Ziel der Studie war es zu analysieren, welchen Einfluss eine angiographisch sichtbare Kollateralisierung vor Revaskularisation bei Patienten mit einem akuten ST-Elevations-Myokardinfarkt (STEMI) und primärer perkutaner Koronarintervention (PCI) auf verschiedene in der kardialen Magnetresonanztomographie messbare Parameter und auf die klinische Prognose hat. Es wurden 235 Patienten mit STEMI und einem Symptombeginn <12 Stunden in die Analyse eingeschlossen. Alle Patienten wiesen einen funktionell insuffizienten antegraden Fluss in der Infarktarterie auf. Die Patienten wurden in zwei Gruppen unterteilt: Gruppe A mit fehlender oder nur geringer Kollateralversorgung (n=166) und Gruppe B mit einer signifikanten Kollateralisierung (n=69). Es wurden Infarktgröße, mikrovaskuläre Obstruktion und linksventrikuläre Funktion mittels Magnetresonanztomographie im Median 3 Tage nach dem Infarktereignis bestimmt sowie die Patienten über einen Zeitraum von >2 Jahren nachbeobachtet. Das Ausmaß der frühen mikrovaskulären Obstruktion war in Gruppe B signifikant geringer (3,3% gegenüber 2,1% der linksventrikuläre Masse, p = 0,009). Die mittels maximaler Kreatinkinase-MB-Ausschüttung gemessene Infarktgröße war in Gruppe B kleiner (p=0,02). Bei 227 Patienten (97%) wurde nach im Median 2,2 Jahren eine klinische Verlaufskontrolle durchgeführt. Insgesamt starben während des Kontrollzeitraums 25 Patienten: 22 Patienten (13,8%) der Gruppe A mit fehlender oder nur schwacher Kollateralisierung und 3 Patienten (4,4%) der Gruppe B mit signifikanter Kollateralversorgung vor Behandlungsbeginn (p=0,04). In Gruppe A traten 12 (7,5%) nicht-tödliche Reinfarkte auf im Vergleich zu 2 (2,9%) in Gruppe B (p=0,18). Ein kombinierter Endpunkt aus Tod oder nicht-tödlichem Reinfarkt trat in Gruppe B signifikant seltener auf als in Gruppe A (p=0,02). Zusammenfassend lässt sich formulieren, dass gut ausgebildete Kollateralgefäße vor einer Revaskularisation mittels PCI bei Patienten mit akuten STEMI mit einer schützenden Wirkung auf die koronare Mikrozirkulation und einem besseren Langzeit-Überleben assoziiert sind.:1 BIBLIOGRAPHISCHE BESCHREIBUNG 2 ABKÜRZUNGSVERZEICHNIS 3 EINFÜHRUNG 4 AUFGABENSTELLUNG 5 MATERIALIEN UND METHODEN 5.1 Überblick über das Studiendesign 5.2 Koronarintervention 5.3 Enzymatische Infarktgröße 5.4 Kardiale Magnetresonanztomographie 5.4.1 Linksventrikuläre Volumina und Ejektionsfraktion 5.4.2 Infarktgröße 5.4.3 Mikrovaskuläre Obstruktion 5.5 Klinisches Follow-up 5.6 Statistik 6 ERGEBNISSE 6.1 Patientencharakteristika 6.2 Enzymatische Infarktgröße 6.3 Magnetresonanztomographie 6.4 Klinische Ereignisse im Langzeitverlauf 6.5 Prädiktoren klinischer Ereignisse 6.5.1 Univariate Cox-Regressions-Analyse 6.5.2 Multivariate Cox-Regressions-Analyse 6.6 Klinische Ergebnisse in Abhängigkeit von der Zeit zwischen Symptombeginn und Reperfusion 6.7 Magnetresonanztomographische Ergebnisse in Abhängigkeit von der Zeit zwischen Symptombeginn und Reperfusion 7 DISKUSSION 7.1 Limitationen 8 ZUSAMMENFASSUNG DER ARBEIT 9 LITERATURVERZEICHNIS 10 DANKSAGUNG 11 ERKLÄRUNG ÜBER DIE EIGENSTÄNDIGE ABFASSUNG DER ARBEIT 12 LEBENSLAUF 13 PUBLIKATIONEN

<p>Uvod: Stratifikacija rizika je postala integralna komponenta savremenog pristupa tretmanu u kliničkoj praksi. Danas se u dijagnostici i lečenju akutnog infarkta miokarda (AIM) koriste različiti skorovi rizika kao prognostički instrumenti za kratkoročan i dugoročan ishod bolesti. Nužni proceduralni procesi, u toku primarne perkutane koronarne intervencije (pPKI), kao i saznanja o distribuciji i vrstama lezija koronarnih arterija su od velikog značaja, te se preporučuje finalna evaluacija rizika neposredno nakon izvr&scaron;ene pPKI. Metode istraživanja podataka omogućavaju pronalaženje skrivenih obrazaca u podacima, otkrivanje njihovih uzročno-posledičnih veza I odnosa, te razvoj savremenih prediktivnih modela. Cilj: Kreiranje i testiranje jednostavnog, praktičnog i u svakodnevnoj praksi upotrebljivog prediktivnog modela za procenu intra-hospitalnog ishoda lečenja pacijenata obolelih od AIM sa ST-elevacijom (STEMI) lečenih pPKI. Metode: Istraživanje je unicentrična, retrospektivna, ali I prospektivna studija. U retrospektivnu studiju je uključeno 1495 pacijenta sa STEMI koji su lečeni na Klinici za kardiologiju Instituta za kardiovaskularne bolesti Vojvodine (IKVBV) kod kojih je u cilju rekanalizacije infarktne arterije izvr&scaron;ena pPKI, u periodu od decembra 2008. godine do decembra 2011. godine. Svaki pacijent je inicijalno predstavljen sa 629 obeležja sadržanih u postojećem IKVBV informacionom sistemu, koja čine demografske karakteristike, podaci iz anamneze i kliničkog nalaza, parametri biohemijskih analiza krvi priprijemu, parametri ehokardiografskog pregleda, angiografski i proceduralni detalji i &scaron;ifre prijemnih dijagnoza. U svrhu istraživanja podataka kori&scaron;ćeno je programsko re&scaron;enje otvorenog koda Weka. Tokom evaluacije različitih algoritama izabran je algoritam koji daje najbolje rezultate po tačnosti predikcije i ROC parametru. U sklopu retrospektivnog dela izvr&scaron;ena je validacija prediktivnog modela&nbsp; desetostrukom unakrsnom validacijom na celom skupu podataka. Prospektivnom studijom je na uzorku od 400 pacijenata sa STEMI lečenih pPKI u toku 2015. godine izvr&scaron;ena dodatna validacija razvijenog prediktivnog modela. Za iste pacijente je izračunavat i GRACE skor rizika, te je upoređena njegova, i prediktivna moć razvijenog modela. Rezultati: Alternativno stablo odluke (ADTree) izdvojen je kao algoritam sa najboljim performansama u odnosu na ostale evaluirane algoritme. Cost sensitive klasifikacija je kori&scaron;ćena kao dodatna metodologija da bi se pojačala tačnost. ADTree stablo odluke izdvojilo je osam ključnih parametara koji najvi&scaron;e utiču na ishod intra-hospitalnog lečenja: sistolni krvni pritisak pri prijemu, ejekciona frakcija leve komore, udarni volumen leve komore, troponin, kreatinin fosfokinaza, ukupni bilirubin, T talas i<br />rezultat intervencije. Performanse razvijenog modela su: tačnost predikcije je 93.17%, ROC 0.94. Razvijeni model je na prospektivnoj validaciji zadržao performanse: tačnost predikcije 90.75%, ROC 0.93. &Scaron;iroko kori&scaron;ćeni GRACE skor je na prospektivnom skupu postigao ROC=0.86, &scaron;to pokazuje da je razvijeni prediktivni model superiorniji u odnosu na njega. Zaključak: Razvijeni prediktivni model je jednostavan i pouzdan. Njegova implementacija u svakodnevnu kliničku praksu, omogućila bi kliničarima da izdvoje visokorizične pacijente, nakon reperfuzionog tretmana, a potom kod njih intenziviraju tretman i kliničko praćenje, a sa ciljem smanjenja incidence intra-hospitalnih komplikacija i povećanja njihovog preživljavanja.