The class of Novel Oral Anticoagulants (NOACs) known as direct Factor Xa (FXa) inhibitors has consistently demonstrated comparable or superior efficacy and/or safety relative to its predecessors, Vitamin K Antagonists (VKAs) and Low Molecular Weight Heparins (LMWHs). These agents (apixaban [Eliquis®], betrixaban [BevyxXa®], edoxaban [Savaysa®], rivaroxaban [Xarelto®]) are approved for the prevention of serious thromboembolic outcomes (e.g., stroke, deep vein thrombosis, pulmonary embolism) and have become widely used in the United States (US) and worldwide. One limitation to the use of FXa inhibitors has been the lack of an antidote to be used in cases of severe and/or life-threatening bleeding events. Acute major bleeding occurs at observed rates of 2-4% in pivotal stroke prevention trials in patients with nonvalvular atrial fibrillation [1-3], and such events are often catastrophic. Given the wide adoption and increasing use of FXa inhibitors, the prospect of major bleeding, especially in Intracranial Hemorrhage (ICrH) patients, has become a significant unmet medical need.
- An acute intracerebral bleeding episode, defined as an estimated blood volume > 0 to ≤ 60 mL acutely observed radiographically within the cerebrum. Patients may have extracerebral (e.g., subdural, subarachnoid) or extracranial (e.g., gastrointestinal, intraspinal) bleeding additionally, but the intracerebral hemorrhage must be considered the most clinically significant bleed at the time of enrollment.
- Performance of a head CT or MRI scan demonstrating the intracerebral bleeding within 2 hours prior to randomization (the baseline scan may be repeated to meet this criterion).
- Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], rivaroxaban [last dose 10 mg or greater], or edoxaban [last dose 30 mg or greater]):
- ≤ 15 hours prior to randomization.
- > 15 hours prior to randomization or unknown time of last dose, if documented anti-fXa activity is > 100 ng/mL (or over the equivalent IU/mL threshold on a LMWH assay; see Laboratory Manual) within 2 hours prior to consent. Note: Patients enrolled in this manner should receive a high andexanet dosing regimen.
- Planned surgery, including Burr holes for hematoma drainage, within 12 hours after randomization. Minimally invasive surgery/procedures not directly related to the treatment of intracranial bleeding and that are not expected to significantly affect hematoma volume are allowed (e.g., Burr holes for intracranial pressure monitoring, endoscopy, bronchoscopy, central lines).
- Glasgow Coma Scale (GCS) score < 7 at the time of consent. If a patient is intubated and/or sedated at the time of consent, they may be enrolled if it can be documented that they were intubated/sedated for non-neurologic reasons within 2 hours prior to consent.
- Any bleeding into the epidural space.
Your participation in this study will most likely last about 30-37 days but could be as many as 120 days. You will stay in the hospital for as long as your doctors think you need - this is not affected by whether you join the study. However, whether or not you are still in the hospital, you will have follow-up visits for the study in about 2, 3, 7, 14 and 30 days after you are enrolled. If you have been discharged from the hospital, you must return to the hospital to undergo the remainder of these follow-up study visits. Some of these follow-up visits may take place over the phone. While your involvement in the study will most likely end after the 30-day follow-up visit, there is a small chance that you may need to return for another follow-up visit in about 17 weeks if certain blood tests performed early in the study show abnormal results
Blood samples will be taken from a vein about 6 times during the study. Approximately 78 milliliters of blood (about 5 tablespoons) will be taken over the total time you are in the study (about 30-37 days). Each blood sample will be taken from either a small hollow tube already placed in your vein (IV) or some may require a new needlestick.
Your vital signs (heart rate, breathing rate, blood pressure, and temperature) will be measured. There is low or no risk of negative effects from these assessments.
CT and MRI SCANS
If you take part in this research, you will have had a Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan of your head when you arrived at the hospital as part of standard medical care. If a head CT or MRI scan has not already been done, one (either a CT or MRI, but not both) must be done before your eligibility for the study can be confirmed. One additional head CT or MRI scans will be performed as part of the study.