Search

The history of interventional cardiology has been marked by several technologic revolutions since the late 1970s. The first key step was the use of inflatable balloon angioplasty as an alternative to CABG surgery for coronary revascularization, followed by intracoronary delivery of bare metal stent (BMS) and drug eluting stents (DES) to drastically reduce intracoronary restenosis observed with BMS. Improved stents platforms and polymers (absorbable or biocompatible) led to a dramatic reduction in the rate of late stent thrombosis. Self-expanding stents are now available to improve stent a position especially in acute myocardial infarction. The emergence of new fully bioabsorbable stents that can be combined with antiproliferative drugs is the ongoing revolution. A new generation of stents is continuously improving and likely to become the ideal stent for coronary revascularization in the near future.

Platelet P2YI2 receptor inhibition with clopidogrel, prasugrel or ticagrelor plays a key role to prevent recurrent ischaemic events after percutaneous coronary intervention in acute coronary syndromes or elective settings. The degree of platelet inhibition depends on the antiplatelet medication used and is influenced by clinical and genetic factors. A concept of therapeutic window exists. On one side, efficient anti-aggregation is required in order to reduce cardio-vascular events. On the other side, an excessive platelet inhibition represents a risk of bleeding complications. This article describes the current knowledge about some platelet function tests and genetic tests and summarises their role in the clinical practice.

Thienopyridines have become the cornerstone of treatment of percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses. Newly developed P2Y(12) inhibitors are more potent, more predictable and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for high-risk PCI. Four new P2Y(12) inhibitors have been tested each of them having particular individual properties. Prasugrel is an oral prodrug leading to irreversible blockade of the P2Y(12) receptor and is approved worldwide for ACS PCI. Ticagrelor is a direct-acting and reversible inhibitor of the P2Y(12) receptor with potentially more pleiotropic effects. Cangrelor is an intravenous direct and reversible inhibitor of the P2Y(12) receptor providing the highest level of inhibition and elinogrel is an intravenous and oral P2Y(12) antagonist with a direct and reversible action. Both prasugrel and ticagrelor, opposed to clopidogrel, have shown that stronger P2Y(12) inhibition led respectively to significant 19 % and 16 % relative risk reduction of a similar primary endpoint combining cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Both drugs showed a significant 0.6 % absolute excess of TIMI major bleeding not related to CABG surgery. The effect of these new compounds is prompt, predictable and powerful as compared to clopidogrel. Their net benefit is particularly marked in PCI for STEMI patients, in which there is no significant increase in major bleeding when compared with clopidogrel. However, because in clinical trials patients perceived to be at higher risk for bleeding usually are excluded, the risk of major and even fatal bleeding might even be higher in a "real-world" setting i.e. in the elderly patient with comorbidities.

This thesis focused on premature coronary atherosclerosis, the clinical and biological profile of affected individuals, with a pathophysiological approach aiming to assess the contribution of inflammation and vascular age. Studies 1 and 2 described the very high-risk cardiovascular profile of these patients and the factors of poor long-term outcomes. These studies have demonstrated that premature coronary atherosclerosis is a progressive disease with a rapid multi-arterial involvement, leading to a mortality rate of 20% over 10 years. Study 3 demonstrated the significant contribution of subclinical inflammation to the genesis of coronary atherosclerosis in younger individuals, compared with older populations. This observation relied on the use of a new biomarker of chronic inflammation, GlycA, a composite signal of the glycosylation of proteins in the acute phase. Study 4 demonstrated the significant involvement of IL-1β in the post-myocardial infarction inflammatory cascade, and its association with short and long-term death. Study 5 evaluated the stiffness of the aortic root measured by MRI as a new risk marker for premature coronary artery disease, introduction a new tool for an integrative measure of vascular aging. Studies 6 and 7 have highlighted the lack of performance of American and European international guidelines in detecting and treating individuals at high risk of premature atherosclerosis, and the missed opportunities for intensive treatment after a first myocardial infarction. premature., Cette thèse s’est intéressée à la question de l’athérosclérose coronaire prématurée, du profil clinique et biologique des individus qui en sont touchés, avec une approche physiopathologique permettant d’évaluer la contribution de l’inflammation et l’âge vasculaire. Les études 1 et 2 ont décrit le profil cardiovasculaire à très haut risque de ces patients et les facteurs d’évolution péjorative sur le long-terme. Ces études ont démontré que l’athérosclérose coronaire est une maladie évolutive avec une atteinte multi artérielle rapide, menant à un taux de mortalité de 20 % sur 10 ans. L’étude 3 a démontré la contribution importante de l’inflammation infraclinique dans la genèse de l’athérosclérose coronaire chez les individus les plus jeunes, en comparaison avec les populations plus âgées. Cette observation a pu être effectuée grâce à l’utilisation d’un nouveau biomarqueur de l’inflammation chronique le GlycA, signal composite de la glycosylation des protéines de phase aiguë. L’étude 4 a mis en avant l’importante implication de l’ IL-1β dans la cascade inflammatoire post infarctus du myocarde, et son association avec la mortalité à court et long terme. L’étude 5 a évalué la rigidité de la racine de l’aorte mesurée en IRM comme nouveau marqueur de risque de la maladie coronaire prématurée, en ouvrant la voie vers une mesure intégrative du vieillissement vasculaire. Les études 6 et 7 ont mis en évidence la difficulté qu’ont les recommandations internationales américaines et européennes à détecter et traiter les individus à haut risque d’athérosclérose prématurés, et les opportunités manquées de traitement intensif après un premier infarctus du myocarde prématuré.

