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Acute coronary syndrome (ACS) is a continuum of disease that includes non-ST-segment elevation ACS and ST-segment elevation myocardial infarction. The purpose of this article is to define the developing role of ticagrelor in ACS and compare it to currently available P2Y12 receptor inhibitors. While clopidogrel remains the "workhorse" P2Y12 receptor inhibitor for many patients with ACS and prasugrel has an established role in select situations, clinicians must now assimilate the evolving role of ticagrelor. Although ticagrelor offers important advances in the management of ACS (eg, reversibility), there are also notable clinical considerations (eg, unique adverse effects such as dyspnea). Based on the current evidence, we propose an algorithm to aid clinicians in the selection of a P2Y12 receptor inhibitor for patients with ACS in various clinical situations.

O ticagrelor é um novo fármaco destinado para a prevenção de síndromes coronarianas agudas (SCA) caracterizadas pela formação de placas ateroscleróticas que se rompem no interior das artérias. Atua de forma diferenciada na inibição da ação plaquetária, inibindo de forma reversível e não competitiva o receptor P2Y12, o qual atua diretamente na agregação das plaquetas. Este medicamento está registrado no Brasil desde 2011, sob nome comercial de Brilinta®, na forma de comprimidos revestidos de 90 mg, e, até o presente momento, são poucos os estudos publicados a respeito do controle de impurezas e produtos de degradação do fármaco. No presente trabalho foi desenvolvido um método por cromatografia líquida de alta eficiência (CLAE) adaptado para a análise de impurezas orgânicas do ticagrelor. O método por CLAE foi estabelecido utilizando equipamento Agilent 1200 Series, acoplado a detector de arranjo de diodos (DAD) em 270 nm, com coluna cromatográfica Zorbax Plus C8 (150 x 4,6 mm, 5,0 μm), fluxo de 0,7 ml/min, volume de injeção de 20 μl e temperatura constante de 25ºC. A fase móvel foi composta de acetonitrila: acetato de amônio 50 mM (57:43, v/v), pH 8,2. O método demonstrou ser específico, linear, preciso, exato e robusto, sendo adequado para a finalidade a que foi proposto. Além disso, foram elucidados os principais produtos de degradação originados quando as amostras dos comprimidos de ticagrelor em solução foram expostas à radiação UVC por duas horas, com base em um estudo preliminar de estabilidade do mesmo. Os mecanismos envolvidos na degradação fotolítica do ticagrelor também foram propostos. / Ticagrelor is a new drug intended for the prevention of acute coronary syndromes (ACS) characterized by the formation of atherosclerotic plaques that rupture inside the arteries. Ticagrelor reversibly binds to P2Y12 receptor, which acts directly on platelet aggregation. The drug was approved in Brazil in 2011, under the comercial name Brilinta® in the form of coated tablets of 90 mg, and until now has few published studies about the impurities control and degradation products. In this study, it was developed a method by high-performance liquid chromatography (HPLC) for the analysis of organic impurities of ticagrelor. The HPLC method was established using Agilent 1200 Series equipment coupled to photodiode array detector (PDA) at 270 nm with a Zorbax Plus C8 column (150 x 4.6 mm, 5.0 μm), flow rate of 0.7 ml/min, injection volume of 20 μL, and a constant temperature of 25°C. The mobile phase consisted of acetonitrile: ammonium acetate 50 mM (57:43 v/v), pH 8.2. The method demonstrated to be specific, linear, precise, accurate and robust, being suitable for the intended purpose. Besides, the mayor degradation products formed when samples of ticagrelor tablets in solution were exposed to UVC radiation for two hours were elucidated based on a preliminary stability study. The mechanisms involved in photolytic degradation of ticagrelor have also been proposed.

