pathogenesis of Coronary Artery Disease. Stable atherosclerotic

plaques are usually responsible of stable angina. They can still lead to SCA in
case of increased oxygen demand that cannot met by a similar increase in blood
flow due to the coronary narrowing. Plaque rupture leads to thrombus formation
with partial or complete coronary obstruction, responsible of acute coronary
syndromes complicated in some cases by SCA. MI: Myocardial Infarction
17
1.3.1.1. Acute Coronary Events
Acute coronary syndromes, including STEMI, account for a great proportion of SCA. The
prevalence of acute coronary thrombus or active coronary lesion in autopsy series of SCD
varies depending on autopsy protocol and histological techniques, and ranges from 19 to
74%.(27)(28)(29)
Through an analysis of acute coronary syndromes mortality in Sweden between 1991
and 2006, Dudas et al confirmed general trends suggesting that both incidence and mortality
of acute coronary syndromes dramatically decreased over time (Figure 3). However, they also
emphasized that this global result hides great disparities regarding the timing of death
occurrence. Indeed, despite a decrease of 50% in in-hospital mortality, out-of-hospital
mortality only decreased by 15%. Accordingly, nowadays, 80% of deaths due to CAD occur
outside the hospital, through SCA.(5)
Figure 3: Trends in Out-of-Hospital and In-Hospital Mortality Within 28 Days of

