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1.
Medicine (Baltimore) ; 99(36): e22084, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899083

RESUMO

RATIONALE: Dabigatran is a direct thrombin inhibitor that is widely used to prevent the formation of thrombus formation. Amiodarone can increase the plasma concentration of dabigatran. CES1 (carboxylesterase 1) and ABCB1 (ATP-binding cassette subfamily B member 1) genetic polymorphisms associate with the pharmacokinetics of dabigatran. PATIENT CONCERNS: A 62-year-old woman was admitted to the hospital due to chest tightness, fatigue, and discomfort despite long-term anticoagulation with dabigatran 110 mg twice daily for 6 months, with concomitant use of amiodarone. DIAGNOSES: Left atrial appendage thrombus formation with a history of atrial fibrillation. INTERVENTIONS: The clinician changed dabigatran to warfarin. To explore the causes of insufficient anticoagulation using dabigatran in this patient, we examined the ABCB1 and CES1 genes. Results showed that she carried ABCB1 variant alleles with 3 heterozygote single nucleotide polymorphisms (SNPs: rs4148738, rs1045642, rs2032582) and CES1 variant alleles with 2 heterozygote SNPs (rs2244613, rs4580160). OUTCOMES: The left atrial appendage thrombus disappeared. LESSONS: Multiple mutations in the ABCB1 and CES1 genes may influence the pharmacokinetics of dabigatran and could have contributed to the thrombus formation in the left atrial appendage.


Assuntos
Apêndice Atrial/patologia , Fibrilação Atrial/complicações , Hidrolases de Éster Carboxílico/genética , Trombose/etiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Antitrombinas/administração & dosagem , Antitrombinas/farmacocinética , Apêndice Atrial/diagnóstico por imagem , Dabigatrana/administração & dosagem , Dabigatrana/farmacocinética , Feminino , Humanos , Pessoa de Meia-Idade , Trombose/prevenção & controle
2.
Int Heart J ; 61(5): 905-912, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921660

RESUMO

There is little data on management and outcomes of atrial fibrillation (AF) patients on direct oral anticoagulants (DOAC) undergoing general surgery.We retrospectively assessed 98 surgeries in 85 nonvalvular AF patients aged 73 ± 8 (59 men) receiving DOACs. Cardiac, emergency, and minimally invasive surgeries were excluded.The CHA2DS2-VASc score ranged from 0 to 8. The DOACs being given were: dabigatran, 16; rivaroxaban, 25; apixaban, 28; and edoxaban, 16. While the DOACs were not suspended in 11 cases, they were interrupted for a median of 2.0 days before surgery and restarted at a median of 3.0 days after surgery. There were 9 complications (9.2%), 3 instances of thromboembolism and 6 bleeding. Thromboembolism occurred at a mean of 3.0 postoperative days, all of which occurred before resumption of DOACs, while bleeding events occurred at a mean of 4.0 postoperative days. Two of the 3 patients with thromboembolism went into cardiopulmonary arrest during the event, but were resuscitated. There were significantly more patients with congestive heart failure or combined antiplatelets in the patients with complications. The complication group had a significantly higher HAS-BLED score and lower preoperative hemoglobin level. There were no significant differences in the management of DOAC interruption between those with complications and without.The perioperative complication rate in nonvalvular AF patients undergoing elective surgery treating with DOACs was 9.2%. Patients with congestive heart failure, receiving combined therapy with antiplatelets, a higher HAS-BLED score, or lower preoperative hemoglobin level were at higher risk. Further studies evaluating the ideal perioperative DOAC protocol are warranted.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Doenças das Artérias Carótidas/epidemiologia , Infarto Cerebral/epidemiologia , Inibidores do Fator Xa/administração & dosagem , Infarto do Miocárdio/epidemiologia , Assistência Perioperatória/métodos , Hemorragia Pós-Operatória/epidemiologia , Tromboembolia/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Fibrilação Atrial/complicações , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Dabigatrana/administração & dosagem , Procedimentos Cirúrgicos do Sistema Digestório , Procedimentos Cirúrgicos Eletivos , Embolia/epidemiologia , Endoscopia , Feminino , Humanos , Masculino , Procedimentos Ortopédicos , Complicações Pós-Operatórias/epidemiologia , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Piridonas/administração & dosagem , Estudos Retrospectivos , Rivaroxabana/administração & dosagem , Tiazóis/administração & dosagem , Tromboembolia/etiologia , Procedimentos Cirúrgicos Urológicos , Procedimentos Cirúrgicos Vasculares
3.
Khirurgiia (Mosk) ; (7): 68-75, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32736466

