Le traitement AVK concerne plus d’1% de la population française. Il représente un problème de santé publique majeur en raison de son importante iatrogénie. Les causes peuvent être notamment reliées à la complexité du parcours de soins des patients, à leurs erreurs, méconnaissances et incompréhensions. L’éducation thérapeutique (ETP) permettrait de contribuer à rendre ce patient autogestionnaire de ses propres risques. Cette recherche qualitative vise à proposer un modèle d’ETP en en identifiant les compétences d’auto-soins et d’adaptation à la maladie et en en précisant le programme, les méthodes pédagogiques et d’évaluation. Le protocole de recherche comporte une revue de la littérature sur les connaissances des patients, des entretiens de type semi-directifs de patients traités par AVK et de soignants-éducateurs, et enfin des entretiens avec un groupe d’experts. Trente-six entretiens associés à une revue extensive de la littérature ont permis d’élaborer un référentiel de huit compétences. Vingt-et-un objectifs pédagogiques découlent de ces compétences. Les principales difficultés des patients concernaient la mise en lien des concepts constitutifs du paradigme du traitement par AVK. Les huit compétences du référentiel correspondent à la gestion intelligible et sans danger d’un traitement anticoagulant. Les différents types de soignants-éducateurs envisagés pour ce modèle d’ETP se retrouvent dans le parcours de soins habituel des patients. Notre modèle pédagogique se veut applicable à différents contextes de soins. Les propositions tentent de répondre à la problématique de l’intelligibilité du traitement AVK et de rendre accessible aux patients l’éducation thérapeutique. / The VKA treatment concerns more than 1% of the french population. It represents a major public health problem beacause of its consirable drug related iatrogny....

This thesis combines five published research papers investigating methods of improving the safety and control of oral anticoagulation, with the use of computer assisted dosage and the standardisation of the International Normalised Ratio (INR). The INR is a conventional measurement derived from the time it takes blood of a patient to form a clot and is used to monitor the effects of widely used oral anticoagulants such as warfarin for the prevention of stroke and other related disorders. The first paper investigates whether the use of computer-assisted programs was as safe and effective as medical staff manual dosage in the prevention of bleeding or thrombotic complications during oral anticoagulant treatment. This was an international multi-centre randomised study conducted by the European Action on Anticoagulation (EAA) investigating the clinical benefit of two computer programs, PARMA 5 (Italy) and DAWN AC (UK). Composite clinical events were reduced by 7.6% using computer programs, though not achieving statistical significance (p=0.1), showing computer programs to be not dissimilar to medical staff dosage. The second paper recommends guidelines for screening safety and effectiveness of other marketed computer programs based on the results of the EAA study. A process for a candidate computer program to achieve non-inferiority relative to the medical staff dosage arm from the EAA study is explained. The third paper introduces a modified approach to the 'Direct INR' method for the standardisation of INR termed the 'Prothrombin Time/INR Line' (PT/INR). This was directly compared to the local International Sensitivity Index (ISI) calibration procedure originally approved by the World Health Organisation and later by the United States Food and Drug Administration (FDA). Using manually certified lyophilised plasmas tested by specialist centres, the PT/INR Line using a set of 5 calibrant plasmas to establish a fitted line to estimate local INR was shown to be as effective as the FDA procedure. The fourth paper investigates the PT/INR Line further by using simulated sets of calibrant plasmas across the therapeutic range of 2.0-4.5 INR and determining the PT/INR Line. Local INR of five validation plasmas, certified by 3 centres using the manual PT technique, was determined using the estimated PT/INR Lines and compared with local ISI calibration. Using 4 or 5 calibrant plasmas to determine the PT/INR Line was shown to be as accurate as local ISI calibrations for reliable local INR.The fifth and final paper assessed INR variability and control in oral anticoagulant therapy using a method termed the Variance Growth Rate (VGR), and compared its predictive ability of adverse events with the Time in Target INR range (TIR), the conventional method used in evaluating the quality of oral anticoagulant therapy. The VGR method was shown to be a better predictor of adverse bleeding or thrombotic episodes in the short term period prior to an event (3 and 6 months) compared with TIR.

