RESUMO
BACKGROUND: Optimal antithrombotic treatment after transcatheter aortic valve replacement (TAVR) is unknown and determined empirically. The direct factor Xa inhibitor rivaroxaban may potentially reduce TAVR-related thrombotic complications and premature valve failure. DESIGN: GALILEO is an international, randomized, open-label, event-driven, phase III trial in more than 1,520 patients without an indication for oral anticoagulation who underwent a successful TAVR (ClinicalTrials.govNCT02556203). Patients are randomized (1:1 ratio), 1 to 7days after a successful TAVR, to either a rivaroxaban-based strategy or an antiplatelet-based strategy. In the experimental arm, subjects receive rivaroxaban (10mg once daily [OD]) plus acetylsalicylic acid (ASA, 75-100mg OD) for 90days followed by rivaroxaban alone. In the control arm, subjects receive clopidogrel (75mg OD) plus ASA (as above) for 90days followed by ASA alone. In case new-onset atrial fibrillation occurs after randomization, full oral anticoagulation will be implemented with maintenance of the original treatment assignment. The primary efficacy end point is the composite of all-cause death, stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep venous thrombosis, and systemic embolism. The primary safety end point is the composite of life-threatening, disabling, and major bleeding, according to the Valve Academic Research Consortium definitions. CONCLUSIONS: GALILEO will test the hypothesis that a rivaroxaban-based antithrombotic strategy reduces the risk of thromboembolic complications post-TAVR with an acceptable risk of bleeding compared with the currently recommended antiplatelet therapy-based strategy in subjects without need of chronic oral anticoagulation.
Assuntos
Estenose da Valva Aórtica/cirurgia , Aspirina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Inibidores do Fator Xa/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Rivaroxabana/uso terapêutico , Substituição da Valva Aórtica Transcateter , Doenças Cardiovasculares/epidemiologia , Causas de Morte , Clopidogrel , Quimioterapia Combinada , Embolia/epidemiologia , Embolia/prevenção & controle , Doenças das Valvas Cardíacas/epidemiologia , Doenças das Valvas Cardíacas/prevenção & controle , Humanos , Mortalidade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Cuidados Pós-Operatórios/métodos , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/prevenção & controle , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Trombose/epidemiologia , Trombose/prevenção & controle , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Trombose Venosa/epidemiologia , Trombose Venosa/prevenção & controleRESUMO
AIMS: X-VeRT is the first prospective randomized trial of a novel oral anticoagulant in patients with atrial fibrillation undergoing elective cardioversion. METHODS AND RESULTS: We assigned 1504 patients to rivaroxaban (20 mg once daily, 15 mg if creatinine clearance was between 30 and 49 mL/min) or dose-adjusted vitamin K antagonists (VKAs) in a 2:1 ratio. Investigators selected either an early (target period of 1-5 days after randomization) or delayed (3-8 weeks) cardioversion strategy. The primary efficacy outcome was the composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular death. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group and in 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15-1.73]. In the rivaroxaban group, four patients experienced primary efficacy events following early cardioversion (0.71%) and one following delayed cardioversion (0.24%). In the VKA group, three patients had primary efficacy events following early cardioversion (1.08%) and two following delayed cardioversion (0.93%). Rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKAs (P < 0.001). Major bleeding occurred in six patients (0.6%) in the rivaroxaban group and four patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21-2.67). CONCLUSION: Oral rivaroxaban appears to be an effective and safe alternative to VKAs and may allow prompt cardioversion. NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov; TRIAL REGISTRATION NUMBER: NCT01674647.
Assuntos
Fibrilação Atrial/terapia , Cardioversão Elétrica/métodos , Inibidores do Fator Xa/administração & dosagem , Morfolinas/administração & dosagem , Tiofenos/administração & dosagem , Vitamina K/antagonistas & inibidores , Administração Oral , Idoso , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Rivaroxabana , Acidente Vascular Cerebral/prevenção & controle , Tiofenos/efeitos adversos , Tromboembolia/prevenção & controle , Resultado do TratamentoRESUMO
BACKGROUND: Anticoagulation before, during, and after cardioversion is effective in reducing stroke risk in patients with atrial fibrillation. OBJECTIVE: The objective of this study is to explore the efficacy and safety of rivaroxaban 20 mg once daily (15 mg if creatinine clearance is 30-49 mL/min) compared with dose-adjusted vitamin K antagonists (VKAs; international normalized ratio 2.0-3.0) in patients scheduled for elective cardioversion. METHODS: This is a prospective, randomized, open-label, parallel group comparison of approximately 1,500 patients from 17 countries with hemodynamically stable nonvalvular atrial fibrillation of >48 hours or unknown duration. Patients will be randomized 2:1 (rivaroxaban:VKA) using 2 cardioversion strategies: the first approach is early cardioversion with the precardioversion anticoagulation goal of 1 to 5 days using rivaroxaban or usual therapy (heparin + VKA). In these patients, transesophageal echocardiography will be encouraged to exclude atrial thrombi. The alternative approach is delayed cardioversion. Rivaroxaban or VKA will be administered for 21 to 56 days before cardioversion. All patients will receive study treatment for 6 weeks postcardioversion. The primary efficacy end point is a composite of all strokes, transient ischemic attacks, noncentral nervous system systemic emboli, myocardial infarctions, and cardiovascular deaths. Each primary end point component will be evaluated separately, and additional composites will be investigated. The principal safety end point is major bleeding. CLINICAL CONTEXT: This will be the first prospective study of a novel oral anticoagulant in the setting of cardioversion. It will provide important information regarding the use of rivaroxaban in the periods preceding and after cardioversion in a broad patient population.
