NIH Halts Rivaroxaban Arm of Major Stroke Prevention Trial Due to Safety Concerns
Key Insights
The National Institutes of Health discontinued the low-dose rivaroxaban arm of the CAPTIVA stroke (search) prevention trial following safety concerns and evidence of treatment futility.
The Data Safety and Monitoring Board recommended halting the rivaroxaban treatment due to increased safety events in patients with intracranial arterial stenosis (search).
The CAPTIVA trial continues with two remaining treatment arms, comparing ticagrelor and clopidogrel combinations against standard care in up to 1,683 participants.
The National Institutes of Health has halted the rivaroxaban treatment arm of a major stroke (search) prevention clinical trial after safety monitoring revealed increased adverse events and evidence that the low-dose anticoagulant approach was unlikely to benefit patients.
The decision to discontinue the rivaroxaban arm of the Comparison of Anti-coagulation and Anti-platelet Therapies for Intracranial Vascular Atherostenosis (search) (CAPTIVA) study came following a routine safety review by the Data Safety and Monitoring Board (DSMB), an independent expert panel that regularly evaluates trial safety. The NIH's National Institute of Neurological Disorders and Stroke accepted the DSMB's recommendation due to an increase in safety events and evidence of futility—a pre-specified stopping criterion that allows trials to end early when treatments show little promise of helping patients.
Trial Design and Patient Population
CAPTIVA is a large, two-stage, double-blind randomized trial enrolling participants aged 30 and older who have experienced a stroke (search) attributed to 70-99% narrowing of a major intracranial artery. The study aims to evaluate up to 1,683 volunteers across more than 100 study sites over a four-year period as part of NIH's StrokeNet initiative.
The trial originally randomized participants in a 1:1:1 ratio to receive one year of treatment with one of three regimens:
- Ticagrelor (180 mg loading dose, then 90 mg twice daily) plus aspirin (81 mg daily)
- Low-dose rivaroxaban (2.5 mg twice daily) plus aspirin (81 mg daily) - now discontinued
- Clopidogrel (600 mg loading dose, then 75 mg daily) plus aspirin (81 mg daily)
All participants receive intensive risk factor management and lifestyle coaching, with evaluations scheduled at one month, four months, eight months, and one year after randomization. These assessments include blood pressure monitoring, risk factor optimization, and outcome evaluation.
Rivaroxaban Safety Profile
Rivaroxaban is a U.S. Food and Drug Administration-approved anticoagulant medication typically used to treat or prevent blood clots. However, the low-dose formulation tested in CAPTIVA proved problematic in this specific patient population with intracranial arterial stenosis (search).
All study sites with active participants randomized to the discontinued rivaroxaban arm have received instructions for drug discontinuation. Study participants who completed their evaluation in the discontinued arm will be contacted by their treatment sites, with participant safety remaining NIH's top priority.
Continuing Trial Objectives
Despite the setback with rivaroxaban, CAPTIVA continues with its two remaining treatment arms. The study is designed to determine whether either of the new treatments—ticagrelor or clopidogrel combinations—works better than current standard treatment to prevent recurrent stroke (search). However, the trial will not directly compare the two remaining experimental treatments, as such a comparison would require significantly more patients.
The ongoing CAPTIVA study will still provide important safety and efficacy data on the remaining novel therapies for this challenging patient population with severe intracranial atherosclerosis.
Research Implications
This development underscores the complexities involved in treating patients with intracranial vascular atherostenosis (search), a condition that carries high risk for recurrent stroke (search). The failure of low-dose rivaroxaban in this setting highlights the need for careful evaluation of anticoagulation strategies in patients with severe arterial narrowing in the brain.
The CAPTIVA study and NIH's StrokeNet are funded by the National Institute of Neurological Disorders and Stroke, which serves as the nation's leading funder of research on the brain and nervous system.