Objetivo: Avaliar o uso de antitrombóticos em pacientes com fibrilação atrial (FA) em hospital cardiológico no Brasil (InCor).Métodos e resultados: Um estudo observacional transversal analisou os prontuários de todos os pacientes atendidos no InCor em cada um de 5 dias separados no ano de 2002 (Fase 1), sendo prospectivamente reanalisados após 1 ano (Fase 2). A prevalência da FA nos 3764 prontuários analisados foi de 8%. Antiplaquetários foram prescritos para 21,26% e 19,93%, anticoagulantes para 46,51% e 57,81%, e 32,23% e 22,26% não usavam nenhum antitrombótico nas Fases 1 e 2, respectivamente. Somente 15,60% e 23,25% apresentavam níveis de RNI terapêuticos.Conclusão: A anticoagulação é subutilizada nos pacientes com FA apesar do fato de serem tratados por cardiologistas em um hospital universitário / Objective: To assess antithrombotic therapy among atrial fibrillation (AF) patients in a Brazilian University Heart Hospital (InCor).Methods and results: A cross sectional study analyzed the charts of all patients treated at InCor in 5 separate days of 2002 (Phase 1), and prospectively reviewed them after one year (Phase 2). The prevalence of AF in the 3,764 assessed charts was of 8.0%. Antiplatelets were prescribed to 21.26% and 19.93%, anticoagulants to 46.51% and 57.81%, and 32.23% and 22.26% were not receiving any antithrombotic in Phases 1 and 2, respectively. Only 15.60% and 23.25% were within INR therapeutic range.Conclusion: Anticoagulation is underused in AF patients besides the fact of being treated by cardiologists in a University Hospital

