PhD Thesis / Long-term persistence with oral anticoagulants (OAC) in atrial fibrillation (AF) is associated with improved outcomes. However, 1-year discontinuation of vitamin K antagonists (VKA) is as high as 50%. Persistence to non-VKA oral anticoagulants (NOAC) show some signal of improvement but the estimates are variable. This thesis includes a prospective evaluation of newly diagnosed AF patients in 44 countries using physician reported start and stop dates of anticoagulation. One-year persistence to dabigatran was 75.6% and 69.2% at 2 years. Approximately half of discontinuers switched to another OAC, increasing estimates of general overall 2-year OAC persistence to 84.1%. Probability of discontinuation was highest in the first 6 month period (83.7%, 95% confidence interval [CI] 82.7-84.8%) and lower in successive periods. Patients persistent with dabigatran at 1 year had >90% probability of remaining persistent at 2 years. Patients with symptomatic AF, and prior bleeding had higher discontinuation, those with prior stroke, lower discontinuation. Standardized stroke incidence rates post-discontinuation were (95% CI) 1.76 (0.89 to 2.76) in non-switchers, and 1.02 (0.43 to 1.76) in those who switched, consistent with the expected benefit of remaining on treatment. Supplemental patient education may be one mechanism to improve persistence to treatment and improve patient outcomes. A systematic review of the impact of education on outcomes in 9 randomized clinical trials showed low to very low certainty of evidence for benefit of education over usual care. Sufficiently powered trials or different approaches are required to further assess the impact of education on patient outcomes. Finally, important considerations for interpreting available research in OAC persistence, including differences in study methodology, setting, and timing are examined, and patient factors associated with higher or lower persistence reported. A framework for assessing persistence studies is presented to assist researchers and clinicians in evaluating current research and to support planning of future studies. / Dissertation / Doctor of Philosophy (PhD) / Oral anticoagulants (OAC) are approved for stroke prevention in atrial fibrillation (AF) patients, however discontinuation rates are high and associated with poor patient outcomes. Prior to the last decade, medications to reduce blood clotting by reducing vitamin K action [vitamin K antagonists (VKA)] were primarily used. However, up to 50% of patients discontinue VKA within one year. The introduction of non-VKA (NOAC) anticoagulants that do not require continuous monitoring or dose adjustments, show some promise of improvement in persistence. This thesis examines and reports on long-term persistence over 2 years to the first NOAC available, dabigatran. Reasons, clinical predictors, and periods of risk for discontinuation as well as outcomes following discontinuation are prospectively examined. A systematic review of educational interventions examines existing evidence for improving outcomes with structured education. Finally, important considerations for interpreting OAC persistence research as well as recommendations for future research in this area are discussed.

The use of extracorporeal membrane oxygenation (ECMO) in the treatment of acute respiratory failure patients has demonstrated improvement on patient survivability when compared to conventional treatment using mechanical ventilation. The purpose of this project was to complete a retrospective review of the data acquired over the six years the ECMO program has been operating at BUMCP in order to describe relationships between different anticoagulation strategies and patient outcomes. Data was collected from patients who were over the 18 years of age, treated with the veno-venous modality of ECMO, with an acute respiratory failure, and treated between May 1st, 2010 and June 31, 2016. Several dependent were analyzed seeking to explain potential relationships between different anticoagulation strategies and patient outcomes. Overall, the patients treated with veno-venous ECMO at BUMCP experienced a 55% survival to discharge rate. The group that received no heparin had the lowest survival to discharge rate at 33% which suggests that the use of heparin may be beneficial in ECMO patients. The titrated heparin group had the highest average hemoglobin (10.5 g/dl, SD 1.2) yet required the most units of PRBCs to be transfused (17.9 units, SD 21.6). The average ACT for this group was also highest at 174.8 (SD 24.7) suggesting that more transfusions were required due to bleeding complications from the use of heparin. A higher ACT also was associated with an increased length of stay. The only statistically significant relationship noted in the study was a positive relationship between ACT and hemoglobin level in the titrated heparin group (r = .450, p = .005) suggesting that as the ACT increased so did the patient’s average hemoglobin level. Conclusions: This study found evidence that suggested the use of heparin in ECMO patients may have a positive impact on their survival. Furthermore, patients who were exposed to a set rate of heparin experienced a greater survival to discharge rate and required fewer transfusions of PRBCs during their hospital stay. However, further research is needed to address potential co-morbidities that may have had an impact on patient survival as well as transfusion requirements.

