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

Table 1

Randomized controlled trials assessing neurologic outcomes after aneursymal Subarachnoid hemorrhage—completed trials.


Trial name	Study design	Treatment group	Control group	Outcome measure	Results	Reference

Calcium channel blockers—nimodipine

Cerebral Arterial Spasm—a controlled Trial of Nimodipine in Patients with Subarachnoid Hemorrhage	Randomized, placebo-controlled, double-blind, multicenter prospective study of Hunt Hess grade I-II SAH patients	Nimodipine 0.7 mg/kg PO bolus, then 0.35 mg/kg q 4 × 21 days. Starting within 96 h of SAH ()	Placebo ()	Primary outcome: neurological deficit from arterial spasm and severity of neurologic deficit at 21 days	Nimodipine significantly reduced death or severe deficits from spasm at 21 days (2% versus 13% with placebo, )	Allen et al., NEJM 1983 [3]
Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial	Randomized, multicenter, double-blind, placebo-controlled trial	Nimodipine 90 mg PO q 4 h × 21 d ()	Placebo ()	Primary outcome: 3-month GOS Secondary outcomes: delayed ischemic deficits, angiographic vasospasm	Better 3-month GOS in treatment group (29% versus 9% of treatment group, ). Significantly less delayed cerebral ischemia in treatment group, no difference in angiographic vasospasm	Petruk et al., J Neurosurg 1988 [4]
Controlled study of nimodipine in aneurysm patients treated early after subarachnoid hemorrhage	Randomized, double-blind, placebo-controlled trial of all Hunt-Hess grades within 96 hours of SAH	Nimodipine 60 mg q 4 h PO × 21 days + Nimodipine 200 mcg IV intraoperatively into basal cistern ()	Placebo ()	Primary outcome: mortality, cerebral blood flow measured by Xenon CT Secondary outcomes: 3-month intellectual or neurological deficit	Mortality was lower in the nimodipine group (4% versus 24% with placebo, ). Nimodipine did not significantly increase cerebral blood flow	Mee et al., Neurosurgery 1988 [5]
Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid hemorrhage: British aneurysm nimodipine trial	Randomized, double-blind, placebo-controlled, multicenter trial within 96 h of SAH	Nimodipine 60 mg q 4 PO × 21 d ()	Placebo ()	Primary outcome: 3-month cerebral infarction Secondary outcome: 3-month GOS	Significantly less cerebral infarction in the nimodipine group (22% compared to 33% in placebo, ). Poor GOS outcomes significantly reduced in nimodipine group at 3-months	Pickard et al., BMJ 1989 [6]
Early aneurysm surgery and preventive Therapy with intravenously administered nimodipine: A multicenter, double-blind, dose-comparison study	Randomized, double-blind, dose-comparison, multicenter study	Nimodipine 2 mg/h IV for 9–15 days ()	Nimodipine 3 mg/h IV for 9–15 days ()	Primary outcome: delayed neurological deficits, adverse drug reactions	No difference in delayed neurological deficits between the two groups	Gilsbach et al., Neurosurgery 1990 [7]
Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery	Randomized, double-blind, placebo-controlled of Hunt-Hess I–III SAH patients	Nimodipine IV 0.5 mcg/kg/min × 7–10 days followed by 60 mg q 4 h PO × 21 days total ()	Placebo ()	Primary outcome: delayed ischemic deterioration and CT infarcts Secondary outcomes: GOS at 1–3 years	Significantly fewer deaths caused by delayed cerebral ischemia in nimodipine group () and fewer cerebral infarcts on CT (). No differences in 1–3 year GOS or CT scan	Ohman et al., J Neurosurg 1991 [8]
A randomized outcome study of enteral versus intravenous nimodipine in 171 patients after acute aneurysmal subarachnoid hemorrhage	Randomized, single-center study	Nimodipine 2 mg/h IV × 10 days then changed to PO × 6 d ()	Nimodipine 60 mg PO q 4 × 16 days ()	Primary outcome: delayed ischemic neurological deficit Secondary outcomes: 12 month GOS, mRS, Karnofsky, MRI infarcts, HRQoL	No difference in delayed ischemic neurological deficits (20% in enteral versus 16% in IV group, ), no difference in 12-month clinical outcomes	Soppi et al., World Neurosurgery 2012 [9]