RESUMO

The paper is a narrative review of the literature on the use of direct oral anticoagulants (DOACs) for the VTE treatment in challenging patients: senile age (≥75 years), impaired renal function (estimated glomerular filtration rate ≤50 ml/min), fragility (one of the previous characteristics and/or bodyweight ≤50 kg). The paper discusses the studies of EINSTEIN DVT and PE (rivaroxaban), AMPLIFY (apixaban), HOKUSAI-VTE (edoxaban), RE-COVER I and II (dabigatran) in the focus of the secondary analysis in the pre-specified patient's subgroups, as well as their pooled analyzes and meta-analyzes. Based on the results of this review, it was concluded that in a subgroup of senile age patients, dabigatran increases the risk of major bleeding by 4.8 times and has no advantages over vitamin K antagonists (VKA); rivaroxaban and apixaban retain superiority over VKA on the safety outcomes and reduce the risk of major bleeding by 73% and 77%. In the subgroup of patients with impaired renal function, the use of apixaban and dabigatran is associated with an increase in the risk of major bleeding by 6.5 and 7.3 times, and these DOACs do not have advantages over VKA; rivaroxaban retains its superiority over VKA and reduces the risk of major bleeding by 78%. For fragile patients, a secondary analysis is available only for rivaroxaban, which remains superior to VKA on safety endpoints and reduces the risk of major bleeding by 73%. In the absence of direct comparisons between the available DOACs, the presented data can be used as a rational approach for the choice of appropriate treatment for VTE in challenging patients.


Assuntos
Dabigatrana/efeitos adversos , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Insuficiência Renal/complicações , Rivaroxabana/efeitos adversos , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Fatores Etários , Idoso , Antitrombinas , Dabigatrana/administração & dosagem , Idoso Fragilizado , Humanos , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Tromboembolia Venosa/complicações
4.
Clin Drug Investig ; 40(9): 839-845, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32607688

RESUMO

BACKGROUND AND OBJECTIVE: Current guidelines recommend anticoagulation with a vitamin K antagonist (warfarin) after a bioprosthetic valve replacement. There is minimal literature evaluating direct oral anticoagulants (DOACs) in patients who have just received a bioprosthetic aortic valve replacement (AVR) or mitral valve replacement (MVR). The purpose of this study was to investigate any differences in efficacy and safety for patients taking a DOAC, compared with warfarin, after a bioprosthetic AVR or MVR. METHODS: A retrospective cohort study was performed to evaluate anticoagulation in patients who received bioprosthetic valve replacements at a large teaching hospital from 2014 to 2018. Patients included in this study received either warfarin or a DOAC following bioprosthetic AVR or MVR, and were maintained on the same agent throughout the 6-month follow-up period. The primary efficacy outcome was the incidence of thromboembolic complications and the primary safety outcome was the incidence of major bleeding within 6 months following surgery. The rate of readmission was assessed as a secondary endpoint. RESULTS: A total of 197 patients were included; 70 patients received warfarin and 127 patients received a DOAC (apixaban, n = 86; rivaroxaban, n = 40; dabigatran, n = 1). Three patients experienced thromboembolic events, all of which occurred in the DOAC group (0% vs. 2.4%; p = 0.20). Major bleeding occurred in 11 patients-two in the warfarin group and nine in the DOAC group (2.9% vs. 7.1%; p = 0.22). Sixty-one patients were readmitted within the 6-month time frame, with 26 readmissions in the warfarin group and 35 readmissions in the DOAC group (37% vs. 27%; p = 0.16). CONCLUSIONS: This small, exploratory study found similar rates of thromboembolic complications and major bleeding events in patients who received a DOAC versus warfarin after a recent bioprosthetic AVR or MVR. This study was limited by its retrospective nature and its sample size. Larger, randomized controlled trials are needed to further determine the efficacy and safety of DOACs in this patient population.


Assuntos
Anticoagulantes/uso terapêutico , Bioprótese , Dabigatrana/uso terapêutico , Próteses Valvulares Cardíacas , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Varfarina/uso terapêutico , Administração Oral , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Estudos Retrospectivos , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Tromboembolia/induzido quimicamente , Varfarina/administração & dosagem , Varfarina/efeitos adversos
5.
J Stroke Cerebrovasc Dis ; 29(8): 104924, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689602

RESUMO

Dabigatran is an orally active direct thrombin inhibitor, initially approved by FDA for the prophylaxis of stroke and systemic embolism in the setting of non-valvular atrial fibrillation (NVAF). Major bleeding is its most common adverse event which is of great concern. However, other types of adverse events such as esophagitis, esophageal ulcer, exanthem and pustular eruptions were reported increasingly in recent years. We present a case of immune hemolytic anemia (IHA) due to dabigatran use in a 72-year-old male with NVAF. This new and rare reported type of adverse event associated with dabigatran suggests that dabigatran may be a new cause of drug-induced immune hemolytic anemia (DIIHI).