Acute Coronary Event per 100 000 Population Aged 35 to 84 years between 1991
and 2006 (Dudas et al, Circulation 2011)
18
STEMI is a clinical syndrome defined by characteristic symptoms of myocardial
ischemia in association with persistent ST elevation on the electrocardiogram (EKG) and
subsequent release of biomarkers of myocardial necrosis.(30) Diagnosis of ST elevation in the
absence of left ventricular hypertrophy or left bundle-branch block is defined by the European
Society of Cardiology/ACCF/AHA/World Heart Federation Task Force for the Universal
Definition of Myocardial Infarction as new ST elevation at the J point in at least 2 contiguous
leads of ≥2 mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads V2–V3 and/or of
≥1 mm (0.1 mV) in other contiguous chest leads or the limb leads.(31) New or presumably
new left bundle-branch block has been considered a STEMI equivalent. However, in most
cases of left bundle-branch block at time of presentation, prior EKG is not available for
comparison and it is not possible to confirm whether it previously existed, which complicates
the diagnosis of STEMI in this situation.(32)
Given the pathophysiology of STEMI that is related to acute coronary occlusion,
prompt reperfusion, either by fibrinolysis or by percutaneous coronary intervention, is the
cornerstone in the management of STEMI. Guidelines from the American Heart
Association/American College of Cardiology and from the European Society of Cardiology
favor revascularization by primary percutaneous coronary intervention over fibrinolysis if it
can be performed in a timely manner (Figure 3).(30)(33) The development of reperfusion
strategies have drastically improved the course and prognosis of STEMI.
19
Figure 4: ESC Guidelines for the Management of Acute Myocardial Infarction
in Patients Presenting with ST-segment Elevation. PCI: Percutaneous Coronary
Intervention; EMS: Emergency Medical Service; FMC: First Medical Contact
Ventricular arrhythmias are relatively frequent during STEMI, whether before or after
hospital arrival, and SCA is the main mode of death in STEMI. Ventricular tachycardia
degenerates first to VF, following an increase in the ventricular tachycardia rate and QRS
width, and later to asystole.(20)(34) The most common hypothesis for a VF mechanism in the
acute phase of STEMI is electrolyte and autonomic imbalances, low pH, and reentry. Reentry
is caused by inhomogeneity and instability of electrical conduction, and it appears to be the
major pathophysiological cascade responsible for VF.(18) The highest estimates of the
incidence of ventricular arrhythmias due to STEMI were reported in studies on the use of
thrombolytic therapy in STEMI. In the Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, which included
40,895 STEMI patients, the overall incidence of ventricular arrhythmias in this trial was
10.2%.(35) Reports from high-volume percutaneous coronary intervention centers indicate
20
that 4% to 11% of patients with STEMI who undergo coronary angiography are brought to
cardiac catheterization after being resuscitated from out-of-hospital SCA.(36)(37) However,
these percentages do not really represent the incidence of pre-hospital SCA during STEMI
since patients who died before hospital admission, and those who did not undergo coronary
angiography were not taken into account.
Data on the short-term and long-term prognosis of VF during STEMI in the era of
PPCI are limited and inconsistent.(38)(39)(40) Furthermore, caution should be taken when
interpreting their results, since patients who died before hospital admission were
systematically excluded from the studies. The mortality rate and the impact of early SCA on
STEMI prognosis were therefore underestimated. While retrospective analyses of the Primary
Angioplasty in Myocardial Infarction (PAMI) trial suggested no increase in in-hospital
mortality or one-year mortality,(39) retrospective analyses of the Assessment of Pexelizumab
in Acute Myocardial Infarction (APEX-AMI) trial, showed an increased 90-day mortality
rate.(37) In line with the APEX-AMI trial results, observational case-control studies
suggested an increase in in-hospital mortality for VF patients with STEMI but no increase in
the long-term mortality rate for these patients compared with STEMI patients without
VF.(40)(41) Considering these conflicting data, the current guidelines for the secondary
prevention of sudden arrhythmic death in patients who survived a VF event do not
recommend early treatment with ICD.(42)
1.3.1.2. Chronic Coronary Artery Disease
In most series, stable plaques and/or chronic changes alone are found in ~50% of SCD
victims with CHD on autopsy.(28)(43)(44) In these cases, a mismatch between myocardial
oxygen demand such as during exercise, and supply in the setting of severe significant
coronary lesion, induces a myocardial ischemia which triggers ventricular arrhythmias.
21
Interestingly, chronic ischemia may exert a protective effect by causing the
development of coronary collaterals that can help mitigate the extent of ischemia produced by
sudden coronary occlusion. Therefore, an acute occlusion of a minimally narrowed coronary
artery can result in a more disastrous outcome than occlusion of a severely narrowed coronary
artery with the jeopardized myocardium protected by collaterals.
Left ventricular systolic dysfunction and severity of heart failure symptoms are
currently the strongest predictors of SCA risk among patients with prior STEMI and/or
chronic ischemic cardiomyopathy.(45) After STEMI, mortality risk increases gradually until
the left ventricular ejection fraction declines to 40%, and then exponentially increases as it
decreases further.(46) SCA rates reach 10% over a median follow-up of approximately 2
years among patients with left ventricular ejection fraction below 30% and chronic heart
failure in clinical trials.(47)
1.3.2. Non-Ischemic Cardiac Etiologies
Non-ischemic cardiac causes of SCA include non-CAD related cardiomyopathies, other
structural cardiac diseases, and non-structural cardiac diseases.
1.3.2.1. Non-ischemic Cardiomyopathies
Non-CAD related cardiomyopathies account for 10 to 15% of causes of SCA. The three major
etiologically-distinct cardiomyopathies are non-ischemic dilated cardiomyopathy,
hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy.
Dilated cardiomyopathies, most often idiopathic, and characterized by cardiac cavities
dilation and ventricular dysfunction, are the most common types of cardiomyopathies causing
SCA. Ventricular arrhythmias are present in most patients with dilated cardiomyopathies, and
SCA is common in this population.(48)(49)(50) The presence and severity of ventricular
22
arrhythmias increase along with the severity of the disease, but their value to predict SCA is
unclear.(51)(52) Indeed, identification of increased risk of SCA in dilated cardiomyopathy
patients has been notoriously difficult, and the only consistent and independent association
has been reported with the severity of left ventricular dysfunction reflected by the left
ventricular ejection fraction.(16)
Hypertrophic cardiomyopathy is defined by the presence of increased left ventricular
wall thickness that is not solely explained by abnormal loading conditions. Its prevalence
ranges between 0.02–0.23% in adults. While HCM is most frequently transmitted as an
autosomal-dominant trait, most studies report a small male preponderance (53) The annual
rate of SCA is between 0.5 – 2% in contemporary series, and SCD from a lethal ventricular
arrhythmia remains one of the common modes of death.(54) (55) SCA is more likely to occur
in young patients (<30 years) and is uncommon in older patients (>60 years).(55)
Arrhythmogenic right ventricular cardiomyopathy is a genetically determined heart
muscle disorder characterized by fibrofatty replacement of the right ventricular myocardium
(and of the left ventricle with disease progression).(56) According to clinical studies and data
from pre-participation screening for sport activity, the estimated prevalence of the disease in
the general population ranges from 1 in 1000 to 1 in 5000.(57) Ventricular fibrillation is the
mechanism of SCA in previously asymptomatic young people and athletes, while it becomes
rare in older patients, who rather have scar-related, hemodynamically stable ventricular
tachycardia.(58)
1.3.2.2. Other Structural Cardiac Causes of SCA
Valvular heart disease is reported to be the cause of death in 1% to 5% of the SCA cases.
Among them, mitral valve prolapse (MVP), the most common cardiac valvular disorder (2.4 –
6% of the population) has been well investigated in SCA, with controversial conclusions
23
regarding the association between MVP and SCA.(59)(60) MVP is characterized by an
expansion, thickening and ballooning of one or both leaflets of the mitral valve with a systolic
displacement into the left atrium. It has been suggested that MVP could potentially accounts
for a greater proportion of SCA among young subjects. Basso and colleagues evaluated 200
cases of SCA in the young (≤ 35 years) and reported that MVP was observed in 10% of
cases.(61) Autopsy series described several cases of SCA where MVP was the sole
abnormality documented,(60) and a “malignant” form of MVP has been identified with a
predisposition for SCA. All this data lends further support to the hypothesis that there may be
a small but definite risk of SCA associated with MVP. Aortic stenosis is another valvular
disease associated to SCA, particularly among symptomatic patients. Among asymptomatic
patients with severe AS, the annual rate of SCA ranges between 1 and 3 % prior to valve
replacement, and recent observational data suggest that this risk may be lowered by early
surgery.(62)(63)(64)
Medical and surgical breakthroughs in the care of children born with heart defects
have resulted in a striking improvement in survival, particularly in the younger age strata and
in those with severe forms of congenital heart disease. Consequently, most children now
survive to adulthood, leading to a shift in population demographics with adults making up
two-thirds of the entire congenital heart disease population.(65) In this context, SCA is a
leading cause of mortality, occurring in otherwise relatively stable patients, typically in the
third or fourth decade of life and accounting for around 25% of the total mortality.(66)
1.3.2.3. Non-Structural Cardiomyopathies
Approximately 5 to 10% of SCA occur in patients with a structurally normal but electrically
abnormal heart in the context of inherited arrhythmic disorders.(67)
24
Congenital long QT (LQT) syndrome is a hereditary disorder, characterized by
delayed myocardial repolarization, resulting in prolongation of the QT interval on EKG and
predisposition to torsade de pointes which can result in SCA.(68) The estimated incidence of
SCA before the age of 40 in untreated patients is varies between 0.30% and 0.60% per year,
according to the type of LQT syndrome.(69) Most arrhythmic events occur during exercise or
emotional stress in LQT1, at rest or with sudden noises in LQT2, and at rest or during sleep in
LQT3.
Brugada syndrome is a primary electrical disorder affecting middle-aged males with
their first arrhythmic event typically developing during sleep at a mean age of 40 years.(70)
The clinical phenotype is 8 to 10 times more prevalent in men than in women. The incidence
of the cardiac events (SCA, ventricular fibrillation, and/or appropriate ICD shocks) in type I
Brugada syndrome ranged from 7.7–10.2% per year, 0.6–3.0% per year, and 0.5–0.8% per
year in those with a history of aborted SCD due to VF, syncopal episodes, and no symptoms,
respectively.(71)(72)
1.4. Prognosis of SCA
Despite major advances in cardiopulmonary resuscitation and post-resuscitation care, survival
to hospital discharge after SCA remains poor.(73)(74) Overall survival to hospital discharge is
less than 10% in most cities.(75) SCA survival is strongly related to the presenting underlying
rhythm and the setting in which the event occurs. SCA with shockable rhythms (ventricular
tachycardia or fibrillation) that account for approximately 25% of cases, have a significantly
better prognosis, with an overall survival of 30.5%. In contrast, the overall survival rate of
pulseless electrical activity SCA is approximately 8% with 7.5% for home arrests and 14.9%
for public arrests.(76)
25
Efforts to improve survival based on in-hospital interventions have shown limited
impact. Despite the valuable effect of targeted temperature control and early coronary
angiography on survival, the two techniques are only applicable to patients admitted alive to
hospital. Increasing the number of patients admitted alive and improving strategies addressing
the entire population of SCA are therefore required, and a better focus on pre-hospital
resuscitation is needed.
The key elements of successful resuscitation, also called basic life support, include
cardiopulmonary resuscitation (CPR) maneuvers and early defibrillation when appropriate
(Figure 5).(74)(77) The importance of rapid CPR initiation cannot be overemphasized,
because the probability of successful resuscitation quickly declines over time. This is
particularly true for witnessed SCA caused by VF or pulseless ventricular tachycardia, for
which the survival rates decrease by 7–10% for every minute between collapse and the first
defibrillation.(78) Early initiation of high-quality CPR extends the successful defibrillation
window by delaying the degeneration of shockable rhythms into ventricular asystole.(78)
High-quality CPR can deliver up to 25–33% of normal cardiac output and is a substantial
contributor to intact neurologic function in resuscitated patients.(77)
The role of early defibrillation has also been well demonstrated.(79) Community
strategies that improve the delivery of early defibrillation to SCA victims include training and
equipping first responders (fire and law enforcement), EMS personnel, and paramedics to
defibrillate, as well as placing AEDs in highly populated locations such as airports,
commercial aircraft, and gambling casinos, with education of the public to the use of AEDs
through Public Access Defibrillation programs.(73)(80)(81) The latter strategy has been
shown to approximately double the number of neurologically intact out-of-hospital cardiac
arrest survivors when laypersons are trained and equipped to provide early CPR and
26
defibrillation with AED, compared with providing CPR alone while awaiting arrival of EMS
personnel.(61)
Figure 5: The Chain of Survival. The Chain of Survival summarises the vital links
needed for successful resuscitation. The 4 links in the out-of-hospital Chain of
Survival are 1) Recognition of cardiac arrest and activation of the emergency response
system; 2) Early CPR with an emphasis on chest compressions; 3) Rapid
defibrillation; 4) Post resuscitation care. CPR: CardioPulmonary Resuscitation
However, basic life support is not systematically performed, since witnesses are not
always present, and when present, they are not always educated to basic life support and/or
aware of the necessity initiating resuscitative maneuvers. When performed, the efficacy of
basic life support is often limited by the relatively long delay elapsed before it is initiated,
knowing that each additional minute of delay reduces the likelihood of survival by 7 to
10%.(82) Besides, it is also limited by the irregular availability of AEDs at the site of SCA
due to the difficulty in matching the location of SCA and AED.(83) According to a Danish
study, a nearby AED was inaccessible in more than half of off-hours OHCA, even though it
was located within walking distance of the OHCA.(84)
27
2. Chapter 1
2.1. Introduction
It has been proven that STEMI occurring during off-hours have a worse prognosis compared
to those occurring during regular hours. Whether the same impact is observed on pre-hospital
SCA has not been well assessed yet. The first part of the thesis aimed to assess the impact of
the time of SCA occurrence on its prognosis.
Using data from the SDEC registry that includes all out-of-hospital SCA occurring in
Paris and its suburbs since 2011, we compared characteristics, management, and outcomes of
SCA occurring during off-hours to those occurring during regular hours. Among 9,834 SCA
included between 2011 and 2014, 63.4% occurred during off-hours. Witnesses were more
often present (74.4% vs. 72.1%, P=0.01) but they less often performed CPR (48.4% vs.
52.1%, P=0.001) and used AEDS (0.6% vs. 6.1%, P=0.004). Time delay between the call to
EMS and EMS arrival was similar in the two groups. In-hospital management did not differ in
terms of targeted temperature central, coronary angiography, and coronary angioplasty.
Survival at hospital discharge was lower during off-hours (4.7% vs. 6.5%, P<0.0001).
However, after adjustment for time of occurrence, age, sex, shockable initial rhythm,
bystander initiated CPR, and OHCA location, there was no difference in survival rate between
regular-hours and off-hours OHCA (OR 0.85, 95% CI 0.69–1.06, P=0.15).
As in STEMI, a lower survival rate is observed during off-hours compared to regular-
hours SCA, despite a similar EMS and in-hospital management. This difference seems to be
due to a difference in the initial management by bystanders present on site, highlighting the
major impact of the initial management of SCA on its prognosis.
28
2.2. Article
29
30
31
32
33
34
3. Chapter 2
3.1. Introduction
Given the major importance of optimal early management of SCA observed in the first paper
of the thesis, and the potential benefit that could be obtained from planning this early SCA
management before its occurrence, the second part of the thesis tested the hypothesis that
identification of patients at high risk of imminent SCA among STEMI patients is feasible.
Using data from the e-MUST registry that includes all STEMI occurring in Paris and
its suburbs since 2003, we identified 5 simple predictors for the occurrence of out-of-hospital
SCA at the early phase of STEMI using the characteristics routinely assessed by EMS
dispatchers on the phone in cases of chest pain: younger age, absence of obesity, absence of
diabetes mellitus, shortness of breath, and a short delay between pain onset and call to EMS.
Using those variables, we built an SCA prediction score that we than validated internally on
one third of the population, and externally on a STEMI population from another French
region (Haute Savoie). The risk of pre-hospital SCA increased 2-fold in patients with a score
between 10 and 19, 4-fold in those with a score between 20 and 29, and >18-fold in patients
with a score ≥30 compared with those with scores <10. The SCA rate was 28.9% in patients
with a score ≥30 compared with 1.6% in patients with a score ≤9 (P for trend <0.001). The
area under the curve values were 0.7033 in the internal validation sample and 0.6031 in the
external validation sample. Sensitivity and specificity varied between 96.9% and 10.5% for
scores ≥10 and between 18.0% and 97.6% for scores ≥30, with scores between 20 and 29
achieving the best sensitivity and specificity (65.4% and 62.6%, respectively).
Early identification of patients at risk of SCA during STEMI is feasible via this simple
5-variables score that is easily obtainable at the phone might help the EMS manage and
dispatch the STEMI cases according to their risk of SCA.
35
3.2.Article
36
37
38
39
40
41
42
43
44
45
46
SUPPLEMENTAL MATERIAL
Supplementary Table 1 – Repartition of the e-MUST and of the external validation populations
Total Sample e-MUST