Estudo descritivo, correlacional, de delineamento longitudinal, com 78 pacientes que iniciaram anticoagulante oral (ACO) entre abril de 2008 a junho de 2009 em três serviços de saúde de um município do oeste do Paraná. Os objetivos foram avaliar a adesão medicamentosa e comparar a qualidade de vida relacionada à saúde (QVRS) e o estado global de saúde no início e com seis meses de tratamento. Os dados foram coletados por entrevistas individuais com instrumentos específicos para adesão farmacológica (Medida de Adesão ao Tratamento), QVRS (Medical Outomes Survey Short form - SF-36; Duke Anticoagulation Satisfaction Scale DASS), todos validados para o uso no Brasil, e o estado global de saúde (Escala Visual analógica EVA). Foram realizados testes de comparação de médias (Teste t de Student pareado e para amostras independentes), de correlação (coeficiente de correlação de Pearson) e de regressão linear múltipla. O nível de significância foi 0,05. Entre os sujeitos, 53,8% eram mulheres, com idade média de 56,8 anos, casados (71,8%), com baixa escolaridade e 48,7% não desempenhavam atividades remuneradas. As principais indicações para o uso do ACO foram fibrilação atrial (34,6%) e prótese cardíaca mecânica (26,9%) e o ACO mais usado foi a varfarina sódica (91%). Os resultados apontaram que após seis meses, apenas dois participantes foram classificados como não aderentes ao tratamento com ACO e que, no geral, houve melhora na QVRS avaliada por ambos os instrumentos. A avaliação pelo SF-36 mostrou que as diferenças entre os oito domínios foram estatisticamente significantes, exceto para saúde mental. Entretanto, as comparações das médias dos domínios do DASS foram estatisticamente significantes apenas para os domínios Impacto psicológico negativo e Impacto psicológico positivo. O estado global de saúde avaliado pela EVA apresentou valores médios que aumentaram da primeira para segunda avaliação, de 74 para 83, respectivamente, em um intervalo possível de zero a 100. Considerando como variável resposta a medida do DASS total, um modelo de regressão linear multivariada composto pelas variáveis idade, escolaridade, número de medicamentos em uso, indicação para o ACO, dosagem semanal do ACO, Saúde mental (domínio do SF-36), Vitalidade (domínio do SF-36) e intervalo terapêutico explicaram 39,3% da variância da medida da QVRS. Neste modelo, as variáveis com maiores valores de coeficiente beta () e estatisticamente significantes foram: idade (= - 0,317; p=0,017), número de medicamentos usados pelo indivíduo (= -0,353; p=0,005) e saúde mental (= -0,364; p=0,032). Um segundo modelo de regressão linear multivariada foi feito tendo como variável resposta a medida do estado global de saúde. As variáveis explanatórias foram: escolaridade, número de medicamentos em uso, Vitalidade, Saúde mental, Aspectos emocionais e intervalo terapêutico que explicaram 40,4% da variância desta medida. Os resultados obtidos podem subsidiar a prática dos profissionais da saúde na prevenção de fatores que possam afetar à adesão ao medicamento e a qualidade de vida dos usuários de ACO. / A descriptive, correlational design of longitudinal, with 78 patients who initiated oral anticoagulant taking (OAC) within the months of April, 2008 and June, 2009 in three health care services from a municipality of the state of Parana. The aims of this study were to evaluate the medication adherence and compare the health-related quality of life (HRQL) and the global health status in its beginning and within six months of treatment. The datas were all collected through individual interviews making use of specific instruments for pharmacological adherence (Means of Adherence to Treatment), QVRS (Medical Outcomes Survey Short form - SF-36; Duke Anticoagulation Satisfaction Scale DASS), which ones are validated to use in Brazil, and the global health status (Visual Analog Scale VAS).Comparison of average tests were applied (Students test t for paired and independent samples), of correlation (Pearsons correlation test) and of multiple linear regression. The significance level was set at 0,05. Among the subjects, 53,8% were women, at the average age of 56.8, married (71.8%), with low education and 48,7% did not performed any paid job. The main indications to the use of OAC were atrial fibrillation (34,6%) and mechanical cardiac prosthesis (26,9%) and the most used OAC was the warfarin sodium (91%). The results pointed out that after six months, only two participants were classified as not-adherent to treatment with OAC and that, by and large, there was improvement in the HRQL evaluated by both instruments. The evaluation with SF-36 showed that the differences among the eight domains were statistically significant, except for mental health. However, the average comparisons of domains of the DASS were statistically significant only to the negative psychological impact and positive psychological impact domains.The global health status evaluated by VAS presented average score increase from the first to the second evaluation, from 74 to 83, respectively, in a possible interval from zero to 100. Considering it as a variable response to the measurement of the total DASS, a model of linear regression multivariate made up by age variables, education, number of chemicals in use, indication to the OAC, weekly dose of OAC, mental health (domain of SF-36), Vitality (domain of SF-36) and interval therapy explained 39,3% of the variability of the measurement of HRQL. In this model, the variables with higher beta () coefficient scores and statistically significant, were: age (= -0,317; p=0,017), number of chemicals taken by the individual (= -0,353; p=0,005) and mental health (= -0,364; p=0,032).A second model of linear multivariate regression was done, taking into account as a variable response to the measurement of global state of health. The explanatory variables were: education, number of chemicals in use, Vitality, Mental health, Emotional functioning and interval therapy explained 40,4% of the variability of this measurement. The results obtained may subside the practice of healthcare professionals in the prevention of factors that may affect the adherence to the medication and the health-related quality of life of OAC users.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia with a prevalence of 15% of patients over 80 years. Coronary artery disease co-exists in 20–30% of patients with atrial fibrillation. The need for triple anticoagulation therapy makes the management of these patients challenging following PCI. Methods: Nationwide inpatient sample which is a set of longitudinal hospital inpatient databases was used to evaluate the outcome of patients with AF who underwent PCI. All patients undergoing PCI between 2002 and 2011 were included in the study. Specific ICD-9-CM codes were used to identify the study patients and their outcomes. Results: There were 3,226,405 PCIs during the time period of the study of which 472,609 (14.6%) patients had AF. AF patients were older and predominantly male (60%). The number of PCIs had a declining trend from 2002 to 2011. Age adjusted inpatient mortality was significantly higher in PCI AF group compared to the PCI non-AF group (100.82 ± 9.03 vs 54.07 ± 8.96 per 100,000; P < 0.01). Post PCI predictors of mortality were AF (OR 1.56, CI 1.53–1.59), CKD (OR 1.41, CI 1.37–1.46), PAD (OR 1.20, CI 1.15–1.24), acute myocardial infarction (OR 2.42 CI 2.37–2.46 and cardiogenic shock (OR 13.92 CI 13.60–14.24) P < 0.001. Conclusion: AF is common in patients undergoing PCI and those AF patients have a higher age-adjusted all cause inpatient mortality. There is a decline in total number of PCIs over time in US. Atrial fibrillation, chronic kidney disease, peripheral artery disease, MI and cardiogenic shock were associated with increased mortality following PCI.

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.