This thesis suggests that bitherapy with a new oral anticoagulant and clopidogrel should now be the rule in stented patients requiring long-term anticoagulation. This strategy is superior to a triple therapy with a vitamin K antagonist and a dual anti-platelet therapy in reducing the risk of bleeding, with a similar risk of ischemic events. There is no modification effect of lesion/ procedure characteristics and international normalized ratio on the occurrence of clinical endpoints. The benefit of this strategy has been also demonstrated in comparison with a combination of vitamin K antagonist and a single antiplatelet therapy. In an analysis of the ATLAS-ACS TIMI 48 trial, rivaroxaban is associated with a decrease of D-dimers levels, also associated with a reduction of the risk of atherothrombotic events. Beyond this classic marker of thrombosis, the measurement of interleukin-1beta was associated with the occurrence of atherothrombotic events among a cohort of patients with acute myocardial infarction. In this setting and during the acute phase, the choice of the anticoagulant, left to the discretion of the investigator in the ATLANTIC study, was not associated with the occurrence of clinical events. Nevertheless, the assessment of the benefit / risk ratio associated with the use of antithrombotic therapies, conventionally based on the net clinical benefit, can now benefit from more efficient mathematical tools, considering both the reduction of the risk of bleeding and the search for a non-inferiority on the ischemic events, as demonstrated in the bivariate analysis of two pivotal trials or with the use of machine learning., Cette thèse suggère que la bithérapie nouvel anticoagulant oral et clopidogrel doit être la règle chez les patients stentés nécessitant une anticoagulation au long cours. Cette bithérapie est supérieure à une trithérapie comprenant un antagoniste de la vitamine K et une double antiagrégation plaquettaire sur la réduction du risque hémorragique, avec un risque ischémique similaire, sans que la gravité de la maladie coronaire, la complexité de l’angioplastie, ou l’équilibre de l’INR n’interagissent sur ce résultat. Le bénéfice clinique de cette stratégie est aussi démontré en comparaison à une bithérapie comprenant un antagoniste de la vitamine K et une simple antiagrégation plaquettaire. Cette thèse démontre également que l’utilisation du rivaroxaban est associée à une réduction du taux plasmatique de D-Dimères du risque d’évènements athérothrombotiques. Au-delà, des marqueurs classiques de thrombose, la mesure de l’interleukine-1beta au sein d’une cohorte de patient présentant un infarctus, permettait de prédire la survenue d’évènement athérothrombotique. Dans ce contexte, le type d’anticoagulation parentérale, dont le choix était laissé à l’appréciation de l’investigateur dans l’étude ATLANTIC, n’était pas associé à la survenue d’événements cliniques. Néanmoins, l’évaluation de la balance bénéfice/risque des antithrombotiques, classiquement basée sur l’évaluation du bénéfice clinique net, peut désormais tirer bénéfice d’outils mathématiques plus performant prenant en compte à la fois la réduction du risque de saignement et la recherche de non-infériorité sur le critère ischémique, comme démontrée dans l’analyse bivariée ou l’utilisation de machine learning.