Supplementary Table 1: Randomized, blinded clinical trials for treatment of subarachnoid haemorrhage (not directed at aneurysm repair or preventing
rebleeding)
Reference
Treatment
Study design
Total
number
of
patients
Study end points
Follow up period
Results
Mendelow et al.
(1982)34
Acetylsalicylic acid
RCT, doubleblind, placebo
53
Neurological
deficits, death
6 months
Allen et al.
(1983)2
Nimodipine
RCT, doubleblind, placebo
116
21 days
Rosenwasser et
al. (1983)49
Volume expansion and vasodilators
versus diuretics
RCT, unblinded
30
Neurological deficit
from angiographic
vasospasm,
severity of deficit
at 21 days
Clinical
vasospasm, death
Saito et al.
(1983)50
Nizofenone
RCT, unblinded
90
Not stated
Ono et al.
(1984)43
Ticlopidine
RCT, doubleblind, placebo
133
Neil-Dwyer et al.
(1985)40
Propranolol +/- phentolamine
RCT, doubleblind, placebo
224
Angiographic
vasospasm,
delayed ischaemic
neurological
deficit, clinical
outcome
Excellent (normal
life, no or mild
neurological
deficit), good (with
neurological
deficits but live
without help), poor
(vegetative or
dead)
Return to work or
capable of working
without
appreciable
neurological deficit
(good result) or
appreciable
deficits and
No effect of
acetylsalicylic acid
on neurological
deficits or outcome
Significantly fewer
deficits from
angiographic
vasospasm with
nimodipine
Volume expansion
plus vasodilator
therapy had
significantly lower
mortality and clinical
vasospasm
No overall effect on
clinical outcome,
other effects not
clear
Not stated
3 months
No difference in
angiographic or
clinical vasospasm,
significantly more
excellent and good
outcomes with
ticlopidine
28 days
Significantly better
outcome if treated
with propranolol +/phentolamine
incapable of
returning to work
(poor result)
Shaw et al.
(1985)54
Dipyridamole
RCT, unblinded,
placebo
677
Neurologist
assessment
3 months
Ohta et al.
(1986)42
Nizofenone
RCT, doubleblind, placebo
208
Clinical outcome
on 9-point scale
1 month
Philippon et al.
(1986)46
Nimodipine
RCT, doubleblind, placebo
70
Angiographic
vasospasm, deficit
due to vasospasm
Not stated
Neil-Dwyer et al.
(1987)39
Nimodipine
RCT, doubleblind, placebo
75
3 months
Messeter et al.
(1987)35
Nimodipine
RCT, unblinded
20
Jan et al.
(1988)24
Nimodipine
RCT, doubleblind, placebo
188
Cerebral blood
flow, blood
pressure, clinical
outcome (good,
poor, dead)
Cerebral blood
flow, delayed
neurological
deficit, clinical
outcome (good,
fair, dead)
Deficit due to
angiographic
vasospasm, GOS
score
Mee et al.
(1988)33
Nimodipine
RCT, doubleblind, placebo
75
3 months
Hashi et al.
(1988)22
Hydrocortisone
RCT, doubleblind, placebo
140
Cerebral blood
flow, death, clinical
outcome (good
[normal life with no
or only cranial
nerve deficit] or
poor)
Clinical outcome
No effect on
outcome or
neurological
deterioration
attributed to delayed
ischaemia
Significantly better
outcome if treated
with nizofenone
No difference in
angiographic or
clinical vasospasm,
no overall difference
in outcome
Decreased mortality
with nimodipine
Not stated
No significant effect
on any end point
Discharge
Nimodipine reduced
deficits due to
angiographic
vasospasm, and
improved clinical
outcome
No difference in
cerebral blood flow,
significantly lower
mortality with
nimodipine
30 days
No significant effect
on outcome
Petruk et al.
(1988)45
Nimodipine
RCT, doubleblind, placebo
154
Angiographic
vasospasm, deficit
due to vasospasm,
GOS score
3 months
Pickard et al.
(1989)47
Nimodipine
RCT, doubleblind, placebo
554
Delayed cerebral
infarction, GOS
score
3 months
Suzuki et al.