</p> / <p>Introduction: Risk stratification has become an integral component of modern treatment in clinical practice. Today, the diagnosis and treatment of acute myocardial infarction (AMI) use different risk scores as a prognostic instruments for short-term and long-term outcome of the disease. The necessary procedural processes during primary percutaneous coronary intervention (pPCI) as well as knowledge about the distribution and types of lesions in coronary arteries are of great importance, and a final risk evaluation is recommended directly after the pPCI. Methods of data mining allow finding hidden patterns in data, disclosure of their causal connections and relationships, and the development of modern predictive models. Aim: To create and test a simple, practical and usable predictive model in daily practice for the&nbsp; assessment of intrahospital treatment outcome of patients with AMI with STsegment elevation (STEMI) treated with pPCI. Methods: Presented research is unicentric, retrospective but also prospective study. Retrospective study included 1495 patients with STEMI who were admitted to the Clinics of cardiology of the Institute of Cardiovascular Diseases Vojvodina (IKVBV). For the purpose of recanalization of the infarct artery, pPCI has been performed to these patients during the period from December 2008 to December 2011. Each patient was initially described with 629 attributes from the existing information system of IKVBV. Those attributes consist of demographic characteristics, data from history and clinical findings, biochemical parameters of blood tests on admission, the echocardiographic parameters, angiographic and procedural details and admission diagnosis codes. For model development, an open source software solution Weka was used. During the evaluation of different algorithms, algorithm that gives the best results in terms of accuracy and ROC parameter was chosen. As part of the retrospective study, in order to assess the models performance, ten-fold cross-validation on the entire data set was used. A prospective study, on a sample of 400 patients with STEMI, treated with pPCI in 2015, performed additional validation of the developed predictive model. GRACE risk score was calculated for the prospective study patients and comparison with the developed model has been performed. Results: Alternative decision tree (ADTree) was isolated as an algorithm with the best performance in relation to other algorithms evaluated. Cost sensitive classification was used as an additional methodology to enhance accuracy. ADTree selected eight key parameters that most influence the outcome of intra-hospital treatment: systolic blood pressure on admission, left ventricular ejection fraction, stroke volume of the left ventricle, troponin, creatine phosphokinase, total bilirubin, T wave and the result of the intervention. The performance of the developed model are: the accuracy of the prediction is 93.17%, ROC 0.94. The developed model kept its performance in prospective validation: accuracy of prediction 90.75%, ROC 0.93. Widely used GRACE score achieved ROC = 0.86 in the prospective study patients, indicating that developed predictive model is superior to him. Conclusion: Developed predictive model is simple and reliable. Its implementation in everyday clinical practice, would allow clinicians to distinguish high-risk patients after reperfusion treatment, and then for them to intensify treatment and clinical follow-up, with an aim of reducing the incidence of intra-hospital complications and increase their survival.</p>

Contexte L’occlusion d’une artère du cœur cause un syndrome coronarien aigu (SCA) soit avec une élévation du segment ST (IAMEST) ou sans élévation du segment ST (1). Le traitement des patients avec un IAMEST requiert soit une intervention coronarienne d’urgence (ICP primaire) ou une thérapie fibrinolytique (FL). La thérapie FL peut être administrée soit dans un contexte pré-hospitalier (PHL) ou à l’hôpital. Une prise en charge précoce des patients avec SCA peut être améliorée par un simple indice de risque. Objectifs Les objectifs de cette thèse étaient de : 1) comparer l’ICP primaire et la thérapie FL (2); décrire plusieurs systèmes internationaux de PHL; (3) développer et valider un indice de risque simplifié pour une stratification précoce des patients avec SCA. Méthodes Nous complétons des méta-analyses, de type hiérarchique Bayésiennes portant sur l’effet de la randomisation, d’études randomisées et observationnelles; complétons également un sondage sur des systèmes internationaux de PHL; développons et validons un nouvel indice de risque pour ACS (le C-ACS). Résultats Dans les études observationnelles, l’ICP primaire, comparée à la thérapie FL, est associée à une plus grande réduction de la mortalité à court-terme; mais ce sans bénéfices concluants à long terme. La FL pré-hospitalière peut être administrée par des professionnels de la santé possédant diverses expertises. Le C-ACS a des bonnes propriétés discriminatoires et pourrait être utilisé dans la stratification des patients avec SCA. Conclusion Nous avons comblé plusieurs lacunes importantes au niveau de la connaissance actuelle. Cette thèse de doctorat contribuera à améliorer l’accès à des soins de qualité élevée pour les patients ayant un SCA. / Background Acute occlusion of an artery of the heart results in acute coronary syndromes (ACS), either with ST-segment elevation (STEMI) or without ST-segment elevation (1). STEMI requires urgent treatment to restore coronary artery flow either by primary percutaneous coronary intervention (PCI) or fibrinolytic