Calcium channel blockers—nicardipine

A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the cooperative aneurysm study	Randomized, double-blind, placebo-controlled, multicenter study	Nicardipine IV 0.15 mg/kg/h ()	Placebo ()	Primary outcome: 3-month GOS Secondary outcomes: angiographic vasospasm, TCD vasospasm, mortality, disability from vasospasm, symptomatic vasospasm, CT infarction, NIHSS	No difference in 3-month GOS. Less symptomatic vasospasm in treatment group (32% versus 46% in placebo group, P < 0.001) and less angiographic vasospasm in treatment group (33% versus 51% of placebo, P < 0.01) and less TCD vasospasm (23% versus 49% of placebo, P < 0.001)	Haley et al., J Neurosurg 1993 [10, 11]
A randomized trial of two doses of nicardipine in aneurysmal subarachnoid hemorrhage. A report of the cooperative aneurysm study	Randomized, double-blind, multicenter study	Nicardipine IV 0.15 mg/kg/h × 14 days (N = 184)	Nicardipine IV 0.075 mg/kg/h × 14 days (N = 181)	Primary outcome: symptomatic vasospasm, adverse drug events Secondary outcomes: 3-month GOS and NIHSS, mortality, disability due to vasospasm, CT infarction	No difference in symptomatic vasospasm or 3-month outcome. More adverse effects in high-dose nicardipine group	Haley et al., J Neurosurg 1994 [12]
Effect of nicardipine prolonged-release implants on cerebral vasospasm and clinical outcome after severe aneurysmal subarachnoid hemorrhage. A prospective, randomized, double-blind phase IIa Study	Randomized, prospective double-blind phase IIa study in clipped SAH patients	Nicardipine prolonged-release implants (10 × 4 mg prolonged release rod shaped polymers) placed in basal cisterns (N = 16)	Control-basal cisterns opened and washed out (N = 16)	Primary outcome: angiographic vasospasm Secondary outcome: delayed ischemic lesion on HCT, 1-year mRS and NIHSS	Angiographic vasospasm significantly reduced in treatment group (7% versus 73% in controls, P < 0.05). No significant difference in CT infarct. Decreased mortality in treatment group (6% versus 38% in control group, P = 0.042) and better 1-year mRS and NIHSS (P = 0.0001)	Barth et al., Stroke 2007 [13]

Antifibrinolytics

Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: A consecutive controlled clinical trial	Randomized, placebo-controlled, study	Tranexamic acid 1 g q 4 h IV × 1 week then 1 g q 6 h IV × 1 week then 1.5 g q 6 h PO × 1 week (N = 30)	Placebo (N = 29)	Primary outcome: recurrent hemorrhage diagnosed by LP, HCT, echoencephalogram or autopsy. Secondary outcome: angiographic vasospasm, delayed cerebral ischemia, death	Tranexamic acid protected against rebleeding during the first 2 weeks of treatment but also resulted in cerebral ischemic complications	Fodstad et al., Neurosurgery 1981 [14]
Comparative clinical trial of epsilon amino-caproic acid and tranexamic acid in the prevention of early recurrence of subarachnoid hemorrhage	Randomized trial	Epsilon amino-caproic acid 6 g q 6 h IV continued until surgery or discharge (N = 90)	Tranexamic acid 1 g q 6 h IV continued until surgery or discharge (N = 61)	Primary outcome: recurrent hemorrhage diagnosed clinically by HCT, LP, or autopsy Secondary outcome: delayed ischemic deficit diagnosed by clinical deterioration, angiographic vasospasm, and infarct on HCT	Rebleeding occurred in 8% of aminocaproic-acid-treated patients and 10% of tranexamic acid treated patients. Delayed ischemic deficits occurred in 7% of aminocaproic acid patients and 5% of tranexamic acid patients. Mortality was 11% in each group. P = NS for all outcomes	Chowdhary and Sayed, JNNP 1981 [15]
Antifibrinolytic treatment in subarachnoid hemorrhage	Randomized, double-blind, placebo-controlled, multicenter study	Tranexamic acid 1 g q 4 h IV × 1 week then 1 g q 6 h IV × 3 weeks (N = 241)	Placebo (N = 238)	Primary outcome: 3-month GOS Secondary outcome: neurological deterioration, rebleeding, infarction, hydrocephalus, edema, epilepsy	Rebleeding reduced from 24% in control group to 9% in treatment group (P < 0.001), but with concurrent increase in ischemic complications (24% in treatment group versus 15% in placebo, P < 0.01). No difference in 3 month GOS	Vermeulen et al., NEJM 1984 [16]
Antifibrinolytic treatment in subarachnoid hemorrhage: a randomized placebo-controlled trial (STAR)	Prospective, double-blind, placebo-controlled, multicenter, randomized trial within 96 hours of SAH onset in whom aneurysm repair was delayed beyond 48 hours	Tranexamic acid 1 g IV q 4 h × 1 week then 1.5 g PO q 6 h × 2 weeks (N = 229)	Placebo (N = 233)	Primary outcome: 3-month GOS Secondary outcomes: rebleeding, delayed cerebral ischemia, hydrocephalus, postoperative ischemia	No difference in 3-month GOS. Significant decrease in rebleeding from 33% in placebo group to 19% in treatment group. No difference in delayed cerebral ischemia, hydrocephalus, or postoperative ischemia	Roos, Neurology 2000 [17]
Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study	Randomized, placebo-controlled trial	Tranexamic acid 1 g IV bolus, then 1 g IV q 6 hours until aneurysm repair or 72 hours post ictus. (N = 254)	Placebo (N = 251)	Primary outcome: Rebleeding by HCT Secondary outcome: 6 -month GOS, clinical vasospasm/delayed ischemic neurological deficit, TCD spasm	Treatment group had reduced rebleeding rate of 2.4% compared to 10.8% in the placebo group (P < 0.01). More favorable outcome in the treatment group (74.8% compared to 70.5% in the control group, P = NS). No increased risk of ischemia	Hillman et al., J Neurosurg 2002 [18]