O ticagrelor é um novo fármaco destinado para a prevenção de síndromes coronarianas agudas (SCA) caracterizadas pela formação de placas ateroscleróticas que se rompem no interior das artérias. Atua de forma diferenciada na inibição da ação plaquetária, inibindo de forma reversível e não competitiva o receptor P2Y12, o qual atua diretamente na agregação das plaquetas. Este medicamento está registrado no Brasil desde 2011, sob nome comercial de Brilinta®, na forma de comprimidos revestidos de 90 mg, e, até o presente momento, são poucos os estudos publicados a respeito do controle de impurezas e produtos de degradação do fármaco. No presente trabalho foi desenvolvido um método por cromatografia líquida de alta eficiência (CLAE) adaptado para a análise de impurezas orgânicas do ticagrelor. O método por CLAE foi estabelecido utilizando equipamento Agilent 1200 Series, acoplado a detector de arranjo de diodos (DAD) em 270 nm, com coluna cromatográfica Zorbax Plus C8 (150 x 4,6 mm, 5,0 μm), fluxo de 0,7 ml/min, volume de injeção de 20 μl e temperatura constante de 25ºC. A fase móvel foi composta de acetonitrila: acetato de amônio 50 mM (57:43, v/v), pH 8,2. O método demonstrou ser específico, linear, preciso, exato e robusto, sendo adequado para a finalidade a que foi proposto. Além disso, foram elucidados os principais produtos de degradação originados quando as amostras dos comprimidos de ticagrelor em solução foram expostas à radiação UVC por duas horas, com base em um estudo preliminar de estabilidade do mesmo. Os mecanismos envolvidos na degradação fotolítica do ticagrelor também foram propostos. / Ticagrelor is a new drug intended for the prevention of acute coronary syndromes (ACS) characterized by the formation of atherosclerotic plaques that rupture inside the arteries. Ticagrelor reversibly binds to P2Y12 receptor, which acts directly on platelet aggregation. The drug was approved in Brazil in 2011, under the comercial name Brilinta® in the form of coated tablets of 90 mg, and until now has few published studies about the impurities control and degradation products. In this study, it was developed a method by high-performance liquid chromatography (HPLC) for the analysis of organic impurities of ticagrelor. The HPLC method was established using Agilent 1200 Series equipment coupled to photodiode array detector (PDA) at 270 nm with a Zorbax Plus C8 column (150 x 4.6 mm, 5.0 μm), flow rate of 0.7 ml/min, injection volume of 20 μL, and a constant temperature of 25°C. The mobile phase consisted of acetonitrile: ammonium acetate 50 mM (57:43 v/v), pH 8.2. The method demonstrated to be specific, linear, precise, accurate and robust, being suitable for the intended purpose. Besides, the mayor degradation products formed when samples of ticagrelor tablets in solution were exposed to UVC radiation for two hours were elucidated based on a preliminary stability study. The mechanisms involved in photolytic degradation of ticagrelor have also been proposed.

O ticagrelor é um novo fármaco destinado para a prevenção de síndromes coronarianas agudas (SCA) caracterizadas pela formação de placas ateroscleróticas que se rompem no interior das artérias. Atua de forma diferenciada na inibição da ação plaquetária, inibindo de forma reversível e não competitiva o receptor P2Y12, o qual atua diretamente na agregação das plaquetas. Este medicamento está registrado no Brasil desde 2011, sob nome comercial de Brilinta®, na forma de comprimidos revestidos de 90 mg, e, até o presente momento, são poucos os estudos publicados a respeito do controle de impurezas e produtos de degradação do fármaco. No presente trabalho foi desenvolvido um método por cromatografia líquida de alta eficiência (CLAE) adaptado para a análise de impurezas orgânicas do ticagrelor. O método por CLAE foi estabelecido utilizando equipamento Agilent 1200 Series, acoplado a detector de arranjo de diodos (DAD) em 270 nm, com coluna cromatográfica Zorbax Plus C8 (150 x 4,6 mm, 5,0 μm), fluxo de 0,7 ml/min, volume de injeção de 20 μl e temperatura constante de 25ºC. A fase móvel foi composta de acetonitrila: acetato de amônio 50 mM (57:43, v/v), pH 8,2. O método demonstrou ser específico, linear, preciso, exato e robusto, sendo adequado para a finalidade a que foi proposto. Além disso, foram elucidados os principais produtos de degradação originados quando as amostras dos comprimidos de ticagrelor em solução foram expostas à radiação UVC por duas horas, com base em um estudo preliminar de estabilidade do mesmo. Os mecanismos envolvidos na degradação fotolítica do ticagrelor também foram propostos. / Ticagrelor is a new drug intended for the prevention of acute coronary syndromes (ACS) characterized by the formation of atherosclerotic plaques that rupture inside the arteries. Ticagrelor reversibly binds to P2Y12 receptor, which acts directly on platelet aggregation. The drug was approved in Brazil in 2011, under the comercial name Brilinta® in the form of coated tablets of 90 mg, and until now has few published studies about the impurities control and degradation products. In this study, it was developed a method by high-performance liquid chromatography (HPLC) for the analysis of organic impurities of ticagrelor. The HPLC method was established using Agilent 1200 Series equipment coupled to photodiode array detector (PDA) at 270 nm with a Zorbax Plus C8 column (150 x 4.6 mm, 5.0 μm), flow rate of 0.7 ml/min, injection volume of 20 μL, and a constant temperature of 25°C. The mobile phase consisted of acetonitrile: ammonium acetate 50 mM (57:43 v/v), pH 8.2. The method demonstrated to be specific, linear, precise, accurate and robust, being suitable for the intended purpose. Besides, the mayor degradation products formed when samples of ticagrelor tablets in solution were exposed to UVC radiation for two hours were elucidated based on a preliminary stability study. The mechanisms involved in photolytic degradation of ticagrelor have also been proposed.