Assuntos
Anemia Hemolítica Autoimune/induzido quimicamente , Antitrombinas/efeitos adversos , Dabigatrana/efeitos adversos , Idoso , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/tratamento farmacológico , Anemia Hemolítica Autoimune/imunologia , Antitrombinas/administração & dosagem , Doença Crônica , Dabigatrana/administração & dosagem , Progressão da Doença , Substituição de Medicamentos , Glucocorticoides/administração & dosagem , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Resultado do Tratamento , Varfarina/administração & dosagem
6.
Medicine (Baltimore) ; 99(25): e20570, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569181

RESUMO

The CHA2DS2-VASc scale does not include potential risk factors for left atrial appendage thrombus (LAAT) formation such as a form of atrial fibrillation (AF) and impaired kidney function. The real risk of thromboembolic complications in AF patients is still unclear as well as an optimal anticoagulant treatment in males with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2.The aim of this study was to compare the predictive value of the CHA2DS2-VASc scale and other scales to estimate the risk of LAAT formation in AF patients treated with non-vitamin K oral anticoagulants (NOACs) and to assess the prevalence of thrombi in patients at intermediate risk of stroke.The observational study included consecutive patients with a diagnosis of non-valvular AF treated with NOACs, admitted to 3 high-reference institutions between 2013 and 2018. All individuals underwent transoesophageal echocardiography before cardioversion or ablation.Out of 1163 enrolled AF patients (62.1% male, mean age 62 years) the LAAT had been detected in 50 individuals (4.3%). Among patients with LAAT, 1 patient (2.0%) was classified as a low-risk category, 9 (18.0%) were at intermediate-risk, and 40 (80.0%) were at high risk of thromboembolic complications according to CHA2DS2-VASc scale. All patients were treated with NOACs: 51.0% rivaroxaban, 47.1% dabigatran, and 1.9% apixaban.Patients at intermediate stroke-risk with detected LAAT had higher R2CHADS2 score (2.1 ±â€Š1.2 vs 1.2 ±â€Š0.8, P = .007), higher CHA2DS2-VASc-RAF score (6.4 ±â€Š4.4 vs 3.7 ±â€Š2.6, P = .027) and more often had an estimated glomerular filtration rate below 56 mL/min/1.73 m (44.4% vs 13.2%, P = .026) compared to patients without LAAT. The receiver operating characteristics revealed that the CHA2DS2-VASc-RAF scale had better predictive ability to distinguish between patients with and without LAAT in the study group than CHA2DS2-VASc (P = .0006), CHADS2 (P = .0006) and R2CHADS2 scale (P = .0140).The CHA2DS2-VASc scale should be supplemented with an assessment of renal function and form of AF to improve stroke risk estimation. The application of additional scales to estimate the risk of LAAT might be especially useful among males with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Idoso , Apêndice Atrial/efeitos dos fármacos , Ecocardiografia Transesofagiana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Tromboembolia/prevenção & controle
7.
Ulus Travma Acil Cerrahi Derg ; 26(3): 343-350, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32436968

RESUMO

BACKGROUND: Management of the skin degloving injuries is still a problematic issue, and the avulsed part of the skin may become necrotic. We hypothesized that the anticoagulant pharmacological agents, fondaparinux and dabigatran may be beneficial in the treatment of degloving injuries by enhancing the viability of the reattached flap. METHODS: Twenty four Wistar rats were divided into three groups as follows: control group (Group 1), fondaparinux group (Group 2) and dabigatran group (Group 3). A model of a degloving injury on the tail of rats was developed in all groups. After 15 minutes, the avulsed flaps were sutured back. Group 1 received 1ml/day saline intraperitoneally for 10 days. Group 2 received 0.3 ml/kg/day fondaparinux intraperitoneally for 10 days. Group 3 received 30 mg/kg/day dabigatran orally for 10 days. At the end of the treatments, gross morphological and histopathological tail tissue survivals were evaluated. RESULTS: Histopathological examination of the fondaparinux and dabigatran groups revealed that the tail skin was mostly viable with mild inflammation. The mean necrotic length in tails and severity of inflammation was significantly higher in the control group compared to the fondaparinux and dabigatran groups (p<0.05). No statistically significant differences were noted between the fondaparinux and dabigatran groups in histopathologic evaluations. There was no significant difference in necrosis lengths and the other histopathological parameters between dabigatran and fondaparinux groups. CONCLUSION: Dabigatran and fondaparinux improved tissue survival in skin degloving injuries concerning gross morphological and histopathological findings. However, the findings of this study should be supported and improved by new experimental and especially clinical studies.