(1989)59
OKY-046
RCT, doubleblind, placebo
256
3 months
Hasan et al.
(1989)21
Fludrocortisone
RCT, doubleblind, placebo
91
Ohman et al.
(1991)41
Nimodipine
RCT, doubleblind, placebo
213
Angiographic
vasospasm, low
density areas on
CT, clinical
outcome on a 9point scale
Delayed cerebral
infarction, GOS
score
Deficit due to
angiographic
vasospasm,
cerebral infarction,
clinical outcome
(independent,
dependent, dead)
Papo et al.
(1991)44
Monosialoganglioside
RCT, doubleblind, placebo
119
Change from
baseline Glasgow
Coma Scale score
21 days
Tokiyoshi et al.
(1991)60
OKY-046
RCT, placebo
24
Symptomatic
vasospasm, GOS
score
1 month
Shibuya et al.
(1992)56
AT-877
RCT, doubleblind, placebo
267
Angiographic
vasospasm,
delayed cerebral
ischaemia, GOS
score
1 month
3 months
1–3 years
Nimodipine reduced
deficits due to
angiographic
vasospasm, and
improved clinical
outcome
Nimodipine reduced
cerebral infarction
and improved
clinical outcome
OKY-046 reduced
angiographic
vasospasm and lowdensity areas, no
effect on clinical
outcome
No effect on delayed
cerebral ischaemia
or clinical outcome
No difference in
overall outcome,
nimodipine reduced
chances of death
from delayed
ischaemia and
decreased cerebral
infarction
Patients treated with
drug had better
Glasgow Coma
Scale scores at 21
days
OKY-046 reduced
neurological deficits
from symptomatic
vasospasm, no
effect on clinical
outcome
AT877 reduced
angiographic
vasospasm, lowdensity areas
associated with
vasospasm and
delayed cerebral
ischaemia, no effect
on clinical outcome
European CGRP
SAH group
(1992)1
Haley et al.
(1993)16,17
Calcitonin gene related peptide
RCT, single-blind,
placebo
117
GOS score
3 months
No significant effect
on clinical outcome
Nicardipine
RCT, doubleblind, placebo
906
3 months
Han et al.
(1993)19
Nimodipine
RCT, placebo
322
Nicardipine reduced
symptomatic
vasospasm, no
difference in
cerebral infarction,
clinical outcome or
NIHSS score
No significant effect
on any end point
Findlay et al.
(1995)11
Recombinant tissue plasminogen
activator
RCT, doubleblind, placebo
100
Haley et al.
(1995)14
Tirilazad
RCT, doubleblind, placebo
245
Asano et al.
(1996)3
(+/-)-N,N'-propylenedinicotinamide (AVS,
nicaraven)
RCT, doubleblind, placebo
162
GOS score, death
and disability due
to vasospasm,
delayed cerebral
ischaemia,
cerebral infarction,
NIHSS score
Mortality, GOS
score, delayed
ischaemic deficits
Angiographic
vasospasm,
delayed
neurological
worsening, GOS
score
Neurological
worsening due to
vasospasm, GOS
score, NIHSS
score
Delayed ischaemic
neurological deficit
due to vasospasm,
GOS score
Kassell et al.
(1996)25
Tirilazad
RCT, doubleblind, placebo
1,015
Neurological
worsening due to
vasospasm,
cerebral infarction,
GOS score,
NIHSS score
3 months
3–6 months
3 months
3 months
3 months
No significant effect
on angiographic
vasospasm, delayed
neurological
worsening or clinical
outcome
No difference in
neurological
worsening or clinical
outcome
Nicaraven
significantly reduced
delayed ischaemic
neurological deficit,
reduced mortality,
no effect on clinical
outcome
No overall effect on
symptomatic
vasospasm or
clinical outcome,
significantly reduced
mortality with
tirilazad,
6 mg/kg/day
Haley et al.
(1997)15
Tirilazad
RCT, doubleblind, placebo
897
Saito et al.
(1998)51
Ebselen
RCT, doubleblind, placebo
286
Lanzino et al.
(1999)27
Tirilazad
RCT, doubleblind, placebo
Lanzino et al.
(1999)26
Tirilazad
Hop et al.