The P2Y inhibitor, ticagrelor, has been shown to prevent thrombotic events and hence, improve morbidity and mortality in patients with acute coronary syndrome following coronary artery stent placement. Despite many clinical benefits, ticagrelor has been associated with several adverse effects, including dyspnea, easy bruising, and gastrointestinal bleeding. We report the case of a 67-year-old patient with an acute coronary artery syndrome requiring percutaneous coronary artery intervention with stenting who developed ticagrelor-induced diarrhea. The patient's ticagrelor medication was replaced with clopidogrel, and his diarrhea completely resolved within one week with no complications observed at his one-month follow-up visit. Clinicians should be aware of this adverse effect of ticagrelor so as to guide them toward possible underlying etiologies and appropriate workup of chronic diarrhea.

Les scandales sanitaires ayant émaillé le médicament ont mis la sécurité d’utilisation au cœur des préoccupations des acteurs de santé. Tout au long de son cycle de vie, le médicament est susceptible d’exposition à des conditions de stress pouvant conduire à sa dégradation et potentiellement, à la modification du rapport bénéfice/risque. Ce problème est d’autant plus marqué en milieu hospitalier où les médicaments en post – AMM sont manipulés pour des besoins spécifiques des patients. Quid de la maîtrise des modifications de leurs microenvironnements ? Etendre son espace de connaissances est admis comme étant le meilleur moyen pour circonscrire ces phénomènes. Dans le cadre de ce projet doctoral, une stratégie d’étude du cycle de vie des médicaments en post – AMM a été mise en place afin de renforcer leur sécurité d’utilisation. Compte tenu de la place prépondérante des formes solides dans l’arsenal thérapeutique, le ticagrelor, un récent antiagrégant plaquettaire (AAP) présenté sous forme de comprimés, a été choisi pour cette étude. La première étape a consisté à l’utilisation des conditions de stress pour évaluer sa stabilité intrinsèque et l’élucidation structurale des produits de dégradations grâce au couplage LC-HR-MSn donnant accès aux compositions élémentaires. Les voies de dégradation ont été proposées et la sécurité des produits a été évaluée grâce à l’approche in silico. Par ailleurs, compte tenu de l’utilisation des AAP en association, dans la seconde partie de ce travail, l’extension de l’espace de connaissances du ticagrelor a permis d’envisager une stratégie de préformulation avec l’aspirine à l’état solide en utilisant des techniques complémentaires comme la LC-HR-MSn, la DSC, la DRX ou l’ATG. La formation d’un simple eutectique a été observée avec le mélange des deux principes actifs. Nous avons démontré que la dégradation du ticagrelor est liée à la décomposition de l’aspirine, modulée par les conditions environnementales. Le modèle d’étude du ticagrelor ouvre clairement des perspectives sur la maîtrise de la sécurité en l’élargissant à d’autres médicaments et pourra contribuer à leur recyclage approprié. / Tragedies caused by the misuse of pharmaceuticals have put the drug safety at the core of the concerns of healthcare providers. Throughout its life cycle, a drug may be subjected to environmental stresses, which can lead to its degradation. Thorough understanding about the susceptibility of a drug to degrade is an essential step to avoid it. This problem is in particular relevant in a hospital setting, where commercial drugs are usually applied to specific cases without a clear understanding of its limitations. As part of this PhD project, a life cycle study strategy for a commercial drug has been implemented in order to increase its safety in use. Given the prominence of solid forms in the therapeutic arsenal, ticagrelor, a recent antiplatelet agent (APA) in tablet form, was chosen for this study. The first step was devoted to the evaluation of the intrinsic stability and the structural elucidation of the degradation products making use of LC-HR-MSn, providing access to the elemental composition. Degradation pathways have been proposed and the safety of the products has been evaluated via an in silico toxicological approach. Furthermore because antiplatelet agents are often used in combination therapy, in the second part, a preformulation strategy with aspirin in the solid state has been studied using the complementary techniques LC-HR-MSn, DSC, PXRD, and TGA. The mixture of the two active pharmaceutical ingredients gave rise to a simple eutectic. We have demonstrated that the degradation of ticagrelor in these mixtures is closely related to the stability of aspirin, which is modulated by environmental conditions. The ticagrelor study provides a model for the safety management of other drugs and can contribute to their appropriate recycling.

