A anticoagulação inadequada pode ocasionar eventos tromboembólicos e hemorrágicos, representando um desafio para a medicina. A varfarina, anticoagulante oral de amplo uso, está associada a reações adversas graves, frequentes nos pacientes em tratamento com múltiplos fármacos. Objetivo: Este estudo pretende avaliar as potenciais interações medicamentosas com a varfarina, descrever e quantificar as intervenções farmacêuticas para minimizá-las, verificar o grau de aceitação da equipe médica em relação às intervenções e a repercussão no resultado do RNI. Método: Estudo de coorte, realizado entre os meses de agosto de 2009 a janeiro de 2010, envolvendo pacientes internados que iniciaram o tratamento com varfarina em duas unidades de clínica médica em um hospital universitário localizado no sul do Brasil. As potenciais interações medicamentosas com a varfarina (graves e moderadas) foram identificadas no sistema Drug-Reax, Micromedex Healthcare. Outras informações foram obtidas diretamente no prontuário. As intervenções com a equipe médica ocorreram por meio de registro em prontuário ou por informação verbal. O valor do RNI (Relação Normatizada Internacional) foi constantemente monitorado e serviu como medida do resultado da intervenção. Resultados: Foram acompanhados 202 pacientes. O total de medicamentos prescritos foi de 2071, com média de 10 (DP=3,6) por paciente. Todos pacientes apresentaram pelo menos uma interação medicamentosa potencial grave ou moderada com a varfarina, sendo a média de 3,6 (DP=1,6) por paciente. Pacientes com mais de 4 interações medicamentosas potenciais apresentaram maior risco para eventos hemorrágicos (RNI > 5 - RR = 2,57; IC95% 1,37–4,80). Foram identificadas 737 potenciais interações; 675 (91,5%) com possibilidade de potencializar o efeito anticoagulante e 29 (3,9%) de reduzir este efeito. Os medicamentos mais envolvidos em interações de potencialização foram enoxaparina (32,2%), sinvastatina (27,6%), omeprazol (22,5%) e tramadol (21,5%). Das intervenções realizadas com a equipe médica, 116 (57,4%) se deram através de registros em prontuário e 86 (42,6%) de forma verbal. Para 32 pacientes (15,8%) as intervenções não foram aceitas e estes apresentaram maior risco (RR = 2,17; IC95% 1,10 –4,27) para exame alterado (RNI > 5). Análise multivariada mostrou que idade, tempo de internação, apresentar 4 ou mais interações potenciais graves ou moderadas e não aceitar a intervenção farmacêutica contribuem significativamente para o paciente apresentar resultado de RNI > 5, o que implica em risco para eventos hemorrágicos. Conclusão: Interações medicamentosas graves e moderadas envolvendo a varfarina são muito comuns nos pacientes internados e estão associadas à maior risco do paciente apresentar RNI fora da faixa terapêutica desejada. A participação do farmacêutico no manejo das interações através de informações e orientações aos prescritores mostrou ter boa aceitação em nosso meio e parece contribuir para a segurança do paciente. / Introduction: Inadequate anticoagulation may cause bleeding and thromboembolic events, representing a challenge for medicine. Warfarin, an oral anticoagulant in wide use, has severe adverse reactions, common in patients taking multiple drugs. Objectives: This study aims to evaluate potential drug interactions with warfarin; to describe and quantify pharmaceutical interventions in order to minimize them; to assess the degree of acceptability by the medical team in relation to interventions as well as the impact on the outcome of the INR. Method: A Cohort study, done between August 2009 and January 2010 involving hospitalized patients who started warfarin therapy in two internal medicine units in a university hospital located in southern Brazil. Potential pDDIs with warfarin with warfarin (major and moderate) were identified in the online system Drug-Reax, Micromedex Healthcare. Additional information was obtained directly from medical records. Interventions with medical team were through medical record notes or verbal information. The value of the INR (international normalized ratio) was continuously monitored and served as a measure of the outcome of the intervention. Results: Two hundred and two inpatients were followed. The total number of prescribed drugs was 2071, with mean of 10 (SD = 3.6) per patient. All inpatients had at least one potential moderate or severe pDDIs with warfarin, the mean was 3.6 (SD = 1.6) per patient. Patients with more than four potential drug interactions showed a higher risk for hemorrhagic problems (INR> 5 - RR = 3.00, 95% CI 1.59-5.70). For 737 pDDIs identified, 675 (91.5%) may result in increased anticoagulation activity and 29 (3.9%) may reduce this effect. The drugs most commonly involved in these pDDIs were enoxaparin (32.2%), simvastatin (27.6%), omeprazole (22.5%) and tramadol (21.5%). The medical team’s intervention were 116 (57.4%) through medical records and 86 (42.6%) were orally. For 32 patients (15.8%), interventions were not accepted and they had higher risk (RR = 2.17; 95% CI 1.10 – 4.27) for amended exam (INR > 5). Multivariate analysis showed that age, length of hospital stay, having four or more major or moderate potential interactions and unwillingness to accept pharmaceutical intervention contribute significantly to the patient current values of INR> 5, which implies a risk of bleeding. Conclusion: Major and moderate drug interactions involving warfarin are very common in hospitalized patients and are associated with patient’s high risk of having an INR outside the target range. The collaboration of pharmacists in the management of interactions with information and guidance to physicians showed a good acceptance and seems to contribute to patient safety.

