NIH Halts Low-Dose Rivaroxaban Arm in CAPTIVA Trial for Intracranial Atherosclerotic Stroke

In a recent news release, the National Institutes of Health (NIH) announced it discontinued the low-dose rivaroxaban (Xarelto; Janssen) arm of the ongoing CAPTIVA trial (NCT05047172) trial after an interim review identified increased safety events and evidence of futility. The decision followed a recommendation from the study’s independent Data and Safety Monitoring Board (DSMB) and was accepted by the National Institute of Neurological Disorders and Stroke, which sponsors the trial.¹

The trial is led by co–principal investigators Brian L. Hoh, MD, MBA, chair of the Lillian S. Wells Department of Neurosurgery at the University of Florida, and Marc I. Chimowitz, MBChB, professor of neurology at the Medical University of South Carolina. For context, CAPTIVA evaluates antithrombotic strategies for secondary stroke prevention in patients with symptomatic intracranial atherosclerotic stenosis (ICAS), a population at particularly high risk for recurrent ischemic events. All told, the halting of the rivaroxaban 2.5 mg twice daily plus aspirin arm underscored the ongoing uncertainty surrounding the role of direct oral anticoagulants in noncardioembolic cerebrovascular disease.

CAPTIVA Trial Overview

CAPTIVA is a 2-stage, double-blind, randomized trial enrolling adults 30 years and older who experienced a recent ischemic stroke attributed to 70% to 99% stenosis of a major intracranial artery. The study aimed to enroll up to 1683 participants across more than 100 US sites within the NIH StrokeNet network. Participants are randomly assigned 1:1:1 to 1 of 3 regimens for 12 months, as follows:

1. Ticagrelor (180-mg loading dose, then 90 mg twice daily) plus aspirin 81 mg daily
2. Low-dose rivaroxaban (2.5 mg twice daily) plus aspirin 81 mg daily
3. Clopidogrel (600-mg loading dose, then 75 mg daily) plus aspirin 81 mg daily

All participants receive intensive risk factor management and lifestyle counseling. The primary outcome is recurrent stroke, with safety end points including major bleeding and other serious adverse events.¹

According to NIH, the DSMB determined that the rivaroxaban arm demonstrated an increased rate of safety events and met a prespecified futility boundary, indicating that continued enrollment would be unlikely to demonstrate superiority over standard therapy. Specific event rates have not been publicly reported.

Interpretation and Next Steps

The early discontinuation of the rivaroxaban arm suggests that low-dose factor Xa inhibition combined with aspirin may not offer a favorable risk-benefit balance in patients with severe symptomatic ICAS. Without detailed event rates, it remains unclear whether excess harm was driven primarily by intracranial hemorrhage, systemic bleeding, or other adverse outcomes.

Importantly, CAPTIVA was not designed to compare ticagrelor and rivaroxaban directly, nor to establish superiority between the 2 investigational regimens. With the rivaroxaban arm halted, the ongoing evaluation of ticagrelor plus aspirin vs clopidogrel plus aspirin may still provide clinically meaningful data.¹

Clinical Context

Symptomatic ICAS remains one of the highest-risk stroke mechanisms, with recurrent stroke rates approaching 15% to 20% within 1 year despite medical therapy.² The landmark SAMMPRIS trial (NCT00576693) demonstrated that aggressive medical management—including dual antiplatelet therapy (aspirin plus clopidogrel for 90 days), high-intensity statin therapy, and strict risk factor control—was superior to intracranial stenting in this population.² As a result, dual antiplatelet therapy followed by single antiplatelet therapy has become the standard of care.

The rationale for testing rivaroxaban in ICAS stems in part from findings in stable atherosclerotic vascular disease. The previously completed COMPASS trial (NCT01776424) showed that low-dose rivaroxaban (2.5 mg twice daily) plus aspirin reduced major adverse cardiovascular events compared with aspirin alone in patients with chronic coronary or peripheral artery disease, albeit with increased major bleeding.³ However, COMPASS largely excluded patients with recent stroke, and its findings have not been directly extrapolated to symptomatic intracranial stenosis.

In contrast, prior trials of full-dose anticoagulation in intracranial atherosclerosis have not demonstrated benefit. The WASID trial (NCT03354429) found that warfarin was associated with higher rates of adverse events and offered no advantage over aspirin in patients with symptomatic ICAS.⁴ These historical data have led to caution regarding anticoagulation strategies in this population.

Rivaroxaban Background

Rivaroxaban is an oral factor Xa inhibitor approved by the FDA for stroke prevention in nonvalvular atrial fibrillation, treatment and secondary prevention of venous thromboembolism, and reduction of cardiovascular risk in patients with chronic coronary artery disease or peripheral artery disease when used with aspirin.⁵ Its role in noncardioembolic ischemic stroke prevention remains investigational.

Ticagrelor, a reversible P2Y12 receptor antagonist, has been evaluated in acute noncardioembolic stroke and transient ischemic attack in the SOCRATES and THALES trials. In THALES, ticagrelor plus aspirin modestly reduced stroke or death compared with aspirin alone but increased severe bleeding.⁶ Clopidogrel plus aspirin remains the most studied dual antiplatelet regimen in symptomatic ICAS, particularly based on SAMMPRIS.²

REFERENCES
1. ClinicalTrials.gov. Comparison of anti-coagulation and anti-platelet therapies for intracranial vascular atherostenosis (CAPTIVA). Updated January 30, 2026. Accessed February 12, 2026. https://clinicaltrials.gov/study/NCT05047172
2. Chimowitz M, Lynn M, Derdeyn C, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993-1003. doi:10.1056/NEJMoa1105335
3. Eikelboom J, Connolly S, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. doi:10.1056/NEJMoa1709118
4. Chimowitz M, Lynn M, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352(13):1305-1316. doi:10.1056/NEJMoa043033
5. Xarelto. Prescribing information. Janssen; 2021. Accessed February 12, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215859s000lbl.pdf 6. Johnston S, Amarenco P, Denison H, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J Med. 2020;383(3):207-217. doi:10.1056/NEJMoa1916870