Cardiovascular disease is the leading cause of death worldwide and ischemic heart disease is the most common manifestation. Despite improved outcomes during the last decades, patients with acute coronary syndromes (ACS) are still at substantial risk of recurrent ischemic events and mortality. The aims of this thesis were to investigate the effect of the novel antiplatelet agent ticagrelor versus clopidogrel in patients with non-ST-elevation ACS (NSTE-ACS), overall and in relation to initial revascularization, and to explore this effect in relation to cardiac biomarkers. The impact of timing of revascularization in non-ST-elevation myocardial infarction (NSTEMI) was also studied, by assessing risk of mortality and recurrent myocardial infarction in relation to delay of percutaneous coronary intervention (PCI) in a nation-wide cohort. Finally, a novel clinical prediction model based on angiographic findings, biomarkers, and clinical characteristics was developed to estimate risk of ischemic events after performed revascularization. Ticagrelor treatment compared with clopidogrel was associated with a reduction in the composite endpoint of cardiovascular death/myocardial infarction/stroke and mortality alone, without any increase in overall major bleeding, but increased non-CABG-related major bleeding. The effect of ticagrelor over clopidogrel was consistent independent of initial revascularization. Elevated high-sensitivity cardiac troponin-T predicted benefit of ticagrelor over clopidogrel, while no difference between treatments was detected at normal levels. In patients with NSTEMI, PCI treatment within two days after hospital admission was associated with lower risk of all-cause death and recurrent myocardial infarction compared with delayed PCI. The new clinical prediction model included the following variables: prior vascular disease, extent of coronary artery disease, level of N-terminal pro-B-type natriuretic peptide and estimated glomerular filtration rate; and showed good discriminatory ability for the risk prediction of cardiovascular death/myocardial infarction/stroke and cardiovascular death alone. In conclusion, these results show that ticagrelor reduces the risk of recurrent ischemic events and mortality in patients with NSTE-ACS when compared with clopidogrel, and this effect seems independent of performed revascularization. The results also indicate that biomarkers could be used to select patients who would benefit most from more intense platelet inhibition. Furthermore, early PCI in NSTEMI seems to be associated with improved outcome. Finally, the novel clinical prediction model based only on four variables showed good discriminatory ability, which makes it a potentially effective and simple tool for tailored treatment based on individual risk of recurrent events.

