Effects of Edoxaban on Platelet Aggregation in Patients With Stable Coronary Artery Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 61
- 试验地点
- 1
- 主要终点
- Main objective:
研究概览
简要总结
Rationale: The interaction between nonvitamin K oral anticoagulants (NOACs) and platelet aggregation is complex. The direct activated factor X inhibitors (factor Xa inhibitors) an NOAC antagonizes thrombin generation, one of most important platelet agonist, so that, factor Xa inhibitors has a potential effect in decreasing thrombin-mediated platelet aggregation. On the other hand, patients who experience ACS continue to have a hypercoagulable state for long periods after the index event. The COMPASS trial showed that, in patients with stable coronary artery disease (SCAD), Rivaroxaban (a direct anti-Xa inhibitor) in addition to antiplatelet agent, compared to antiplatelet therapy alone, reduced the composite endpoint of myocardial infarction, stroke and death.
Objective: Analyze the role of edoxaban on platelet aggregation in SCAD patients.
Methods and Results: This is a prospective, non-randomized, interventional study of SCAD patients taking low-dose acetylsalicylic acid (ASA). Subjects initially will receive in the following sequence: ASA 100 mg once daily (QD) plus edoxaban 60 mg QD, clopidogrel 75 mg QD alone, clopidogrel 75 mg QD plus edoxaban 60 mg QD, and edoxaban 60 mg QD alone. Platelet function will be assessed by standard of care technology, at baseline and after each intervention phase, by Multiplate-ADP® (primary endpoint), Multiplate-Aspi® and Multiplate-TRAP®. In addition to immature platelets fraction (% IPF) and count (IPC). Coagulability will be assessed, at baseline and after each intervention phase, by thromboelastogram (TEG) assessment. Specifically, after the phases in which edoxaban will be administered activated factor X (FXa) level and Plasminogen activator inhibitor-1 (PAI-1) will be evaluated in addition to previous. Finally, inflammatory markers will be, at same way, assessed at baseline and after intervention each phase: ultrasensitive C-reactive protein (us-PCR).
Keywords: edoxaban, direct factor Xa inhibitor, stable coronary artery disease, aspirin, clopidogrel, platelet aggregation.
详细描述
- Introduction:
Stable coronary artery disease (SCAD) is the leading cause of deaths attributable to cardiovascular disease in the United States. 720,000 new coronary events are expected - defined as the first acute myocardial infarction (AMI) hospitalized or death from SCAD - and approximately 335,000 recurring events per year.
Patients who survive the initial phase of acute coronary syndrome (ACS) remain at risk of cardiac complications: sudden death, (re) infarction or recurrent rest angina, complications related to the development of coronary thrombosis.
The most common cause of coronary thrombosis is plaque rupture followed by plaque erosion. The plaque rupture represents a stimulus for both thrombosis and coagulation, because thrombin activates platelets and converts fibrinogen into fibrin, characteristic of the "white" arterial thrombus. Therefore, the process of arterial thrombus generation involves both platelet aggregation and blood coagulation.
The importance of the coagulation system underlying plaque complications was addressed by Ardissino et al. in the Global Use of Strategies To Open ocluded coronary artteries (GUSTO) IIb, a prospective multicenter cohort study that evaluated the importance of persistently elevated thrombin generation for outcome in 319 consecutive patients with ACS. In this study, the authors concluded that after an episode of ACS, thrombin generation levels were significantly correlated with a worse U-shaped result.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients aged between 18 and 75 years
- •Confirmed diagnosis of CAD using ASA 100 mg once a day. The following will be considered for CAD diagnosis: previous history of type 1 AMI (at least one year ago), according to the fourth universal definition of myocardial infarction (Thygesen, Alpert et al. 2018) and/or coronary angioplasty and/or coronary artery bypass graft surgery myocardium and/or coronary angiography showing at least 50% obstruction in one of the main epicardial vessels.
- •Agreement to sign the free and informed consent form.