N=8112 External
Derivation sample (2/3) Validation sample (1/3) validation
N=5353 N=2759 sample
N=606
4902 patients with complete data 2520 patients with complete data
47
Supplementary Table 2 – Characteristics of the patients in the total e-MUST population, the
derivation and the validation samples
Derivation Validation
All patients
sample sample P
(n=8112)
(n=5353) (n=2759)
Age
Median (IQR) 60 (51 - 73) 60 (51 - 73) 60 (51 – 73) 0.63
≤ 40 years, n (%) 414 (5.1) 272 (5.1) 142 (5.2) 0.99
41 – 50 years, n (%) 1,530 (19.0) 1,008 (18.9) 522 (19.0)
51 – 60 years, n (%) 2,258 (28.0) 1,496 (28.1) 762 (27.8)
61 – 70 years, n (%) 1,568 (19.4) 1,032 (19.4) 536 (19.5)
> 70 years, n (%) 2,300 (28.5) 1,518 (28.5) 782 (28.5)
Male, n (%) 6,322 (78.1) 4,181 (78.3) 2,141 (77.7) 0.49
Risk factors
Past history of CAD, n (%) 1,505 (19.0) 1,004 (19.2) 501 (18.6) 0.47
Familial CAD history, n (%) 1,470 (18.5) 963 (18.4) 507 (18.8) 0.72
Current smoking, n (%) 4,188 (52.8) 2,770 (53) 1,418 (52.5) 0.65
Diabetes, n (%) 1,195 (15.1) 785 (15) 410 (15.2) 0.86
Hypertension, n (%) 3,166 (40) 2,088 (40) 1,078 (39.9) 0.96
Dyslipidemia, n (%) 2,826 (35.7) 1,875 (35.9) 951 (35.2) 0.54
Obesity, n (%) 1,963 (24.8) 1,310 (25.1) 653 (24.2) 0.4
Shortness of breath, n (%) 281 (3.6) 187 (3.6) 94 (3.6) 0.9
Chest pain onset-to-call delay
Median (IQR) 60 (26 – 165) 60 (25 – 166) 60 (26 – 162) 0.83
≤ 30 minutes, n (%) 2,409 (30.4) 1,592 (30.4) 817 (30.3) 0.48
31 – 60 minutes, n (%) 1,561 (19.7) 1,022 (19.6) 539 (20)
61 – 120 minutes, n (%) 1,410 (17.8) 910 (17.4) 500 (18.5)
> 120 minutes, n (%) 2,544 (32.1) 1,702 (32.6) 842 (32.2)
Call to EMS arrival delay
20 (14 – 28) 20 (14 – 28) 20 (14 – 28) 0.83
Median (IQR)
SCA occurrence, n (%) 452 (5.6) 297 (5.5) 155 (5.6) 0.92
Total Death, n (%) (N=7791) 459 (5.9) 308 (6.0) 151 (5.7) 0.56
P values are for comparison between the derivation and validation sample using the Chi-square test or
Kruskal-Wallis test, as appropriate.
SCA: Sudden Cardiac Arrest; CAD: Coronary Artery Disease; EMS: Emergency Medical Services
48
Supplementary Table 3 – Univariate analysis in the derivation sample
Derivation sample Without SCA With SCA

P
(n=5353) (n=5056) (n=297)
Age
Median (IQR) 60 (51 - 73) 60 (51 - 73) 57 (48 - 69) < 0.0001
≤ 40 years, n (%) 272 (5.1) 248 (4.9) 24 (8.1) 0.003
41 – 50 years, n (%) 1,008 (18.9) 934 (18.6) 74 (25.1)
51 – 60 years, n (%) 1,496 (28.1) 1,420 (28.2) 76 (25.8)
61 – 70 years, n (%) 1,032 (19.4) 978 (19.4) 54 (18.3)
> 70 years, n (%) 1,518 (28.5) 1,451 (28.8) 67 (22.7)
Male, n (%) 4,181 (78.3) 3,946 (78.3) 235 (79.1) 0.53
Risk factors
Past history of CAD, n (%) 1,004 (19.2) 951 (19.3) 53 (18.1) 0.61
Familial CAD history, n (%) 963 (18.4) 918 (18.6) 45 (15.4) 0.16
Current smoking, n (%) 2,770 (53.0) 2,615 (53.0) 155 (52.9) 0.96
Diabetes, n (%) 785 (15.0) 756 (15.3) 29 (9.9) 0.01
Hypertension, n (%) 2,088 (40.0) 1,994 (40.5) 94 (32.1) 0.005
Dyslipidemia, n (%) 1,875 (35.9) 1,782 (36.1) 93 (31.7) 0.13
Obesity, n (%) 1,963 (24.8) 1,261 (25.6) 49 (16.7) < 0.0001
Shortness of breath, n (%) 187 (3.6) 135 (2.8) 52 (19.3) < 0.0001
Chest pain onset-to-call delay < 0.0001
Median (IQR) 60 (25 - 166) 63 (26 – 170) 36 (13 – 78) < 0.0001
≤ 30 min, n (%) 1,592 (30.4) 1,464 (29.6) 128 (45.1)
31 – 60 min, n (%) 1,022 (19.6) 959 (19.4) 63 (22.2)
61 – 120 min, n (%) 910 (17.4) 868 (17.6) 42 (14.8)
> 120 min, n (%) 1,702 (32.6) 1,651 (33.4) 51 (18.0)
Call to EMS arrival delay
20 (14 - 28) 20 (14 – 28) 18 (13 – 30) 0.07(*)
Median (IQR)
Total Death, n (%) (N=5131) 308 (6.0) 203 (4.2) 105 (35.9) < 0.0001
P values were obtained with a Kruskal-Wallis or a Chi-square test as appropriate. SCA: Sudden
Cardiac Arrest; CAD: Coronary Artery Disease; EMS: Emergency Medical Services
49
Supplementary Figure – Predicted and observed numbers of sudden cardiac arrest in the
internal validation sample, by decile of predicted risk of sudden cardiac arrest
SCA : Sudden Cardiac Arrest; n: number; STEMI: ST-Elevation Myocardial Infarction. The properties
of the model were assessed in the validation sample (n=2520)
50
Supplementary Table 4 – Characteristics of the external validation sample for factors included
in the score
All patients Without SCA With SCA