Assuntos
Antitrombinas , Dabigatrana , Desenluvamentos Cutâneos , Fondaparinux , Animais , Antitrombinas/administração & dosagem , Antitrombinas/uso terapêutico , Dabigatrana/administração & dosagem , Dabigatrana/uso terapêutico , Desenluvamentos Cutâneos/tratamento farmacológico , Desenluvamentos Cutâneos/patologia , Fondaparinux/administração & dosagem , Fondaparinux/uso terapêutico , Masculino , Ratos , Ratos Wistar , Cauda/lesões
8.
Stroke ; 51(6): 1758-1765, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32404035

RESUMO

Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the impact of age, renal function (both predefined), and dabigatran dose (post hoc) on the rates of recurrent stroke and major bleeding. Methods- RE-SPECT ESUS was a multicenter, randomized, double-blind trial of dabigatran 150 or 110 mg (for patients aged ≥75 years and/or with creatinine clearance 30 to <50 mL/minute) twice daily compared with aspirin 100 mg once daily. The primary outcome was recurrent stroke. Results- The trial, which enrolled 5390 patients from December 2014 to January 2018, did not demonstrate superiority of dabigatran versus aspirin for prevention of recurrent stroke in patients with embolic stroke of undetermined source. However, among the population qualifying for the lower dabigatran dose, the rate of recurrent stroke was reduced with dabigatran versus aspirin (7.4% versus 13.0%; hazard ratio, 0.57 [95% CI, 0.39-0.82]; interaction P=0.01). This was driven mainly by the subgroup aged ≥75 years (7.8% versus 12.4%; hazard ratio, 0.63 [95% CI, 0.43-0.94]; interaction P=0.10). Stroke rates tended to be lower with dabigatran versus aspirin with declining renal function. Risks for major bleeding were similar between treatments, irrespective of renal function, but with a trend for lower bleeding rates with dabigatran versus aspirin in older patients. Conclusions- In subgroup analyses of RE-SPECT ESUS, dabigatran reduced the rate of recurrent stroke compared with aspirin in patients qualifying for the lower dose of dabigatran. These results are hypothesis-generating. Aspirin remains the standard antithrombotic treatment for patients with embolic stroke of undetermined source. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.


Assuntos
Aspirina , Dabigatrana , Fibrinolíticos , Embolia Intracraniana , Nefropatias , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Aspirina/administração & dosagem , Aspirina/farmacocinética , Dabigatrana/administração & dosagem , Dabigatrana/farmacocinética , Método Duplo-Cego , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/farmacocinética , Humanos , Embolia Intracraniana/sangue , Embolia Intracraniana/tratamento farmacológico , Nefropatias/sangue , Nefropatias/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico
9.
J Thromb Haemost ; 18(6): 1320-1323, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-116313

RESUMO

BACKGROUND: Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. METHODS: All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. RESULTS: Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period. CONCLUSION: DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.


Assuntos
Antitrombinas/sangue , Antivirais/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Dabigatrana/sangue , Inibidores do Fator Xa/sangue , Pneumonia Viral/tratamento farmacológico , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Tiazóis/sangue , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Antivirais/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Darunavir/efeitos adversos , Interações Medicamentosas , Monitoramento de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Itália , Lopinavir/efeitos adversos , Masculino , Pandemias , Segurança do Paciente , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Medição de Risco , Fatores de Risco , Ritonavir/efeitos adversos , Índice de Gravidade de Doença , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos
10.
Open Heart ; 7(1): e001202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32257246