(2000)23
Mortality, GOS
score, cerebral
infarction,
neurological
worsening due to
vasospasm
GOS score,
delayed ischaemic
neurological deficit
due to vasospasm,
low-density areas
on CT
3 months
No significant effect
of tirilazad on any
end point
3 months
817
Mortality, GOS
score, cerebral
infarction,
neurological
worsening due to
vasospasm
3 months
RCT, doubleblind, placebo
823
3 months
Aspirin
RCT, doubleblind, placebo
50
Shaw et al.
(2000)55
TAK-044
RCT, doubleblind, placebo
420
Lennihan et al.
(2000)28
Hypervolaemia
RCT, single-blind,
placebo
82
Mortality, GOS
score, cerebral
infarction,
neurological
worsening due to
vasospasm
mRS score, quality
of life,
postoperative
clinical
deterioration,
delayed cerebral
ischaemia, new
hypodensity on
CT, haemorrhage
Delayed ischaemic
events, cerebral
infarction, GOS
score
Cerebral blood
flow, blood
volume,
symptomatic
vasospasm,
physiological
variables, GOS
No effect on lowdensity areas,
clinical outcome or
delayed ischaemic
neurological deficits
in intention-to-treat
analysis
Tirilazad reduced
neurological
worsening due to
vasospasm and
cerebral infarction,
no effect on clinical
outcome
Tirilazad reduced
mortality in poorgrade patients, no
overall effect on
outcome or other
end points
No overall effect on
any end point
4 months
3 months
No significant effect
on any end point
1 year
No significant effect
on cerebral blood
flow, blood volume,
symptomatic
vasospasm or GOS
score
score
Egge et al.
(2001)9
Haemodynamic therapy
RCT, unblinded
32
Veyna et al.
(2002)67
Magnesium
RCT, single-blind,
placebo
40
Hamada et al.
(2003)18
Urokinase
RCT, blinded
110
Siironen et al.
(2003)57
Enoxaparin
RCT, doubleblind, placebo
170
Wurm et al.
(2004)71
Enoxaparin
RCT, doubleblind, placebo
117
Physiological
variables,
Scandinavian
Neurological
Stroke Scale
score, transcranial
Doppler
ultrasound, CT,
single-photon
emission CT,
neuropsychologica
l testing, GOS
score
GOS score,
transcranial
Doppler
ultrasound,
symptomatic
vasospasm
Symptomatic
cerebral
vasospasm,
angiographic
vasospasm, GOS
score
GOS score, mRS
score, delayed
ischaemic
neurological
deficit,
complications,
bleeding,
hydrocephalus
Cerebral
vasospasm,
delayed ischaemic
deficit, cerebral
infarction, GOS
score
1 year
No significant effect
on any end point
3 months
No significant effect
on any end point
6 months
Urokinase reduced
symptomatic
vasospasm and
improved clinical
outcome
3 months
No effect on clinical
outcome
1 year
Enoxaparin
significantly reduced
delayed ischaemic
deficit, cerebral
infarction,
hydrocephalus and
improved clinical
outcome
Reinert et al.
(2004)48
Nitroglycerin
RCT, single-blind
17
Lynch et al.
(2005)29
Simvastatin
RCT, doubleblind, placebo
39
Vajkoczy et al.
(2005)63
Clazosentan
RCT, doubleblind, placebo
32
Van den Bergh et
al. (2005)65
Magnesium
RCT, doubleblind, placebo
283
SchmidElsaesser et al.
(2006)52
Magnesium
RCT, single-blind
113
Van den Bergh et
al. (2006)64
Aspirin
RCT, doubleblind, placebo
161
Wong et al.