N (n=606) (n=567) (n=39)
Age (year) 606
Median (IQR) 62 (54-74) 62 (53-74) 61 (55-78)
≤ 40 years, n (%) 16 (2.6) 15 (2.7) 1 (2.6)
41 – 50 years, n (%) 91 (15) 87 (15.3) 4 (10.3)
51 – 60 years, n (%) 170 (28.1) 155 (27.3) 15 (38.4)
61 – 70 years, n (%) 132 (21.8) 125 (22.1) 7 (17.9)
> 70 years, n (%) 197 (32.5) 185 (32.6) 12 (30.8)
Male, n (%) 606 475 (78.4) 447 (78.8) 28 (71.8)
Risk factors
Diabetes, n (%) 604 75 (12.4) 71 (12.5) 4 (10.3)
Obesity, n (%) 575 160 (27.8) 151 (28.1) 9 (23.1)
Shortness of breath, n (%) 600 15 (2.5) 13 (2.3) 2 (5.1)
Chest pain onset-to-call delay 586
(minutes)
Median (IQR) 65 (25-153) 65 (25-153) 16.5 (2.5-175.0)
≤ 30 minutes, n (%) 188 (32.1) 168 (30.5) 20 (57.1)
31 – 60 minutes, n (%) 100 (17.1) 98 (17.8) 2 (5.7)
61 – 120 minutes, n (%) 1 24 (21.1) 119 (21.6) 5 (14.3)
> 120 minutes, n (%) 174 (29.7) 166 (30.1) 8 (22.9)
51
4. Discussion
Among 9,834 all-comers SCA in the general population of Paris and its suburbs between
2011 and 2014 (SDEC population), the survival rate at hospital discharge was 5.4%. This
survival was even lower during off-hours, mainly due to an insufficient early management by
the witnesses on site, while EMS arrival delays and in-hospital management were similar in
the two groups. In contrast, among EMS-witnessed SCA at the early phase of STEMI (e-
MUST population), the survival rate was of 64%. Those results highlight the major
importance of early minutes of SCA management. In order to improve initial SCA
management through a better anticipation, we created an SCA prediction score, easy to obtain
on the phone, and that was able to predict SCA in STEMI with a good performance.
4.1. Strategies to Reduce SCA Burden
So far, two strategies have been used in order to reduce SCA burden: the resuscitation
strategy and the prevention strategy.
4.1.1. Resuscitation Strategy
Resuscitation strategies aim on improving pre-hospital management and optimizing treatment
during the hospital phase once SCA has occurred.
The in-hospital phase is mainly based on targeted temperature control and coronary
angiography.(26)(85)(86) After initial positive results of therapeutic hypothermia in SCA,(87)
several reports showed that mild targeted temperature control can be sufficient.(88)
Accordingly, the optimal target temperature still needs to be defined and better understanding
of its mechanisms and impacts is needed.(89) Besides, therapeutic hypothermia has only been
shown to improve overall survival and rates of favorable neurological survival in patients with
SCA due to VF.(90) As for early coronary angiography and angioplasty, registry data
suggests a favorable impact on survival, due to the high rate of occluded arteries in
52
SCA.(91)(26) However, there is no randomized study on this topic. Globally, the benefit of
coronary angiography is not observed if it is not followed by angioplasty.(92) Therefore,
patients presenting ST-segment elevation on their EKG benefit the most from systematic early
coronary angiography due to the high rate of occluded arteries on their coronary angiography,
which it is frequently followed by angioplasty.(92)(26) Among patients who do not present
ST-elevation, the rate of occluded arteries is lower, and the benefit of early coronary
angiography is still under investigation with several on-going randomized trials comparing
early to delayed coronary angiography.(93) Regardless of the in-hospital strategy used to
improve SCA prognosis, the main limitation is that it only targets patients admitted alive to
hospital, which limits its impact on the global SCA prognosis. Therefore, increasing the
number of SCA admitted alive through appropriate pre-hospital management is essential for
successful resuscitation.
In the SDEC population, the similar in-hospital management, including rates of
coronary angiography and targeted temperature control, between regular and off-hours could
not make up for the difference in the initial pre-hospital management. The survival rate was
ultimately lower during off-hours, highlighting the major importance of early management of
SCA.
At the pre-hospital phase, basic life support with early CPR and AED use has proven
its efficacy when initiated early after SCA occurrence, and is the cornerstone in
resuscitation.(4)(94) However, this strategy faces a major limitation, which is the relatively
long delay elapsed before it is initiated, knowing that each additional minute of delay reduces
the likelihood of survival by 7 to 10%.(82) This delay is due both to the irregular presence of
bystanders at the time of SCA occurrence, and to their insufficient awareness of their role in
initiating resuscitation when present, due to the lack of public education on basic life support.
We previously demonstrated that major regional disparities exist in the actual implementation
53
of public access defibrillation programs, whether in terms of density of persons educated in
basic life support, or of cumulative density of AEDs deployed.(95) According to the same
study, the quality of resuscitation is also influenced by the lack of basic life support education,
since population education was still an independent predictor of survival, even after
adjustment to the rate of CPR.(95)
When considering the difference between the survival rates in the SDEC and e-MUST
populations, the survival rate is more than ten times higher in the e-MUST study, where all
SCA cases were due to STEMI, and were witnessed by EMS who immediately started
resuscitation. It is known that cardiac causes of SCA are associated with a higher survival rate
compared to other causes of SCA.(96)(97)(98) The even higher survival rate observed in the
e-MUST study is most probably the result of EMS presence at the time of SCA occurrence,
which have proven to be a predictor of favorable outcome in SCA, by allowing immediate
initiation of CPR and defibrillation when SCA occurred.(79)(99) In comparison, the survival
rate in the SDEC is more in line with the usual survival rates in SCA series. CPR was only
performed in around a third of the population, while AEDs were used in less than 2% of
cases. Besides, the quality of CPR performed by witnesses could have been inferior to that
performed by EMS. This survival difference was even higher during off-hours where survival
was 4.7% with a lower rate of witness presence, CPR and AED use, for which the similar
EMS and in-hospital management compared to regular hours, could not compensate. All these
finding highlights the major impact of the early minutes after SCA occurrence, and the
advantage of having a bystander on site who is able to start efficient resuscitation without any
delay.
54
4.1.2. Prevention Strategy
Prevention strategies aim on detecting individuals at high-risk for SCA at mid- or long-term,
mainly for selecting patients who would benefit from implantable cardioverter-defibrillator.
Several risk factors were investigated whether at the patient or at the general population
levels. Among them, ejection fraction was identified as the main SCA risk factor, and it is
currently used to guide implantation of implantable cardioverter defibrillators.(100) However,
it has its limitation and it is globally admitted that ejection fraction alone is not an optimal risk
factor, due to its poor sensitivity and specificity, as well as its limited positive predictive
value.(101) In a study conducted in Portland, Oregon between 2002 and 2012, on cases of
SCA with echocardiographic evaluation before the event, 67.9% of the patients were initially
deemed ineligible to implantable cardioverter defibrillators implantation because of left
ventricular ejection fraction >35%.(102) Other risk factors have also been investigated
including electrical abnormalities such as prolonged QTc and QRS intervals,(103)(104)
increased heart rate,(105) family history of SCA,(106)(107) and genetic
determinants.(108)(109) Even though prevention globally allowed the identification of several
SCA risk factors in the general population, it did not allow a specific risk assessment for a
given patient. Therefore, the idea of combining risk factors emerged, and several risk scores
were created to improve SCA risk assessment.(110) However, those SCA scores were not
eventually deemed specific for SCA since they predicted to the same extent the risk of non-
sudden cardiac death as well.(111) In practice, current prevention technique lack specificity in
SCA prediction, and are not able to efficiently assess the individual risk of SCA, and to
provide an estimation of the potential time of SCA occurrence.
The e-MUST score allowed a reliable assessment of imminent SCA risk using a
simple score of five simple variables easily obtained on the phone by EMS dispatchers. In the
high-risk category, almost a third of patients presented SCD compared to 1.6% in the low risk
55
group. The use of this score might help EMS organize the STEMI management according to
the risk of SCA, which implies an optimization of EMS dispatching and a more rapid
deployment of interventions in the field when high risk is detected. Actions can therefore be
initiated even before EMS arrival such as advising bystanders to locate the nearest automated
external defibrillator, and sending firefighters on site before EMS arrival.
4.2. Burden of STEMI-Related SCA
According to the analysis from the e-MUST study, pre-hospital SCA is a relatively frequent
event at the early phase of STEMI, occurring in one of 20 patients. Two approaches have
traditionally been used to evaluate the incidence of pre-hospital SCA in the setting of STEMI.
The first approach has been built on STEMI databases, which were conducted in
catheterization laboratories or in intensive care unit since the diagnosis of STEMI could not
be made before, due to the infrequent availability of pre-hospital EKG in most
EMS.(112)(113)(114)(115) These studies therefore only included patients admitted alive to
hospital, which led to an underestimation of the real burden of pre-hospital SCA in the setting
of STEMI. The second approach has been based on SCA registries, where efforts were made
to identify retrospectively among SCA, those related to STEMI.(5) The latter approach
encountered major difficulties in identifying STEMI-related SCA cases, given the limited
predictive value of EKG in this setting, the poor survival rate to hospital admission, and the
low proportion of SCA patients who eventually undergo coronary angiography to ascertain
the diagnosis of STEMI. (116) The e-MUST study was able to provide a better estimate of the
real incidence of pre-hospital SCA in STEMI, even though it could not include patients who
presented SCA before EMS arrival.
Regarding the impact of early SCA on the short-term and long-term STEMI , data are
inconsistent.(112)(113)(114)(115) While retrospective analyses of the PAMI trial indicated no
56
increase in in-hospital mortality or one-year mortality for SCA,(39) retrospective analyses of
the APEX-AMI trial revealed an increased 90-day mortality rate.(38) In line with the APEX-
AMI trial results, observational case-control studies suggested an increase in in-hospital