排除标准
- •Clinically active bleeding or clinically significant bleeding in the last year.
- •Peptic ulcer active in the last 60 days
- •Previous history of high gastrointestinal bleeding
- •Hemoglobin <10 g / dl at randomization;
- •Platelets <100,000 or >500,000 µ/L
- •Need for lumbar puncture
- •Atrial fibrillation
- •Metal valve prosthesis
- •Percutaneous coronary intervention (PCI) in the last 3 months with conventional stent and in the last 6 months with drug-eluting stent.
- •Surgical myocardial revascularization (CABG) in the last 90 days
- •Percutaneous coronary intervention (PCI) or surgical myocardial revascularization (CABG) planned within the next 60 days;
- •Previous hemorrhagic stroke;
- •Moderate or severe liver failure associated with coagulation disorders (Child-Pugh B or C)
- •Hypersensitivity to edoxaban or formula components;
- •Pregnant women or women of childbearing potential;
- •Chronic kidney disease: glomerular filtration rate estimated at <50 mL/min/1.73m², calculated using the Cockcroft-Gault equation;
- •Current or last 30 days use of anticoagulant or antiplatelet therapy, except ASA;
- •Weight <60 kg;
- •HAS-BLED score ≥ 3 points;
- •Concomitant use of P-glycoprotein inhibitors such as azithromycin, clarithromycin, erythromycin, itraconazole, ketoconazole, verapamil, quinidine, except amiodarone;
- •Concomitant use of P-glycoprotein inducers, such as Rifampicin;
- •Known abuse of alcohol, drugs, or medications in the 12 months prior to consent for this study;
- •Cancer therapy 5 years prior to consent for this study;
- •Medicines that will further increase the risk of bleeding (such as nonsteroidal anti-inflammatory drugs).
- •Participation in another study within 30 days of signing the consent form.
研究组 & 干预措施
ASA baseline
Patients in chronic use of ASA
干预措施: ASA (Drug)
ASA + Edoxaban
During this intervention phase, eligible patients will sequentially receive ASA 100 mg 1x/day + edoxaban 60 mg 1x/day for a period of 10 ± 2 days.
干预措施: ASA (Drug)
ASA + Edoxaban
During this intervention phase, eligible patients will sequentially receive ASA 100 mg 1x/day + edoxaban 60 mg 1x/day for a period of 10 ± 2 days.
干预措施: Edoxaban (Drug)
Clopidogrel
Subsequently, ASA and edoxaban will be suspended and clopidogrel 75 mg once a day will be administered for 10 ± 2 days (washout period of the ASA).
干预措施: Clopidogrel (Drug)
Clopidogrel + Edoxaban
Subsequently, it will be associated with edoxaban 60 mg once a day to clopidogrel 75 mg once a day for 10 ± 2 days
干预措施: Clopidogrel (Drug)
Clopidogrel + Edoxaban
Subsequently, it will be associated with edoxaban 60 mg once a day to clopidogrel 75 mg once a day for 10 ± 2 days
干预措施: Edoxaban (Drug)
Edoxaban
Finally, only edoxaban 60 mg once a day for 10 ± 2 days will be administered.
干预措施: Edoxaban (Drug)
结局指标
主要结局
Main objective:
时间窗: 24 months
To compare platelet aggregability in patients with CAD using the Multiplate-TRAP® method at the start of ASA use and after 10 ± 2 days of the association of edoxaban and ASA.
次要结局
- Platelet reactivity after edoxaban plus ASA vs ASA(24 months)
- Platelet reactivity after edoxaban plus Clopidogrel vs Clopidogrel(24 months)
- Platelet reactivity after edoxaban vs after Clopidogrel(24 months)
- Platelet reactivity after edoxaban vs after ASA(24 months)
- Platelet reactivity after edoxaban plus ASA vs after edoxaban plus Clopidogrel(24 months)
研究者
Jose Carlos Nicolau
Professor
University of Sao Paulo