therapy (FL) (2). Although several randomized controlled trials (RCTs) demonstrate the superiority of primary PCI in reducing mortality compared to FL (2), the benefit of primary PCI over FL remains uncertain in unselected “real-life” patients (3,4). FL can be administered either in the pre-hospital setting (i.e., pre-hospital FL (PHL)) or at the hospital. PHL is rarely available outside Europe (5,6). Insights into the organization of PHL systems of care may promote more widespread use of PHL. Risk stratification of ACS patients should be prompt to ensure timely PCI for high-risk patients and to avoid unnecessary intervention in low-risk patients (7). Despite the availability of numerous ACS risk scores, there is still no simple risk score that can be easily applied in the initial management of ACS patients (8). Objectives The objectives of this doctoral dissertation were to address these current knowledge gaps in the optimal management of ACS. The objectives were to: 1) evaluate the efficacy, effectiveness, and safety of primary PCI and FL, (2) describe the infrastructure, processes and outcomes of several international PHL systems; and (3) develop and validate a novel clinical risk score for early risk stratification of ACS patients. Methods To address these objectives, I completed Bayesian hierarchical random-effects meta-analyses of published RCTs and observational studies which compare primary PCI and FL in patients with STEMI. I undertook a survey of the infrastructure, processes and outcomes of PHL in several European and North American pre-hospital emergency systems. Finally, I developed and validated an ACS risk score called the Canadian ACS (C-ACS). Results Primary PCI was superior to FL in reducing short-term mortality in RCTs and observational studies. However, the long-term survival benefit of primary PCI was noted only in RCTs, and not in the observational studies. PHL can be effectively delivered by health care professionals with variable levels of expertise. The new risk score, C-ACS, has good discriminant properties for short- and long-term mortality in patients with ACS. Conclusions The first manuscript of this dissertation has been recognized as one of the most valuable recent publications in STEMI management and has contributed to reorganization of STEMI care in Ontario. The other two manuscripts in this dissertation provide practical information and tools for health professionals caring for patients with ACS. In summary, this doctoral dissertation has and will continue to contribute to improve access to high quality care for patients with ACS.

Introdução. A intervenção coronária percutânea (ICP) é um dos tratamentos para pacientes com doença arterial coronária (DAC). Essa intervenção deve ser acompanhada de outras medidas terapêuticas com o intuito de reduzir as incapacidades e o risco de novos eventos coronários; de controlar a progressão da doença; e de melhorar a qualidade de vida. Essas medidas compreendem a prevenção secundária da DAC e estão, principalmente, relacionadas às mudanças no estilo de vida para o manejo de fatores de risco para DAC. O contato por telefone tem sido utilizado por profissionais da área da saúde para o seguimento do paciente e da família no cuidado com diversas condições crônicas, incluindo a DAC. Objetivo. Desenvolver, implementar e avaliar um programa educativo com seguimento por telefone, durante o período de quatro meses após a alta hospitalar, para pacientes submetidos à ICP com o objetivo de melhorar o estado de saúde percebido, a autoeficácia, a adesão aos medicamentos e o estado emocional desses pacientes, bem como comparar desfechos do Programa Educativo com os de serviços de rotina hospitalar. Método. Ensaio clínico controlado e aleatorizado, realizado no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto. A amostra deste estudo foi constituída pelos pacientes submetidos à primeira ICP, entre agosto de 2011 e junho de 2012. Os participantes foram aleatorizados para o Programa Educativo com Seguimento por Telefone (grupo intervenção [GI]: 30 participantes) ou cuidado conforme a rotina da instituição (grupo controle [GC]: 30 participantes). O referencial teórico que fundamentou o Programa Educativo aplicado neste estudo foi o construto de autoeficácia, presente na Teoria Social Cognitiva de Albert Bandura. O desfecho principal foi o estado de saúde percebido, avaliado pelo Medical Outcomes Survey 36- Item Short Form (SF-36), e os desfechos secundários foram a autoeficácia avaliada pela Escala de Autoeficácia Geral Percebida, a adesão aos medicamentos por meio do instrumento Medida de Adesão aos Tratamentos (MAT) e o estado emocional (ansiedade e depressão) avaliado pela Escala Hospitalar de Ansiedade e Depressão (HADS). Os desfechos foram avaliados antes do procedimento (T0) e seis meses após a ICP (T1). A análise foi por análise descritiva, análise de variância para medidas repetidas, teste de Qui-quadrado e risco relativo com intervalo de confiança de 95%. O nível de significância foi de 0,05. Este ensaio clínico foi registrado sob o número NCT01341093. Resultados. Na avaliação do estado de saúde percebido, com um nível de significância de 0,05, nenhuma interação (tempo e grupo) ou grupo foi estaticamente significante, mas houve interação entre tempo e grupo com valores de nível de significância entre 0,05 e 0,10 no Sumário do Componente Mental (p=0,08) e no domínio Aspectos Emocionais (p=0,07) e melhora no domínio Aspectos Sociais no GI (p=0,10). Na avaliação da autoeficácia, não houve diferenças entre os grupos ou tempos. Houve alta percentagem de participantes que relataram adesão aos medicamentos nos tempos T0 e T1, nos dois grupos (mais de 90% inicial e no seguimento). Na avaliação da ansiedade, seis meses após a ICP, houve aumento de não-caso de ansiedade no GI e diminuição no GC, e a associação entre as variáveis foi estatisticamente significante (p=0,04). Ao final do seguimento, o risco relativo do GI de ser não-caso de ansiedade foi de 1,6 (intervalo de confiança [IC] de 95%=1,0 a 2,4) quando comparado com o GC. Em relação à depressão, não houve evidência de diferenças no percentual de pacientes não- caso de