A anticoagulação inadequada pode ocasionar eventos tromboembólicos e hemorrágicos, representando um desafio para a medicina. A varfarina, anticoagulante oral de amplo uso, está associada a reações adversas graves, frequentes nos pacientes em tratamento com múltiplos fármacos. Objetivo: Este estudo pretende avaliar as potenciais interações medicamentosas com a varfarina, descrever e quantificar as intervenções farmacêuticas para minimizá-las, verificar o grau de aceitação da equipe médica em relação às intervenções e a repercussão no resultado do RNI. Método: Estudo de coorte, realizado entre os meses de agosto de 2009 a janeiro de 2010, envolvendo pacientes internados que iniciaram o tratamento com varfarina em duas unidades de clínica médica em um hospital universitário localizado no sul do Brasil. As potenciais interações medicamentosas com a varfarina (graves e moderadas) foram identificadas no sistema Drug-Reax, Micromedex Healthcare. Outras informações foram obtidas diretamente no prontuário. As intervenções com a equipe médica ocorreram por meio de registro em prontuário ou por informação verbal. O valor do RNI (Relação Normatizada Internacional) foi constantemente monitorado e serviu como medida do resultado da intervenção. Resultados: Foram acompanhados 202 pacientes. O total de medicamentos prescritos foi de 2071, com média de 10 (DP=3,6) por paciente. Todos pacientes apresentaram pelo menos uma interação medicamentosa potencial grave ou moderada com a varfarina, sendo a média de 3,6 (DP=1,6) por paciente. Pacientes com mais de 4 interações medicamentosas potenciais apresentaram maior risco para eventos hemorrágicos (RNI > 5 - RR = 2,57; IC95% 1,37–4,80). Foram identificadas 737 potenciais interações; 675 (91,5%) com possibilidade de potencializar o efeito anticoagulante e 29 (3,9%) de reduzir este efeito. Os medicamentos mais envolvidos em interações de potencialização foram enoxaparina (32,2%), sinvastatina (27,6%), omeprazol (22,5%) e tramadol (21,5%). Das intervenções realizadas com a equipe médica, 116 (57,4%) se deram através de registros em prontuário e 86 (42,6%) de forma verbal. Para 32 pacientes (15,8%) as intervenções não foram aceitas e estes apresentaram maior risco (RR = 2,17; IC95% 1,10 –4,27) para exame alterado (RNI > 5). Análise multivariada mostrou que idade, tempo de internação, apresentar 4 ou mais interações potenciais graves ou moderadas e não aceitar a intervenção farmacêutica contribuem significativamente para o paciente apresentar resultado de RNI > 5, o que implica em risco para eventos hemorrágicos. Conclusão: Interações medicamentosas graves e moderadas envolvendo a varfarina são muito comuns nos pacientes internados e estão associadas à maior risco do paciente apresentar RNI fora da faixa terapêutica desejada. A participação do farmacêutico no manejo das interações através de informações e orientações aos prescritores mostrou ter boa aceitação em nosso meio e parece contribuir para a segurança do paciente. / Introduction: Inadequate anticoagulation may cause bleeding and thromboembolic events, representing a challenge for medicine. Warfarin, an oral anticoagulant in wide use, has severe adverse reactions, common in patients taking multiple drugs. Objectives: This study aims to evaluate potential drug interactions with warfarin; to describe and quantify pharmaceutical interventions in order to minimize them; to assess the degree of acceptability by the medical team in relation to interventions as well as the impact on the outcome of the INR. Method: A Cohort study, done between August 2009 and January 2010 involving hospitalized patients who started warfarin therapy in two internal medicine units in a university hospital located in southern Brazil. Potential pDDIs with warfarin with warfarin (major and moderate) were identified in the online system Drug-Reax, Micromedex Healthcare. Additional information was obtained directly from medical records. Interventions with medical team were through medical record notes or verbal information. The value of the INR (international normalized ratio) was continuously monitored and served as a measure of the outcome of the intervention. Results: Two hundred and two inpatients were followed. The total number of prescribed drugs was 2071, with mean of 10 (SD = 3.6) per patient. All inpatients had at least one potential moderate or severe pDDIs with warfarin, the mean was 3.6 (SD = 1.6) per patient. Patients with more than four potential drug interactions showed a higher risk for hemorrhagic problems (INR> 