Assuntos
Fibrilação Atrial/terapia , Cardioversão Elétrica , Embolia/prevenção & controle , Morfolinas/administração & dosagem , Tiofenos/administração & dosagem , Vitamina K/antagonistas & inibidores , Administração Oral , Idoso , Anticoagulantes/administração & dosagem , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Ecocardiografia Transesofagiana , Embolia/etiologia , Inibidores do Fator Xa , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Rivaroxabana , Fatores de Tempo , Resultado do TratamentoRESUMO
Macrophage migration inhibitory factor (MIF), a structurally and functionally unique pleiotropic mediator in inflammation and immune processes, was identified decades ago. There is now strong evidence that MIF promotes revascularization and is involved in wound healing processes. However, its exact role in wound healing is still a matter of debate. A cohort of 33 patients was recruited, including 14 patients with acute and 19 patients with chronic wounds. Both serum and wound fluid samples were collected from each patient, and MIF and cortisol concentrations were determined. To functionally underscore MIF's potential role in wound revascularization, a chemotaxis assay was adapted to test whether and to what extent serum samples and wound fluids of each group promote the chemotactic migration of endothelial progenitor cells (EPCs). MIF serum levels were significantly higher in chronic wound patients than in acute wound patients. Wound exudates of chronic wounds, however, contained a significantly lower concentration of MIF. In chronic wound patients, EPC migration might be delayed, as suggested by in vitro chemotaxis experiments. Despite the overall descriptive nature of this study, we conclude that MIF is correlated with occurrence of chronic wound. The increased MIF levels in the serum of chronic wound patients might be due to MIF's systemic effect of its proinflammatory activities, while its locally decreased levels in chronic wound exudates might be responsible for impaired recruitment of EPCs. Additional prospective data and detailed in vivo models are needed for a more comprehensive understanding of the role of MIF in chronic wound healing.
Assuntos
Quimiocina CXCL12/imunologia , Quimiotaxia/imunologia , Células Endoteliais/imunologia , Fatores Inibidores da Migração de Macrófagos/farmacologia , Células-Tronco/imunologia , Cicatrização/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Movimento Celular , Células Cultivadas , Quimiocina CXCL12/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Doença Crônica , Estudos de Coortes , Células Endoteliais/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Glucocorticoides/farmacologia , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/imunologia , Células-Tronco/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Adulto JovemRESUMO
Regulatory authorities interpret the results of randomized controlled trials according to published principles. The European Medicines Agency (EMA) is planning a revision of the 2000 and 2003 guidance documents on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (ACS) to achieve consistency with current knowledge in the field. This manuscript summarizes the key output from a collaborative workshop, organized by the Cardiovascular Round Table and the European Affairs Committee of the European Society of Cardiology, involving clinicians, academic researchers, trialists, European and US regulators, and pharmaceutical industry researchers. Specific questions in four key areas were selected as priorities for changes in regulatory guidance: patient selection, endpoints, methodologic issues and issues related to the research for novel agents. Patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) should be studied separately for therapies aimed at the specific pathophysiology of either condition, particularly for treatment of the acute phase, but can be studied together for other treatments, especially long-term therapy. Unstable angina patients should be excluded from acute phase ACS trials. In general, cardiovascular death and reinfarction are recommended for primary efficacy endpoints; other endpoints may be considered if specifically relevant for the therapy under study. New agents or interventions should be tested against a background of evidence-based therapy with expanded follow-up for safety assessment. In conclusion, new guidance documents for randomized controlled trials in ACS should consider changes regarding patient and endpoint selection and definitions, and trial designs. Specific requirements for the evaluation of novel pharmacological therapies need further clarification.
Assuntos
Síndrome Coronariana Aguda/terapia , Cardiologia/organização & administração , Educação/métodos , Infarto do Miocárdio/terapia , Infarto do Miocárdio sem Supradesnível do Segmento ST/terapia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Síndrome Coronariana Aguda/fisiopatologia , Angina Instável/terapia , Morte , Determinação de Ponto Final/métodos , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Infarto do Miocárdio/mortalidade , Intervenção Coronária Percutânea/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Reperfusão/métodos , Medição de Risco , Terapia Trombolítica/métodosRESUMO
Atrial fibrillation (AF) is a major healthcare concern, being associated with an estimated five-fold risk of ischaemic stroke. In patients with AF, anticoagulants reduce stroke risk to a greater extent than acetylsalicylic acid (ASA) or dual antiplatelet therapy (DAPT) with ASA plus clopidogrel. Non-vitamin K antagonist oral anticoagulants (NOACs) are now a widely-accepted therapeutic option for stroke prevention in non-valvular AF (NVAF). There are particular patient types with NVAF for whom treatment challenges remain, owing to sparse clinical data, their high-risk nature or a need to harmonise anticoagulant and antiplatelet regimens if co-administered. This article focuses on three randomised controlled trials (RCTs) that are investigating the utility of rivaroxaban, a direct, oral, factor Xa inhibitor, in additional areas of stroke prevention where data for anticoagulants are lacking: oPen-label, randomized, controlled, multicentre study explorIng twO treatmeNt stratEgiEs of Rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment (PIONEER AF-PCI); New Approach riVaroxoban Inhibition of factor Xa in a Global trial vs Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS); and Global study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based strategy after transcatheter aortIc vaLve rEplacement to Optimize clinical outcomes (GALILEO). Data from these studies present collaborative efforts to build upon existing registrational Phase III data for rivaroxaban, driving the need for effective and safe treatment of a wider range of patients for stroke prevention.