mortality for VF patients with STEMI but no increase in the long-term mortality rate for these
patients compared with STEMI patients without VF.(117)(118) None of these studies could
assess the pre-hospital mortality, and therefore a complete analysis of the prognostic impact
of SCA on STEMI prognosis was not possible. According to the e-MUST study, more than a
third of deaths in the SCA group occurred before hospital admission, all of which would have
been excluded in traditional STEMI databases. By including those patients in our study, even
though patients who died before EMS were missed, we were able to better assess the real
impact of pre-hospital SCA on STEMI prognosis. The survival rate in the SCA group was
64%. Even though this is an outstanding survival rate for a SCA series, it remains much lower
than the 95% survival rate observed among STEMI patients who did not present SCA.
Accordingly, early SCA is a potentially fatal complication that needs to be better addressed in
future health plans focused on STEMI.
4.3. Predictors of Pre-Hospital STEMI-Related SCA
When going through the variables included in the e-MUST score, the more frequent anterior
location of STEMI in the SCA group is in line with previous studies that showed, among
patients who present SCA, a higher rate of left main and left anterior descending coronary
artery disease, which are the culprit lesions in anterior myocardial infarction.(114)(119)
Similarly, the higher rate of extensive myocardial infarction, and therefore of acute heart
failure and dyspnea, in the SCA group were also expected.(120)(121)(122)(123)
By contrast, the association of short delays between pain onset and EMS arrival with
an increased risk of SCA deserves specific consideration. Although one would expect a higher
57
rate of SCA due to greater myocardial damage with prolonged ischemia, large amount of data
now support the presence in some patients of an intrinsic susceptibility to develop severe
ventricular arrhythmias during myocardial ischemia, called the rhythmic vulnerability, and
leading to SCA early after ischemia onset, mainly within the first minutes.(124)(125)(126)
This rhythmic vulnerability has been well demonstrated in the past decade, with pivotal
studies providing clear evidence for a familial clustering of SCA cases in this setting of acute
myocardial ischemia. (107)(106)(127)(128)(129)
The analysis of factors associated with pre-hospital SCA at the early phase of STEMI
in the e-MUST study shows the presence of a “risk factors paradox”. Traditional
cardiovascular risk factors include advanced age, smoking, hypertension, diabetes mellitus,
hyperlipidemia, obesity and family history of CAD.(130). In the e-MUST population, all
those risk factors were less frequent among patients who presented SCA. Besides, young age,
absence of diabetes, and absence of obesity were independent predictors of SCA.
Accordingly, even though traditional cardiovascular risk factors lead to an increased
prevalence of CAD and STEMI, they are associated to a lower risk of SCA once STEMI has
occurred. We may hypothesize that chronic CAD in patients with multiple cardiovascular risk
factors leads to a progressive development of collateral circulation, which alleviates the
consequences of an abrupt coronary artery occlusion, while patients with fewer risk factors
potentially have more recent CAD with less collaterals to compensate for an acute coronary
occlusion .(131)(132)
Strength and Limitations
Both the SDEC and the e-MUST registries provide unique opportunities to obtain an
exhaustive inclusion of all SCA and STEMI cases in Paris and its suburbs. The 2 registries
have a great exhaustiveness of more than 90%.
58
The SDEC registry is part of the SDEC that was created in 2011through a close
collaboration between the National Institute of Health and Medical Research (INSERM),
different Parisian Universities, the Assistance Publique des Hôpitaux de Paris, the Regional
Agency of Health and the Agency of Biomedicine, and with the partnership of all the
Reference Centres that already exist for specific cardiac conditions throughout French
territory. Its 3 axes of development patient care, education and research. Inclusion of patients
in the SDEC registry occurs through both a passive (systematic sent by the EMS within hours
of every assessed SCA) and an active (electronic query algorithm is also performed in the
advanced cardiac life support computer system to identify every case of SCA) process.
Moreover, regular controls based on diagnostic codes are conducted in selected intensive care
units. Therefore, the exhaustiveness of the database is above 98%. Of note, contrary to
traditional SCA registries, the SDEC registry includes all SCA assessed by the EMS, even if
resuscitation is not attempted, which gives a complete picture of all SCA cases in Paris and its
suburbs.
The e-MUST registry was initiated in 2003 under the auspices of the French Ministry
and is funded by the Health Regional Agency of the Greater Paris Area, and coordinated by
its registry department and by a scientific board. Its data is analyzed in the Paris Sudden
Death Expertise Center. It benefits from the unique organization of the French EMS that
allows the diagnosis of STEMI and the inclusion of the patients in the registry right in the
field. Most EMS worldwide either do not perform EKGs in the field, or do not have
physicians on board to confirm STEMI diagnosis before hospital arrival. The French EMS has
the specificity of having both the possibility to perform an EKG in the field, and a physician
present with the EMS team in case of chest pain. The diagnosis of STEMI is therefore
obtained minutes after EMS arrival and the patients can be included in the registry even if
they are not admitted to the hospital. We were therefore able to perform the first analysis of
59
STEMI-related SCA mortality that included patients who died before hospital admission who
had never been described so far.
Several limitations have to be acknowledged. First, both registries are conducted in
Paris and its suburbs. The extent to which their results can be applied to different regions with
different EMS systems remains to be demonstrated. However, an external validation of the e-
MUST score was performed on a population from another French region and it showed a
good performance. Second, the e-MUST registry did not include patients who presented SCA
before EMS arrival, due to the limited reliability of EKGs in diagnosing STEMI once SCA
has occurred. Besides, despite providing valuable information for understanding STEMI-
related SCA, several variables specific to SCA, such as family history of SCA and low flow
delays, were not available in the e-MUST registry, since this is initially a STEMI registry.
Finally, even though a difference in the quality of CPR can be expected between the all-comer
laypersons' CPR in the SDEC study, and EMS-provided CPR in the e-MUST study, this
difference could not be assessed in any of the registries.
60
5. Conclusion
Global survival of SCA remains extremely low (5.4%) in Paris and its suburbs. The rates of
bystander presence, bystander CPR, and bystander AED use are still suboptimal. SCA
occurring during off hours have a lower survival rate compared to regular-hours SCA, despite
similar EMS arrival delays and in-hospital management. This difference seems to be due to a
difference in the initial management by bystanders present on site, which is worse during off
hours. This highlights the major impact of the initial management of SCA on its prognosis,
and the need to optimize this phase of resuscitation.
Pre-hospital SCA is a relatively frequent complication of STEMI, with an incidence of
EMS-witnessed SCA of 5.6%. Despite a lower survival rate compared to STEMIs who did
not present SCA, survival rate of STEMI-related SCA witnessed by EMS was extremely high
for a SCA series (64%). This survival rate is partially due to the ischemic cause of SCA that
carries a better prognosis, but the main explanation of this rate is probably the presence of
EMS at the time of SCA allowing immediate and efficient resuscitation.
Five simple predictors of STEMI-related SCA were identified: younger age, absence
of obesity, absence of diabetes mellitus, shortness of breath, and a short delay between pain
onset and call to EMS. Using these variables, we created a SCA prediction score that allowed
a good estimation of the pre-hospital SCA risk among STEMI patients. The use of this score
would help EMS planning STEMI management according to the risk of SCA, and anticipating
SCA occurrence in order to limit the burden of this fatal complication.
61
6. Perspectives
The persistent huge burden of SCA despite the traditional methods for SCA burden reduction
highlights the need for a novel approach. Anticipation can be a potential solution by
identifying high risk of SCA in a given individual a few moments before its occurrence.
Accordingly, when an imminent SCA is suspected, early management can be planned
allowing resuscitation to be initiated rapidly and in an optimized setting if SCA occurs.
The e-MUST score demonstrates that SCA anticipation is feasible among patients with
symptoms due to STEMI, and opens the path for future research in this regard. On a more
global level, a valuable opportunity can be foreseen to develop a new strategy based on near-
term prevention to ensure that resuscitation will be initiated early enough after SCA, or even
that prophylactic therapy will be initiated in this well targeted population for preventing SCA.
This approach becomes even more attractive with current advances in technologies that now
allow EKG monitoring of heart rhythm and repolarization abnormalities through smartphone
applications which data can be shared with the EMS dispatcher who would be able to plan
SCA management even before the dispatching of an EMS team. The addition of
“anticipation” as a new link in the chain of survival can therefore be suggested in order to
incorporate this strategy (Figure 6). The large-scale applicability and efficacy of this novel yet
complementary approach requires testing in prospective studies in the near future.
62
Figure 6. Revised Chain of Survival. Sudden cardiac death management was initially
restricted to health professionals till the 1970s when the first mass citizen training in CPR
was held in Seattle, Washington. In 1990s, early Public Access Defibrillation programs
were developed to provide training and resources for the public to be able to aid in the
resuscitation of cardiac arrest victims. In 2017, we suggest the introduction of a new link to
the chain of survival, aimed on near-term prevention through Anticipation. CPR:
CardioPulmonary Resuscitation. (Karam et al, International Journal of Cardiology 2017)
63
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Appendix: Summary in French
1. Introduction
La mort subite constitue un problème majeur de santé publique avec plus de 40 000 cas par an
en France, constituant environ la moitié des décès d’origine cardiovasculaire. Malgré les
investissements majeurs visant à améliorer leur prise en charge et leur pronostic, la mortalité