5 - RR = 3.00, 95% CI 1.59-5.70). For 737 pDDIs identified, 675 (91.5%) may result in increased anticoagulation activity and 29 (3.9%) may reduce this effect. The drugs most commonly involved in these pDDIs were enoxaparin (32.2%), simvastatin (27.6%), omeprazole (22.5%) and tramadol (21.5%). The medical team’s intervention were 116 (57.4%) through medical records and 86 (42.6%) were orally. For 32 patients (15.8%), interventions were not accepted and they had higher risk (RR = 2.17; 95% CI 1.10 – 4.27) for amended exam (INR > 5). Multivariate analysis showed that age, length of hospital stay, having four or more major or moderate potential interactions and unwillingness to accept pharmaceutical intervention contribute significantly to the patient current values of INR> 5, which implies a risk of bleeding. Conclusion: Major and moderate drug interactions involving warfarin are very common in hospitalized patients and are associated with patient’s high risk of having an INR outside the target range. The collaboration of pharmacists in the management of interactions with information and guidance to physicians showed a good acceptance and seems to contribute to patient safety.

Vitamin K Antagonists [VKA] are the most frequently used oral anticoagulants in clinical practice; however, many patients fail to achieve adequate anticoagulation control. We conducted a randomized, placebo controlled, double blind study of Vitamin K1 (200mcg per day, Swanson Vitamins) in a population with predominantly venous thromboembolism aimed at evaluating its effectiveness in improving anticoagulation control in unstable patients. This study also aimed to evaluate the impact that clinical variables, patient anticoagulation knowledge, and genetic polymorphisms in genes known to impact warfarin and Vitamin K metabolism [VKORC1, CYP4F2, CYP2C9] had on anticoagulation control and intervention effectiveness. A total of N=54 patients were enrolled in the study over 15 months [January 2009 to June 2010]. Change score analysis and multivariate linear regression modelling of anticoagulation control measures were performed. No statistically significant reduction was observed in the Vitamin K1 arm for percent time in therapeutic range; however, reduction was observed in standard deviation of INRs [Change Score Vitamin K = -0.259, p=0.0261; Regression Model 95% C.I Beta Vitamin K = 0.38 to -0.08] during the intervention period. Adjusting for treatment group allocation, independent predictors of increased INR standard deviation included: >5 alcoholic drinks per week [95% C.I Beta = 0.04 to 0.41], self-reported dosing errors [95% C.I Beta = 0.13 to 0.47], and missed INR appointments [95% C.I Beta = 0.002 to 0.05]

Class of 2010 Abstract / OBJECTIVES: To compare the INR-based results of pharmacist anticoagulation management services to non-pharmacist managed anticoagulation therapy. METHODS: A meta-analysis was performed using studies that reported on pharmacists’ services and interventions in anticoagulation. Two reviewers independently assessed each record retrieved by the literature search, and studies were eliminated if both reviewers agreed that the study did not meet the inclusion criteria. The analysis found eight studies that were eligible for inclusion. The primary independent variable was the presence or absence of pharmacist services. The primary dependent variables were the proportion of patients within INR range, the duration of time within that range, and the time required to achieve that range. Extracted data were pooled and entered into the meta-analysis, and a forest plot was constructed. The a-priori alpha level was 0.05. RESULTS: The eight studies were divided into two groups: The INR group consisted of four studies which used INR test data points as the unit of analysis. The Patient group included four studies which measured the patient’s INR only at the end of the study. The INR group demonstrated a significant difference favoring pharmacist services, with a p-value of 0.02 for the group. There was no significant difference between pharmacist services and the control group with respect to the Patient group. When all eight studies were pooled together, the overall forest plot did demonstrate significant favorability for pharmacist services, with an odds ratio of 1.58, indicating that pharmacist provided services improved care by 58% (Z = 2.8;p p = 0.01). CONCLUSIONS: The advantage of a pharmacist service in reaching goal INR was significant compared to the control group of non- pharmacist care.

