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，与中风的风险非常高。虽然氯吡格雷+阿司匹林和强化风险因素管理被认为是SICA的标准治疗，但在SAMMPRIS试验中，在出现症状性脑梗塞和70%-99%SICA的受试者中，这种疗法的1年内所有中风和血管死亡的比率为27%。显然，我们需要更好的治疗。替卡格雷与阿司匹林联合治疗SICA可能比氯吡格雷+阿司匹林更有效，因为替卡格雷比氯吡格雷提供更快、更强和更一致的血小板抑制。此外，替卡格雷是一种直接的P2Y12受体拮抗剂，在携带CYP2C19细胞色素P450酶基因单核苷酸功能丧失(LOF)多态的患者中可能比氯吡格雷更有效，该酶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SICA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、促凝血活性和凝血酶生成增加，这为在动脉粥样硬化患者中联合使用抗凝和抗血小板药物提供了机制基础。然而，全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)。这引起了人们对联合使用低剂量NOAC和低剂量阿司匹林治疗动脉粥样硬化患者的兴趣。我们建议在115个地点进行一项无缝的II/III期适应性、前瞻性、双盲、3臂临床试验，将1683名患有SICA的高风险受试者随机分为三组，其中一组接受一年的治疗：1)替卡格雷(180毫克负荷量，然后每天两次90毫克)，2)小剂量利伐沙班(每天两次，2.5毫克)，或3)氯吡格雷(600毫克负荷量，然后每天75毫克)。所有受试者还将按照SAMMPRIS方案接受阿司匹林(每天81毫克)和强化风险因素管理。3-ARM II/III期适应性设计提高了我们评估两种新的SICA潜在疗法的效率，使用共享的对照组和共享的试验基础设施。第二阶段的主要目标是确定利伐沙班或替卡格雷手臂中有过多的脑出血或非脑出血大出血，可能导致这两个手臂中的一个或两个提前终止。第三阶段的主要目标是确定从第二阶段进展到第三阶段的实验ARM(S)(利伐沙班或替卡格雷或两者)在降低70%-99%SICA患者的主要终点(缺血性中风、脑出血或血管死亡)的1年发生率方面是否优于氯吡格雷ARM。探索性目的是评估与氯吡格雷相比，CYP2C19 LOF携带者状态对替卡格雷或低剂量利伐沙班在降低主要终点方面可能产生的任何益处的影响。这项创新的试验将评估两种新的抗血栓治疗方法，以最大限度地增加为SICAS建立更有效疗法的机会。SICAS是全球最常见和高风险的脑血管疾病之一。

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.