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

症状性颅内动脉粥样硬化性狭窄（siICAS）是一种常见的疾病，与卒中的风险非常高。尽管氯吡格雷+阿司匹林和强化风险因素管理被认为是sICAS的标准治疗，但在SAMMPRIS试验中，在有症状性梗死和70- 99% sICAS的受试者中，使用该治疗的1年所有卒中和血管性死亡率为27%。显然，我们需要更好的治疗。替格瑞洛与阿司匹林联合治疗sICAS可能比氯吡格雷+阿司匹林更有效，因为替格瑞洛比氯吡格雷提供更快、更大和更一致的血小板抑制作用。此外，替格瑞洛是一种直接的P2 Y12受体拮抗剂，在携带将氯吡格雷代谢为其活性形式所必需的CYP 2C 19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。新型口服抗凝剂（NOAC）也可能为sICAS患者提供潜在优势。动脉粥样硬化疾病进展至不稳定状态的特征是血小板活化增加、促凝血活性升高和凝血酶生成，这为动脉粥样硬化患者联合抗凝治疗和抗血小板药物提供了机制依据。然而，全剂量抗凝与抗血小板药物联合使用会增加大出血的风险，包括脑出血（ICH）。这导致了在动脉粥样硬化患者中将低剂量NOAC与低剂量阿司匹林组合的兴趣。我们提议在115家临床试验机构进行一项无缝II/III期适应性、前瞻性、双盲、3组临床试验，将1683例sICAS高风险受试者随机分配至3组之一接受1年治疗：1）替格瑞洛（180 mg负荷剂量，然后90 mg每日两次），2）低剂量利伐沙班（2.5 mg每日两次），或3）氯吡格雷（600 mg负荷剂量，然后75 mg每日一次）。所有受试者还将根据SAMMPRIS方案接受阿司匹林（每日81 mg）和强化风险因素管理。3组II/III期适应性设计提高了我们使用共享对照组和共享试验基础设施评价两种新的潜在sICAS疗法的效率。II期研究的主要目的是确定利伐沙班或替格瑞洛组中可能导致其中一组或两组提前终止的ICH或非ICH严重出血过多。III期主要目的是确定从II期进展至III期的试验组（利伐沙班或替格瑞洛或两者）在降低70-99% sICAS受试者的1年主要终点（缺血性卒中、ICH或血管性死亡）发生率方面是否优于氯吡格雷组（上级）。探索性目的是评估CYP 2C 19 LOF携带者状态对替格瑞洛或低剂量利伐沙班组与氯吡格雷组相比在降低主要终点方面可能产生的任何获益的影响。这项创新性试验将评估两种新的抗血栓形成方法，以最大限度地提高为全球最常见和高风险的脑血管疾病之一siICAS建立更有效治疗的机会。

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.