RESUMO

Objective: We evaluated atrial fibrillation (AF) patients' perceptions of anticoagulation treatment with dabigatran or a vitamin K antagonist (VKA) for stroke prevention, according to accepted indications. Methods: The RE-SONANCE observational, prospective, multicentre, international study used the validated Perception on Anticoagulant Treatment Questionnaire (PACT-Q) to assess patients with AF already taking a VKA who were switched to dabigatran (cohort A), and newly diagnosed patients initiated on either dabigatran or a VKA (cohort B). Visit 1 (V1) was at baseline, and visit 2 (V2) and visit 3 (V3) were at 30-45 and 150-210 days after baseline, respectively. Primary outcomes were treatment satisfaction and convenience in cohort A at V2 and V3 versus baseline, and in cohort B for dabigatran and a VKA at V2 and V3. Results: The main analysis set comprised 4100 patients in cohort A and 5365 in cohort B (dabigatran: 3179; VKA: 2186). In cohort A, PACT-Q2 improved significantly (p<0.001 for all) for treatment convenience (mean change V1 vs V2=20.72; SD=21.50; V1 vs V3=24.54; SD=22.85) and treatment satisfaction (mean change V1 vs V2=17.60; SD=18.76; V1 vs V3=21.04; SD=20.24). In cohort B, mean PACT-Q2 scores at V2 and V3 were significantly higher (p<0.001 for all) for dabigatran versus a VKA for treatment convenience (V2=18.38; SE =0.51; V3=23.34; SE=0.51) and satisfaction (V2=15.88; SE=0.39; V3=19.01; SE=0.41). Conclusions: Switching to dabigatran from long-term VKA therapy or newly initiated dabigatran is associated with improved patient treatment convenience and satisfaction compared with VKA therapy.


Assuntos
Anticoagulantes/administração & dosagem , Antitrombinas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Conhecimentos, Atitudes e Prática em Saúde , Satisfação do Paciente , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Dabigatrana/efeitos adversos , Substituição de Medicamentos , Europa (Continente) , Feminino , Hemorragia/induzido quimicamente , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Proteção , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Resultado do Tratamento , Vitamina K/antagonistas & inibidores , Adulto Jovem
11.
Open Heart ; 7(1): e001232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341789

RESUMO

Objective: To assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs. Methods: We conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted. Results: A total of 73 989 patients were eligible for analysis. Notably, 52.8%-81.9% of patients received reduced doses of NOACs. After applying s-IPTW, patient characteristics were well balanced across warfarin/NOAC cohorts. The mean within-cohort age, CHADS2 score and CHA2DS2-VASc score were 76 years, 2.2-2.3 and 3.8, respectively. In all age categories, the majority of the HRs for major bleeding, any bleeding and stroke/SE were equal to or below 1 for all NOACs versus warfarin. Apixaban was the only NOAC associated with a significantly lower risk of any bleeding. There was a trend towards increased risk reduction with NOACs versus warfarin in patients with body weight ≥60 kg. In patients with renal disease, the HRs for apixaban versus warfarin were below 1 for major bleeding, any bleeding and stroke/SE, with statistical significance observed for the risk reduction in stroke/SE versus warfarin. In the sensitivity analysis, there were no large differences in HRs between the two observational periods. Conclusions: In patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.


Assuntos
Anticoagulantes/administração & dosagem , Antitrombinas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Varfarina/administração & dosagem , Administração Oral , Demandas Administrativas em Assistência à Saúde , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Dabigatrana/administração & dosagem , Registros Eletrônicos de Saúde , Feminino , Hemorragia/induzido quimicamente , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Piridonas/administração & dosagem , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Rivaroxabana/administração & dosagem , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Tiazóis/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Vitamina K/antagonistas & inibidores , Varfarina/efeitos adversos
12.
J Thromb Haemost ; 18(6): 1320-1323, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32329231

RESUMO

BACKGROUND: Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. METHODS: All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. RESULTS: Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period. CONCLUSION: DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.


Assuntos
Antitrombinas/sangue , Antivirais/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Dabigatrana/sangue , Inibidores do Fator Xa/sangue , Pneumonia Viral/tratamento farmacológico , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Tiazóis/sangue , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Antivirais/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Darunavir/efeitos adversos , Interações Medicamentosas , Monitoramento de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Itália , Lopinavir/efeitos adversos , Masculino , Pandemias , Segurança do Paciente , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Medição de Risco , Fatores de Risco , Ritonavir/efeitos adversos , Índice de Gravidade de Doença , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos
13.
BMC Cardiovasc Disord ; 20(1): 42, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013886