(2006)69
Magnesium
RCT, doubleblind, placebo
60
Transcranial
Doppler
ultrasound,
cerebral blood
flow, delayed
ischaemic
neurological deficit
Clinical
vasospasm in
combination with
transcranial
Doppler ultrasound
or angiography
Safety,
angiographic
vasospasm,
NIHSS score,
GOS score
Not stated
Nitroglycerin
reduced some
transcranial Doppler
flow velocities and
increased cerebral
blood flow
Not stated
Simvastatin reduced
transcranial Doppler
flow velocities and
clinical vasospasm
14 days
Delayed cerebral
infarction, mRS
score
Clinical
vasospasm,
cerebral infarction,
transcranial
Doppler flow
velocities,
angiographic
vasospasm,
biochemical
markers, GOS
score
Delayed cerebral
infarction, mRS
score
GOS score,
Barthel Index
score, NIHSS
score, clinical
vasospasm
3 months
Clazosentan
reduced incidence
and severity of
angiographic
vasospasm, no
effect on clinical
outcome
No effect on delayed
cerebral infarction or
clinical outcome
No significant effect
on any end point
1 year
3 months
6 months
No effect on delayed
cerebral infarction or
clinical outcome
Magnesium
decreased duration
of transcranial
Doppler flow velocity
elevations, no
significant effect on
clinical outcome
Barth et al.
(2007)4
Nicardipine
RCT, single blind
32
Angiographic
vasospasm,
cerebral infarction,
mRS score,
NIHSS score
1 year
Tseng et al.
(2007)61
Pravastatin
RCT, doubleblind, placebo
80
Transcranial
Doppler flow
velocities,
autoregulation,
delayed ischaemic
neurological
deficit, mRS score,
short form 36
6 months
Springborg et al.
(2007)58
Erythropoietin
RCT, doubleblind, placebo
54
6 months
Chou et al.
(2008)7
Simvastatin
RCT, doubleblind, placebo
39
Macdonald et al.
(2008)32
Clazosentan
RCT, doubleblind, placebo
413
GOS score,
transcranial
Doppler flow
velocities,
symptomatic
vasospasm,
cerebral
metabolism,
biochemical
markers
Death, drug
morbidity,
transcranial
Doppler flow
velocities,
angiographic or
clinical
vasospasm,
cerebral infarction,
mRS score
Angiographic
vasospasm,
mortality, cerebral
infarction, delayed
ischaemic
neurological deficit
due to vasospasm,
Nicardipine pellets
reduced
angiographic
vasospasm, cerebral
infarction and
mortality and
improved outcome
on mRS and NIHSS
Pravastatin reduced
transcranial Doppler
flow velocities,
duration of
vasospasm and
impaired
autoregulation,
delayed ischaemic
neurological deficit,
poor outcome and
mortality
No significant effect
on any end point
Discharge
No significant effect
on any endpoint
3 months
Clazosentan
reduced incidence
and severity of
angiographic
vasospasm, no
effect on clinical
outcome
rescue therapy,
GOS score
Muroi et al.
(2008)37
Magnesium
RCT, single-blind,
placebo
58
Zwienenberg-Lee
et al. (2008)73
Prophylactic balloon angioplasty
RCT, single-blind
170
Hanggi et al.
(2009)20
Multimodal therapy
RCT
20
Munakata et al.
(2009)36
Edaravone
RCT, single-blind
91
Tseng et al.
(2009)62
Erythropoietin
RCT, doubleblind, placebo
80
Vergouwen et al.
(2009)66
Simvastatin
RCT, doubleblind, placebo
32
Delayed ischaemic
neurological
deficit, cerebral
infarction, GOS
score
GOS score,
delayed ischaemic
neurological
deficit, transcranial
Doppler flow
velocities
1 year
No significant effect
on any end point
3 months
Delayed
neurological
deficit, transcranial
Doppler flow
velocities, CT
perfusion, CT
angiography,
clinical outcome
Delayed ischaemic
neurological
deficit, cerebral
infarction, GOS
score
Incidence, duration
and severity of
transcranial
Doppler flow
velocity change,
autoregulation,
delayed ischaemic
deficit, GOS score,
NIHSS score
Not stated
Prophylactic balloon
angioplasty reduced
the need for
therapeutic
angioplasty but no
effect on other end
points
Translumbar lavage
with urokinase and
nimodipine, head
shaking, stopped
early due to two
patients with
paraparesis
Biological effects,
transcranial
Doppler flow
velocities, delayed
cerebral
ischaemia, GOS
6 months
3 months
Edaravone reduced
cerebral infarction
but no overall effect
on clinical outcome
6 months
Erythropoietin
associated with
lower severity of
vasospasm, reduced
cerebral infarction,
duration of impaired
autoregulation and
delayed ischaemic
deficit, and no
difference in clinical
outcome
Simvastatin lowered
some serum lipids
but had no
significant effect on
other end points
score
Gomi, et al.
