Design and early progress of the Comparison of Anticoagulation and anti-Platelet Therapies for Intracranial Vascular Atherostenosis (CAPTIVA) trial

Abstract

Background: The usual antithrombotic treatment for symptomatic intracranial atherosclerotic stenosis (ICAS) consists of dual treatment with clopidogrel and aspirin for 90 days followed by aspirin alone but the risk of recurrent stroke remains high up to 12 months. The Comparison of Anticoagulation and anti-Platelet Therapies for Intracranial Vascular Atherostenosis (CAPTIVA) trial was designed to determine whether other combinations of dual antithrombotic therapy are superior to clopidogrel and aspirin.

Methods: CAPTIVA is an ongoing, prospective, double-blinded, three-arm clinical trial at over 100 sites in the United States and Canada that will randomize 1683 high-risk subjects with a symptomatic infarct attributed to 70-99% stenosis of a major intracranial artery to 12 months of treatment with (1) ticagrelor (180 mg loading dose, then 90 mg twice daily), (2) low-dose rivaroxaban (2.5 mg twice daily), or (3) clopidogrel (600 mg loading dose, then 75 mg daily). All subjects receive aspirin (81 mg daily), intensive risk factor management, and will undergo blinded CYP2C19 genotype analysis. The primary goal of the trial is to determine whether rivaroxaban or ticagrelor or both are superior to clopidogrel for lowering the primary endpoint (ischemic stroke, intracerebral hemorrhage (ICH), or vascular death) within 12 months. A prespecified interim safety analysis will be conducted when the first 450 randomized subjects have been followed for 12 months to evaluate the risk of major hemorrhage in the rivaroxaban and ticagrelor arms.

Results: Enrollment began in August 2022 and, as of 26 June 2024, the 450th subject was randomized into the study.

Conclusion: CAPTIVA is evaluating two alternative dual antithrombotic therapies to clopidogrel and aspirin to maximize the chance of establishing more effective antithrombotic therapy for symptomatic ICAS, one of the most common and high-risk cerebrovascular diseases worldwide.

Keywords: Intracranial arteriosclerosis; anticoagulants; antiplatelet; ischemic stroke.

Figure 1.

Trial flow diagram. When the first 450 randomized subjects have completed 12 months of follow-up, the safety analysis will determine whether either experimental arm (ticagrelor + aspirin or low-dose rivaroxaban + aspirin) demonstrates an excess risk of ICH and non-ICH major hemorrhage, using the historical rates from the SAMMPRIS trial as the comparator. If an experimental arm crosses the safety boundary, this will initiate an early futility analysis to weigh the risk: benefit ratio of the corresponding experimental arm. Otherwise, the futility analysis will be conducted after the first 842 subjects have been randomized, by comparing each experimental arm to the standard of care arm. If an experimental arm crosses the futility boundary, the corresponding experimental arm will be terminated. If neither arm crosses the futility boundary, the trial will continue with both experimental arms.