Neuroprotectives drugs

A double-blind clinical evaluation of the effect of nizofenone on delayed ischemic neurological deficits following aneurysmal rupture	Randomized, placebo controlled trail	Nizofenone for 5–10 days (N = 42)	Placebo (N = 48)	Primary outcome: delayed ischemic neurological deficits with angiographically confirmed vasospasm. Secondary outcomes: one-month disability index, motor, and speech function	No difference in delayed ischemic events between treatment groups. Among patients with vasospasm, those who received nizofenone had better one-month functional outcomes (P < 0.05)	Saito et al., Neurol Res 1983 [19]
Nizofenone administration in the acute stage following subarachnoid hemorrhage. Results of a multicenter controlled double-blind clinical study	Randomized, double-blind, placebo-controlled, multicenter study of Hunt Hess grade I–IV	Nizofenone 5 mg × 2 weeks (N = 102)	Placebo (N = 106)	Primary outcome: neurological exam at 1-month and discharge	Significantly improved one-month or discharge functional outcome in treatment group compared to placebo (P < 0.05). No difference in mortality	Ohta et al., J Neurosurg 1986 [20]
Effect of a free radical scavenger, edaravone, in the treatment of patients with aneurysmal subarachnoid hemorrhage	Randomized, controlled, single-center study	Edaravone 30 mg IV BID × 14 days (N = 49)	Control (usual treatment) (N = 42)	Primary outcome: delayed ischemic neurological deficits Secondary outcomes: cerebral infarction due to vasospasm, 3-month GOS	No difference in delayed ischemic neurological deficits between treatment and control groups. Less cerebral infarction in treatment group (0% versus 66%, P = 0.028). Poor outcome caused by vasospasm 0% in treatment group and 71% in control group (P = 0.046)	Munakata et al., Neurosurgery 2009 [21]
Eicosapentaenoic Acid Cerebral Vasospasm Therapy Study (EVAS)	Randomized, controlled, open label, multicenter, efficacy study of surgically clipped SAH patients	Eicosapentaenoic acid (omega 3 fatty acid) 900 mg TID × 30 days (N = 81)	Control (usual treatment) (N = 81)	Primary outcome: symptomatic vasospasm or infarct on HCT Secondary outcome: 1-month GOS	Symptomatic vasospasm occurred significantly less in the treatment group (15% versus 30% in controls, P = 0.022) as did infarction from vasospasm (7% versus 21% in controls, P = 0.012)	Yoneda et al., World Neurosurg 2012 [22]
Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomized, double-blind, placebo-controlled trial	Randomized, double-blind, placebo-controlled study of ruptured (WFNS 1–3) and unruptured aneurysms undergoing endovascular repair	NA-1 2.6 mg/kg infusion over 10 minutes (N = 92)	Placebo (N = 93)	Primary outcome: safety, number and volume of ischemic strokes on MRI DWI and FLAIR 12–96 hours after infusion Secondary outcome: 30-day mRS, NIHSS, neurocognitive outcome	No difference in MRI lesion volume, but fewer ischemic lesions in NA-1 group compared to placebo (P = 0.012). In the SAH subgroup (20% of cohort) their MRI number and ischemic volume was significantly less in the treatment group. No difference in 30 day NIHSS or mRS between groups	Hill et al., Lancet Neurol 2012 [23]