Class of 2015 Abstract / Objectives: Argatroban is the current drug of choice for type II heparin induced thrombocytopenia. Primarily metabolized by the liver, this direct thrombin inhibitor has a volume of distribution of approximately 174 mLs per kg. While few studies suggested no differences in coagulation parameters or clinical outcomes between obese and non-obese populations receiving argatroban, a recent case report revealed elevated anticoagulation parameters for 20 days post argatroban discontinuation in a morbidly obese female. The purpose of this study is to assess anticoagulation parameters in obese and non-obese patients in an intensive care unit (ICU) setting who received argatroban treatment during their stay. Methods: This is a retrospective, observational, single-centered study. Participants of the study must be adults, at least 18 years of age. Patient must be an inpatient and have received argatroban for either suspected or confirmed heparin-induced thrombocytopenia (HIT). All patients in the study were screened for the above criteria between November 2008 and September 2013. Patients admitted to the cardiac ICU were excluded from the study. Main anticoagulation parameters post discontinuation evaluated were daily international normalized ratio (INR) and activated partial thromboplastin time (aPTT), while safety outcomes included major, minor and non-bleed events. All data were analyzed with STATA 13 with P less than 0.05 being considered as statistically significant. Results: The study included a total of 51 patients, 37 were non-obese with body mass index (BMI) less than 30 kg per m2 (73 percent), and 14 were obese with BMI greater or equal to 30 kg per m2 (27 percent). Among basic demographic data, no differences were found between age, sex, race, height and SOFA scores at baseline between the two groups, BMI less than 30 kg per m2 and BMI greater or equal to 30 kg per m2. (P equals 0.7, 0.21, 1.0, 0.41, 0.51 respectively). However, as expected, weight was the only characteristic that was different at baseline (P less than 0.01). Primary outcome of time of INR to normalization post argatroban administration (2.73 seconds plus or minus 0.27 seconds) as well as safety outcomes including major, minor, and non-bleed adverse events (P equals 0.61) were statistically non-significant between the two groups. Conclusions: In this retrospective, observational, single centered study, no differences were identified between non-obese and obese groups in terms of argatroban administration, primary anticoagulation parameters, and safety outcomes. The length of time required for coagulation parameters to normalize after discontinuation of argatroban therapy for HIT does not appear to be influenced by BMI. Large, multicenter, and random controlled trials are needed to evaluate obesity on pharmacokinetic parameters and clinical outcomes of argatroban.

Isolated distal deep vein thrombosis (IDDVT) is a condition recently suggested to be a different entity to that of proximal disease. There is currently little evidence defining the clinical importance of detection and treatment. International guidelines vary regarding management advice.An observational cohort study, prospective service evaluation and pilot randomised controlled trial were performed within a United Kingdom ambulatory thrombosis service. This project aimed to describe the burden of disease and explore three poorly researched aspects of IDDVT assessment and management: whole-leg compression ultrasound (CUS) performed by non-physicians within an ambulatory framework as a principal diagnostic modality; clinical presentation data and risk profile in comparison to that of proximal disease; the feasibility of further interventional randomised research and the risk/benefit profile of therapeutic anticoagulation.Within this ambulatory cohort, IDDVT accounted for 49.7% of acute thrombosis and differed significantly to proximal disease regarding provocation and symptomatology at clinical presentation. A negative whole-leg CUS excluded deep vein thrombosis with an adverse event rate (diagnosis of symptomatic venous thromboembolism during the 3 month follow up period) of 0.47% (95% CI 0.08 to 2.62). Future interventional research was proved feasible within an ambulatory setting.The randomised controlled trial conducted within this project is the largest to date comparing therapeutic anticoagulation against conservative strategy for the management of acute IDDVT. Patients allocated to therapeutic anticoagulation had significantly less overall propagation of thrombus (Absolute risk reduction [ARR] 25.7%, 95% Confidence interval 5.9 to 44.3 p<0.01), less short-term symptomatic progression (ARR 16.7%, 95% CI 2.6 to 32.1 p=0.05) and a result trending towards significance for reduction in serious thromboembolic complications (ARR 11.4%, 95% CI -1.5 to 26.7 p=0.11).IDDVT is a condition of equal prevalence to proximal venous thrombosis, which varies significantly regarding risk profile and clinical presentation. Using a single whole leg CUS reported by a non-physician within an emergency department pathway is associated with a low adverse event rate. This contemporary data also suggests that therapeutic anticoagulation is beneficial for reduction of short-term complications in IDDVT. The risk of false positive diagnosis and excess anticoagulation remains.This data can inform and direct future design of adequately powered randomised studies, in order to attempt external validation of these findings.