depressão entre os grupos (GI e GC), tanto na internação como no seguimento. Ao final do seguimento, o risco relativo do GI de ser não-caso de depressão foi de 0,8 (intervalo de confiança [IC] de 95%=0,6 a 1,1), quando comparado com o GC. Conclusão. O Programa Educativo com Seguimento por Telefone é uma intervenção promissora para melhorar o estado de saúde percebido e para reduzir a ansiedade de pacientes submetidos à ICP. Pode ser necessário aperfeiçoar a intervenção para que haja efeitos na autoeficácia e na depressão. Os instrumentos para medidas de autoeficácia e de adesão aos medicamentos precisam ser melhorados / Introduction. Percutaneous coronary intervention (PCI) is one of the treatments available for coronary artery disease (CAD) patients. This intervention should be accompanied by other therapeutic interventions with the aim of reducing disabilities and the risk of new coronary events, controlling the progression of the disease, and improving the quality of life. These interventions comprise the secondary prevention of CAD and are mainly related to lifestyle changes, aiming to manage risk factors for CAD. Health professionals have used telephone follow-up to monitor patients and families in the delivery of care to different chronic conditions, including CAD. Objective. To develop, to implement and to assess an educational program with telephone follow-up, during four months after hospital discharge, for patients submitted to PCI, with the aim of improving the perceived health status, self-efficacy, medication adherence and emotional status of these patients, as well as to compare outcomes of the Educational Program with routine hospital services. Method. Randomized controlled clinical trial, developed at the Ribeirão Preto Medical School Hospital das Clínicas, Brazil. The study sample included patients who had been submitted to their first PCI between August 2011 and June 2012. The participants were randomly assigned to the Educational Program with Telephone Follow-up (intervention group [IG]: 30 participants) and routine care (control group [CG]: 30 participants). The theoretical framework that supported the Educational Program applied in this study was the self-efficacy construct in Albert Bandura\'s Social Cognitive Theory. The main outcome was the perceived health status, assessed using the Medical Outcomes Survey 36- Item Short Form (SF-36); and the secondary outcomes were self-efficacy, assessed using the Perceived General Self-Efficacy Scale; medication adherence, assessed using the Medida de Adesão ao Tratamento (MAT); and the emotional status (anxiety and depression), assessed using the Hospital Anxiety and Depression Scale (HADS). The outcomes were evaluated before the procedure (T0) and six months after the PCI (T1). Descriptive analysis was applied, as well as variance analysis for repeated measures, the chi-square test and relative risk, with the confidence interval set at 95%. Significance was set at 0.05. This clinical trial was registered under number NCT01341093. Results. In the assessment of the perceived health status, with significance set at 0.05, no interaction (time and group) or group was statistically significant, but interaction between time and group was verified, with significance levels ranging between 0.05 and 0.10 in the Mental Component Summary (p=0.08) and in the Emotional Aspects domain (p=0.07); as well as improvement in the Social Aspects domain for the IG (p=0.10). In the assessment of self-efficacy, no differences were found between the groups or times. Many participants indicated medication adherence at T0 and T1 in the two groups (more than 90% initially and during the follow-up). In the assessment of anxiety levels six months after the PCI, the number of non-cases of anxiety increased in IG and dropped in CG, with a statistically significant association between the variables (p=0.04). At the end of the monitoring, the relative risk of being a non-case of anxiety in IG corresponded to 1.6 (95% confidence interval [CI]=1.0 - 2.4) when compared to CG. As regards depression, no evidence was found of differences in the percentage of patients non-case of depression between the groups (IG and CG), neither during hospitalization nor during follow-up. At the end of the follow-up, the relative risk of IG being a non-case of depression corresponded to 0.8 (95% confidence interval [CI]= 0.6 - 1.1) when compared to CG. Conclusion. The Educational Program with Telephone Follow-up is a promising intervention to improve the perceived health status and reduce the anxiety of patients submitted to PCI. The intervention may need further development to influence self-efficacy and depression. Self-efficacy and medication adherence instruments need improvements

Contexte L’occlusion d’une artère du cœur cause un syndrome coronarien aigu (SCA) soit avec une élévation du segment ST (IAMEST) ou sans élévation du segment ST (1). Le traitement des patients avec un IAMEST requiert soit une intervention coronarienne d’urgence (ICP primaire) ou une thérapie fibrinolytique (FL). La thérapie FL peut être administrée soit dans un contexte pré-hospitalier (PHL) ou à l’hôpital. Une prise en charge précoce des patients avec SCA peut être améliorée par un simple indice de risque. Objectifs Les objectifs de cette thèse étaient de : 1) comparer l’ICP primaire et la thérapie FL (2); décrire plusieurs systèmes internationaux de PHL; (3) développer et valider un indice de risque simplifié pour une stratification précoce des patients avec SCA. Méthodes Nous complétons des méta-analyses, de type hiérarchique Bayésiennes portant sur l’effet de la randomisation, d’études randomisées et observationnelles; complétons également un sondage sur des systèmes internationaux de PHL; développons et validons un nouvel indice de risque pour ACS (le C-ACS). Résultats Dans les études observationnelles, l’ICP primaire, comparée à la thérapie FL, est associée à une plus grande réduction de la mortalité à court-terme; mais ce sans bénéfices concluants à long terme. La FL pré-hospitalière peut être administrée par des professionnels de la santé possédant diverses expertises. Le C-ACS a des