Statins

Simvastatin reduces vasospasm After aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial	Randomized, placebo-controlled pilot trial	Simvastatin 80 mg qd for 14 days (N = 19)	Placebo (N = 20)	Primary outcome: delayed ischemic neurological deficit confirmed by TCD or angiography. Secondary outcomes: liver transaminases, CK, von Willebrand factor, S100	Vasospasm occurred in 26% of treatment group compared to 60% of placebo group (P < 0.05). No differences in transaminitis or myositis. VWF and S100 were significantly lower in the treatment group (P < 0.05)	Lynch et al., Stroke 2005 [24]
Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed Ischemic deficits after aneurysmal subarachnoid hemorrhage. A phase II randomized placebo-controlled trial	Randomized placebo-controlled, phase II Trial	Pravastatin 40 mg PO qd × 14 d (N = 40)	Placebo (N = 40)	Primary outcome: incidence, severity, and duration of vasospasm on TCD, duration of impaired autoregulation measured by transient hyperemic response on TCD Secondary outcome: vasospasm-related delayed ischemic deficits, disability at discharge	TCD vasospasm and severe vasospasm were reduced in the treatment group (P = 0.006 and P = 0.044, resp.). Duration of impaired autoregulation shortened in treatment group (P < 0.01). Vasospasm-related delayed ischemic deficits was reduced (P < 0.001) and mortality was reduced (P = 0.037)	Tseng et al., Stroke 2005 [25]
A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage	Randomized, double-blind, placebo-controlled pilot study	Simvastatin 80 mg qd in statin naïve Fisher 3 SAH until discharge or 21 days (N = 19)	Placebo (N = 20)	Primary outcome: death and drug morbidity (elevated CK, transaminases) Secondary outcomes: TCD, angiographic or clinical vasospasm, vasospasm-related infarcts, clinical outcomes at discharge, cardiac, and infectious morbidities	Mortality in 0% treatment group and 15% placebo group. Angiographically confirmed vasospasm in 26% treatment group and 25% placebo group. Vasospasm infarcts in 11% treatment group and 25% placebo group. All differences P = NS	Chou et al., Stroke 2008 [26]
Biological effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial	Double-blind, placebo-controlled randomized trial	Simvastatin 80 mg PO × 15 days (N = 16)	Placebo (N = 16)	Primary outcome: effect of simvastatin on laboratory parameters of endothelial function, fibrinolysis, coagulation, inflammation and cholesterol Secondary outcomes: TCD vasospasm, clinical signs of DCI, 3- and 6-month GOS	Simvastatin group had significantly lower total cholesterol and LDL, but no differences in coagulation, fibrinolysis, endothelium function, or inflammation. No differences in TCD vasospasm, clinical DCI, or poor outcome	Vergouwen et al., J Cereb Blood Flow Metab 2009 [27]

Aneurysm repair

Timing of operation for ruptured supratentorial aneurysms: a prospective randomized study	Randomized, prospective study of Hunt Hess grade I–III SAH patients	Acute surgery (day 0–3 after SAH) (N = 71)	Intermediate surgery (day 4–7 after SAH) (N = 70) Late surgery (day 8 or later after SAH) (N = 70)	Primary outcome: 3-month dead, dependent or independent. Secondary outcomes: Neurological deficit from direct effect of initial bleed, complication of surgery, confirmed rebleeding, delayed ischemic deterioration, hydrocephalus, extracranial complications	Acute surgery patients were more often independent at 3-months (92% versus 79% in intermediate timing and 80% in the late timing group, P < 0.01). Mortality was 6% in the early surgery group versus 13% in the late surgery group (P = NS)	Ohman and Heiskanen, J Neurosurg 1989 [28]
International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial	Randomized, unblinded trial of SAH patients with an aneurysm judged technically suitable for either clipping or coiling and clinical equipoise	Surgical clipping (N = 1070)	Endovascular treatment by detachable platinum coils (N = 1073)	Primary outcome: 1-year mRS 3–6 versus 1-2 Secondary outcomes: rebleeding, quality of life at 1 year (euroQol), frequency of epilepsy, cost effectiveness, neuropsychological outcomes	Dependent or dead at 1 year: 23.7% endovascular versus 30.6% clipping (P = 0.0019).	Molyneux et al., ISAT Collaborative Group, Lancet 2002 [29]
International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion	Randomized, unblinded trial of SAH patients with an aneurysm judged technically suitable for either clipping or coiling and clinical equipoise	Surgical clipping (N = 1070)	Endovascular treatment by detachable platinum coils (N = 1073)	Primary outcome: 1-year mRS 3–6 versus 1-2 Secondary outcomes: rebleeding, quality of life at 1-year (Euroqol), frequency of epilepsy, cost effectiveness, neuropsychological outcomes	Dead or dependent at 1-year: 23.5% of endovascular group versus 30.9% of clipping group. ARR 7.4%. Early survival advantage of coiling maintained up to 7 years (P = 0.03). Lower risk of epilepsy in coiled group but higher late rebleeding risk in coiled group	Molyneux et al., Lancet 2005 [30]
The barrow ruptured aneurysm trial	Randomized, open-label, prospective, single-center study	Surgical clipping (N = 238)	Endovascular coiling (N = 233)	Primary outcome: 1-year mRS > 2	Poor outcome in 33.7% of clipped and 23.2% of coiled patients (P = 0.02)	McDougall et al., J Neurosurg 2012 [31]