Patients with valvular pathology who require heart valve replacement surgery are faced with the option between a bioprosthetic heart valve (BHV) or a mechanical heart valve (MHV). BHVs have a limited lifespan and are prone to structural degeneration. In contrast, MHVs are free from structural deterioration, but necessitate lifelong anticoagulation due to a more robust activation of coagulation. This is usually achieved in the outpatient setting with the use of vitamin K antagonists (VKAs), such as warfarin. Due to the cumbersomeness of managing warfarin with regular monitoring and its numerous food- and drug-drug interactions, other oral anticoagulants were sought. Within the last decade, the advent of the direct oral anticoagulants (DOACs) has largely supplanted warfarin and other VKAs for numerous indications, including stroke prevention in atrial fibrillation and prevention and treatment of venous thromboembolism. When evaluated in a clinical trial in patients with MHVs however, use of the thrombin-directed DOAC, dabigatran, led to an increase in both bleeding and clotting; prompting a halt to the study and a black box warning against the use of dabigatran and other DOACs in patients with MHVs. The cause of this failure at the time was not understood and prompted the investigations detailed in this thesis. The work described within this thesis sought primarily to understand why dabigatran failed to adequately provide thrombo-protection for patients with MHVs. Firstly, the mechanism of thrombin generation on MHVs was identified as being initiated and propagated through the contact and intrinsic pathways, respectively. Within this same work, a mechanism for the failure of dabigatran and the efficacy of warfarin was presented. It was shown that dabigatran concentrations of greater than 250ng/mL were required to suppress thrombin generation, whereas the same effect could be achieved with warfarin at an INR of 1.5 or greater. Secondly, the effect of the other DOACs, rivaroxaban and apixaban, on MHV-induced thrombin generation was assessed, and we showed that individually, these two DOACs were unable to suppress thrombin generation within clinically-relevant dosing regimens. We also evaluated a combination of dabigatran and rivaroxaban to determine whether the combination would be superior to either agent alone at suppressing MHV-induced thrombin generation. Lastly, the capacity of two assays – the ecarin chromogenic assay and the dilute thrombin time – to detect both on treatment and low levels of dabigatran is presented as a tool for clinicians to determine whether patients taking dabigatran can safely undergo procedures or whether they necessitate rapid reversal in emergent situations. / Thesis / Doctor of Philosophy (PhD)

One of the most fundamental aspects of extracorporeal membrane oxygenation (ECMO) is maintaining proper anticoagulation management in order to prevent hemorrhagic or thrombotic events. Anticoagulation on ECMO is most commonly achieved with the use of unfractionated heparin to maintain a minimum anticoagulation level as monitored by activated clotting time (ACT). Heparin's main effect is exerted by binding to and potentiating antithrombin III. Many factors may contribute to a sub-therapeutic ATIII level that may decrease the effectiveness of heparin. A retrospective record review was performed on all adult ECMO patients at the University of Arizona Medical Center between 2008 and 2011, in order to determine optimal ATIII levels for maintaining proper anticoagulation. In addition, we investigated correlations between ATIII levels and hemorrhagic and/or thrombotic events. Variables measured include, ACTs, heparin dose, ATIII dose, ATIII levels, blood product use, and adverse events. Thirty-five patients received ATIII over the course of the ECMO run. Six patients did not receive ATIII and they were found to have used significantly more blood products than those who did receive ATIII. Also, heparin dose dropped significantly 24h after the first dose of ATIII. There is a significant positive correlation between the amount of ATIII given per day and the amount of packed red blood cells transfused per day. The results suggest an ideal therapeutic range of ATIII dosing, where lack of or too much ATIII administration can lead to excessive bleeding.