bonnes propriétés discriminatoires et pourrait être utilisé dans la stratification des patients avec SCA. Conclusion Nous avons comblé plusieurs lacunes importantes au niveau de la connaissance actuelle. Cette thèse de doctorat contribuera à améliorer l’accès à des soins de qualité élevée pour les patients ayant un SCA. / Background Acute occlusion of an artery of the heart results in acute coronary syndromes (ACS), either with ST-segment elevation (STEMI) or without ST-segment elevation (1). STEMI requires urgent treatment to restore coronary artery flow either by primary percutaneous coronary intervention (PCI) or fibrinolytic therapy (FL) (2). Although several randomized controlled trials (RCTs) demonstrate the superiority of primary PCI in reducing mortality compared to FL (2), the benefit of primary PCI over FL remains uncertain in unselected “real-life” patients (3,4). FL can be administered either in the pre-hospital setting (i.e., pre-hospital FL (PHL)) or at the hospital. PHL is rarely available outside Europe (5,6). Insights into the organization of PHL systems of care may promote more widespread use of PHL. Risk stratification of ACS patients should be prompt to ensure timely PCI for high-risk patients and to avoid unnecessary intervention in low-risk patients (7). Despite the availability of numerous ACS risk scores, there is still no simple risk score that can be easily applied in the initial management of ACS patients (8). Objectives The objectives of this doctoral dissertation were to address these current knowledge gaps in the optimal management of ACS. The objectives were to: 1) evaluate the efficacy, effectiveness, and safety of primary PCI and FL, (2) describe the infrastructure, processes and outcomes of several international PHL systems; and (3) develop and validate a novel clinical risk score for early risk stratification of ACS patients. Methods To address these objectives, I completed Bayesian hierarchical random-effects meta-analyses of published RCTs and observational studies which compare primary PCI and FL in patients with STEMI. I undertook a survey of the infrastructure, processes and outcomes of PHL in several European and North American pre-hospital emergency systems. Finally, I developed and validated an ACS risk score called the Canadian ACS (C-ACS). Results Primary PCI was superior to FL in reducing short-term mortality in RCTs and observational studies. However, the long-term survival benefit of primary PCI was noted only in RCTs, and not in the observational studies. PHL can be effectively delivered by health care professionals with variable levels of expertise. The new risk score, C-ACS, has good discriminant properties for short- and long-term mortality in patients with ACS. Conclusions The first manuscript of this dissertation has been recognized as one of the most valuable recent publications in STEMI management and has contributed to reorganization of STEMI care in Ontario. The other two manuscripts in this dissertation provide practical information and tools for health professionals caring for patients with ACS. In summary, this doctoral dissertation has and will continue to contribute to improve access to high quality care for patients with ACS.

Introdução. A intervenção coronária percutânea (ICP) é um dos tratamentos para pacientes com doença arterial coronária (DAC). Essa intervenção deve ser acompanhada de outras medidas terapêuticas com o intuito de reduzir as incapacidades e o risco de novos eventos coronários; de controlar a progressão da doença; e de melhorar a qualidade de vida. Essas medidas compreendem a prevenção secundária da DAC e estão, principalmente, relacionadas às mudanças no estilo de vida para o manejo de fatores de risco para DAC. O contato por telefone tem sido utilizado por profissionais da área da saúde para o seguimento do paciente e da família no cuidado com diversas condições crônicas, incluindo a DAC. Objetivo. Desenvolver, implementar e avaliar um programa educativo com seguimento por telefone, durante o período de quatro meses após a alta hospitalar, para pacientes submetidos à ICP com o objetivo de melhorar o estado de saúde percebido, a autoeficácia, a adesão aos medicamentos e o estado emocional desses pacientes, bem como comparar desfechos do Programa Educativo com os de serviços de rotina hospitalar. Método. Ensaio clínico controlado e aleatorizado, realizado no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto. A amostra deste estudo foi constituída pelos pacientes submetidos à primeira ICP, entre agosto de 2011 e junho de 2012. Os participantes foram aleatorizados para o Programa Educativo com Seguimento por Telefone (grupo intervenção [GI]: 30 participantes) ou cuidado conforme a rotina da instituição (grupo controle [GC]: 30 participantes). O referencial teórico que fundamentou o Programa Educativo aplicado neste estudo foi o construto de autoeficácia, presente na Teoria Social Cognitiva de Albert Bandura. O desfecho principal foi o estado de saúde percebido, avaliado pelo Medical Outcomes Survey 36- Item Short Form (SF-36), e os desfechos secundários foram a autoeficácia avaliada pela Escala de Autoeficácia Geral Percebida, a adesão aos medicamentos por meio do instrumento Medida de Adesão aos Tratamentos (MAT) e o estado emocional (ansiedade e depressão) avaliado pela Escala Hospitalar de Ansiedade e Depressão (HADS). Os desfechos foram avaliados antes do procedimento (T0) e seis meses após a ICP (T1). A análise foi por análise descritiva, análise de variância para medidas repetidas, teste de Qui-quadrado e risco relativo com intervalo de confiança de 95%. O nível de significância foi de 0,05. Este ensaio clínico foi registrado sob o número NCT01341093. Resultados. Na avaliação do estado de saúde percebido, com um nível de significância de 0,05, nenhuma interação (tempo e grupo) ou grupo foi estaticamente significante, mas houve interação entre tempo e grupo com valores de nível de significância entre 0,05 e 0,10 no Sumário do Componente Mental (p=0,08) e no domínio Aspectos Emocionais (p=0,07) e melhora no domínio Aspectos Sociais no GI (p=0,10). Na avaliação da autoeficácia, não houve