Vitamin K Antagonists [VKA] are the most frequently used oral anticoagulants in clinical practice; however, many patients fail to achieve adequate anticoagulation control. We conducted a randomized, placebo controlled, double blind study of Vitamin K1 (200mcg per day, Swanson Vitamins) in a population with predominantly venous thromboembolism aimed at evaluating its effectiveness in improving anticoagulation control in unstable patients. This study also aimed to evaluate the impact that clinical variables, patient anticoagulation knowledge, and genetic polymorphisms in genes known to impact warfarin and Vitamin K metabolism [VKORC1, CYP4F2, CYP2C9] had on anticoagulation control and intervention effectiveness. A total of N=54 patients were enrolled in the study over 15 months [January 2009 to June 2010]. Change score analysis and multivariate linear regression modelling of anticoagulation control measures were performed. No statistically significant reduction was observed in the Vitamin K1 arm for percent time in therapeutic range; however, reduction was observed in standard deviation of INRs [Change Score Vitamin K = -0.259, p=0.0261; Regression Model 95% C.I Beta Vitamin K = 0.38 to -0.08] during the intervention period. Adjusting for treatment group allocation, independent predictors of increased INR standard deviation included: >5 alcoholic drinks per week [95% C.I Beta = 0.04 to 0.41], self-reported dosing errors [95% C.I Beta = 0.13 to 0.47], and missed INR appointments [95% C.I Beta = 0.002 to 0.05]

Class of 2011 Abstract / OBJECTIVES: To assess the outcomes of care for patients enrolled in a pharmacist-run anticoagulation clinic. METHODS: A retrospective chart review was conducted of patients who received warfarin anticoagulation therapy management at the pharmacist-managed clinic at a community health center. To be eligible for the study patients had to be between the ages of 18-80 and have at least 6 recorded INRs during the first 6 months of treatment in the clinic. The patient data were reviewed for a time period of 24 weeks from the initial visit. The primary dependent variable was whether or not a patient’s INR is within range. Secondary outcomes included frequency of adverse events (blood in urine or stool). A data extraction form was used to collect patient demographics and initial INR values from the patient charts. An odds ratio was used to compare the proportion of INRs in range upon entry into the clinic and after 6 months of care in the clinic. In addition, outcomes were evaluated for differences by gender and age. RESULTS: Sixty-six patients were included in the study; 50% (33) were men and the average age was 55.9 years old (SD = 12.9 years). At baseline, 24 patients had INRs within the therapeutic range. Patients were 5 times more likely to have INRs in range (N = 49; OR = 5.04; p < 0.001) after 6 months of treatment in the pharmacist-managed clinic than at baseline. About 59% of men and 54% of women had INRs in range during 6 months of therapy in the clinic (p=0.326). Patients under 55 were in range about 55% of the time over 6 months, while patients over 55 were in range about 59% of the time (p=0.366). CONCLUSION: Patients enrolled in the pharmacist-run anticoagulation clinic were more likely to have therapeutic INRs after 6 months of care in the clinic compared to baseline.

