Trial Purpose and Description
1. Demonstrate the safety of a low-dose intravenous infusion of
unfractionated heparin (LDIVH) in aSAH patients treated with coil
2. Demonstrate a positive clinical effect of LDIVH in aSAH patients through
measurement of significantly better mean Montreal Cognitive Assessment
(MoCA) scores in the LDIVH treated subjects at a 90 day follow-up visit
compared to control patients.
Ages: 18 - 70 years
- Age ≥ 18 and ≤ 70 years
- Historical modified Rankin Scale Score 0-1
- WFNS SAH Scale grade ≤ 2, due to a spontaneous subarachnoid hemorrhage attributable to a ruptured cerebral aneurysm. Cranial nerve deficit (e.g. CN III paresis) is permissible even for WFNS grade 2.• Initial WFNS grade may be determined at admission or enrollment, preferably after the patient's mental status has been optimized by resuscitation and interval treatment of hydrocephalus (i.e., placement of intraventricular catheter) or reversal/wearing-off of sedating medications used commonly during patient transfers and transport or procedure related anesthesia.
- Admission head CT showing modified Fisher grade 3 aSAH primarily in the supratentorial space. Snapshot images of up to four relevant axial cuts from the admission head CT will need to be uploaded via the imaging database to confirm the modified Fisher grade 3 eligibility of the potential subject prior to enrollment. Minimal intraventricular hemorrhage is acceptable.The Modified Fisher CT rating scale: Grade 1 (minimal or diffuse thing SAH without IVH); Grade 2 (minimal or thin SAH with IVH), Grade 3 (thick cisternal clot without IVH), Grade 4 (thick cisternal clot with IVH) [From: Claassen J et al. Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 2001;32:2012-2020.]
- Location and pattern of the SAH must have the majority of the SAH in the supratentorial space caused by either an intradural anterior circulation aneurysm OR a basilar apex posterior circulation aneurysm with primarily supratentorial hemorrhage extension. Angiographic location of the aneurysm will be confirmed by catheter digital subtraction angiography (DSA) usually obtained during the coil embolization procedure. Patients with PICA or other posterior circulation aneurysms as the cause of the SAH will be excluded.
- Onset of symptoms of aSAH (ictus) occurred < 24 hours prior to presentation at the treating facility.
- Initiation of aneurysm securement procedure occurred < 48 hours from the ictus AND less than 36 hours from admission to the treating facility.• In patients where the exact time of the ictus is uncertain, an estimated time of ictus may be assigned and that time will be used for the inclusion criteria above assuming the estimation is deemed to be reasonably reliable [i.e., actual time is highly likely to be within 6 hours of estimated time].
- All aneurysm(s) suspected to be responsible for the hemorrhage or potentially responsible for the hemorrhage must be secured in the following manner prior to enrollment:• Endovascular Coil Embolization with a post-embolization Raymond-Roy Score of 1 (Complete) or 2 (Residual Neck)
- Ability to screen the patient and obtain a head CT 2-12 hours after the completion of the coiling procedure and then ability to initiate the study drug 12 ± 4 hours after the completion of aneurysm coiling procedure..
- After recovering from anesthesia following the aneurysm coiling procedure, the patient must remain a WFNS SAH grade ≤ 2 without evidence of a significant new focal neurological deficit including monoparesis / monoplegia, hemiparesis / hemiplegia, or receptive, expressive or global aphasia. New minor cranial nerve defect without any other new findings is permissible. If an NIHSS score was obtained prior to the aneurysm coiling procedure, a post-coiling (pre-enrollment) NIHSS score must not have increased by ≥ 4 points and GCS score must not be decreased by ≤ 2 points. The clinician at the local site should use their best clinical judgment as to whether a significant neurological decline has occurred due to the procedure.
- Patient is willing and able to return for study follow-up visits.
- Patient or their Legally Authorized Representative (LAR) has provided written informed consent.
- Angio-negative SAH.
- A likely hemorrhage event within several days prior to admission related hemorrhage ictus due to the increased risk of early vasospasm. Prior sentinel headache with negative CT or prior sentinel headache where the patient did not seek medical attention does not exclude the patient.
- Surgical clipping of the ruptured aneurysm or any non-ruptured aneurysm on the same admission prior to enrollment.
- SAH not caused by aneurysm rupture or aneurysm is identified to be traumatic, mycotic, blister or fusiform type by catheter DSA.