<p>I put department up there as Biomedical Engineering. The full title should be: School of Biomedical Engineering.</p> / <p>The work presented in this thesis was focused on the surface modification of biomaterials with combinations of polyethylene glycol (PEG) and bioactive molecules (protein anticoagulants) for improved blood compatibility. Since the fate of biomaterials in contact with blood depends significantly on plasma protein-surface interactions, the objective of this work was to reduce non-specific protein adsorption using PEG and to promote specific protein interactions that could inhibit clot formation using protein anticoagulants as modifiers.</p> <p>Two anticoagulant molecules were used in this work: hirudin, a specific inhibitor of thrombin and corn trypsin inhibitor (CTI), a specific inhibitor of clotting factor XIIa. Gold, used as a model substrate, was modified with PEG and anticoagulant molecules using two methods referred to as sequential and direct. In the sequential method PEG was first immobilized on the surface and then the bioactive molecule was attached (conjugated) to the PEG. In the direct method, a PEG-bioactive molecule conjugate was first formed and then immobilized on the surface. Surfaces were characterized by contact angle, ellipsometry and x-ray photoelectron spectroscopy (XPS). Uptake of the bioactive molecules was measured by radiolabeling. Biointeraction studies included plasma protein adsorption, bioactivity assays using chromogenic substrates and clotting time assays. For PEG-hirudin and PEG-CTI surfaces (both direct and sequential) the protein resistance was similar to that of the PEG-alone surfaces. Despite having a lower density of bioactive molecule (both hirudin and CTI), the sequential surfaces showed superior bioactivity compared to the direct ones.</p> <p>To determine the optimal ratio of free PEG and bioactive molecule-PEG conjugate on the surface (best combination of protein resistance and bioactivity), PEG-CTI was immobilized on gold substrate with varying ratio of conjugated to free PEG using both direct and sequential methods. As the ratio increased, protein resistance was maintained while specific interactions (bioactivity) increased. The optimal composition appeared to be where all PEG molecules are conjugated to a CTI molecule.</p> <p>In the final part of this project, PEG and CTI were immobilized on polyurethane as a material with applicability to medical device construction. A sequential method was developed for this substrate. Comparison of the PEG-CTI surface with PEG only or CTI only surfaces indicated that the combination of PEG-CTI was effective both in reducing non-specific protein adsorption and promoting the specific interactions of CTI with its target plasma protein, factor XIIa. In fact, the presence of PEG improved CTI interactions with FXIIa compared with CTI only surfaces. Thus, sequential attachment of PEG and CTI may be effective for modifying polyurethane surfaces used in blood-contacting medical devices.</p> / Doctor of Philosophy (PhD)

<p>The serpin α-1 proteinase inhibitor (API) normally only impacts the coagulation cascade through its ability to inactivate factor XIa. However, the point mutation (Met to Arg) at position 358 results in a potent thrombin inhibitor, API M358R. This mutation also enhances this serpin’s ability to inhibit the anticoagulant protein, activated protein C (APC) and hence this property limits its therapeutic potential. As a result, various modifications to this protein have been engineered in order to enhance its specificity towards thrombin. Previously, the Heparin Cofactor II (HCII) N-terminal tail, HCII 1-75, which binds exosite 1 of thrombin, was tethered to the N-terminus of API M358R, creating HAPI M358R. Although this change did not alter anti-APC activity, it did augment the anti-thrombin activity of API M358R. In addition, further changes in the reactive center loop, the region that interacts with the thrombin active site, resulted in a significant reduction in APC activity while maintaining antithrombotic activity similar to HAPI M358R; this variant was termed HAPI RCL5.</p> <p>Preliminary experiments were performed with the C-terminal tridecapeptide of Hirudin Variant 3 (HV3) to determine its exosite 1 binding capacity compared to HCII 1-75. Three different variants of this peptide were tested: one with a hexahistidine tag (H₆HV3_54-66), another that also had a hexa-glycine C-terminal addition (H₆HV3_54-66G₆) and a third without either addition. All were found to bind exosite 1 with a greater affinity than HCII 1-75. Thus, the H₆HV3_54-66G₆peptide was fused to API M358R and API RCL5 in hopes of creating an inhibitor with heightened specificity compared to HAPI M358R and HAPI RCL5, respectively.</p> <p>HV3API M358R and HV3API RCL5 were expressed in a bacterial system and purified by nickel-chelate and ion exchange chromatography. Second order rate constants for the inhibition of thrombin and APC by the API variants and fusion proteins were determined. The K₂ values for α-thrombin inhibition ranged from 186 M^-1min^-1 to 22 M^-1min^-1 with an order of inhibitory potency observed as follows: HAPI M358R > HAPI RCL5 > HV3API M358R > HV3API RCL5>API RCL5 > API M358R.</p> <p>The ability of recombinant chimeric serpins to bind thrombin exosite 1 in a manner independent of RCL-thrombin active site interactions was also investigated through competitive inhibition of the binding of active site-inhibited thrombin to immobilized HCII 1-75. It was found that the order of exosite 1 binding affinity was HV3API RCL5 > H₆HV3_54-66G₆> HCII 1-75 > HAPI RCL5. Our results indicate that fusing the C-terminal tridecapeptide of HV3 to API variants enhanced their ability to inhibit thrombin, but to a lesser extent than fusing the N-terminal 75 residues of HCII. This finding likely reflects a requirement for the exosite 1-binding motif of the fusion protein to bind exosite 1 in a way that allows for subsequent optimal active site attack on the RCL by the serpin moiety of the fusion protein. In general, this work provides a second novel example of how the activity of a thrombin-inhibitory serpin can be enhanced by fusion to an exosite-1 binding motif.</p> / Master of Health Sciences (MSc)