(2010)13
Methylprednisolone
RCT, doubleblind, placebo
95
Westermaier et
al. (2010)68
Magnesium
RCT, single-blind,
placebo
110
Naidech et al.
(2010)38
Transfusion
RCT, single-blind
44
Wong et al.
(2010)70
Magnesium
RCT, doubleblind, placebo
327
Yamamoto et al.
(2010)72
Tisokinase
RCT, single-blind
60
Macdonald et al.
(2011)30
Clazosentan
RCT, doubleblind, placebo
1,157
Clinical
deterioration
associated with
angiographic
vasospasm or
transcranial
Doppler flow
velocity elevation,
mRS score, GOS
score
Delayed ischaemic
infarction,
transcranial
Doppler flow
velocities,
angiographic
vasospasm,
delayed ischaemic
neurological
deficit, GOS score
mRS score,
NIHSS score,
cerebral infarction
1 year
Methylprednisolone
had no effect on
symptomatic
vasospasm but
improved clinical
outcome
6 months
Extended GOS
score, mRS score,
Barthel Index
score, clinical
vasospasm
Symptomatic
vasospasm, lowdensity areas on
CT, GOS score,
mRS score
6 months
Magnesium
decreased delayed
ischemic infarction
and transcranial
Doppler/angiographi
c vasospasm, no
effect on delayed
ischaemic
neurological deficit
or clinical outcome
No significant
difference in
transfusion
thresholds of 10 or
11.5 g/dl
No significant effect
on any end point
Composite of
mortality,
vasospasm-related
cerebral infarct,
delayed ischaemic
neurological deficit
or rescue therapy,
3 months
6 months
3 months
Tisokinase may
improve outcome if
administered
intermittently, may
reduce low density
areas
No significant effect
on any end point
extended GOS
score
Dorhout-Mees et
al. (2012)8
Macdonald et al.
(2012)31
Magnesium
Bradford et al.
(2013)5
RCT, doubleblind, placebo
RCT, doubleblind, placebo
1,204
mRS score
3 months
571
Composite of
mortality,
vasospasm-related
cerebral infarct,
delayed ischaemic
neurological deficit
or rescue therapy,
extended GOS
score
3 months
Magnesium
RCT, doubleblind, placebo
162
3 months
Bulters et al.
(2013)6
Intra-aortic balloon counterpulsation
RCT, single-blind
71
Incidence and
severity of
angiographic
vasospasm,
clinical outcome
GOS score, short
form 36,
physiological
parameters,
cerebral blood flow
Etminan et al.
(2013)10
Recombinant tissue plasminogen
activator and head shaking
RCT, single-blind
60
GOS score, clot
clearance, delayed
cerebral infarction,
hydrocephalus
3 months
Garg et al.
(2013)12
Simvastatin
RCT, doubleblinded, placebo
38
6 months
No significant effect
on any end point
Senbokuya et al.
(2013)53
Cilostazol
RCT, open-label,
no placebo
109
Clinical cerebral
vasospasm, GOS
score, mRS score,
Barthel Index
score
Symptomatic
vasospasm,
angiographic
vasospasm,
cerebral infarction,
mRS score
6 months
Cilostazol reduced
symptomatic
vasospasm,
angiographic
vasospasm, and
cerebral infarction
Clazosentan
6 months
No significant effect
on any end point
One dose of
clazosentan reduced
composite outcome
of mortality,
vasospasm-related
cerebral infarct,
delayed ischaemic
deficit or rescue
therapy, but no
overall effect on
clinical outcome
No significant effect
on any end point
No significant effect
on clinical outcome
or cerebral blood
flow, intra-aortic
balloon lowered
cardiac output and
increased systemic
vascular resistance
No significant effect
on any end point
but had no effect on
clinical outcome
Abbreviations: GOS, Glasgow Outcome Scale; mRS, modified Rankin Scale; NIHSS, NIH Stroke Scale; RCT, randomized controlled trial.
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