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

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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.