Aneurysmal Subarachnoid Hemorrhage Trial RandOmizing Heparin

Trial end date:
Target enrollment:
Participant gender:
A Blind-adjudication Multi-center Phase II Randomized Clinical Trial of Continuous Low-dose Intravenous Heparin Therapy in Coiled Low-grade Aneurysmal Subarachnoid Hemorrhage Patients with Significant Hemorrhage Burden.
Phase 2
Accepts Healthy Volunteers?
Lead Sponsor:
Robert F James, MD, FACS, FAANS
Robert F. James
Indiana University School of Medicine
Calcium heparin
Inclusion Criteria:

1. Age ≥ 18 and ≤ 70 years

2. Historical modified Rankin Scale Score 0-1

3. Aneurysmal subarachnoid hemorrhage caused by a ruptured saccular aneurysm confirmed by
catheter angiography that is repaired by endovascular coil embolization. Initiation of
the coil embolization procedure should occur within 48 hours from the time of the
aneurysm rupture (ictus). In patients where the exact time of the ictus is uncertain,
a reasonable estimate of the time of ictus may be assigned. This reasonable time
estimate should be considered likely accurate to within hours of the true unknown

4. Quality of aneurysm embolization is interpreted to be Raymond-Roy Score of 1
(Complete) or 2 (Residual Neck) indicating that the aneurysm is adequately secured. A
tiny amount of contrast in the body of the aneurysm is acceptable as long as the
physician considers the aneurysm secured and to NOT represent a Raymond-Roy Score of 3
(Residual Aneurysm).

5. WFNS grade 1 or 2 as assessed after repair of the aneurysm during screening but prior
to randomization. A patient who presents with a WFNS greater than 2 who then improves
with resuscitation, ventriculostomy, or time is acceptable.

6. The pre-repair, admission head CT demonstrates an aSAH bleed pattern of "thick and
diffuse" or "thick and focal" hemorrhage within the subarachnoid basal cisterns
measuring ≥ 4 mm in the short axis and ≥ 20 mm in the long axis which is consistent
with a modified Fisher grade 3 or 4. Intraventricular hemorrhage is acceptable.
Enrollable patients must NOT have a parenchymal hemorrhage greater than 10 cc. Please
refer to diagram below for examples. The hemorrhage location should be substantially
within the supratentorial space and not isolated to the infratentorial space.

7. The location of the aneurysm should be the anterior circulation, posterior
communicating, OR a basilar terminus (apex). Angiographic location of the aneurysm
should 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 should not be included because they
typically cause primarily infratentorial bleed patterns.

8. Ability to screen the patient and obtain a head CT 2-12 hours after the completion of
the coiling procedure and the ability to initiate the study drug 12 ± 8 hours after
the completion of aneurysm coiling procedure.

9. 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.

10. Patient is willing and able to return for study follow-up visits.

11. Patient or their Legally Authorized Representative (LAR) has provided written informed

Exclusion Criteria:

1. Angio-negative SAH.

2. History or imaging suggesting that the current hemorrhage presentation is a recent
re-rupture of the aneurysm. Prior sentinel headache with negative CT or prior sentinel
headache where the patient did not seek medical attention does not exclude the

3. Surgical Clipping (or plan for clipping) of the ruptured aneurysm or any non- ruptured
aneurysm on the same admission.

4. Aneurysm is identified to be traumatic, mycotic, blister or fusiform type by catheter

5. Any intracranial stent placement or non-coil intra-aneurysmal device where dual-
antiplatelet therapy is needed during admission.

6. Patient has additional 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.

7. Patient received heparin in any form within the last 100 days prior to current
presentation / admission.

8. Thrombocytopenia (platelet count less than 100,000 - assuming clumping has been ruled
out as a cause).

9. New intraparenchymal 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 hyperdensity on CT scan related to
contrast staining is not an exclusion.

10. Patient has a documented history of heparin induced thrombocytopenia (HIT).

11. Patient developed SAH-induced cardiac stunning prior to enrollment, with an ejection
fraction <30%, or requiring IV medications for blood pressure maintenance.

12. 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, or malignant brain tumor.

13. Thrombolytic therapy within 24 hours prior to enrollment (rtPA, urokinase, etc.)

14. 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. A single 325 mg Aspirin (or lower dose) given
during the coil embolization peri-procedural period is acceptable if this is the local
standard of care but should be documented.

15. Concomitant serious or uncontrolled disease such as severe infection, active (non-
remission) cancer, severe organ dysfunction (severe heart failure, severe chronic
kidney impairment requiring dialysis or severe chronic liver disease) or any
coagulopathy (including DIC or bleeding diathesis).

16. Uncontrollable hypertension (>180 systolic and/or >110 diastolic) that is not
correctable prior to enrollment.

17. Prior neurological disease/deficit or psychiatric disease that may continue to alter
the results of neuropsychological evaluation, such as dementia, Multiple sclerosis,
seizure disorder, severe traumatic brain injury, previous ruptured cerebral aneurysm
or active major depression. Childhood seizures that have resolved and no longer
require treatment are not part of this exclusion criteria.

18. Active Immunosuppression therapy including chronic corticosteroid usage.

19. History of gastrointestinal hemorrhage or major systemic hemorrhage within 30 days
(including large flank or large retroperitoneal hematoma due to current admission
coiling procedure requiring treatment), hemoglobin less than 6 g/dL, INR ≥1.5 after
reversal of anticoagulants.

20. Major surgery (including open femoral, aortic, or carotid surgery) within previous 30

21. Currently pregnant.

22. Enrollment in another research study that prescribes a therapeutic treatment that
differs from the local standard of care, or that would conflict with this study in
some other significant fashion. Registries or coil comparison studies are appropriate.