diferenças entre os grupos ou tempos. Houve alta percentagem de participantes que relataram adesão aos medicamentos nos tempos T0 e T1, nos dois grupos (mais de 90% inicial e no seguimento). Na avaliação da ansiedade, seis meses após a ICP, houve aumento de não-caso de ansiedade no GI e diminuição no GC, e a associação entre as variáveis foi estatisticamente significante (p=0,04). Ao final do seguimento, o risco relativo do GI de ser não-caso de ansiedade foi de 1,6 (intervalo de confiança [IC] de 95%=1,0 a 2,4) quando comparado com o GC. Em relação à depressão, não houve evidência de diferenças no percentual de pacientes não- caso de depressão entre os grupos (GI e GC), tanto na internação como no seguimento. Ao final do seguimento, o risco relativo do GI de ser não-caso de depressão foi de 0,8 (intervalo de confiança [IC] de 95%=0,6 a 1,1), quando comparado com o GC. Conclusão. O Programa Educativo com Seguimento por Telefone é uma intervenção promissora para melhorar o estado de saúde percebido e para reduzir a ansiedade de pacientes submetidos à ICP. Pode ser necessário aperfeiçoar a intervenção para que haja efeitos na autoeficácia e na depressão. Os instrumentos para medidas de autoeficácia e de adesão aos medicamentos precisam ser melhorados / Introduction. Percutaneous coronary intervention (PCI) is one of the treatments available for coronary artery disease (CAD) patients. This intervention should be accompanied by other therapeutic interventions with the aim of reducing disabilities and the risk of new coronary events, controlling the progression of the disease, and improving the quality of life. These interventions comprise the secondary prevention of CAD and are mainly related to lifestyle changes, aiming to manage risk factors for CAD. Health professionals have used telephone follow-up to monitor patients and families in the delivery of care to different chronic conditions, including CAD. Objective. To develop, to implement and to assess an educational program with telephone follow-up, during four months after hospital discharge, for patients submitted to PCI, with the aim of improving the perceived health status, self-efficacy, medication adherence and emotional status of these patients, as well as to compare outcomes of the Educational Program with routine hospital services. Method. Randomized controlled clinical trial, developed at the Ribeirão Preto Medical School Hospital das Clínicas, Brazil. The study sample included patients who had been submitted to their first PCI between August 2011 and June 2012. The participants were randomly assigned to the Educational Program with Telephone Follow-up (intervention group [IG]: 30 participants) and routine care (control group [CG]: 30 participants). The theoretical framework that supported the Educational Program applied in this study was the self-efficacy construct in Albert Bandura\'s Social Cognitive Theory. The main outcome was the perceived health status, assessed using the Medical Outcomes Survey 36- Item Short Form (SF-36); and the secondary outcomes were self-efficacy, assessed using the Perceived General Self-Efficacy Scale; medication adherence, assessed using the Medida de Adesão ao Tratamento (MAT); and the emotional status (anxiety and depression), assessed using the Hospital Anxiety and Depression Scale (HADS). The outcomes were evaluated before the procedure (T0) and six months after the PCI (T1). Descriptive analysis was applied, as well as variance analysis for repeated measures, the chi-square test and relative risk, with the confidence interval set at 95%. Significance was set at 0.05. This clinical trial was registered under number NCT01341093. Results. In the assessment of the perceived health status, with significance set at 0.05, no interaction (time and group) or group was statistically significant, but interaction between time and group was verified, with significance levels ranging between 0.05 and 0.10 in the Mental Component Summary (p=0.08) and in the Emotional Aspects domain (p=0.07); as well as improvement in the Social Aspects domain for the IG (p=0.10). In the assessment of self-efficacy, no differences were found between the groups or times. Many participants indicated medication adherence at T0 and T1 in the two groups (more than 90% initially and during the follow-up). In the assessment of anxiety levels six months after the PCI, the number of non-cases of anxiety increased in IG and dropped in CG, with a statistically significant association between the variables (p=0.04). At the end of the monitoring, the relative risk of being a non-case of anxiety in IG corresponded to 1.6 (95% confidence interval [CI]=1.0 - 2.4) when compared to CG. As regards depression, no evidence was found of differences in the percentage of patients non-case of depression between the groups (IG and CG), neither during hospitalization nor during follow-up. At the end of the follow-up, the relative risk of IG being a non-case of depression corresponded to 0.8 (95% confidence interval [CI]= 0.6 - 1.1) when compared to CG. Conclusion. The Educational Program with Telephone Follow-up is a promising intervention to improve the perceived health status and reduce the anxiety of patients submitted to PCI. The intervention may need further development to influence self-efficacy and depression. Self-efficacy and medication adherence instruments need improvements