<p>The effect of direction thrombin inhibition on acute deep vein thrombosis (DVT) stability has not been defined and could contribute to pulmonary embolism (PE) risk. Direct thrombin inhibitors (DTIs) effectively inhibit free and clot-bound thrombin, which could potentiate thrombus instability through disruption of platelet, fibrin, and FXIIIa stabilizing mechanisms. This could manifest as increased thrombus embolization. A clinically relevant mouse model of DVT stability could further our understanding of venous thrombosis pathophysiology and define the effect of direct thrombin inhibition on PE. We hypothesized that acute DTI administration would decrease acute DVT stability and potentially increase PE risk. Platelets were labeled <em>in vivo</em>, femoral vein thrombosis was induced using FeCl₃, and lepirudin (8U/g) was administered <em>after</em> clot formation. Using intravital videomicroscopy (IVM), real time embolization was quantified as a measurement of thrombus stability. Thrombus stability increased in the control group and decreased in the lepirudin-treated group over two hours. The decrease in α₂-antiplasmin (α₂-AP) content within lepirudin-treated thrombi, compared to control thrombi, could possibly contribute to the observed decrease in thrombus stability. Continued growth and embolization established the dynamic nature of formed thrombi. In both groups, emboli were detected in the pulmonary artery circulation. Therefore, we successfully developed a mouse model of venous thrombus stability, which imitated the clinical progression of DVT to PE. DTI administration in the acute DVT setting could decrease thrombus stability, demonstrated through increased embolization and PE. This model could be useful in examining the effect of other antithrombotics and risk factors settings on DVT stability.</p> / Master of Science (MSc)

<p>The management of thrombosis in the presence of thrombocytopenia is challenging because the inherent risk of bleeding associated with anticoagulant use may increase due to low platelet counts. Guidelines regarding anticoagulant use in this situation are based mainly on expert opinions and anecdotal data. We developed an <em>in-vitro</em> model to study the effect of anticoagulants on plasma clot formation in the presence of low platelet counts. We used thromboelastography (TEG) to measure global viscoelastic properties of clot formation and scanning electron microscopy (SEM) to observe and quantify changes in the fibrin clot structure. Experiments were conducted in plasma with varying platelet concentrations from <10 >– 150 × 10⁹/L. Clotting was activated with tissue factor (TF) and calcium, in the presence of factor XIIa inhibitor, corn trypsin inhibitor. One of the following anticoagulants at therapeutic concentration was added to the mixture: unfractionated heparin (UFH), dalteparin, fondaparinux, rivaroxaban or dabigatran. We found clotting had different sensitivity to TF concentration depending on the anticoagulant present. Effects on TEG parameters varied at a fixed TF concentration with each anticoagulant. UFH had the greatest influence, delaying clotting significantly at low platelet counts. The factor-specific anticoagulants had the least impact on TEG parameters. SEM revealed that UFH had the greatest impact on clot structure. UFH caused significant increase in porosity and fibrin widths and had significantly less fibers when platelets decreased. In conclusion, this study may provide fundamental data to understand clot formation in the presence of anticoagulants at low platelet counts. At low platelets the anticoagulants can jeopardize clot formation, especially UFH. The mechanism of each anticoagulant may contribute to the variation in response to TF initiated clotting. AT-dependent anticoagulants compromised plasma clotting more than the newer factor specific anticoagulants, possibly related to the multiple, non-specific inhibition of coagulation factors.</p> / Master of Science (MSc)

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 / 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;