Pendant plus de six décennies, les antivitamines K (AVK) ont été la seule classe d’anticoagulants oraux disponibles sur le marché. L’arrivée des Anticoagulants Oraux Directs (AOD) en 2008 a marqué un réel tournant dans l’anticoagulation par voie orale. La première partie de ce travail s’est intéressée aux caractéristiques des patients traités par anticoagulants, et les conséquences en termes d’hospitalisations pour évènement hémorragique ou ischémique. Au sein d’une cohorte de patients hospitalisés pour AVC (cohorte BIOSTROKE, Lille), aucun facteur d’influence particulier, intervenant sur la survenue et l’évolution (mortalité, de déclin cognitif, et de handicap à 3 mois) de l’AVC n’était mis en évidence. En parallèle, une étude menée dans le service d’urgences du Centre Hospitalier de Béthune sur 3 années (2012, 2014, 2016) pour suivre l’évolution des prescriptions d’anticoagulants oraux et observer l’impact de la mise sur le marché des AOD, montrait une population dont certaines caractéristiques semblaient être associées à une utilisation plus volontiers des AOD ou des AVK. Le nombre d’évènements hémorragiques et thrombotiques sous AVK restait cependant stable sur les trois périodes d’étude (770 patients inclus au total). Forts de ces données rassurantes, la deuxième partie de ce travail s’est intéressée aux pratiques de prescription et au bon usage des anticoagulants, avec un focus particulier sur les AOD, à travers trois études : la première réalisée auprès des médecins généralistes du Nord et du Pas de Calais qui montrait une population de prescripteurs plutôt méfiants envers les AOD et ayant une préférence pour les anti-Xa. Les deux autres études portaient sur le bon usage des AOD, à partir de prescriptions à l’officine (grâce à la participation des étudiants en pharmacie de la faculté de Lille en stage d’officine) et à l’hôpital (Centre Hospitalier Régional de Lille). Ces études retrouvaient globalement des chiffres de prescriptions d’AOD transposables aux données françaises, avec cependant des disparités ville/hôpital. En termes de bon usage, les prescriptions étaient pour moins d’un tiers d’entre elles non-conformes aux recommandations en vigueur, avec une forte proportion de situations de sous-dosages. En conclusion, ce travail de thèse a permis de mettre à jour des pistes de formation/information des professionnels de santé sur ces nouvelles molécules anticoagulantes qui vont participer à une prise en charge avisée et optimale des patients. / For over six decades, vitamin K antagonists (VKAs) were the only class of oral anticoagulants available on the market. The arrival of Direct Oral Anticoagulants (DOAs) in 2008 marked a real turning point in the oral anticoagulation. The first part of this work was interested in the characteristics of patients treated with anticoagulants and the consequences in terms of hospitalizations for ischemic or hemorrhagic events. In a cohort of patients hospitalized for stroke (cohort BIOSTROKE Lille), no particular influencer, on the onset and course (mortality, cognitive decline, and disability at 3 months) of stroke was highlighted. In parallel, a study conducted in the emergency department of the Hospital of Bethune on three years (2012, 2014, 2016) to observe oral anticoagulants prescriptions and the impact of DOAs arriving, showed a population where many characteristics appear to be associated with a more readily using DOAs or VKAs. The number of bleeding and thrombotic events with VKAs remained stable during the three study periods (in total 770 patients were included). With these reassuring data, the second part of this work has focused on prescribing practices and the appropriate use of anticoagulants, with a particular focus on DOAs, through three studies: one conducted among general practitioners of Nord and Pas de Calais departments, which showed a rather wary about DOAs but with a preference for anti-Xa. The other two studies focused on the appropriate use of DOAs, estimated from pharmacy (with the participation of pharmacy students of the Faculty of Lille) and hospital (Lille Regional Hospital Center) prescriptions. Data about DOAs prescriptions were transposable to French data, albeit with city / hospital disparities. Non-appropriate prescriptions were observed in less than one-third file, with a high proportion of under dosing situations. In conclusion, this work has allowed updating training tracks / information for health care professionals on these new anticoagulant molecules to improve information and optimal patients’ care.