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<p>Ishemijska bolest srca najče&scaron;će nastaje kao posledica razvoja aterosklerotskih promena na koronarnim krvnim sudovima koji dovode do suženja lumena i posledičnog pada protoka arterijske krvi u području vaskularizacije. Akutni oblik koronarne bolesti koji zahteva hitnu primenu reperfuzione terapije je ST elevirani infarkt miokarda. EKG ima veliki značaj u postavljanju dijagnoze ali i u proceni uspe&scaron;nosti same reperfuzije. &Scaron;irina QRS kompleksa jedan je od EKG parametara čija dinamika promena može ukazati na uspe&scaron;nost pPKI i veličinu infarktne zone. Evaluacija &scaron;irine QRS kompleksa kao prediktora veličine infarkta miokarda i reperfuzije nakon pPKI kod pacijenata sa STEMI. Ispitivanje je sprovedeno kao prospektivna, opservaciona klinička studija na Klinici za kardiologiju, Instituta za kardiovaskularne bolesti Vojvodine u periodu od januara 2016. do decembra 2018. godine. U isptivanje je uključeno 200 pacijenata sa STEMI kod kojih je urađena pPKI. Na osnovu dužine trajanja tegoba formirane su dve grupe od po 100 pacijenata. Grupa A kod kojih je totalno ishemijsko vreme bilo &lt;6h i grupa B kod kojih je totalno ishemijsko vreme između 6 i 12h. . Sprovedeno je EKG praćenje radi procene &scaron;irine QRS kompleksa intrahospitalno (pre procedure, odmah nakon pPKI kao i posle 1h i 72h) i na dve vizite ambulantno tokom &scaron;estomesečnog praćenja (nakon mesec dana i &scaron;est meseci). Ehokardiografija je urađena kod svih pacijenata intrahospitalno i na &scaron;estomesečnom ambulantnom pregledu. &Scaron;irine QRS kompleksa su korelirane sa rezultatima interventne procedure procenjene TIMI protokom i TMPG, dinamikom kardiospecifičnih enzima i ehokardiografskim nalazima. U istraživanje je uključeno 71% mu&scaron;karaca i 29% žena, prosečna starost uzorka iznosila je 60.6&plusmn;11.39. Dužina trajanja tegoba značajno se razlikovala između grupa. U grupi A tegobe su trajale prosečno 120 minuta (90-180), dok su u grupi B trajale 420 minuta (360-600) (p&lt;0.0005). DTB nije se značajno razlikovao, 42 minuta (31-54.5) u odnosu na 40.5 minuta (34.5-55) (p=0.818). Prosečna &scaron;irina QRS kompeksa na EKG-u pre pPKI nije se značajno razlikovala između grupa, 100 msec (90-110) u odnosu na 100 msec (93-110) (p=0.308). Nakon reperfuzije uočena je značajna razlika u &scaron;irini QRS kompleksa između grupa na svim intrahospitalnim kao i EKG-ima načinjenim tokom perioda praćenja. QRS kompleks je &scaron;iri kod pacijenata iz grupe B (p&lt;0.0005). Pacijenti iz grupe A koji su imali prohodnu infarktnu arteriju sa TIMI 3 protokom pre implantacije stenta imali su značajno uži QRS kompleks na incijilanom EKG-u u odnosu na pacijente kod kojih je IRA bila sub/okludirana sa TIMI protokom &le;2 (p=0.001). U grupi B prohodna infarktna arterija sa TIMI 3 protokom nije značajno uticala na &scaron;irinu QRS kompleksa na inicijalnom EKG-u (p=0.144). Na EKG-ima nakon procedure QRS kompleks bio je značajno &scaron;iri kod pacijenata kod kojih je TIMI protok &le;2, ali samo za grupu pacijenata koja se javila unutar 6h od početka tegoba (p=0.001). QRS kompleks kod pacijenata koji su se javili nakon 6h od početka tegoba jeste bio uži, ali bez statistički značajne razlike (p=0.336). Pearsonovim testom registrovano je postojanje negativne korelacije &scaron;irine QRS kompleksa i istisne frakcije leve komore, ali i pozitivne korelacije sa WMSI i indeksiranim end sistolnim i end dijastolnim volumenom. ROC analizom pokazano je da ukoliko je QRS kompleks &scaron;iri od 89 msec nakon mesec dana, 8.5 puta je veći rizik od snižene EF na &scaron;estomesečnoj kontroli (p&lt;0.0005, AUC=0.808, cut-off=89msec.). ROC analiza pokazala je i da ukoliko je QRS kompleks &scaron;iri od 99msec 1h nakon procedure, 5 puta je veći rizik od pojave MACE (p&lt;0.0005, AUC=0.744, cut-off=99msec). Izvedena su dva matematička modela zasnovana na &scaron;irini QRS kompleksa koja vr&scaron;e predikciju snižene EF i pojave MACE tokom perioda praćenja. &Scaron;irina QRS kompleksa je pokazatelj reperfuzije kod pacijenata sa STEMI kod kojih se načini revaskularizacija unutar 6h od nastanka tegoba. &Scaron;irina QRS kompleksa mesec dana nakon STEMI predstavlja nezavisni prediktor snižene EF. Pro&scaron;irenje preko 89msec 8.5 povećava rizik od snižene EF. &Scaron;irina QRS kompleksa jedan sat nakon pPKI predstavlja nezavisni prediktor za MACE. Pro&scaron;irenje preko 99msec 5 puta povećava rizik od neželjenog kardiolo&scaron;kog događaja. Izvedena su dva matematička modela koja koriste &scaron;irinu QRS kompleksa i sa visokom precizno&scaron;ću vr&scaron;e predikciju MACE-a, odnosno snižene EF nakon &scaron;est meseci.&nbsp;</p> / <p>Ischemic heart disease most commonly occurs as a result of the atherosclerotic changes in the coronary vessels that lead to the narrowing of the lumen and consequent fall in arterial blood flow in the vascularization area. An acute form of coronary artery disease requiring immediate reperfusion therapy is ST-elevation myocardial infarction. The ECG is of great importance not only in making the diagnosis but also in evaluating the success of the reperfusion itself. The duration of the QRS complex is one of the ECG parameters whose change in dynamics can indicate the success of pPCI as well as the size of the infarct zone. Evaluation of the width of the QRS complex as a predictor of myocardial infarction size and reperfusion after pPCI in patients with STEMI. The study was conducted as a prospective, observational clinical study at the Cardiology Clinic of the Institute of Cardiovascular Diseases of Vojvodina between January 2016 and December 2018. The study included 200 patients with STEMI in whom pPCI was performed. Based on the length of discomforts two groups with 100 patients were formed. Group A had a total ischemic time &lt;6h and the total ischemic time in group B was between 6-12h. To assess the duration of the QRS complex, the ECG monitoring was performed intrahospital (before the procedure, immediately after pPCI as well as 1h and 72h after the procedure) and on two outpatient visits during the six-month follow-up period (after one month and six months). Echocardiography was performed in all patients intrahospital and at a six-month outpatient visit. The duration of the QRS complex correlated with the results of the interventional procedure that was evaluated by the TIMI flow and TMPG, the dynamics of cardiospecific enzymes and echocardiography findings. The survey included 71% of men and 29% of women with an average age of 60.6 &plusmn; 11.39. The duration of the discomforts varied significantly between the groups. In group A the discomforts lasted 120 minutes in an average (90-180), while they lasted 420 minutes in group B (360-600) (p &lt;0.0005). DTB did not differ significantly, 42 minutes (31-54.5) versus 40.5 minutes (34.5-55) (p = 0.818). The average duration of the QRS complex