Dans les syndromes coronariens aigus, le ticagrelor améliore la survie comparativement au clopidogrel. Les effets pléiotropiques de ce médicament ne sont pas entièrement compris. La métabolomique non ciblée, couplée avec des analyses computationnelles, a le potentiel d’élucider les changements pathophysiologiques du métabolisme cellulaire associés aux différentes maladies et aux traitements. L’objectif de cette étude est de dévoiler une signature métabolomique discriminante entre le clopidogrel et le ticagrelor dans le traitement de l’infarctus du myocarde avec élévation du segment ST (STEMI). La population de l’étude est formée de 175 participants de l’essai PLATO avec STEMI ayant subi une intervention percutanée (PCI), randomisés à recevoir le clopidogrel (n=88) ou le ticagrelor (n=87), appariés pour l’âge, le sexe, le statut de dyslipidémie et de diabète. Un profil métabolomique plasmatique non ciblé, obtenu par spectrométrie de masse (MS), est effectué pour chaque individu à l’état de base (BL; maladie aiguë) et au congé de l’hôpital après en moyenne 4 jours d’hospitalisation (DC; état post-traitement). L’étude des données a été effectuée par une analyse de quantification différentielle, une analyse de la variance, la construction d'un réseau de co-modulation et des techniques d'apprentissage automatique. Huit (8) métabolites étaient modulés de façon différentielle entre les deux groupes de traitement au congé, dont six (6) appartenant aux voies de biosynthèse des acides gras polyinsaturés omega-3 (n3) et omega-6 (n6). Les participants traités avec ticagrelor présentent des niveaux plasmatiques significativement plus élevés des acides gras suivants : α et de γ-linolénate (n3 and n6), dihomo-linolénate (n6), stéaridonate (n3), docosahexaenoate (DHA; n3), eicosapentaenoate (EPA; n3) et arachidonate (AA; n6). Chez les patients avec STEMI traités par PCI, des analyses de métabolomique non ciblées révèlent que les métabolites impliqués dans la biosynthèse des omega-3 et des omega-6 sont significativement plus élevé au congé dans le groupe traité par le ticagrelor, comparativement au clopidogrel, suggérant que le remodelage du réseau métabolique après un infarctus du myocarde pourrait interagir avec la réponse aux antiplaquettaires. / Background: In acute coronary syndromes, ticagrelor improved survival compared to clopidogrel. Pleiotropic effects of this drug are not entirely elucidated. Untargeted metabolomics coupled with computational analyses has the potential to help understanding pathophysiological changes of cellular metabolism associated with different disease states and therapies. Objectives: The purpose of this study is to unveil a discriminant metabolomics signature comparing ST-elevation myocardial infarction (STEMI) patients treated with clopidogrel and ticagrelor. Methods: The study population consists of 175 participants with STEMI from the PLATO Trial who underwent percutaneous coronary intervention (PCI), randomized to receive clopidogrel (n=88) or ticagrelor (n=87), matched for age, sex, dyslipidemia and diabetes status. Untargeted mass spectrometry (MS)-based metabolomics profiling in plasma was performed at baseline (BL; acute disease state) and repeated at hospital discharge after an average of 4 days of hospitalization (DC; post-treatment state), for each individual. Data analysis was done through differential quantification analysis, analysis of variance, co-modulation network construction and machine learning techniques. Results: Eight (8) metabolites were differentially modulated by treatment between groups at DC, six (6) of which belong to the polyunsaturated fatty acids omega-3 (n3) and omega-6 (n6) biosynthesis pathways. Participants treated with ticagrelor harbor a significantly higher plasmatic level of α and γ linolenate (n3 and n6), dihomo-linolenate (n6), stearidonate (n3), docosahexaenoate (DHA; n3), eicosapentaenoate (EPA; n3) and arachidonate (AA; n6). Conclusion: In patients with STEMI undergoing PCI, untargeted metabolomics reveals that metabolites involved in omega-3 and omega-6 biosynthesis are significantly higher at discharge in the ticagrelor treatment group when compared to clopidogrel, suggesting that the remodeling of the metabolic network after myocardial infarction may interact with the response to antiplatelet drugs.