Thesis (M.S.H.P.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / BACKGROUND: Percent time in therapeutic range (TTR) and INR variability are both used to measure anticoagulation control with warfarin. TTR measures anticoagulation intensity, while INR variability measures anticoagulation stability; both predict definitive clinical outcomes such as stroke, major hemorrhage. Here, we examine whether an intermediate composite measure (ICOMO) predicts warfarin associated complications better than each measure separately. We also examine how the choice of measure changes the ranking order of anticoagulation clinics (ACCs) in the Veterans Health Administration (VHA) healthcare system. METHODS: We calculated TTR and INR variability for the study sample (N=130,897 patients) from 100 VHA ACCs. We constructed ICOMO using an equally weighted method, adding standardized TTR to standardized log-transformed INR variability. We used a subset of patients anticoagulated for atrial fibrillation (N=40,404) and divided them into quintiles based on their level of control, for each anticoagulation measure. We calculated the Hazard ratios for ischemic stroke and major bleeding and compared the ability of our independent variables (TTR, log INR variability, ICOMO) to predict each outcome. We measured mean observed value (O) and mean expected value (E) for each clinic, after adjusting for important clinical and demographic variables, for each anticoagulation measure. We identified outlier anticoagulation clinics if O was one standard deviation different from its corresponding E. We measured Kappa score and Pearson correlation coefficients when ranking sites according to each anticoagulation measure. RESULTS: ICOMO predicted ischemic stroke better than TTR and log INR variability in all quintiles. ICOMO and TTR predicted major bleeding similarly except in the second-best quintile; but both measures were better than log INR variability in all quintiles. Kappa scores identifying outlier and non-outlier clinics among our three profiling measures were moderate between ICOMO and its components (0.59 for TTR and 0.54 for log INR variability) but was weak between TTR and log INR variability (0.025) CONCLUSION: ICOMO predicts ischemic stroke better over TTR and log INR variability alone but it is only better than the latter in predicting major bleeding. The choice of which measure to use for clinic profiling changes clinic rankings considerably. / 2031-01-01

To prevent clotting during dialysis, heparin is used to line the tubing which blood flows through. Unfortunately, many side effects arise from taking heparin, especially when it is used for an extended period of time. As such, long-term exposure for individuals undergoing dialysis every day is unavoidable. To prevent the solubilized heparin from entering the bloodstream, a polymer-based natural material is being investigated. This materials properties include reduction of coagulation and elimination of the long-term effects of heparin such as heparin induced thrombocytopenia and osteoporosis. Cellulose nanocrystals (CNCs) contain the same 1,4 linked pyranose backbone structure as heparin along with desirable mechanical properties, like high stiffness and anisotropic shape. By altering the functionalization on the surface of CNCs to closely mirror that of heparin, it should be possible to make a biomimetic material that counteracts blood clotting, while not introducing soluble small molecule anti-coagulants into the body. Through blood assays and platelet fixing analysis, we have been able to show that this change in functionalization does reduce coagulation. Surface chemistry of CNCs were modified from 'plain' CNCs (70 mmol SO3-/kg residual from hydrolysis) to 500 mmol COO-/kg (TEMPO oxidized) and 330 mmol SO3-/kg CNC (sulfonated CNCs). We will show that by utilizing CNCs reactive functional groups and incredible mechanical properties we are able to create a material that reduces clotting while maintaining the tubing's mechanical strength as well as eliminating heparin's side effects associated with it being a soluble anticoagulant. / MS / To prevent clotting during dialysis, heparin is used to line the tubing which blood flows through. Heparin, an anticoagulant, is more commonly known as a ‘blood thinner’ which is a misnomer because it does not actually thin blood. Heparin works by inhibiting clotting factors in the coagulation cascade pathway which in turn limit the formation of blood clots and create the ‘thinning’ effect mentioned earlier. When dialysis is performed the interaction between blood and the dialyzer tubing initiates the formation of a blood clot. This is where heparin use comes in. Unfortunately, many side effects arise from taking heparin, especially when it is used for an extended period of time. As such, long-term exposure for individuals undergoing dialysis every day is unavoidable. To prevent heparin or its mimics from entering the bloodstream, a polymer-based natural material is being investigated. The properties of this material will include reduction of coagulation and elimination of the long-term effects of heparin. The polymer-based natural material being investigated is cellulose nanocrystals (CNCs). CNCs contain the same ring structure and chemical linkage sites as heparin along with desirable mechanical properties. By altering the surface chemistry on the CNCs to closely mirror that of heparin, it should be possible to make a biomimetic material that counteracts blood clotting, while not introducing a solution based small molecule anticoagulant to the body. Through blood assays and platelet fixing analysis, we have been able to show that this change in functionalization does reduce coagulation. The ‘plain’ CNCs used contained an initial charge density of 70 mmol SO₃⁻ /kg. This residual charge density was a result from the acid hydrolysis performed to acquire CNCs from cellulose. Chemically modified CNCs contained many more negatively charged functional groups with TEMPO oxidized and sulfated CNCs having 500 mmol COO⁻/kg and 330 mmol SO₃⁻ /kg, respectively. We will show that by utilizing CNCs reactive functional groups and incredible mechanical properties we are able to create a material that reduces clotting while maintaining the tubing’s mechanical strength as well as eliminating heparin’s side effects associated with it being a soluble anti-coagulant.