Lipid peroxidation inhibitor

Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand	Double-blind, randomized, vehicle-controlled study in men and women with aneurysmal SAH	Tirilazad 0.6 mg/kg/ (N = 257) Tirilazad 2 mg/kg/d (N = 249) Tirilazad 6 mg/kg/d (N = 256) up to 11 days	Placebo containing citrate vehicle (N = 253)	Primary outcome: Symptomatic vasospasm Secondary outcome: 3-month GOS, NIHSS, infarct volume on head CT	The subgroup 6 mg/kg treatment arm had reduced mortality (P = NS) and better 3-month GOS (P = NS) compared to placebo. Less symptomatic vasospasm in 6 mg/kg group, but not significant. Men showed more benefit than women. No significant improvement with lower dosing groups	Kassell et al., J Neurosurg 1996 [32]
A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America	Double-blind, randomized, vehicle-controlled study in men and women with aneursymal SAH	Tirilazad 2 mg/kg/d (N = 298) Tirilazad 6 mg/kg/d (N = 299) up to 11 days	Placebo containing citrate vehicle (N = 300)	Primary outcome: mortality at 76 days Secondary outcome: 3-month GOS and NIHSS, infarct volume on head CT symptomatic vasospasm, incidence, and severity of angiographic vasospasm	No difference in mortality, favorable GOS outcome, or employment between groups. No differences in symptomatic or angiographic vasospasm	Haley et al., J Neurosurg 1997 [33]
Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I a cooperative study in Europe, Australia, New Zealand, and South Africa	Double-blind, randomized, vehicle-controlled study in women with aneurysmal SAH	Tirilazad mesylate 15 mg/kg/d IV hours for 11 days (N = 405)	Placebo containing citrate vehicle (N = 414)	Primary outcome: 91-day mortality Secondary outcome: 3-month GOS, clinical vasospasm, use of hypervolemic hypertensive therapy, neurological worsening from vasospasm, cerebral infarction, use of angioplasty, safety endpoints	Mortality rates and 3-month GOS not different between groups. Lower symptomatic vasospasm in tirilazad group (24.8% versus 33.7% in placebo group, P = 0.005). Cerebral infarction 8% in treatment group versus 13% in placebo group (P < 0.04)	Lanzino et al., J Neurosurg 1999 [34]
Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneursymal subarachnoid hemorrhage. Part II a cooperative study in North America	Double-blind, randomized, vehicle-controlled study in women with aneurysmal SAH	Tirilazad mesylate 15 mg/kg/d IV up to 11 days (N = 410)	Placebo containing citrate vehicle (N = 413)	Primary outcome: mortality at 91 days in WFNS grade IV-V patients Secondary outcomes: 3 month GOS or clinical vasospasm 1–14 days from dosing, use of hypervolemic hypertensive therapy, neurological worsening from vasospasm, cerebral infarction, use of angioplasty, safety endpoints	No differences in mortality when analyzing the entire population. No difference in GOS, symptomatic vasospasm, vasospasm severity. In WFNS grades IV-V, lower mortality in treatment group (24.6% versus 43.4% in placebo, P = 0.016). In WFNS I–III improved GOS in placebo group (83.3% versus 76.7% in treatment group, P = 0.04)	Lanzino and Kassell, J Neurosurg 1999 [35]

Thrombolytics

Prevention of delayed ischemic deficits after aneurysmal subarachnoid hemorrhage by intrathecal bolus injection of tissue plasminogen activator (rTPA)	Prospective, controlled trial of Fisher III clipped SAH patients	rTPA 10 mg IV intracisternal immediately following aneurysm clipping ± 5–10 mg IV TPA intraventricularly in patients with IVH (N = 52)	No TPA instillation (N = 68)	Primary outcome: clinical delayed ischemic deficits attributed to vasospasm Secondary outcome: 3-month GOS	Significantly less transient and permanent delayed ischemic deficits and better GOS in rTPA group	Seifert et al., Acta Neurochir 1994 [36]
A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm	Randomized, double-blinded, placebo-controlled, multicenter study	rTPA 10 mg intracisternal at the time of aneurysm clipping (N = 51)	Placebo vehicle (N = 49)	Primary outcome: angiographic vasospasm Secondary outcome: mortality, 3-month GOS, symptomatic vasospasm, clot clearance on CT, TCD velocities, use of HHH on angioplasty to treat vasospasm	No difference in angiographic vasospasm, vasospasm treatment, TCD velocities, mortality, or 3-month GOS	Findlay, Neurosurgery 1995 [37]
Efficacy of low-dose tissue-plasminogen activator intracisternal administration for the prevention of cerebral vasospasm after subarachnoid hemorrhage	Randomized, controlled trial	Intermittent Tisokinase 960,000 IU via cisternal drain (N = 20) Continuous infusion Tisokinase 1920 IU/h × 48 h via cisternal drain (N = 20)	Control (standard treatment) (N = 20)	Primary outcome: clearance of subarachnoid clots by HCT Secondary outcome: delayed cerebral ischemia, 3-month mRS and GOS	Subarachnoid clot by HCT and delayed cerebral ischemia were significantly less in the treatment groups compared to control (P < 0.05). The intermittently treated group had better neurological outcomes than the control group (P < 0.05)	Yamamoto et al., World Neurosurgery 2010 [38]

