Stroke Research and Treatment / 2013 / Article / Tab 3

Review Article

Clinical Trials in Cardiac Arrest and Subarachnoid Hemorrhage: Lessons from the Past and Ideas for the Future

Table 3

Randomized controlled trials assessing neurologic outcomes after aneurysmal Subarachnoid hemorrhage—ongoing trials.

Trial nameStudy designTreatment groupControl groupTarget enrollmentOutcome measurePIComments


Statins and cerebral blood flow in SAHRandomized, double-blind efficacy studySimvastatin 80 mg/d for 21 daysPlacebo60Primary outcome: resting CBF and autoregulation 7–10 days after SAH
Secondary outcomes: OEF and CMRO2 7–10 days after SAH
Michael Diringer,
Uses PET to understand the mechanism of statin use in vasospasm
The role of statins in preventing cerebral vasospasm secondary to subarachnoid hemorrhageRandomized, double-blind, parallel assignmentSimvastatin 80 mg PO qd × 21 daysPlacebo80Primary outcome: 6-month clinical outcomeEberval Figueiredo,
Use of simvastatin for the prevention of vasospasm in aneurysmal subarachnoid hemorrhageRandomized, double-blind, parallel assignment efficacy trialTier 1: Simvastatin 40 mg × 21 d or
Tier 2:
Simvastatin 80 mg × 21 d
Placebo150Primary outcome:
21-day GOS, mRS, and Barthel Index
Secondary outcome: clinical vasospasm
Ben Roitberg,
High-dose simvastatin for aneurysmal subarachnoid hemorrhage (HDS-SAH)Randomized, parallel assignment, double-blind efficacy studySimvastatin 80 mg PO × 21 daysSimvastatin 40 mg PO × 21 days240Primary outcome:
delayed ischemic neurological deficit
Secondary Outcomes:
LFTs, rhabdomyolysis, 3-month mRS, cost effectiveness
George Wong, NCT01077206There may be a biochemical and neuroprotective dose-related relationship between simvastatin and delayed ischemic neurological deficits.
Simvastatin in aneurysmal subarachnoid hemorrhage (STASH):
a multicentre randomised controlled clinical trial
Randomized, placebo-controlled, double-blind phase III trialSimvastatin 40 mg PO qd × 21 daysPlacebo1600Primary outcome: 6-month mRS
Secondary outcome: need and intensity of delayed ischemic deficit rescue therapy, incidence and duration of delayed ischemic deficits, incidence and severity of sepsis, length of stay, discharge disposition
Peter Kirkpatrick,
Simvastatin may improve CBF and inflammation following SAH

Aneurysm repair

International subarachnoid aneurysm trial II comparing clinical outcomes of Surgical clipping and endovascular coiling for ruptured intracranial aneurysms not included in the original ISAT study (ISAT II)Randomized, open label, safety/efficacy study of WFNS I–IVSurgical ClippingEndovascular Coiling1724Primary outcome: 12-month mRS > 2
Secondary outcomes: ICH following treatment, failure of aneurysm occlusion, all cause morbidity and mortality, aneurysm recurrence, hospitalization > 20 days or discharge other than home, aneurysm rebleed
Tim Darsaut, Max Findlay, and Jean Raymond,
ISAT included primarily small anterior circulation aneurysms. The optimal treatment of other locations and sizes of aneurysms remains unclear and coiling may not be as durable as clipping

Lipid peroxidation inhibitor

Acetaminophen in aSAH to inhibit lipid peroxidation and cerebral vasospasmRandomized, double-blind, placebo-controlled, safety/efficacy trialGroup1: Acetaminophen 1 g q 6
Group 2:
NAC IV 0.5 g/h
Group 3:
Acetaminophen 1 g q6 + NAC 0.5 g/h
Group 4:
Acetaminophen 1.5 g q 6 + NAC 0.5 g/h
Placebo120Primary outcome: F2-IsoP biomarkers for lipid peroxidation.
Secondary outcome: vasospasm and brain ischemia as assessed by CTA/CTP or MRI DWI
John Oates,
Hemoglobin released from lysed RBCs oxidizes and generates protein radicals that induce lipid peroxidation. Metabolites of peroxidations (F2-isoprostanes) are potent vasoconstrictors. Acetaminophen can inhibit these metabolites and NAC can inhibit lipid peroxidation