des arrêts cardiaques reste élevée et la survie en sortie d’hôpital dépasse rarement les 10%.
L’arrêt cardiaque et la maladie coronaire sont étroitement liés. D'une part, la vaste
majorité des arrêts cardiaques sont d'origine coronaire (≥75% des cas). D'autre part, avec les
progrès dans la prise en charge hospitalière de l'infarctus du myocarde, l’arrêt cardiaque pré-
hospitalier est devenue le principal mode de décès de l'infarctus du myocarde. L’intrication
entre l’infarctus du myocarde et l’arrêt cardiaque rend leurs pronostics étroitement liés. En
vue d’améliorer le pronostic de ces deux entités, une meilleure analyse des points communs et
des relations existant entre elles est donc indispensable.
Utilisant les données de 2 registres prospectifs, le registre francilien du Centre
d’Expertise Mort Subite qui inclue tous les arrêts cardiaques survenant à Paris et en Petite
Couronne depuis 2011, et le registre e-MUST qui inclue tous les infarctus du myocarde pris
en charge par le SAMU en Ile de France depuis 2003, nous avons analysé dans la première
partie de la thèse les déterminants majeurs du pronostic des arrêts cardiaques. Dans la 2ème
partie, nous avons identifié les facteurs associés à un risque accru d’arrêt cardiaque à la phase
aiguë de l’infarctus du myocarde, afin d’anticiper sa survenue et optimiser sa prise en charge
initiale.
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2. Chapitre 1 : Impact de l’Horaire de Survenue sur le Pronostic des Arrêts Cardiaques
2.1. Introduction
Les infarctus du myocarde survenant durant les heures non ouvrables (fin de semaine, jours
fériés et nuits) ont une mortalité accrue par rapport aux infarctus du myocarde survenant
pendant les heures ouvrables. L’impact de l’horaire de survenue sur le pronostic de la mort
subite n’a pas encore été complètement élucidé. A travers une analyse des données du registre
francilien du Centre d’Expertise Mort Subite (CEMS) entre mai 2011 et mai 2014, nous avons
comparé les caractéristiques et le pronostic des morts subites selon leur horaire de survenue.
2.2. Méthodes
Initié en mai 2011, le registre francilien du CEMS collecte de façon prospective tous les arrêts
cardiaques extrahospitaliers survenant à Paris et en Petite Couronne et pris en charge par les
services de secours (le Service d'Aide Médicale Urgente (SAMU) et la Brigade des Sapeurs-
Pompiers (BSPP)). Il couvre ainsi une surface totale de 762 km2 avec 6.6 million d’habitants
(10% de la population française).
Les patients sont inclus dans le registre grâce à 2 méthodes : passive et active. D’une
part, pour chaque arrêt cardiaque pris en charge par les services de secours, des fiches sont
envoyées systématiquement par le SAMU et la BSPP. Cette première approche est complétée
par une recherche informatique systématique afin de déceler tous les cas d’arrêts cardiaque
non signalés. Enfin, un contrôle régulier est effectué dans des unités de soins intensifs afin de
vérifier l’exhaustivité des inclusions qui est de 98.6%. Le suivi des patients est par la suite
continué jusqu’à leur décès ou jusqu’à leur sortie d’hôpital.
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Les données sont collectées d’après les recommandations d’Utstein pour les registres
d’arrêt cardiaque. Elles comportent des informations sur les caractéristiques, la prise en
charge et le pronostic des arrêts cardiaques. Dans le cadre de cette étude, les arrêts survenant
en dehors des heures ouvrables ont été définis comme des arrêts cardiaques survenus entre
18h et 8h, pendant le weekend ou pendant des jours fériés.
Les caractéristiques, la prise en charge et le pronostic des patients ont été comparés en
fonction de leur horaire de survenue. Les variables continues ont été rapportées sous forme de
moyennes (écart-type) et comparées en fonction des horaires de survenue grâce à un test de
student t. Les variables qualitatives ont été rapportées sous forme de proportions et comparées
grâce à des tests de Chi2. Un modèle de régression logistique a été utilisé pour estimer l’Odds
Ratio et l’intervalle de confiance à 95% de l’association entre l’horaire de survenue et la
survie en sortie d’hôpital. La log linéarité des variables a été testées et les variables pour
lesquelles la log linéarité n’a pas été confirmée ont été converties en variables catégorielles.
Les données ont été analysées à l’INSERM, Unité 970, Epidémiologie Cardiovasculaire et
Mort Subite en utilisant le logiciel R, version 3.1.2.
2.3. Résultats
Durant la période d’étude, 9834 cas de mort subite ont été enregistrés (moyenne d’âge 70.3
+/- 17ans, 62.1% d’hommes). Parmi eux, 6239 (63.4%) sont survenus en dehors des heures
ouvrables.
En dehors des heures ouvrables, les arrêts cardiaque ont plus souvent eu lieu au
domicile (84.5% vs. 73.8%, P<0.0001); des témoins étaient plus souvent présents (74.4% vs.
72.1%, P=0.01) mais ont moins fréquemment réalisé un massage cardiaque externe (48.4%
vs. 52.1%, P=0.001) et utilisé les défibrillateurs automatiques externes (1.6% vs. 2.9%,
P=0.01). Le délai entre l’appel des services de secours et leur arrivée était le même dans les 2
84
groupes (10mn en moyenne); à leur arrivée, les patient étaient moins souvent en rythme
choquable (16.3% vs. 19.1%, P < 0.0001) et un rythme spontané a moins souvent été obtenu
(27.5% vs. 31.1%, P<0.0001). La survie jusqu’à l’admission à l’hôpital était plus faible en
dehors des heures ouvrables (21.0% vs.24.5%, P<0.0001).
Il n’y avait pas de différence dans la prise en charge intra-hospitalière en fonction de
l’horaire de survenue, en termes de taux de coronarographie, d’angioplastie et d’hypothermie
thérapeutique.
La survie en sortie d’hôpital était plus faible en heures non ouvrables (4.7% vs. 6.5%,
P<0.0001). En analyse univariée, les variables associées à une meilleure survie étaient la
survenue en lieu public (OR 6.33, IC à 95% 5.28–7.59, P<0.0001), le sexe masculin (OR
1.88, IC à 95% 1.54–2.31, P<0.0001), la présence de témoins (OR 7.97, IC à 95% 5.40–
12.37, P<0.0001), le massage cardiaque par les témoins (OR 13.01, IC à 95% 8.78–20.27,
P<0.0001), et l’utilisation des défibrillateurs automatiques externes par les témoins (OR
47.65, 95% CI 26.32–87.25, P<0.0001), alors que l’âge avancé (OR 0.96, 95% CI 0.95–0.96,
P<0.0001) et la survenue en dehors des heures ouvrables (OR0.71, 95% CI 0.60–0.85,
P=0.0002) étaient associés à une survie plus faible.
Après ajustement sur l’horaire de survenue, l’âge, le sexe, le rythme initial, le massage
cardiaque par le témoin et la localisation de l’arrêt cardiaque, il n’y avait pas de différence en
termes de survie des arrêts cardiaques en fonction de l’horaire de survenue (OR 0.85, IC à
95% 0.69–1.06, P=0.15).
2.4. Discussion
Dans cette étude sur 9834 arrêts cardiaques, 2/3 des cas sont survenus en dehors des heures
ouvrables. Leur survie était inférieure à celle des arrêts cardiaques survenant en heures
ouvrables (jusqu’à 30%), en raison essentiellement d'une prise en charge initiale moins
85
optimale par le témoin en termes de massage cardiaque et de défibrillation externe, alors que
les prises en charge spécialisées pré- et intra-hospitalière ne sont pas être influencées par
l'horaire de survenue.
Malgré quelques études analysant la différence de survie et de prise en charge
extrahospitalière des arrêts cardiaques en fonction de leur horaire de survenue, peu de
données existent concernant la prise en charge par les services de secours et en intra-
hospitalier. Les données fournies dans cette étude montrent que seule la prise en charge
initiale par les témoins diffère en fonction des horaires, alors que la prise en charge
spécialisée n’est pas influencée. Cependant, la mortalité des arrêts cardiaques survenant en
dehors des heures ouvrables est moins bonne que celles des arrêts en heure ouvrable, montrant
l’influence majeure de la prise en charge immédiate des arrêts cardiaques sur leur pronostic.
Une des limites de cette étude est que seules les données intrahospitalière relatives à
l’utilisation de la coronarographie, de l’angioplastie et de l’hypothermie thérapeutique ont été
incluses dans l’analyse ; d’autres variables auraient pu être décrites mais nous nous sommes
limitées aux variables ayant le plus d’impact prouvé sur la survie. Par ailleurs, cette étude a
été menée à Paris et en Petite Couronne et il est possible que des résultats différents soient
obtenus dans d’autres régions.
2.5. Conclusion
Le pronostic des arrêts cardiaques survenant en heures non ouvrables est moins favorable que
celui des arrêts cardiaques survenant en heure ouvrable, en raison d’une prise en charge
initiale sous-optimale, et malgré une prise en charge similaire par les services de secours et
par l’hôpital. Ceci souligne le rôle capital des premières minutes de la prise en charge des
arrêts cardiaques, qui devraient être la cible des futurs efforts visant à améliorer le pronostic
des arrêts cardiaques.
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3. Chapitre 2 : Identification des Patients à Haut Risque d’Arrêt Cardiaque Pré-
Hospitalier à la Phase Aiguë de l’Infarctus du Myocarde
3.1. Introduction
Etant donné l’importance majeure des premières minutes de la prise en charge des arrêts
cardiaques démontrée dans la première partie de la thèse, la deuxième partie a eu pour objectif
d'identifier, parmi les victimes d’infarctus du myocarde incluses dans le registre e-MUST,
celles à risque de présenter une mort subite pré-hospitalière, afin de planifier la prise en
charge de l'arrêt cardiaque juste avant sa survenue en vue d'une meilleure réanimation initiale.
3.2. Méthodes
Le registre e-MUST a été créé en 2003 par l’ARSIF (Agence Régionale de Santé d’Ile de
France). Il inclue de façon prospective tous les infarctus du myocarde survenant en
extrahospitalier et pris en charge par le SAMU. Les patients sont inclus s’ils sont vivants à
l’arrivée du SAMU, présentant un angor depuis au moins 20mn et de moins de 24h, résistant à
la trinitrine et avec un sus-décalage du segment ST ≥ 2mm dans 2 dérivations contiguës en
précordial ou une dérivation sur les dérivations périphériques, ou BBG présumé récent.
Les données collectées concernent l’âge des patients, leur sexe, leurs antécédents
médicaux, leur symptomatologie actuelle, la prise en charge par le SAMU et à l’hôpital (avec
une attention particulière sur les délais d’intervention et de transport). Le type et le pronostic
de l’infarctus sont également renseignés. La collecte de ces données est débutée au téléphone
par le régulateur et complétée par l’équipe du SAMU sur place et par un appel systématique à
l’hôpital visant à obtenir le pronostic en sortie d’hôpital. Elles sont par la suite rentrées dans
une base informatique dans chaque centre puis envoyées au centre des registres de l’ARSIF
87
tous les 4 mois. Un audit externe annuel est réalisé sur 11% des fichiers afin de vérifier
l’exhaustivité du registre qui est de 92%.
Un modèle de régression multivariée prédicteur de l’arrêt cardiaque a été construit en
utilisant les variables associées à un risque accru d’arrêt cardiaque. Par la suite, la population
a été divisée en un échantillon de dérivation (2/3 de la population) et un échantillon de