Anti-platelets

Dipyridamole and postoperative ischemic deficits in aneurysmal subarachnoid hemorrhage	Randomized, placebo-controlled, single-blind controlled trial	Dipyridamole 100 mg PO qd or 10 mg/day IV × 3-months (N = 336)	Placebo (N = 314)	Primary outcome: 3-month GOS Secondary outcome: neurological deterioration following aneurysm repair	No differences in 3-month GOS or delayed neurological deterioration	Shaw et al., J Neurosurg 1985 [39]
Randomized controlled trial of acetylsalicylic Acid in aneurysmal subarachnoid hemorrhage: the MASH study	Randomized controlled pilot study; factorial design (magnesium versus placebo and ASA versus placebo, separated a priori)	Aspirin 100 mg PR qd × 14 days within 12 hours of aneurysm occlusion. (N = 87)	Placebo (N = 74)	Primary outcome: delayed ischemic neurological deficits within 3-months of SAH consisting of HCT infarcts plus clinical decline Secondary outcome: new CT infarcts of any cause, postop hemorrhage, mRS ≥ 4, mRS ≥ 1	No difference in delayed ischemic events, CT infarction, or 3-month outcomes	Van den Bergh, Stroke 2006 [40]
Cilostazol improves outcome after subarachnoid hemorrhage: a preliminary report	Randomized, single-blind, prospective, multicenter study	Cilostazol 100 mg PO BID (N = 49)	Control (usual care) (N = 51)	Primary outcome: symptomatic vasospasm and cerebral infarction, discharge mRS	No difference in symptomatic vasospasm or cerebral infarction. mRS at discharge better in treatment group (1.5 versus 2.6 in controls, P = 0.041)	Suzuki et al., Cerebrovasc Dis 2011 [41]

Steroids

Effect of fludrocortisone acetate in patients with subarachnoid hemorrhage	Randomized, placebo controlled, multicenter trial	Fludrocortisone 400 mcg/day BID × 12 days PO or IV (N = 46)	Placebo (N = 45)	Primary outcome: plasma volume change, fluid balance, sodium balance Secondary outcome: delayed cerebral ischemia within 28 days and 28-day GOS	Treatment reduced negative sodium balance (P = 0.014) but did not affect plasma volume. No significant difference in cerebral ischemia (22% versus 31% in controls, P = 0.349). Similar outcome in each group	Hasan et al., Stroke 1989 [42]
A randomized controlled trial of hydrocortisone against hyponatremia in patients with aneurysmal subarachnoid hemorrhage	Randomized, placebo-controlled study	Hydrocortisone 300 mg q 6 h × 10 d then taper over 4 d (N = 35)	Placebo (N = 36)	Primary outcome: hyponatremia < 140 mmol/L Secondary outcome: 30-day mRS, symptomatic vasospasm	Less sodium excretion and urine volume in treatment group (P = 0.04). No significant differences in vasospasm or mRS	Katayama et al., Stroke 2007 [43]
Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrrhage	Randomized, double-blind, placebo-controlled, single center study	Methylprednisolone 16 mg/kg IV qd × 3 days (N = 49)	Placebo (N = 46)	Primary outcome: symptomatic vasospasm and infarct on HCT Secondary Outcomes: 1 year GOS, functional outcome scale, and severity of delayed ischemic deficits	No significant difference in symptomatic vasospasm or infarct on HCT. No difference in 1-year GOS or delayed ischemic deficits at 3-months. Poor outcome by functional outcome scale was reduced in treatment group (P = 0.02)	Gomis et al., J Neurosurg 2010 [44]

Transfusion/erythropoietin/albumin

Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a phase II randomized, double-blind, placebo-controlled trial	Phase II randomized, double-blind, placebo-controlled trial	Erythropoietin IV (30,000 u) every 48 h for a total of 90,000 U (N = 40)	Placebo (N = 40)	Primary outcome: incidence, duration and severity of TCD vasospasm; duration of impaired autoregulation by TCD Secondary outcome: incidence of delayed ischemic deficits, mRS, GOS, and NIHSS at discharge and 6-months	No differences in incidence of TCD vasospasm or adverse events. Treatment group had less severe TCD vasospasm (P = −0.037), reduced delayed ischemic deficits/delayed cerebral infarcts (P = 0.001), and shortened duration of impaired autoregulation (P < 0.001) and more favorable discharge outcome (P = 0.039)	Tseng et al., J Neurosurg 2009 [45]
Prospective, randomized trial of higher goal hemoglobin after SAH	Prospective, randomized pilot safety, and feasibility study	Packed RBC transfusion to goal Hgb 11.5 g/dL (N = 21)	Packed RBC transfusion to goal Hgb 10 g/dL (N = 23)	Primary outcomes: days of core temp > 100.4 F, ventilator-free days, hemoglobin level Secondary outcomes: NIHSS, mRS, and MRI at 14 days, mRS at 28 days and 3-months	Higher target Hgb resulted in more transfusions. No difference in safety endpoints. Number of MRI infarcts, NIHSS, and mRS similar between both groups at all timepoints	Naidech et al., Neurocrit Care 2010 [46]
The Albumin in Subarachnoid Hemorrhage multicenter pilot clinical trial: safety and neurologic outcomes (ALISAH)	Open label, dose escalation study	Albumin in 3 tier doses: 0.625 g/kg/d (N = 20), 1.25 g/kg/d (N = 20), 1.875 g/kg/d (N = 7) × 7 days (N = 47 total)	NA	Primary outcomes: severe to life threatening heart failure, anaphylaxis Secondary outcomes: functional outcome at 3-months	Doses up to 1.25 g/kg/d × 7 days tolerated without dose-limiting complications. Trend toward better outcomes in 1.25 g/kg/d dose compared to 0.625 g/kg/d	Suarez et al., Stroke 2012 [47]