RESUMO

BACKGROUND: We evaluated adherence to dosing criteria for patients with atrial fibrillation (AF) taking dabigatran or rivaroxaban and the impact of off-label dosing on thromboembolic and bleeding risk. METHODS: We used data for a retrospective cohort from a large U.S. health plan for Medicare beneficiaries age > =65 years with AF who initiated dabigatran or rivaroxaban during 2010-2016. Stroke and major bleeding were quantified in patients who were eligible for low dose but received standard dose, and in patients who were eligible for standard dose but received low dose. RESULTS: We identified 8035 and 19,712 patients who initiated dabigatran or rivaroxaban, respectively. Overall, 1401 (17.4%) and 7820 (39.7%) patients who received dabigatran and rivaroxaban met criteria for low dose, respectively. Of those, 959 (68.5%) and 3904 (49.9%) received standard dose. In contrast, 1013 (15.3%) and 2551 (21.5%) of patients eligible for standard dose dabigatran and rivaroxaban received low dose. Mean follow-up for patients eligible for low and standard dose dabigatran and rivaroxaban were 13.9, 15.1, 10.1, and 12.3 months, respectively. In unadjusted analyses, patients eligible for low or standard dose dabigatran and rivaroxaban but receiving off-label dose, had no differences in the rates of ischemic stroke. Among patients who met criteria for standard dose direct oral anticoagulants (DOAC), use of low dose was associated with significantly higher risk of any major bleeding (Dabigatran: HR = 1.44; 95% CI 1.14-1.8, P = 0.002, Rivaroxaban HR 1.34, 95% CI 1.11-1.6, P = 0.002) and gastrointestinal bleeding (Dabigatran: HR = 1.48; 95% CI 1.08-2, P = 0.016). In patients who met criteria for low dose DOACs, there was lower risk of major bleeding (Dabigatran: HR = 0.59; 95% CI 0.43-0.8, P < 0.001), gastrointestinal (Rivaroxaban: HR 0.79; 95% CI 0.64-0.98, P = 0.03) and intracranial bleeding (Dabigatran: HR = 0.33; 95% CI 0.12-0.9, P = 0.001) with standard dosing. After propensity matching, use of off-label doses was not associated with stroke, major, gastrointestinal or intracranial bleeding for either dabigatran or rivaroxaban. CONCLUSIONS: While a significant number of patients receive higher or lower dose of dabigatran and rivaroxaban than recommended, we found no evidence of significant impact on thromboembolic or hemorrhagic outcomes.


Assuntos
Antitrombinas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Uso Off-Label , Rivaroxabana/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia/prevenção & controle , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Dabigatrana/efeitos adversos , Bases de Dados Factuais , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Medicare , Padrões de Prática Médica , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Tromboembolia/diagnóstico , Tromboembolia/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
14.
J Cardiovasc Pharmacol ; 75(4): 333-335, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31895873

RESUMO

BACKGROUND: Several studies demonstrated that proton pump inhibitors (PPIs) co-administrated with dabigatran in patients with atrial fibrillation (AF) decreased dabigatran trough and peak plasma levels. However, it is still unknown whether this interaction is reversible or not, and whether the withdrawal of PPI would lead to normalization of dabigatran plasma levels. AIM OF STUDY: The aim of this study was to determine the effect of PPI withdrawal on dabigatran plasma levels in patients with AF. METHODS: This pilot prospective study enrolled 23 AF patients on long-term dabigatran and PPI therapy (omeprazole 20 mg twice daily or pantoprazole 40 mg once daily). Dabigatran trough and peak levels (ng/mL) were tested on PPI and after a 2-week period of PPI withdrawal with Hemoclot Thrombin Inhibitor Assay. RESULTS: The analysis of dabigatran plasma levels demonstrated significant elevation in trough dabigatran levels after 2 weeks of PPI withdrawal (97.2 ± 79.7 vs. 163.8 ± 105.5 ng/mL; P < 0.05). Moreover, significantly higher peak dabigatran levels were observed after 2 weeks of PPI withdrawal (142.4 ± 102.8 vs. 255 ± 129.5 ng/mL; P ≤ 0.001). CONCLUSIONS: This study showed that a 2-week period of PPI withdrawal lead to a significant increase in dabigatran trough and peak plasma levels in patients with AF.