validation interne (1/3) ; une validation externe a également été réalisée sur une population
similaire en Haute Savoie. Un score de prédiction de l’arrêt cardiaque a été créé selon les
résultats du modèle multivarié. Un poids a été attribué à chaque prédicteur d’arrêt cardiaque
en multipliant son coefficient beta par 10 et arrondissant au chiffre complet le plus proche ; le
score individuel est donc obtenu en additionnant le poids de ces variables. Les scores médians
des individus ayant présenté un arrêt cardiaque ou pas ont été comparés en utilisant le test de
Kruskal-Wallis. Quatre groupes de score ont été créés et dans chaque groupe, le taux observé
et le taux prédit d’arrêt cardiaque ont été calculés. Les performances du score (aire sous la
courbe, sensibilité, spécificité et rapport de probabilité) ont été estimées pour chaque classe de
score. Les analyses statistiques ont été réalisées en utilisant un logiciel STATA version 11.0
(STATA Corp, College Station, TX).
3.3 Résultats
Entre janvier 2006 et décembre 2010, 8112 patients présentant un infarctus du myocarde ont
été pris en charge par le SAMU et inclus dans le registre e-MUST (médiane d'âge 60ans, 78%
d'hommes).
Comparé aux patients qui n'ont pas présenté d'arrêt cardiaque, les patients ayant
présenté un arrêt cardiaque étaient plus jeune (60ans vs. 57ans, P<0.001). Le diabète,
l'hypertension et l'obésité étaient moins fréquents dans le groupe arrêt cardiaque (9.2% vs.
15.4%, 30.3% vs. 40.5%, and 16.6% vs. 25.3%, respectivement; tous les P<0.001), alors que
88
l'essoufflement était plus souvent présent avant l'arrêt cardiaque (19.4% vs. 2.7%; P<0.001).
Le délai médian entre le début de douleur et l'appel des services de secours était plus court
dans le groupe arrêt cardiaque (34 minutes vs. 63 minutes, P<0.001). Il n'y avait pas de
différence significative en termes de fréquence de dyslipidémie, de tabagisme et d'histoire
personnelle ou familiale de coronaropathie dans les 2 groupes.
Les caractéristiques de base des échantillons de dérivation et de validation étaient
similaires. En analyse univariée, l'âge jeune, l'absence de diabète, d'hypertension et d'obésité,
ainsi que la présence d'un essoufflement et d'un délai court entre le début de douleur et l'appel
des secours. En analyse multivariée, l'âge jeune, l'absence de diabète et d'obésité, la dyspnée,
et un délai court entre le début de douleur et l'appel des secours étaient des prédicteurs
indépendants d'arrêt cardiaque, sans interaction entre eux. L'aire sous la courbe dans
l'échantillon de dérivation était de 0.72 (IC à 95% 0.68–0.77).
Le score médian établi à travers ce modèle était de 18 (IC 13–23) dans la population
générale, 23 (IC 18-28) parmi les patients ayant présenté un arrêt cardiaque et 18 (13-23)
parmi le reste de la population. Le taux d'arrêt cardiaque augmentait avec le score, allant de
1.6% dans la tranche la plus basse à 28.9% dans la tranche à haut risque. Le rapport de risque
passait à 18 chez les patients ayant un score supérieur ≥30. Dans la population de validation
externe (606 patients), l'incidence d'arrêts cardiaques était de 6.4%, augmentant également
avec la tranche de score étudiée. L'aire sous la courbe était de 0.7033 dans l'échantillon de
validation interne et 0.6031 dans l'échantillon de validation externe.
3.4. Discussion
Dans cette étude incluant 8112 infarctus du myocarde, nous avons identifié 5 facteurs associés
à un risque accru d’arrêt cardiaque pré-hospitalier (âge jeune, absence de diabète et d'obésité,
dyspnée, délai court entre le début de douleur et l'appel des secours). Nous avons ainsi créé un
89
score de risque de mort subite que nous avons validé en interne (tiers de la population) et en
externe (population similaire en Haute-Savoie).
Le recours à un score de prédiction du risque d’arrêt cardiaque à la phase aiguë de
l’infarctus permettrait de révolutionner sa prise en charge en l’adaptant au risque estimé.
Ainsi, quoiqu’un délai de 90 minutes (ou 60 minutes pour les infarctus précoces) soit autorisé
avant la revascularisation, une revascularisation plus précoce, y compris par thrombolyse,
pourrait être envisagée en cas de risque élevé d’arrêt cardiaque. L’équipe hospitalière
(anesthésistes, réanimateurs et chirurgiens capables de poser une assistance extracorporelle)
pourrait aussi être avertie de l’arrivée d’un patient à haut risque. L'intérêt de ces stratégies
reste clairement à tester dans des études prospectives randomisées.
Plusieurs limites méritent d’être soulignées. Les patients présentant un arrêt cardiaque
avant l’arrivée du SAMU ne sont pas inclus dans ce registre à cause du manque de fiabilité du
sus-décalage de ST en post-arrêt cardiaque pour le diagnostic de l’infarctus du myocarde. Par
ailleurs, le score aurait probablement pu être amélioré en rajoutant des variables spécifiques à
l’arrêt cardiaque comme les antécédents de mort subite dans la famille et de syncope;
cependant, il s’agirait de poser des questions qui ne sont pas systématiquement posées par le
SAMU lors d’un appel pour douleur thoracique et qui risqueraient de compliquer la tâche du
régulateur. Enfin, en dépit de la validation externe du score, son application en dehors des
zones étudiées et avec des services de secours différents reste à prouver.
3.5. Conclusion
A la phase aiguë de l’infarctus du myocarde, l’arrêt cardiaque peut être prédit grâce à un score
simple, facile à obtenir au téléphone par le régulateur du service de secours. L’usage de ce
score permettrait aux services de secours d’estimer rapidement le risque individuel d’arrêt
cardiaque et d’organiser la prise en charge des infarctus du myocarde en fonction. Il
90
permettrait également d’anticiper l’arrêt cardiaque dans les cas à haut risque et de planifier sa
prise en charge avant même sa survenue.
91
4. Discussion
Parmi 9834 arrêts cardiaques dans la population générale à Paris et en Petite Couronne, la
survie en sortie d'hôpital était de 5.4%, avec un taux encore plus bas en dehors des heures
ouvrables suite à une prise en charge initiale moins optimale par les témoins, alors que la prise
en charge médicalisée en revanche, parmi les arrêts cardiaques survenant en présence des
services de secours à la phase aiguë de l'infarctus du myocarde, la survie était de 64%. Ces
résultats soulignent l'intérêt majeur des premières minutes de la prise en charge des arrêts
cardiaques. En vue d'améliorer la prise en charge initiale des arrêts cardiaques en anticipant
leur survenue, nous avons testé et validé la possibilité de créer un score prédictif de l'arrêt
cardiaque dans l'infarctus du myocarde.
La survie des arrêts cardiaques reste faible en dépit des efforts considérables visant à
améliorer leur pronostic. Deux méthodes ont été utilisées jusque-là dans ce but. D'une part, la
ressuscitation, avec pour but d'améliorer la prise en charge des arrêts cardiaques une fois
survenus. Elle se divise en une phase hospitalière, reposant essentiellement sur la
coronarographie et l'hypothermie thérapeutique; cette phase est limitée par le fait qu'elle ne
concerne que les patients admis vivants. Dans le registre du CEMS, la prise en charge
identique en intrahospitalier n'a pas permis de rattraper la différence de survie constatée à
l'arrivée à l'hôpital en fonction de l'horaire de survenue de l'arrêt cardiaque, montrant
l'importance majeure de la prise en charge initiale. La 2ème phase de la ressuscitation concerne
la prise en charge initiale extrahospitalière et repose essentiellement sur le massage cardiaque
externe et l'utilisation des défibrillateurs automatiques externes. La principale limite à cette
phase est le délai écoulé avant l'initiation de la réanimation et la présence inconstante d'un
témoin formé à la ressuscitation et d'un défibrillateur automatique externe à disposition. En
92
comparant la survie dans les 2 registres (e-MUST et CEMS), nous constatons une survie 10
fois plus élevée dans le registre e-MUST. Bien que l'origine ischémique soit généralement
associée à une meilleure survie, la différence entre les 2 survies est probablement due à la
présence du SAMU au moment des arrêts cardiaques dans e-MUST, permettant une prise en
charge optimale et immédiate, contrairement au registre du CEMS.
La 2ème méthode visant à diminuer l'impact de la mort subite est la prévention, ayant
pour but de détecter les personnes à haut risque d'arrêt cardiaque au moyen et long terme;
Plusieurs prédicteurs d'arrêt cardiaque ont été explorés, avec la fraction d'éjection du
ventricule gauche considérée comme le principal prédicteur du risque. Cependant, ce
marqueur a une sensibilité, une spécificité et une valeur prédictive faibles dans la prédiction
de la mort subite et est reconnu comme un outil imparfait. D'autres marqueurs ont également
été explorés, dont l'histoire familiale de mort subite, les facteurs génétiques et la fréquence
cardiaque élevée. Des scores ont aussi été créés, combinant les facteurs de risque afin de
fournir une estimation du risque de mort subite. Cependant, la prévention reste limitée par sa
faible spécificité dans la prédiction du risque individuel d'arrêt cardiaque, et dans l'estimation
du délai de sa potentielle survenue. Le score e-MUST a permis d'établir une estimation du
risque de mort subite imminente à travers 5 facteurs de risque faciles à obtenir par le
régulateur des services de secours au téléphone. L'utilisation de ce score permettrait ainsi de
guider la prise en charge des infarctus du myocarde selon leur risque d'arrêt cardiaque, avec
une anticipation de la survenue d'arrêt cardiaque et une programmation de sa prise en charge
initiale à l'avance.
Etant données la faible survie persistante des arrêts cardiaques et les limitations des
stratégies actuelles visant à diminuer son impact en termes de santé publique, de nouvelles
approches semblent nécessaires. L'anticipation ou prévention subaiguë serait une solution
possible, en permettant d'identifier un risque élevé d'arrêt cardiaque chez un individu donné,
93
quelques minutes avant sa survenue, permettant ainsi d'optimiser la prise en charge initiale en
l'organisant à l'avance.
5. Conclusion
La survie globale des arrêts cardiaques à Paris et en Petite Couronne reste extrêmement faible
(5.4%), surtout en dehors des heures ouvrables, suite à une prise en charge sous-optimale par
les témoins et en dépit d'une prise en charge similaire par le SAMU et en intra-hospitalier.
Ceci démontre l'importance majeure des premières minutes de la prise en charge des arrêts
cardiaques sur leur pronostic. Cette constatation est renforcée par la survie 10 fois plus élevée
observée dans le cadre des arrêts cardiaques survenant en présence du SAMU à la phase aiguë
de l'infarctus.
Grâce à cinq prédicteurs simples d'arrêt cardiaque dans le cadre de l'infarctus du
myocarde, nous avons pu créer un score de risque permettant d'identifier les patients à haut
risque d'arrêt cardiaque. Quoique l'optimisation de ce score reste encore possible, il ouvre une
piste prometteuse pour l'amélioration des arrêts cardiaques de l'impact en termes de santé
publique grâce à une nouvelle qui serait l'anticipation.
94