Vasodilators—CRGP and endothelin receptor antagonist

Effect of calcitonin-gene-related peptide in patients with delayed postoperative cerebral ischemia after aneurysmal subarachnoid hemorrhage	Randomized, single-blind, controlled, multicenter study	Calcitonin-related gene peptide (0.6mcg/min) × 10 days (N = 62)	Standard medical therapy (N = 55)	Primary outcome: 3-month GOS	No difference in 3-month GOS. Hypotension common in treatment group.	Bell, European CGRP in subarachnoid Hemorrhage study group, Lancet 1992 [48]
Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal SAh undergoing surgical clipping: a randomized, double-blind, placebo-controlled phase 3 trial (CONSCIOUS 2)	Phase 3 randomized placebo-controlled double-blinded	Clazosentan (5 mg/h IV up to 14 days) (N = 748)	Placebo (N = 389)	Primary outcomes: cerebral vasospasm-related morbidity (DCI/DIND/vasospasm therapy), all-cause mortality at 6 weeks Secondary outcomes: 12-week GOSE	No effect on primary endpoint (21% in clazosentan group and 25% in placebo group P = NS). Poor outcome (GOSE) in 29% clazosentan and 25% placebo group	MacDonald et al., Lancet Neuol 2011 [49]
Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling (CONSCIOUS 3)	Phase 3 randomized placebo-controlled double-blinded; terminated early for futility (planned N = 1500)	Clazosentan (5 or 15 mg/h IV up to 14 days) (N = 194)	Placebo (N = 189)	Primary outcomes: cerebral vasospasm related morbidity (DCI/DIND/vasospasm therapy), all-cause mortality at 6 weeks Secondary outcomes: 12-week GOSE	Clazosentan 15 mg/h significantly reduced vasospasm-related morbidity/all-cause mortality at 6 weeks but did not improve long-term outcome Primary outcome: 24% in clazosentan 5 mg/h and 27% in placebo group P = NS and 15% in clazosentan 15 mg/h P = 0.007 Poor outcome in 25% of clazosentan 5 mg/h, 28% clazosentan 15 mg/h, and 24% of placebo group P = NS.	MacDonald et al., Stroke 2012 [50]

Hypertensive, hypervolemic therapy (prophylactic)

Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: A randomized controlled trial	Randomized, controlled, single-center study	High-volume management (with colloid and crystalloid) to target PADP ≥ 14 mmHg or CVP ≥ 8 mmHg (N = 41)	Normal volume management (with colloid and crystalloid) to target PADP ≥ 7 mmHg or CVP ≥ 5 mmHg (N = 41)	Primary outcome: CBF by Xenon CT and blood volume by tagged RBC Secondary outcomes: symptomatic vasospasm, medical complications, GOS and 3, 6, and 12 months	High-volume management patients received significantly more fluid but there was no effect on net fluid balance or blood volume. No difference in CBF or vasospasm	Lennihan et al., Stroke 2000 [51]
Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled trial	Randomized, controlled Prospective, trial of Hunt Hess I–III patients	Hypertensive (MAP 20 mmHg greater than pre-op), hypervolemic (CVP 8–12 mmHg) and hemodilutional (Hct 30–35%) therapy (N = 16)	Normovolemic crystalloid fluid therapy until day 12 (N = 16)	Primary outcome: TCD vasospasm, CBF by SPECT on day 12 Secondary outcomes: 1 year GOS, neuropsych outcomes, and SPECT	No differences in TCD vasospasm or SPECT CBF. No difference in 1-year GOS, SPECT, or neuropsych outcomes	Egge et al., Neurosurgery 2001 [52]

Magnesium

Intravenous magnesium sulfate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized double-blinded, placebo-controlled, multicenter phase III trial	Randomized double-blinded, placebo-controlled, multicenter phase III trial.	MgSO₄ IV infusion to 2x baseline value (20 mmol over 30 minutes then continuous infusion of 80 mmol/d × 14 days; maximum allowed serum Mg of 2.5 mmol/L (N = 169)	Equivalent volume of normal saline infusion. Occasional changes in infusion rates to maintain blinding. (N = 158)	Primary outcome: 6-month GOSE 5–8 Secondary outcome: clinical vasospasm during initial 2 weeks, 6-month mRS, Barthel Index, and Short Form 36	Favorable 6-month GOSE (5–8) 64% of Mg group and 63% placebo (P = NS) No difference in mRS, Barthel, Short Form 36, or clinical vasospasm. No subgroup differences	Wong et al., Stroke 2010 [53]
Magnesium for aneurysmal subarachnoid hemorrhage (MASH-2): a randomized placebo-controlled trial	Randomized, double-blind, placebo controlled, multicenter, phase III trial	MgSO₄ IV 64 mmol/day (N = 606)	Placebo (N = 507)	Primary outcome: 3-month mRS 4–6	No difference in poor outcome in the MgSO₄ group (26.2% versus 25.3% in placebo group)	Mees et al., Lancet 2012 [54]