Au Canada, il y a environ 21 000 décès et 84 069 hospitalisations liés à un infarctus du myocarde (IM) par année, ce qui représente environ 1,27 milliard de dollars canadiens ($ CA) en coûts directs reliés aux traitements aigus et chroniques. Parmi ces traitements, la double thérapie antiplaquettaire (DAPT) a été démontrée efficace pour diminuer le risque de complications reliées à l’IM. Cependant, malgré ces avantages cliniques, la persistance au traitement observée dans la vie réelle au Québec avec le DAPT à base de ticagrélor est inférieure à celle des autres inhibiteurs du récepteur P2Y12. L’objectif de ce projet était d’élaborer un modèle décisionnel permettant d’évaluer le rapport coût-utilité du ticagrélor-DAPT dans des conditions de persistance imparfaite chez les patients québécois souffrant d’IM et ainsi, déterminer si une intervention à l’échelle de la province visant à accroître la persistance serait justifiable. Un arbre de décision, modélisant l’évolution des patients atteints d’un IM sur une période d’un an, a été développé pour comparer quatre durées de persistance avec une observance parfaite avec le ticagrélor-DAPT (3, 6, 9 et 12 mois) à une stratégie d’observance parfaite avec 12 mois de clopidogrel-DAPT (traitement de référence). Trois événements cliniques ont été modélisés : l’IM récurent, le décès cardiovasculaire et le saignement majeur. Les probabilités de ces événements ont été extraites d’essais cliniques randomisés pertinents en utilisant les courbes de survie de Kaplan-Meier publiées. Les utilités nécessaires pour calculer les QALYs ont été dérivées de la littérature. Les coûts ont été estimés à partir de la littérature canadienne et de la liste des médicaments de la Régie de l'assurance maladie du Québec et ont été exprimés en $ CA de 2018. L’analyse principale consistait en une simulation probabiliste de Monte-Carlo. À un coût moyen par année de vie gagnée ajustée pour la qualité de vie (QALY) de 43 398 $ CA, les résultats de l’analyse principale ont démontré que 3 mois de ticagrélor-DAPT avait 59,31 % des chances d’être rentable à un seuil décisionnel (« willingness-to-pay ») de 50 000 $ CA par QALY. De plus, les analyses de sensibilité démontrent que le rapport coût-efficacité du ticagrélor-DAPT était sensible au coût du décès cardiovasculaire et au coût du ticagrélor. En présumant un coût de ticagrélor compatible avec un médicament générique, 3 mois, 6 mois et 9 mois de ticagrélor-DAPT étaient dominants et 12 mois de ticagrélor-DAPT avaient une forte probabilité d'être rentable (98,8 %). Cette analyse en arrive aussi à la conclusion que 3 mois de ticagrélor-DAPT sont probablement rentables par rapport à 12 mois de clopidogrel-DAPT. Avec un niveau de preuve de modéré à fort, nous concluons donc qu'aucune intervention particulière n'est justifiée en ce qui concerne la politique provinciale pour améliorer le taux de persistance au ticagrélor après un IM. / In Canada, there are approximately 21,000 deaths and 84,069 hospitalizations related to myocardial infarction (MI) per year, representing approximately Can$1.27 billion in direct costs related to acute and chronic care. Despite the demonstrated health benefits of dual antiplatelet therapy (DAPT) after an MI, observed real-world persistence to treatment with ticagrelor-based DAPT in Québec is lower than that observed with other P2Y12 receptor inhibitors. The objective of this project was to develop a decision-making model to evaluate the cost-utility ratio of ticagrelor-DAPT under conditions of imperfect persistence in Quebec patients suffering from MI, and thus to determine whether a province-wide intervention to increase persistence would be justifiable. A decision tree describing the patient course in the first year following an MI was developed in order to compare four different durations of persistence with perfect adherence with ticagrelor-DAPT (3, 6, 9 and 12 months) to perfect adherence with a 12-month regimen clopidogrel-DAPT (reference treatment). Three clinical events were modeled: recurrent MI, cardiovascular death and major bleeding. The probabilities of these events were extracted from relevant randomized clinical trials using published Kaplan-Meier survival curves. The utilities needed to calculate the QALYs were derived from the literature. The costs were estimated from the Canadian literature and the list of medications from the Régie de l'assurance maladie du Québec and were expressed in Can$ 2018. The reference case analysis consisted of a probabilistic Monte Carlo simulation. At a mean cost per quality adjusted life year (QALY) gained of Can$43,398, the results of the base case analysis showed that 3 months of ticagrelor-DAPT had a 59.31% likelihood of being considered cost-effective using a willingness-to-pay threshold of Can$50,000/QALY. Moreover, the sensitivity analyses showed that the cost-effectiveness of ticagrelor-DAPT was sensitive to the cost of cardiovascular death and the cost of ticagrelor. Assuming a cost of ticagrelor compatible with a generic drug, the 4 durations of persistence with ticagrelor-DAPT are almost guaranteed to be profitable. When a generic cost of ticagrelor was assumed, 3 months, 6 months and 9 months of ticagrelor-DAPT were dominant and 12 months of ticagrelor-DAPT were highly likely to be cost-effective (98.8%). This analysis also conclude that as little as 3 months of ticagrelor-DAPT is likely to be cost-effective compared to 12 months of clopidogrel-DAPT. With a moderate to strong level of evidence, we therefore conclude that no specific intervention is warranted at the provincial policy level to improve persistence rate with ticagrelor treatment after MI.