Comparison of Anti-coagulation and anti-Platelet Therapies for Intracranial Vascular Atherostenosis

抗凝与抗血小板治疗颅内血管粥样硬化的比较

基本信息

批准号：
10211763
负责人：
MARC IVOR CHIMOWITZ
金额：
$ 862.4万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211763
关键词：
Address Anticoagulants Anticoagulation Antiplatelet Drugs Arterial Fatty Streak Arteries Aspirin Atherosclerosis Blood Platelets Blood Vessels Brain CYP2C19 gene Carotid Stenosis Cerebral hemisphere hemorrhage Cerebrovascular Disorders Cessation of life China Chinese People Clinical Trials Common Data Element Control Groups Coronary Coronary Arteriosclerosis Cytochrome P450 Data Disease Disease Progression Dose Double-Blind Method Enzymes Event Generations Genetic Genetic Polymorphism Heart failure Hemorrhage Infarction Infrastructure Intracranial Hemorrhages Ischemic Stroke Lead Medical Minor National Institute of Neurological Disorders and Stroke Nucleotides Oral Patients Peripheral Pharmaceutical Preparations Phase Platelet Activation Prognosis Protocols documentation Public Health Randomized Recurrence Regimen Risk Risk Factors Site Stenosis Stents Stroke Stroke prevention Thrombin arm carrier status clopidogrel design disorder risk effective therapy experimental arm follow-up hazard high risk improved outcome innovation interest loss of function novel prevent primary endpoint prospective randomized trial receptor standard care stroke risk three-arm clinical trial

项目摘要

Symptomatic intracranial atherosclerotic stenosis (sICAS) is a common disease associated with a very high risk of stroke. Although clopidogrel + aspirin and intensive risk factor management are considered standard care for sICAS, the 1-year rate of all stroke and vascular death in subjects presenting with a symptomatic infarct and 70- 99% sICAS was 27% with this therapy in the SAMMPRIS trial. Clearly, we need better treatment. Combining ticagrelor with aspirin may be more effective than clopidogrel + aspirin for sICAS because ticagrelor provides faster, greater and more consistent platelet inhibition than clopidogrel. Additionally, ticagrelor is a direct P2Y12 receptor antagonist and may be more effective than clopidogrel in patients who carry genetic single-nucleotide loss-of-function (LOF) polymorphisms for the CYP2C19 cytochrome P450 enzyme necessary to metabolize clopidogrel to its active form. The novel oral anticoagulants (NOAC) may also offer potential advantages in patients with sICAS. Atherosclerotic disease progression to an unstable state is characterized by increased platelet activation, elevated procoagulant activity and thrombin generation, which provides the mechanistic rationale for combining anticoagulation with an antiplatelet agent in patients with atherosclerosis. However, combining full dose anticoagulation with an antiplatelet agent increases the risk of major hemorrhage, including intracerebral hemorrhage (ICH). This has led to interest in combining a low dose NOAC with low dose aspirin in patients with atherosclerosis. We propose a seamless Phase II/III adaptive, prospective, double-blinded, 3-arm clinical trial at 115 sites that will randomize 1683 high-risk subjects with sICAS to 1 year treatment in one of three arms: 1) ticagrelor (180 mg loading dose, then 90mg twice daily), 2) low dose rivaroxaban (2.5mg twice daily), or 3) clopidogrel (600mg loading dose, then 75 mg daily). All subjects will also receive aspirin (81mg daily) and intensive risk factor management per the SAMMPRIS protocol. The 3-arm Phase II/III adaptive design increases the efficiency with which we can evaluate two new potential therapies for sICAS, using a shared control group and a shared trial infrastructure. The Phase II Primary Aim is to identify an excess of ICH or non-ICH major hemorrhage in the rivaroxaban or ticagrelor arms that could lead to an early termination of one or both of those arms. The Phase III Primary Aim is to determine if the experimental arm(s) (rivaroxaban or ticagrelor or both) that progress from Phase II to Phase III are superior to the clopidogrel arm for lowering the 1-year rate of the primary endpoint (ischemic stroke, ICH, or vascular death) in subjects with 70-99% sICAS. The Exploratory Aim is to estimate the impact of CYP2C19 LOF carrier status on any benefit that the ticagrelor or low dose rivaroxaban arms may have in lowering the primary endpoint compared with the clopidogrel arm. This innovative trial will evaluate two new antithrombotic approaches to maximize the chance of establishing more effective therapy for sICAS, one of the most common and high-risk cerebrovascular diseases worldwide.

有症状的颅内动脉粥样硬化狭窄（SICAS）是一种常见疾病，与中风的风险很高有关。尽管氯吡格雷 +阿司匹林和密集的危险因素管理被认为是SICAS的标准护理，但在SAMMPRIS试验中，这种疗法的所有中风和血管死亡的1年率和70-99％SICA的受试者的1年率和70-99％的SICA均为27％。显然，我们需要更好的治疗。将ticagrelor与阿司匹林结合使用可能比氯吡格雷 +阿司匹林更有效，因为ticagrelor提供的速度比氯吡格雷更快，更大，更一致的血小板抑制作用。此外，Ticagrelor是一种直接的P2Y12受体拮抗剂，在携带CYP2C19细胞色素P450酶的遗传单核苷酸功能丧失（LOF）多态性的患者中，可能比氯吡格雷更有效。新型的口服抗凝剂（NOAC）也可能在SICAS患者中具有潜在的优势。动脉粥样硬化疾病的进展到不稳定状态的特征是血小板激活增加，降低了凝凝剂活性和凝血酶产生，这提供了在动脉粥样硬化患者中与抗凝剂与抗血小板剂相结合的机械原理。然而，将全剂量抗凝作用与抗血小板剂相结合会增加重大出血的风险，包括脑出血（ICH）。这引起了对动脉粥样硬化患者的低剂量NOAC与低剂量阿司匹林相结合的兴趣。我们在115个地点提出了一个无缝II/III期自适应，前瞻性，双盲的3臂临床试验，将在三个臂之一中随机对1683名高风险受试者进行1年治疗：1年）（180 mg）（180 mg）加载剂量，然后每天两次90mg），2）低剂量利瓦沙班（每天两次2.5mg）或3）氯吡格雷（600mg加载剂量，然后每天75毫克）。根据SAMMPRIS协议，所有受试者还将接受阿司匹林（每天81mg）和密集的风险因素管理。 3臂II/III自适应设计提高了使用共享对照组和共享试验基础架构评估SICA的两种新的潜在疗法的效率。第二阶段的主要目的是确定Rivaroxaban或Ticagrelor Arms中过量的ICH或非小块主要出血，这些出血可能会导致其中一个或两个臂的早期终止。第三阶段的主要目的是确定从II阶段到III阶段进展的实验组（rivaroxaban或ticagrelor或两者）是否优于氯吡格雷臂，以降低主要终点的1年速率SICA的受试者中的ICH或血管死亡）。探索性目的是估计CYP2C19 LOF载体状态对Ticagrelor或低剂量Rivaroxaban臂与氯吡格雷臂相比降低主要终点的影响。这项创新的试验将评估两种新的抗血栓形成方法，以最大程度地建立对SICA的更有效疗法的机会，SICA是全球最常见，最常见的脑血管疾病之一。