Vitamin K Antagonists [VKA] are the most frequently used oral anticoagulants in clinical practice; however, many patients fail to achieve adequate anticoagulation control. We conducted a randomized, placebo controlled, double blind study of Vitamin K1 (200mcg per day, Swanson Vitamins) in a population with predominantly venous thromboembolism aimed at evaluating its effectiveness in improving anticoagulation control in unstable patients. This study also aimed to evaluate the impact that clinical variables, patient anticoagulation knowledge, and genetic polymorphisms in genes known to impact warfarin and Vitamin K metabolism [VKORC1, CYP4F2, CYP2C9] had on anticoagulation control and intervention effectiveness. A total of N=54 patients were enrolled in the study over 15 months [January 2009 to June 2010]. Change score analysis and multivariate linear regression modelling of anticoagulation control measures were performed. No statistically significant reduction was observed in the Vitamin K1 arm for percent time in therapeutic range; however, reduction was observed in standard deviation of INRs [Change Score Vitamin K = -0.259, p=0.0261; Regression Model 95% C.I Beta Vitamin K = 0.38 to -0.08] during the intervention period. Adjusting for treatment group allocation, independent predictors of increased INR standard deviation included: >5 alcoholic drinks per week [95% C.I Beta = 0.04 to 0.41], self-reported dosing errors [95% C.I Beta = 0.13 to 0.47], and missed INR appointments [95% C.I Beta = 0.002 to 0.05]

Statement of the problem: The risk-benefit profile of warfarin anticoagulation in hemodialysis (HD) patients differs compared to the non-HD population. Computerized decision support systems (CDSS) to assist with anticoagulation management are safe and effective in the non-HD population but had not previously been studied in HD outpatients. Methods of investigation: A before – after study compared anticoagulation control during pre-existing, nephrologist-led anticoagulation management to that following implementation of a pharmacist-led, CDSS-assisted strategy, in HD patients on warfarin at The Ottawa Hospital. Results: Forty-two patients were included. Following implementation of the CDSS-assisted strategy, median time-in-range increased by 3.7% (IQR, -9.5% - 20.6%; p = 0.247). Median frequency of INR tests per day decreased: -0.040 (IQR, -0.074 to –0.0008; P = 0.0001). Adverse events were similar. Conclusion: A CDSS-assisted strategy for anticoagulation management in HD patients is effective, safe and may lead to cost savings related to less frequent INR testing.

Pulmonary embolism (PE) is a common clinical problem affecting 600,000 patients per year in the United States. Although the diagnosis can be easily confirmed by imaging techniques, such as computed tomographic angiography of the chest, the identification of underlying mechanism leading to PE is important for appropriate duration of anticoagulation, and prevention of subsequent episodes. The differential diagnosis of underlying mechanism is broad and must include careful review of medication history. Drug-related thromboembolic disease can be easily missed and may have catastrophic consequences. The identification of the culprit drug is important for prevention of subsequent episodes and choosing appropriate duration of anticoagulation. We report a case of a middle-aged man who developed PE after administration of intravenous immunoglobulin.

