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（sICAS）是一种常见的疾病，与卒中的高风险相关。尽管氯吡格雷+阿司匹林和强化危险因素管理被认为是sICAS的标准治疗，但在SAMMPRIS试验中，出现症状性梗死和70- 99% sICAS的受试者的1年卒中和血管死亡率为27%。显然，我们需要更好的治疗。替格瑞洛联合阿司匹林治疗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、更强、更一致的血小板抑制。此外，替格瑞洛是一种直接的P2Y12受体拮抗剂，对于携带基因单核苷酸功能丧失（LOF）多态性的CYP2C19细胞色素P450酶的患者，替格瑞洛可能比氯吡格雷更有效，这种多态性是将氯吡格雷代谢为活性形式所必需的。新型口服抗凝剂（NOAC）也可能为sICAS患者提供潜在的优势。动脉粥样硬化性疾病进展到不稳定状态的特征是血小板活化增加、促凝活性升高和凝血酶生成，这为动脉粥样硬化患者联合使用抗凝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）。这引起了人们对动脉粥样硬化患者将低剂量NOAC与低剂量阿司匹林联合使用的兴趣。我们建议在115个地点进行一项II/III期适应性、前瞻性、双盲、3组临床试验，将1683名sICAS高危患者随机分为3组：1)替格瑞洛（180mg负荷剂量，然后90mg每日2次），2)低剂量利伐沙班（2.5mg每日2次），或3)氯吡格雷（600mg负荷剂量，然后75mg每日）。所有受试者还将按照SAMMPRIS方案接受阿司匹林（每日81mg）和强化风险因素管理。3臂II/III期自适应设计提高了效率，我们可以使用共享对照组和共享试验基础设施来评估两种新的潜在sICAS疗法。II期主要目的是确定利伐沙班或替格瑞洛组中过量的脑出血或非脑出血大出血，这些大出血可能导致其中一个或两个组的早期终止。III期主要目的是确定从II期进展到III期的实验组（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、脑出血或血管性死亡）率方面是否优于氯吡格雷组。探索性目的是评估CYP2C19 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具有的任何获益的影响。这项创新试验将评估两种新的抗血栓治疗方法，以最大限度地提高sICAS（世界上最常见和高风险的脑血管疾病之一）的有效治疗机会。

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.