Assuntos
Antitrombinas/sangue , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/sangue , Omeprazol/administração & dosagem , Pantoprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Dabigatrana/administração & dosagem , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/efeitos adversos , Pantoprazol/efeitos adversos , Projetos Piloto , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
16.
J Wound Care ; 29(1): 44-50, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31930945

RESUMO

OBJECTIVE: This study aims to compare the efficacy of enoxaparin, rivoraxaban and dabigatran on wound healing using a rat model. METHOD: Sprague-Dawley female rats (n=56), 10-12 weeks old, weight 245±30g, were used in this study. The rats were divided into four equally-sized groups. A type 1 (secondary wound healing) and type 2 (primary wound healing) wound was opened surgically on each rat in each group. Anticoagulent drugs enoxaparin, rivoraxaban and dabigatran and physiological saline solution were administered to Groups 1, 2, 3 and 4, respectively. After wound healing was scored tissue samples were taken from euthanised rats at days five and 10 and examined histologically. Since time was used as a classification (days five and 10), a time effect was included. RESULTS: There was no statistically significant difference in total score distribution in rats between type 1 secondary wounds for days five and 10 (p>0.05). There was no statistically significant difference in the overall score distribution in rats between type 2 primary wounds for days five and 10 (p>0.05). CONCLUSION: In addition to the use of low molecular weight heparin with well-known anticoagulation activity, the new generation oral medications are used efficiently in thromboembolic diseases. However, there was no evidence observed in this study that these drugs could be either beneficial or harmful to wound healing.


Assuntos
Anticoagulantes/farmacologia , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Administração Cutânea , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Dabigatrana/administração & dosagem , Dabigatrana/farmacologia , Enoxaparina/administração & dosagem , Enoxaparina/farmacologia , Feminino , Modelos Animais , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Rivaroxabana/administração & dosagem , Rivaroxabana/farmacologia , Solução Salina/administração & dosagem , Solução Salina/farmacologia , Método Simples-Cego , Pele/patologia , Resultado do Tratamento , Ferimentos e Lesões/patologia
17.
Eur Heart J Cardiovasc Pharmacother ; 6(2): 75-85, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942972

RESUMO

AIMS: The aim of this study was to compare the risk of stroke or systemic embolism (SE) and major bleeding in patients with atrial fibrillation (AF) using dabigatran, rivaroxaban, and apixaban in routine clinical practice. METHODS AND RESULTS: Using nationwide registries in Norway from January 2013 to December 2017, we established a cohort of 52 476 new users of non-vitamin K antagonist oral anticoagulants (NOACs) with AF. Users of individual NOACs were matched 1:1 on the propensity score to create three pairwise-matched cohorts: dabigatran vs. rivaroxaban (20 504 patients), dabigatran vs. apixaban (20 826 patients), and rivaroxaban vs. apixaban (27 398 patients). Hazard ratios (HRs) for the risk of stroke or SE and major bleeding were estimated. In the propensity-matched comparisons of the risk of stroke or SE, the HRs were 0.88 [95% confidence interval (CI) 0.76-1.02] for dabigatran vs. rivaroxaban, 0.88 (95% CI 0.75-1.02) for dabigatran vs. apixaban, and 1.00 (95% CI 0.89-1.14) for apixaban vs. rivaroxaban. For the risk of major bleeding, the HRs were 0.75 (95% CI 0.64-0.88) for dabigatran vs. rivaroxaban, 1.03 (95% CI 0.85-1.24) for dabigatran vs. apixaban, and 0.79 (95% CI 0.68-0.91) for apixaban vs. rivaroxaban. CONCLUSION: In this nationwide study of patients with AF in Norway, we found no statistically significant differences in risk of stroke or SE in propensity-matched comparisons between dabigatran, rivaroxaban, and apixaban. However, dabigatran and apixaban were both associated with significantly lower risk of major bleeding compared with rivaroxaban.


Assuntos
Antitrombinas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Embolia/prevenção & controle , Inibidores do Fator Xa/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Dabigatrana/efeitos adversos , Bases de Dados Factuais , Embolia/diagnóstico , Embolia/epidemiologia , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Segurança do Paciente , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Sistema de Registros , Medição de Risco , Fatores de Risco , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo , Resultado do Tratamento
18.
Am J Cardiol ; 125(3): 383-391, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785775