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Background and Objectives Oral anticoagulants (OACs) are among Canada's most frequently prescribed drugs and a top cause of medication-related serious harm leading to emergency department visits, hospitalizations, and fatalities. During the preparation to launch a Canadian Institutes of Health Research (CIHR)-funded randomized controlled trial (RCT) called "Improving Anticoagulant Safety at Hospital Discharge: A Randomized Trial," we faced some issues. First, as the RCT addresses OAC management, we needed to determine the barriers and facilitators for optimal OAC management, which were not identified in our literature search. Second, there is no core outcome set (COS) specific for OACs and the choice of outcomes and their measurement for the trial was not obvious. Finally, the drug-drug interactions between the OACs and other medications are not fully understood, particularly with regards to important clinical outcomes. Identifying the interacting medications and their interaction effect size, is vital to guarantee the safety of patients. To address these issues, the objectives of this thesis were: (1) to determine the barriers and facilitators for optimal OAC management, (2) to define the potential list for the COS of OACs, and (3) to explore the drug-drug interaction of OACs. Methods Several research approaches, including a systematic review, a systematic survey, a scoping review, a population-based retrospective cohort study with time varying methods, and a qualitative study were applied in this thesis. First, we applied both a synthesis review and qualitative research to explore the barriers and facilitators for OACs management to guarantee the evidence's robustness. Next, we used a systematic survey to address the lack of consensus on outcomes used and their v definitions for OAC treatment clinical trials. Finally, we used a systematic review and planned a population-based study to address drug-drug interaction related to OACs. Methodologic challenges and innovation In the scoping review (Chapter 2: Barriers and facilitators to optimal oral anticoagulant management: a scoping review) and the focus group study (Chapter 3: Perceptions on patient education to improve oral anticoagulant management) we employed a qualitative approach. The main methodological challenge for both the scoping review and the focus group focused on the rigorous way to synthesize the themes. In Chapter 4, we used a systematic survey to explore the outcome list for OAC management research. The primary methodological challenge referred to the outcome reporting in the included studies. Not all outcomes performed in the trials can be reported for the space limitation or potential publication bias. In Chapters 5 and 6, a systematic review with meta-analysis and an observational protocol were used to explore the drug-drug interaction for OACs. The main methodological challenge for Chapter 5 was how to evaluate the drug-drug interaction (DDI) evidence systematically. The main methodological challenge for Chapter 6 is to address confounding and bias in a population-based protocol on DOACs drug-drug interaction. Conclusion In summary, this standard thesis describes five different background projects to prepare for an OAC management RCT. The papers contribute to the literature by using several research methodologies to provide useful evidence for OAC management and OAC research. / Thesis / Candidate in Philosophy / Oral anticoagulants (OACs) (blood thinners) are among Canada's most frequently prescribed drugs and a top cause of severe medication-related harm. The objectives of this thesis include (1) to determine the barriers and facilitators for optimal OAC management, (2) to define a potential list for the core outcome set of OACs, and (3) to explore the drug-drug interaction of OACs. First, we applied a scoping review and a qualitative study to explore the barriers and facilitators for OACs management. Then we conducted a systematic survey to address the lack of consensus on outcomes and their definitions for OAC treatment clinical trials. Finally, we used a systematic review and planned a population-based study to address drug-drug interaction related to OACs. Different research approaches, including a systematic review, a systematic survey, a scoping review, a population-based study, and a qualitative study, were involved in this thesis.

Background Our objective was to identify and validate clinical and continuity of care variables associated with Oral anticoagulant (OAC)-related adverse events within 30 days of hospital discharge amongst seniors. Methods and Analysis This was a population-based retrospective cohort study of all adults aged 66 years or older who were discharged from hospital on an OAC from September 2010 to March 2015 in Ontario, Canada. The primary outcome was a composite of the time to first hospitalization or Emergency Department visit for a hemorrhage or thromboembolic event or mortality within 30 days of hospital discharge. A Cox proportional hazards model was used to determine the association between the composite outcome and a set of prespecified covariates. A split sample method was applied to validate the final model. Results We included 120 721 Ontario seniors of which 5423 suffered one of the primary adverse events. Patients discharged on a direct-acting oral anticoagulant (DOAC); dispensed the same OAC in the past 12 months; who had a history of a thromboembolic event; had a recent joint replacement or major surgery; had a cardiologist, hematologist or orthopedic surgeon as compared to a family medicine physician as the physician prescribing the OAC at discharge had a lower risk for the composite outcome. Though continuity of care was a variable in the final multivariate Cox model, it was not significant. The Cox model was stable with acceptable discrimination but poor goodness-of-fit. Conclusion In this study, we found that continuity of care as measured by outpatient follow-up in the 7 days post-discharge was not significantly associated with the composite outcome. Further exploration to improve the current model’s calibration and interpretation are required. / Thesis / Master of Science (MSc) / Background Oral anticoagulants (OACs) are associated with serious adverse events, with high rates immediately post-hospitalization. We aimed to identify and validate clinical and continuity of care variables in seniors discharged from hospital on an OAC, which are associated with OAC-related harm in the short-term high-risk period following hospitalization. Methods Data from administrative health databases in Ontario were used to identify and validate risk factors associated with time to first OAC-related serious events including hospitalization or emergency department visit for a bleeding or thromboembolic event, and mortality. Cox proportional hazards model and split-sample methods were utilized. Results We included 120,721 seniors of which 5423 suffered one of the primary events. Patient-, physician- and index hospitalization-characteristics were all associated with time to the composite outcome. Though continuity of care risk factor was part of the final model, it was not a significant predictor for the outcome. Conclusion Exploration of this model through sensitivity analysis is required.