L'objectif de ce travail est d'évaluer le rôle du facteur tissulaire (FT) dans l'initiation de la coagulation d'un circuit d'hémodialyse. A partir de l'analyse des membranes d'hémodialyse, nous avons observé que les leucocytes et, majoritairement les polynucléaires neutrophiles (PNN) adhéraient aux membranes hémocompatibles (de type AN69ST). Ces cellules expriment un FT fonctionnel. Nous avons développé différents modèles d'étude de l'expression du FT par les PNN. A partir de PNN humains obtenus chez des sujets sains, nous montrons que les PNN expriment le FT après stimulation par le TNF. L'IL-8, chemokine chimioattractante des PNN augmentent, par un effet de priming, l'expression de FT en réponse au TNF. L'inhibition de l'adhésion par un anticorps dirigé contre les β2-intégrines, induit une diminution de l'expression de FT en réponse au TNF. L'inhibition de la voie de signalisation MEK1/2, la p38 MAPK, et des radicaux libres oxygénés, inhibe également cette expression. A partir de PNN provenant de péritonites secondaires à une dialyse péritonéale, nous avons mis en évidence une forte expression de FT par ces PNN (ARNm et protéine). Le FT possède un fort potentiel pro-coagulant. Ce modèle physiopathologique est la conséquence d'une migration et d'une activation inflammatoire comparable au modèle que nous avons développé in-vitro. Dans l'objectif de faire la preuve de ce nouveau concept, nous avons évalué un facteur VII humain recombinant inactivé (FVIIai) dans un modèle d'hémodialyse chez le mouton. Nos résultats sont en faveur d'un effet anticoagulant du circuit d'hémodialyse, sans effet anticoagulant mesurable chez l'animal. / The objective of this study is to analyse the role of Tissue Factor, the unique physiological trigger on thrombin generation. Analysing haemodialysis membranes, we found that leukocytes, mainly polymorphonuclear neutrophils (PMN) adhere to hemocompatible (AN69ST) membranes. These cells express a functional TF. We next showed that human PMN obtained from healthy subjects expressed TF in response to TNF. IL-8, a major chemokine involved in PMN chemoattraction primed TNF-induced TF by PMN. TF expression was down regulated when 2 integrins were blocked by a potent antibody. The inhibition of MEK1/2, p38 MAPK and free radicals reduced TF expression. We observed, that PMN obtained from patients experiencing peritonitis, expressed high levels of TF (mRNA and protein). Functional assays measuring Xa generation and kinetics of thrombinn generation (thrombinography) indicate the stong procoagulant potential of these cells. This physiopathological model is close to our in vitro model as it results from PMN migration and inflammatoty activation. For proof of concept, we evaluated the effect of an inactivated human recombinant factor VIIa ( FVIIai) in a sheep model of hemodialysis. Our results show that FVIIai limits haemodialysis circuit coagulation without any measurable systemic anticoagulant effect

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.