on the ECG before pPCI did not differ significantly between the groups, 100 msec (90-110) versus 100 msec (93-110) (p = 0.308). After the reperfusion, a significant difference in the duration of the QRS complex was observed between the groups at all intrahospital ECGs and the ECGs performed during the follow-up period. The QRS complex was broader in group B patients (p &lt;0.0005). Group A patients who had a patent infarct artery with TIMI 3 flow before the stent implantation had a significantly narrower QRS complex on the initial ECG compared to the patients whose IRA was sub / occluded with TIMI flow &le;2 (p = 0.001). In group B, the patent infarct artery with TIMI 3 flow did not significantly affect the duration of the QRS complex at the initial ECG. (p = 0.144). At the post-procedural ECGs the QRS complex was significantly broader in patients with TIMI flow &le;2, but only in the group of patients who arrived within 6 h from the onset of discomforts (p = 0.001). The QRS complex in patients who arrived 6 h after the onset of discomforts was narrower but without statistically significant difference (p = 0.336). The Pearson test registered the existence of a negative correlation of the QRS complex width and the left ventricular ejection fraction, but also a positive correlation with the WMSI and index end-systolic and end-diastolic volumes. The ROC analysis showed that if the QRS complex was wider than 89 msec after one month, there was an 8.5 times higher risk of decreased EF at the six-month control examination (p &lt;0.0005, AUC = 0.808, cut-off = 89msec.). The ROC analysis also showed that if the QRS complex was wider than 99msec 1h after the procedure, there was a 5 times higher risk of MACE (p &lt;0.0005, AUC = 0.744, cut-off = 99msec). Two mathematical models based on the width of the QRS complex were derived that predicted the lowered EF and the occurrence of MACE during the monitored period. The width of the QRS complex is an indicator of reperfusion in patients with STEMI who undergo revascularization within 6 hours from the onset of discomforts. The width of the QRS complex one month after STEMI is an independent predictor of decreased EF. Broadening over 89msec increases the risk of lowered EF for 8.5 times. The width of the QRS complex one hour after pPCI represents an independent predictor of MACE. Broadening over 99msec increases the risk of an adverse cardiac event 5 times. Two mathematical models have derived that use the width of the QRS complex and predict MACE with high precision as well as reduced EF after six months.</p>

Il y a plus de 40 ans, la cardiologie interventionnelle a vu le jour et n’a cessé de révolutionner la prise en charge de l’athérosclérose coronarienne. Les endoprothèses vasculaires biorésorbables (BVS) avaient été conçues pour pallier les risques liés à la présence permanente de tuteurs métalliques dans les artères. En principe, ils fournissent de manière transitoire un soutien mécanique pour le scellement des dissections et la prévention du vasospasme et du remodelage constrictif en plus d’une élution médicamenteuse avant de se résorber et restaurer la vasomotricité coronarienne. L’enthousiasme autour des endoprothèses biorésorbables ABSORB™ était mitigé par un risque soutenu de thrombose du tuteur. Ce mémoire traitera en premier lieu des bases moléculaires de l’athérosclérose. Il abordera ensuite la prise en charge de la coronaropathie athérosclérotique ainsi que l’histoire de la cardiologie interventionnelle et ses différentes révolutions. Ensuite, deux études cliniques ont été conduites dans le cadre de ce travail et seront présentées. La première étude évalue le rôle du BVS dans la revascularisation de la coronaropathie extensive (multivaisseaux ou diffuse) et a montré que, dans un contexte aussi peu favorable au déploiement d’un tuteur coronarien, ABSORB™ a présenté des résultats cliniques acceptables à très long terme comparativement aux tuteurs métalliques de deuxième génération. La deuxième étude s’intéresse quant à elle aux caractéristiques angiographiques de resténose des BVS. Elle a démontré qu’à long terme, la resténose des BVS devient de plus en plus diffuse, et était associée à des issues cliniques moins favorables. Le dernier chapitre de ce mémoire se constitue d’une ouverture conclusive présentant les différentes endoprothèses biorésorbables actuellement à l’étude ou en cours de développement en soulignant leurs principales différences avec ABSORB™. / More than 40 years ago, interventional cardiology was born and has continued to revolutionize the management of coronary atherosclerosis. Bioresorbable Vascular Scaffolds (BVS) were designed to alleviate the risks associated with the permanent presence of metal stents in the arteries. In theory, they provide a transient mechanical support for sealing dissections and preventing vasospasm and constrictive remodeling in addition to a drug-eluting function before complete bioresorption and restoration of coronary vasomotion. Enthusiasm around the ABSORB™ bioresorbable scaffold was mitigated by a sustained risk of scaffold thrombosis. This thesis will first review the molecular basis of atherosclerosis. It will then discuss the management of atherosclerotic coronary artery disease, the history of interventional cardiology and its multiple revolutions. Then, two clinical studies that were conducted as part of this work will be presented. The first study that evaluates the role of BVS in the revascularization of extensive coronary artery disease (multivessel or diffuse) showed that, in such an unfavorable context for the deployment of a coronary stent, ABSORB™ has shown acceptable clinical results in the very long term compared to second generation drug-eluting stents. The second study focuses on the angiographic patterns of BVS restenosis. It showed that in the long term, the pattern of restenosis tended to be more diffuse than focal and that restenosis was associated with less favorable clinical outcomes. The final chapter of this thesis presents the different bioresorbable scaffolds currently under study or under development while highlighting their main differences with ABSORB™.