- Any intracranial stent placement or non-coil intra-aneurysmal device (i.e., stent- assisted coiling with Neuroform, Enterprise, LVIS, LVIS Jr, Barrel Stent, Pulse Rider, WEB, LUNA, Medina or a similar device) where the stent device is implanted to treat the ruptured aneurysm and / or antiplatelet therapy is needed.
- Patient has remaining aneurysm(s) that are untreated and could reasonably be considered a possible alternate cause of the aSAH based on the observed bleeding pattern. Adequate treatment of these aneurysms by coiling embolization would result in the aneurysms no longer causing an exclusion. MRI may be used in some situations to determine that the associated aneurysms did not rupture based on lack of blood seen adjacent to the additional aneurysms.
- Femoral arteriotomy stick above the inferior epigastric artery OR angiographic, CT, or clinical evidence of an arteriotomy related retroperitoneal hematoma or large flank hematoma. A stable groin hematoma is not an exclusion.
- Patient received heparin in any form within the last 100 days prior to admission (not including coiling procedure).
- Thrombocytopenia (platelet count less than 100,000 - assuming clumping has been ruled out as a cause), confirmed active disseminated intravascular coagulation (DIC) at the time of enrollment OR a documented history of coagulopathy or bleeding diathesis.
- Diagnosis of sepsis (SIRS criteria plus the presence of known or suspected infection) or current documented active bacterial or viral infection prior to enrollment (Example: significant URI, community-acquired pneumonia). A minor non- complicated community-aquired urinary tract infection would not be an exclusion but should be treated promptly.
- New parenchymal hemorrhage or new infarction larger the 15cc in volume, or significant increased mass effect as seen on the post coiling pre-enrollment head CT when compared to baseline admission head CT. New hyyperdensity on CT scan related to contrast staining is not an exclusion.
- Patient has a documented history of heparin induced thrombocytopenia (HIT)
- Patient developed SAH-induced cardiac stunning prior to enrollment, with an ejection fraction< 40%, or requiring IV medicaitons for blood pressure maintenance.
- Pre-admission daily antiplatelet therapy or any oral or subcutaneous anticoagulation therapy prior to, or during the coil embolization procedure. A single 325 mg Aspirin (or lower dose) given duiring the coil embolization peri-procedural period is acceptable if this is the local standard of care, but should be documented.
- Thrombolytic therapy within 24 hours prior to enrollment (rtPA, urokinase, etc.)
- Plan for antiplatelet or oral anticoagulation therapy from the time of the coil embolization procedure until 14 full days after enrollment. Antiplatelet therapy may be resumed after the 14-day window.
- Concurrent significant intracranial pathology identified prior to enrollment, including but not limited to, Moyamoya disease, high suspicion or documented CNS vasculitis, severe fibromuscular dysplasia, arteriovenous malformation, arteriovenous fistula, significant cervical or intracranial atherosclerotic stenotic disease (≥70%), or malignant brain tumor.
- Uncontrollable hypertension (>180 systolic and/or >110 diastolic) that is not correctable prior to enrollment.
- Known seizure or epilepsy disorder (diagnosed prior to this aSAH diagnosis) where anti-epileptic medication was previously taken by the patient or have been recommended to be taken by the patient. Childhood seizures that have resolved and no longer require treatment are not part of this exclusion criteria
- Serious co-morbidities that could confound study results including but not limited to: Multiple Sclerosis, dementia, severe major depression, cancer likely to cause death in 2 years, multi-system organ failure, or any other conditions that could cause any degree of cognitive impairment.
- Immunosuppression therapy including chronic corticosteroid usage.
- Remote history of previous ruptured cerebral aneurysm.
- History of gastrointestinal hemorrhage or major systemic hemorrhage within 30 days, hemoglobin less than 8 g/dL, INR ≥1.5, severe liver impairment (AST< ALT< AP<GGT > 2 x normal or cirrhosis), creatinine > 2.0 mg/dL, or estimated GFR < 60 ml/min.
- Major surgery (including open femoral, aortic, or carotid surgery) within previous 30 days.
- Currently pregnant.
- Enrollment in another research study that would conflict with this study.
University of Louisville
Start Date: 06/01/2017
End Date: 02/01/2018
Last Updated: 02/22/2018
Study HIC#: 1601017127