Neuroprotective drugs

Effects of tiopronin on 3-aminopropanal level and neurologic outcome after aneurysmal SAHRandomized, double-blind, phase 2
TioproninPlacebo60Primary outcome: serum and CSF 3AP levels
Secondary outcomes:
12 month mRS, Barthel, Lawton, NIHSS, TICS
adverse events
E Sander Connolly,
3AP is toxic metabolite produced during cerebral ischemia. It is neutralized by tiopronin
Lycopene following aneurysmal subarachnoid haemorrhage (LASH)Randomized, double-blind, placebo-controlled, efficacy studyLycopene 30 mg PO qd × 21 daysPlacebo124Primary outcome: TCD vasospasm, duration of impaired autoregulation measured by TCD
Secondary Outcomes: LDL, oxy-LDL, CRP, circulating endothelial cells, endothelial progenitor cells
Karol Budohoski,
Lycopene is a natural antioxidant that may reduce vascular injury and inflammation and limit vasospasm


Intraventricular tPA in the management of aneurysmal subarachnoid hemorrhageRandomized, placebo-controlled, double-blind safety trailtPA intraventricular q 12 h × 5 dosesPlacebo administered q 12 h × 5 doses12Primary outcome: HCT rate and variance of ventricular and cisternal clot clearance
Secondary outcome: hemorrhagic complications, ventriculostomy-related infections, TCD vasospasm, CT angio vasospasm, symptomatic vasospasm, CSF cytokines and coagulation measurements, ICP, fever burden, volume of CSF drainage, 6-month GOSE and EuroQOL
Andreas Kramer,
Intraventricular TPA may accelerate clearance of IVH ameliorating vasospasm, hydrocephalus, and ICP


Effect of red blood cell transfusion on brain metabolism in patients with SAHOpen label safety/efficacy study in SAH patients with Hgb < 12.5 g/dL and DCI, high risk for vasospasm or angiographic vasospasmTransfusion of 1 unit of packed RBC over 1 hourNA48Primary outcome: percent of brain regions with low oxygen delivery before and 1 hour after transfusion
Secondary outcomes: relationship of oxygen delivery and angiographic vasospasm
Michael Diringer, NCT00968227Uses PET to assess the relationship between Hct and oxygen delivery in SAH patients


Sildenafil for prevention of cerebral vasospasm (SIPCEVA)Randomized, double-blind, placebo-controlled, safety and efficacy studyTier 1: sildenafil 25 mg PO TID day 3–14 after SAH
Tier 2:
sildenafil 50 mg PO TID day 3–14 after SAH
Placebo18Primary outcome: New neurological deficit due to vasospasm up to 14 days after SAH
Secondary outcomes: TCD spasm, mortality, adverse drug effects, length of stay, discharge mRS
Andre Cerutti Franciscatto,
Safety study of dantrolene in SAHRandomized, double-blind safety studyDantrolenePlacebo30Primary outcome: tolerability, hyponatremia
Secondary outcomes: liver toxicity, hemodynamics, ICP, TCD, angiographic vasospasm treatments, 90-day GOS, mRS, and Barthel
Susanne Muehlschlegel,
Dantrolene is a muscle relaxant that may ameliorate vascular muscle tone and limit vasospasm
Safety and pharmacokinetic evaluation of nitrite for prevention of cerebral vasospasmRandomized, single-blind, parallel assignment safety studyTier 1:
sodium nitrite 32 nmol/kg/min
Tier 2:
sodium nitrite 48 nmol/kg/min
Tier 3:
sodium nitrite 64 nmol/kg/min
Placebo vehicle18Primary outcome: pharmacokinetics of 14-day sodium nitrite infusion
Secondary outcomes: safety and efficacy
Edward Oldfield,
Effects of prostacyclin infusion on cerebral vessels and metabolism in patients with subarachnoid hemorrhageRandomized, placebo controlled, double-blind, parallel assignment, pharmacodynamics studyTier 1:
prostacyclin 1 ng/kg/min day 5–10 after SAH
Tier 2:
prostacyclin 2 ng/kg/min day 5–10 after SAH
Placebo, IV infusion day 5–10 after SAH90Primary outcome: vasospasm measured by CT perfusion
Secondary outcomes: cerebral metabolism measured by microdialysis, 3-month GOS, clinical vasospasm, brain tissue oxygen, CT angio vasospasm, MAP, serum S100b
Rune Rasmussen, NCT01447095Prostacyclin may cause vasodilation and ameliorate vasospasm

Hypertensive, hypervolemic therapy

Induced hypertension for treatment of delayed cerebral ischemia after aneurysmal SAH
Randomized, Single blind safety/efficacy study of patients with SAH and DCI (clinically defined)Induced hypertension with vasopressors and fluids for 48 hoursNo induced hypertension240Primary outcome: mRS at 3 months
Secondary outcomes: proportion of treated patients who did not have clinical improvement of DCI symptoms within 24 hours, 30-day mortality, 3-month Barthel, SSQoL, hospital anxiety and depression scale, cognitive failures questionnaire, hospital complications, CTP results, medical costs
Arjen Slooter and Walter van den Bergh,
CBF measured in all patients using CTP at enrollment and 24–36 hours
Intensive management of pressure and volume expansion in patients with subarachnoid hemorrhage (IMPROVES)Randomized, single-blind, factorial assignmentTier 1: hypervolemia + conventional blood pressure
Tier 2: normovolemia + hypertension
Tier 3:
hypervolemia + hypertension
Normal volume, normal blood pressure20Primary outcome: achievement of hemodynamic goals in each groupMiriam Treggiari,
Though triple H is a common therapy, its safety and efficacy have not been well quantified