RESUMO

Prospective studies evaluating persistence to nonvitamin K antagonist oral anticoagulants in patients with atrial fibrillation are needed to improve our understanding of drug discontinuation. The study objective was to evaluate if and when patients with newly diagnosed atrial fibrillation stop dabigatran treatment and to report outcomes following discontinuation. Patients prescribed dabigatran in diverse clinical practice settings were consecutively enrolled and followed for 2 years. Dabigatran persistence over time, reasons for discontinuation, and outcomes post discontinuation were assessed. Of 4,859 patients, aged 70.2 ± 10.4 years, 55.7% were male. Overall 2-year dabigatran persistence was 70.9% (95% confidence interval [CI] 69.6 to 72.2). Persistence probability was lower in the first 6-month period (83.7% [82.7 to 84.8]) than in subsequent periods for patients on dabigatran at the start of each period (6 to 12 months, 92.5% [91.6 to 93.3]; 12 to 18 months, 95.1% [94.3 to 95.8]; 18 to 24 months, 96.3% [95.6 to 96.9]). Of 1,305 patients (26.9%) who discontinued dabigatran, adverse events were reported as the reason for discontinuation in 457 (35.0%). Standardized stroke incidence rate post discontinuation (per 100 patient-years) in patients discontinuing without switching to another oral anticoagulant was 1.76 (95% CI 0.89 to 2.76) and 1.02 (95% CI 0.43 to 1.76) in those who switched, consistent with the expected benefit of remaining on treatment. Patients persistent with treatment at 1 year had >90% probability of remaining persistent at 2 years suggesting clinical interventions to improve persistence should be focused on the early period following treatment initiation.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Sistema de Registros , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Idoso , Antitrombinas/administração & dosagem , Fibrilação Atrial/complicações , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Saúde Global , Humanos , Incidência , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Taxa de Sobrevida/tendências , Suspensão de Tratamento
19.
Am Heart J ; 218: 123-127, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806087

RESUMO

GLORIA-AF is a large, ongoing, prospective, global registry program run in 3 phases, assessing long-term safety and effectiveness of dabigatran etexilate (dabigatran) in patients with newly diagnosed atrial fibrillation (AF) in clinical practice. This report provides the final analysis of 2-year clinical outcomes of the full cohort of 4873 patients prescribed dabigatran and followed for a mean of 18.0 +/- 9.4 months out of the 15,308 eligible patients enrolled in Phase II (2011-2014). The overall incidence rates per 100 person-years were: stroke 0.65 (95% CI 0.48-0.87), major bleeding 0.97 (0.76-1.23) and myocardial infarction (MI) 0.50 (0.35-0.69), with observed event rates broadly consistent in all study regions, which confirms the sustained safety and effectiveness of dabigatran over 2 years of observation in clinical practice.


Assuntos
Antitrombinas/efeitos adversos , Fibrilação Atrial/complicações , Dabigatrana/efeitos adversos , Sistema de Registros/estatística & dados numéricos , Acidente Vascular Cerebral/prevenção & controle , Antitrombinas/administração & dosagem , Causas de Morte , Estudos de Coortes , Dabigatrana/administração & dosagem , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Incidência , Infarto do Miocárdio/epidemiologia , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Resultado do Tratamento
20.
Int Heart J ; 60(6): 1315-1320, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31735780

RESUMO

Uninterrupted anticoagulation therapy during atrial fibrillation (AF) ablation minimizes the risk of periprocedural thromboembolic events. Although the use of direct oral anticoagulants (DOACs) has rapidly developed in patients undergoing AF ablation, no antidote is available for factor Xa inhibitors. We sought to investigate the feasibility of an uninterrupted DOAC protocol with temporary switching to dabigatran ("dabigatran bridge") for AF ablation.The study consisted of consecutive 137 patients in whom DOACs were interrupted on the procedural day with heparin bridging (interrupted group) and 135 in whom DOACs were uninterrupted with temporary switching to dabigatran during the periprocedural hospitalization period ("dabigatran bridge" group). The coagulation markers were measured just before and after the ablation procedure. The adverse events during and up to 8 weeks after the procedure were compared according to the definition of the International Society on Thrombosis and Hemostasis.The patients were significantly older in the "dabigatran bridge" group; however, the other baseline patient characteristics were similar between the two groups. The incidence of all adverse events was comparable between the two groups (8/137 versus 8/135, P = 0.96); however, one patient from the interrupted group experienced stroke, and another from the "dabigatran bridge" group experienced cardiac tamponade, which was safely managed with an antidote. In the "dabigatran bridge" group, the activated partial thromboplastin time was significantly longer, and coagulation markers (soluble fibrin monomer and thrombin-antithrombin complexes) were significantly lower than in the interrupted group before ablation.The "dabigatran bridge" seems to be a reasonable anticoagulation protocol to minimize the thromboembolic risk while ensuring safety in patients undergoing AF ablation and taking factor Xa inhibitors.


Assuntos
Antitrombinas/administração & dosagem , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Dabigatrana/administração & dosagem , Complicações Pós-Operatórias/prevenção & controle , Tromboembolia/prevenção & controle , Administração Oral , Idoso , Protocolos Clínicos , Esquema de Medicação , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial
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