Adrenergic blockade

Beneficial effects of adrenergic blockade in patients with subarachnoid hemorrhage	Randomized controlled trial	Phentolamine 20 mg q 3 h + propranolol 80 mg q 8 × 3 weeks (N = 68)	Placebo (N = 66)	Primary outcome: neurological deficit at 28 days	Trend toward less neurological deficit in the treated group (P = 0.053)	Walter et al., BMJ 1982 [55]

Endovascular therapy

Effect of prophylactic transluminal balloon angioplasty on cerebral vasospasm and outcome in patients with Fisher grade III subarachnoid hemorrhage: results of a phase II multicenter, randomized clinical trial	Unblinded, randomized phase II trial of Fisher III and Fisher III + IV SAH patients after clipping or coiling within 96 h of rupture	Balloon angioplasty of bilateral A1, M1, P1, basilar, intradural vertebral artery, and supraclinoid ICA. Protocol later revised to exclude A1 and P1 (N = 85)	No prophylactic balloon angioplasty (N = 85)	Primary outcome: 3-month GOS Secondary outcome: delayed ischemic neurological deficit, TCD vasospasm, ICU, and hospital length of stay	Nonsignificant difference in delayed ischemic neurological deficits but less therapeutic angioplasty required in treatment group (P = 0.03). No significant difference in GOS outcomes. LOS similar. Four patients had procedure related vessel perforation, three of whom died	Zwienenberg-Lee et al., Stroke 2008 [56]

Rho kinase inhibitor—fasudil

Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial	Randomized, placebo controlled, double-blind, multicenter study in Hunt Hess I–IV clipped SAH patients	Fasudil (AT877) 30 mg IV over 30 minutes, TID × 14 days (N = 131)	Placebo (N = 136)	Primary outcome: reduction of incidence or severity of angiographic vasospasm, reduction of incidence and size of low-density CT lesions due to vasospasm, reduction of incidence of symptomatic vasospasm, poor outcome (1-month GOS) due to vasospasm	Fasudil significantly reduced angiographic vasospasm (38% in treatment group versus 61% in placebo group, P = 0.0023), infarcts reduced (16% in treatment versus 38% in placebo group, P = 0.0013) and symptomatic vasospasm reduced (35% in treatment versus 50% in placebo, P = 0.0247). Poor outcome (GOS 1–4) attributable to vasospasm occurred in 12% of treatment group and 26% of placebo group (P = 0.0152). No serious adverse events in fasudil group	Shibuya et al., J Neurosurg 1992 [57]
Efficacy and safety of fasudil in patients with subarachnoid hemorrhage: final results of a randomized trial of fasudil versus nimodipine	Randomized, open label, multicenter study of SAH Hunt-Hess grade I–IV clipped patients	Fasudil 30 mg IV TID × 14 days (N = 63)	Nimodipine 1-2 mg/h × 14 days (N = 66)	Primary outcome: symptomatic vasospasm or infarct on HCT Secondary outcome: 1-month GOS	No difference in symptomatic vasospasm or HCT infarcts. Improved GOS outcomes in fasudil group (good outcome in 74.5% versus 61.7% in nimodipine group, P = 0.040)	Zhao et al., Neurol Med Chir (Tokyo) 2011 [58]

Intensive insulin therapy

The effect of intensive insulin therapy on infection rate, vasospasm, neurologic outcome and mortality in neurointensive care unit after intracranial aneurysm clipping in patients with acute subarachnoid hemorrhage: a randomized prospective Pilot trial	Randomized, controlled study	Intensive Insulin Infusion (80–120 mg/dL) × 14 d (N = 40)	Conventional insulin infusion (glucose 80–220 mg/dL) × 14 d ()	Primary outcome: infection Secondary outcomes: vasospasm, 6-month mortality, and mRS	Higher infection rate in the conventional group (42% versus 27% in intensive group, ). Similar vasospasm, mortality, and mRS at 6 months	Bilotta et al., J Neurosurg Anesthesiol 2007 [59]

Hypothermia

Mild intraoperative hypothermia during surgery for intracranial aneurysm (IHAST)	Randomized, prospective, partially blinded, controlled, multicenter trial of WFNS grade I–III SAH patients	Intraoperative hypothermia (target 33°C with surface cooling) (N = 499)	Intraoperative normothermia (target 36.5°C) (N = 501)	Primary outcome: GOS at 90 days Secondary outcomes: 90-day mRS, Barthel Index, NIHSS, neuropsych testing, adverse events	No difference in 90 day GOS. Good GOS in 66% of hypothermia versus 63% of control patients (P = NS). No differences in death, length of stay, or discharge disposition. Postoperative bacteremia more common in the hypothermia group (5% versus 3%, P = 0.05)	Todd et al., NEJM 2005 [60]

Stroke Research and Treatment

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

Table 1