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Myocardial infarction and sudden death : a

To cite this version:

HAL Id: tel-01726269

HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est

ECOLE DOCTORALE PIERRE LOUIS DE SANTE PUBLIQUE A PARIS

EPIDEMIOLOGIE ET SCIENCES DE L'INFORMATION BIOMEDICALE

Infarctus du Myocarde et Mort Subite:

Mlle Nicole KARAM

Pour obtenir le grade de

DOCTEUR de l’UNIVERSITÉ PIERRE ET MARIE CURIE

Directeur et Co-directeur de Thèse : M. Xavier JOUVEN et M. Christian SPAULDING

Rapporteurs : M. Jean BOUYER et Mme Julinda MEHILLI

Examinateur : M. Jean-Philippe COLLET et Mme Vijay KUNADIAN

encouragements whether in the research, technical, or career level.

department and for pushing me forward in my career development

contributed greatly to the improvement of the thesis and of my research in general.

accomplished without your help.

and support throughout this thesis and in my life in general.

Karam N, Bataille S, Marijon E, Giovanetti O, Tafflet M, Savary D, Benamer H, Caussin C,

Karam N, Pechmajou L, Bougouin W, Dumas F, Empana JP, Cariou A, Spaulding C, Jouven

Karam N, Bougouin W, Perier MC, Lamhaut L, Dumas F, Benameur N, Celermajer D,

Karam N, Tafflet M, Bataille S, Marijon E, Empana JP, Spaulding C, Lambert Y, Jouven X.

Karam N, Bataille S, Tafflet M, Marijon E, Empana JP, Lambert Y, Spaulding C, Jouven X.

Karam N, Marijon E, Offredo L, Beganton F, Lamhaut L, Dumas F, Spaulding C, Cariou A,

Karam N, Marijon E, Beganton F, Lamhaut L, Dumas F, Cariou A, Spaulding C, Jouven X.

Karam N, Bataille S, Tafflet M, Marijon E, Lapostolle F, Spaulding C, Lambert Y, Jouven X.

understanding of the associations and the overlap between the two.

witnesses (cardiopulmonary resuscitation and automated external defibrillation), while EMS

resuscitation, planned before SCA occurrence.

l'amélioration manquante du pronostic de la mort subite.

nous avons validé en interne (tiers de la population) et en externe (population similaire en

déterminants de son pronostic et devraient idéalement être planifiées avant sa survenue. La

d'anticiper la survenue de la mort subite et de planifier la prise en charge en fonction. Quoique

la possibilité de généralisation de cette stratégie à d'autres causes de mort subite reste à

subite grâce au développement de la prévention à court terme avec organisation de la prise en

charge des morts subites avant leur survenue.

Publications arising from this Thesis…………………………………………………...….3

Posters and Oral Presentations……………………………………….………………….…4

List of Abbreviations and Acronyms……………….………….………………...………..11

1.1. Definitions of SCA………………………………………………………………...…14

1.2. Incidence and Demographics of SCA…….………………...……………………….14

1.3. Cardiovascular Conditions Associated to SCA Occurrence.....…………………...15

1.3.1. Coronary Artery Disease………………………….……………………………..17

1.3.1.1. Acute Coronary Events……………………………………………………...18

1.3.1.2. Chronic Coronary Artery Disease………………………………………..…21

1.3.2. Non-Ischemic Cardiac Etiologies………………………………………………..22

1.3.2.1. Non-ischemic Cardiomyopathies……………………………………………22

1.3.2.2. Other Structural Cardiac Causes of SCA………………………………….23

1.3.2.3. Non-Structural Cardiomyopathies………………………………………….24

1.4. Prognosis of SCA………..………………………………………………………...…25

4.1. Strategies to Reduce SCA Burden…………………………………..……………...52

4.1.1. Resuscitation Strategy……………………………..…………………...………..52

4.1.1. Prevention Strategy……………………………..………………….......………..55

4.2. Burden of STEMI-Related SCA……………………………………..…….………..56

4.3. Predictors of Pre-Hospital STEMI-Related SCA…...…………………….………..57

4.4. Strength and Limitations…………………….…..…...…………………….………..58

8. Appendix (French summary) …………………………………………………………....82

AED: Automated External Defibrillator