CSF diversion

EARLYDRAIN: outcome after early lumbar CSF: drainage in aneurysmal subarachnoid hemorrhageRandomized, 2-arm controlled trialContinuous lumbar CSF drainage of 120 mg qd × 7 dStandard NICU care300Primary outcome: 6-month mRS
Secondary outcomes: 6-month mortality, angiographic vasospasm, TCD vasospasm, shunt insertion rate at 6 months
Bardutzky J,
Lumbar drainage to remove blood from the basal cisterns may limit delayed cerebral ischemia
Cerebrospinal fluid (CSF) drainage studyRandomized, open label, parallel assignment study of SAH patients requiring external ventricular drainage (EVD)High volume CSF diversion (EVD at 5 mmHg) × 10 daysConventional CSF diversion (EVD at 15 mm Hg), weaned at physician discretion20Primary outcome: 90-day mRS
Secondary Outcome: radiologic infarction, TCD or angiographic vasospasm, shunt placement, ventriculitis, discharge mRS, 90 day mini-mental status exam, length of stay
Giuseppe Lanzino,
More aggressive CSF drainage may improve brain microcirculation and perfusion and lead to better neurological outcomes


Comparison of short duration levetiracetam to extended course for seizure prophylaxis after subarachnoid hemorrhageRandomized, prospective, open label, parallel assignment, phase III, safety/efficacy studyLevetiracetam 1000 mg BID × 3 daysLevetiracetam 1000 mg BID × hospital stay460Primary outcome: In hospital seizures
Secondary outcome: Incidence of seizure after hospital discharge, adverse drug reactions, length of stay, cognitive and functional outcomes
Rajat Dhar,
Antiepileptics can have long-term cognitive side effects. A short course may be just as efficacious as prolonged use
Antiepileptic drugs and vascular risk markersRandomized, open label, parallel assignment studyTier 1: phenytoin 5 mg/kg/d divided in 2 doses
Tier 2: valproate 15 mg/kg/d divided in 3 doses
Tier 3: levetiracetam 1000-1500 mg/d divided in 2 doses
No drug intervention200Primary outcome: serum cholesterol, non-HDL cholesterol, HDL, lipoprotein a, CRP
Secondary outcome: acute seizures, late seizures, mRS at 8 and 16 weeks
Prema Kishna and Scott Mintzer,
Certain seizure medications may raise cholesterol levels and increase the risk of heart attack and stroke


Effects of dexmedetomidine on inflammatory cytokines in patients with aneurysmal subarachnoid hemorrhageRandomized, open label, parallel assignment efficacy studyDexmedetomidine 0.2–1.5 mcg/kg/hPropofol 5–80 mcg/kg/min10Primary outcome: serum and CSF cytokines over 48 hours
Secondary outcomes: sedative and analgesic requirements, RASS and CAM-ICU scores, length of stay, delayed cerebral ischemia, GOSE at discharge
Shaun Keegan and Brittany Woolf,
Dexmedetomidine may cause less inflammation over time than propofol


Rehabilitation of patients after subarachnoid hemorrhageNonrandomized, open label, parallel assignment Early multidisciplinary rehab and mobilizationNo intervention160Primary outcome: 10-week GOS
Secondary outcome: 3–6 month and 12-month GOSE, functional independence measure, coma recovery scale, disability rating scale, High-level Mobility Assessment tool, pain score
Tanja Karic and Angelika Sorteberg,
Early rehab may reduce complications and improve physical and cognitive function after SAH

Blood pressure control

Safety and Efficacy Study of Clevidipine to Control Hypertension in Patients Admitted with Aneurysmal Subarachnoid Hemorrhage (CLASH)Open label, safety, efficacy study, single group assignment (Phase 2)Clevidipine IV 2–32 mg/h for 24–48 hoursNA20Primary: Blood pressure within target rangePanayiotis Varelas,
To assess how rapidly and safely Clevidipine can be used to control blood pressure in SAH patients.


Cervical spinal cord stimulation for the prevention of cerebral vasospasmNonrandomized, open labelSpinal cord stimulation using MTS Trial System 3510NA12Primary outcome: cerebral vasospasm
Secondary outcome: adverse events
Konstantin Slavin, NCT00766844