Yes / Introduction: Oral anticoagulant therapy choices for patients with atrial fibrillation (AF) expanded in the last decade with the introduction of direct oral anticoagulants (DOAC). However, the implementation of DOACs was slow and varied across different health economies in England. There is limited evidence on the patient role in the uptake of new medicines, including DOACs, apart from considering their demographic and clinical characteristics. Hence, this study aimed to address the gap by exploring the view of patients with AF on factors affecting DOAC use. Methods: A qualitative study using semi-structured interviews was conducted in three health economies in the North of England. Adult patients (>18 years) diagnosed with non-valvular AF, prescribed an oral anticoagulant (vitamin K antagonist or DOAC), and able to give written consent were recruited. Data were collected between August 2018 and April 2019. Audio recorded interviews were transcribed verbatim and analyzed using the framework method. Results: Four themes with eleven subthemes discussed identified factors affecting the use of DOACs. They were linked to limited healthcare financial and workforce resources, patient involvement in decision-making, patient knowledge about DOACs, safety concerns about oral anticoagulants, and oral anticoagulant therapy impact on patients' daily lives. Lack of a) opportunities to voice patient preferences and b) information on available therapy options resulted in some patients experiencing difficulties with the prescribed therapy. This was reported to cause negative impact on their daily lives, adherence, and overall satisfaction with the therapy. Conclusion: Greater patient involvement in decision-making could prevent and resolve difficulties encountered by some patients and potentially improve outcomes plus increase the uptake of DOACs. / Pharmacy Research UK (PRUK-2018-GA-1-KM) and Leeds Teaching Hospitals NHS Trust

Yes / Objective: To better understand the factors influencing the uptake of direct oral anticoagulants (DOACs) across different health economies in National Health Service England from the perspective of health professionals and other health economy stakeholders. Design: Qualitative interview study using a critical realism perspective and informed by the Diffusion of Innovations in Service Organisations model. Setting: Three health economies in the North of England, United Kingdom. Participants: Healthcare professionals involved in the management of patients requiring oral anticoagulants, stakeholders involved in the implementation of DOACs and representatives of pharmaceutical industry companies and patient support groups. Intervention: Semistructured interviews (face-to-face or telephone) were conducted with 46 participants. Interviews were analysed using the Framework method. Results: Identified factors having an impact on the uptake of DOACs were grouped into four themes: perceived value of the innovation, clinician practice environment, local health economy readiness for change, and the external health service context. Together, these factors influenced what therapy options were offered and prescribed to patients with atrial fibrillation. The interviews also highlighted strategies used to improve or restrict the uptake of DOACs and tensions between providing patient-centred care and managing financial implications for commissioners. Conclusions: The findings contribute to the wider literature by providing a new and in-depth understanding on the uptake of DOACs. The findings may be applicable to other new medicines used in chronic health conditions. / This work presents research funded by the Pharmacy Research UK (grant number: PRUK-2018-GA-1-KM) and Leeds Teaching Hospitals NHS Trust (grant number: N/A).

Yes / Direct oral anticoagulants (DOACs) uptake for stroke prevention in atrial fibrillation has been slow.[1] This study aimed to profile the prescribing of DOACs over three years to identify factors associated with DOAC prescribing in a Clinical Commissioning Group (CCG) without restrictions to DOACs use. The objectives were to identify: - Characteristics of patients prescribed oral anticoagulant (OAC) in a sample of general practices; - Who initiated the prescribing of OAC; - Recorded reasons for prescribing a DOAC rather than warfarin;

Yes / Warfarin and direct oral anticoagulants (DOACs) have been shown to reduce the risk of stroke in patients with atrial fibrillation, yet many patients are still not being anticoagulated. This article discusses the barriers to the initiation of oral anticoagulants, in particular DOACs, and how these can be overcome.