Orientador: Maria Elvira Pizzigatti Correa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-14T11:31:27Z (GMT). No. of bitstreams: 1 Basso_FernandaGoncalves_M.pdf: 2327570 bytes, checksum: 79b8d36d7cb580fa421c4ca5a21a76a1 (MD5) Previous issue date: 2009 / Resumo: Fibrinólise é o processo responsável pelo restabelecimento do fluxo sanguíneo no interior dos vasos, através da dissolução do coágulo formado após uma injúria vascular. Esse processo pode ser influenciado por diferentes fatores, como trauma tecidual e presença de processos inflamatórios ou infecciosos, que podem causar um aumento da atividade fibrinolítica local. Esse aumento, por sua vez, poderia causar a dissolução precoce do coágulo, aumentando o risco de eventos hemorrágicos pós-procedimentos invasivos, como extrações dentárias, principalmente em pacientes cujo processo hemostático encontra-se alterado, como aqueles sob anticoagulação oral. Portanto, o objetivo deste estudo foi o de avaliar a atividade fibrinolítica da cavidade oral de pacientes sob terapia de anticoagulação cumarínica, avaliando também fatores locais que pudessem influenciar esta atividade. Para tanto, foram selecionados 12 pacientes sob terapia de anticoagulação cumarínica com indicação para extrações dentárias, que foram submetidos a 20 procedimentos. Esses pacientes foram também submetidos à avaliação clínica e radiográfica, além de avaliação dos índices de saúde oral (Índice Gengival, índice de Placa e CPOD). Para avaliar a atividade fibrinolítica, foram coletadas amostras de saliva não-estimulada, pré e pós-procedimento de extração dentária, de sangue alveolar e de sangue periférico. Essas amostras de saliva e de sangue foram submetidas à avaliação da atividade fibrinolítica através do teste de Área de Lise em Placa de Fibrina. Para análise do nível de anticoagulação, foram realizados os testes de Tempo de Protrombina e análise da atividade dos fatores da coagulação dependentes de vintamina K (FII, FVII, FIX e FX). Nenhum evento hemorrágico foi observado no período pós-extração dentária. Os resultados do estudo da atividade fibrinolítica no sangue mostraram que esta foi maior na amostra de sangue alveolar, quando comparada ao sangue periférico (p=0,006). Essa atividade, por sua vez, apresentou correlação estatisticamente significativa com os índices de saúde oral (p=0,003/p=0,002). Os resultados do estudo da atividade fibrinolítica salivar mostraram um aumento significativo desta atividade após o procedimento de extração dentária (p=0,002/ p=0,003). Esse resultado, no entanto, não pôde ser correlacionado à variação do fluxo salivar e tampouco aos índices de saúde oral (IG e IP). Quando correlacionados a atividade fibrinolítica do sangue periférico e o nível de anticoagulação, estes não apresentaram correlação positiva (p=0,28). A correlação entre a atividade fibrinolítica do sangue alveolar e o nível de anticoagulação se mostrou limítrofe (p=0,053). A atividade fibrinolítica da cavidade oral parece estar fortemente associada aos fatores locais, como trauma tecidual e eventos inflamatórios, não apresentando a mesma associação com a anticoagulação. / Abstract: Fibrinolysis is a part of the haemostatic process that is responsible for reestablish the blood flow, by the dissolution of the fibrin clot formed after a vascular injury. This process can be altered by several factors, such as tissue trauma and presence of inflammatory or infectious process, which can increase the local fibrinolytic activity and, by that, cause precocious clot dissolution. This could increase the hemorrhagic risk after invasive procedures, like teeth extractions, especially in patients under oral anticoagulation. The aim of this study was to evaluate the oral fibrinolytic activity of patients under oral anticoagulation with cumarin agents and also to evaluate the local factors that could be involved on this activity. Twelve patients under oral anticoagulation who needed teeth extractions were enrolled on this study and submitted to twenty teeth extractions. These patients were submitted to clinical and radiographic evaluation and oral health analysis, by the measurement of oral health indexes (Gingival Index, Plaque Index and Decayed, Missing and Filled Teeth). Samples of non-stimulated saliva were collected before and after each procedure and samples of alveolar and peripheral blood were also collected. These samples were submitted to fibrinolytic activity analysis, by the Fibrin Plate Method. For the anticoagulation analysis, prothrombin time assay and analysis of activity of vitamin-K-dependent coagulation factors (II, VII, IX and X) were performed. As result, no hemorrhagic event was observed after the procedures. The results of the blood fibrinolytic activity analysis showed that the alveolar blood presented a higher fibriolytic activity than the peripheral blood (p=0,006). This activity also showed a positive correlation with the oral health indexes (p=0,003 - GI/ p=0,002 - PI). The salivary fibrinolytic activity showed a significant increase after the tooth extraction (p=0,002 - supernatant fraction/p=0,003 - precipitated fraction). This activity, however, could not be associated with the oral health indexes. The level of anticoagulation showed no correlation with the fibrinolytic activity of peripheral blood (p=0,28) and showed a bordering correlation with the fibrinolytic activity of the alveolar blood (p=0,053). The fibrinolytic activity of the oral cavity seems to be strongly associated to local factors, such as local trauma and local inflammatory conditions, not showing the same association to the oral anticoagulation itself. / Mestrado / Patologia / Mestre em Estomatopatologia