Online Resource 1. Overview of recent clinical trials of in acute ischemic stroke
a Year in which the manuscript was published or, for unpublished trials, year in which the trial data appeared on the Internet.
b Drug name, dose, administration route and time of administration after symptom onset, as applicable.
c Number of patients included or planned.
Drug class and name / Proposed drug mechanism / Trial name / Datea / Designb / Sample sizec / Result / SupplementalReference
Anti-excitotoxic
ACEA 1021 (licostinel) / NMDA glycine site antagonist / ― / 1999 / Licostinel
versus
placebo / 64 / No significant difference in neurological recovery / s1
AR-R15896AR / NMDA antagonist / ― / 2002 / AR-R15896AR
versus
placebo / 103 / No significant difference in neurological recovery / s2
― / 2001 / AR-R15896AR
versus
placebo / 175 / No significant difference in neurological recovery / s3
Baclofen / GABA-B agonist / ― / 2001 / Baclofen
versus
placebo / 21 / Improvement in neurological recovery / s4
BIII-890-CL / Sodium channel blocker / ― / 2001 / Unpublished data / s5
BMS-204352 / Potassium channel opener / POST / 2002 / BMS-204352
versus
placebo / 1,978 / No significant difference in neurological recovery / s6
CGS 19755 (Selfotel) / NMDA antagonist / ― / 2000 / Selfotel
versus
placebo / 567 / No significant difference in neurological recovery / s7
Clomethiazole
(CMZ, Zendra) / GABA agonist / CLASS-I / 2002 / Clomethiazole
versus
placebo / 1,198 / No significant difference in neurological recovery / s8
CNS1102
(Cerestat, Aptiganel) / NMDA ion channel blocker / ― / 2001 / Aptiganel
versus
placebo / 628 / No significant difference in neurological recovery / s9
CP101, 606 / NMDA ion channel blocker / ― / 2005 / CP101, 606
versus
placebo / 300 / Unpublished data / s10
Dextrorphan / NMDA ion channel blocker / ― / 1995 / Dextrorphan
versus
placebo / 37 / Occurrence of adverse experiences / s11
Eliprodil (SL 82.0715) / NMDA polyamine antagonist
Sigma ligand / Eliprodil trial / Unpublished data / s12
Diazepam (Valium) / Benzodiazepine / ― / 2006 / Diazepam
versus
placebo / 880 / Improvement in neurological recovery / s13
Fosphenytoin / Sodium channel blocker
Glutamate release inhibitor / ― / 2008 / Fosphenytoin
versus
placebo / 462 / No significant difference in neurological recovery / s14
Gavestinel (GV150526A) / NMDA glycine antagonist / GAIN International Trial / 2000 / Gavestinel
versus
placebo / 1804 / No significant difference in neurological recovery / s15
Glycine / NMDA antagonist / ― / 2000 / Glycine
versus
placebo / 200 / Improvement in neurological recovery / s16
GSK249320
(mAb) / Antagonizes or neutralizes myelin-associated glycoprotein (MAG)-mediated inhibition / MAG111539 / 2011 / GSK249320
versus
placebo / 42 / Confirmation of safety / s17
Lifarizine (RS-87476) / Sodium/calcium channel
blocker / ― / 1995 / Lifarizine
versus
placebo / 147 / No significant difference in neurological recovery / s18
Lubeluzole / Sodium/calcium channel
blocker
NOS inhibitor / ― / 2001 / Lubeluzole + alteplase
versus
placebo + alteplase / 89 / No significant difference in neurological recovery / s19
― / 2000 / Lubeluzole
versus
placebo / 1,786 / No significant difference in neurological recovery / s20
― / 1998 / Lubeluzole
versus
placebo / 725 / No significant difference in neurological recovery / s21
Magnesium / NMDA ion channel blocker
Calcium antagonist / FAST-MAG / 2014 / Magnesium sulfate
versus
placebo / 1700 / No significant difference in neurological recovery / s22
NA-1 (Tat-NR2B9c) / Postsynaptic density-95 protein inhibitor / ENACT / 2012 / NA-1
versus
placebo / 197 / Improvement in neurological recovery / s23
Nalmefene / Opioid antagonist / ― / 2000 / Nalmefene
versus
placebo / 368 / No significant difference in neurological recovery / s24
Naloxone / Opioid antagonist / ― / 1991 / Naloxone
versus
placebo / 24 / No significant difference in neurological recovery / s25
Neu2000 / NMDA antagonist / ― / Unpublished data / s26
Nicergoline / 2-adrenoceptor agonist
Enhances glutamate uptake / ― / 1997 / Nicergoline
versus
placebo / 252 / Improvement in neurological recovery / s27
NPS 1506 / NMDA ion channel blocker / ― / 2000 / NPS 1506
versus
placebo / 36 / Confirmation of safety / s28
NS1209/SPD 502 / Glutamate antagonist / ― / 1999 / Unpublished data / s29
Remacemide / NMDA ion channel blocker
Sodium channel blocker / ― / 1999 / Remacemide
versus
placebo / 61 / Confirmation of safety / s30
S-1746 / NMDA glycine/AMPA antagonist / ― / 2001 / Unpublished data / s29
S-18986 / AMPA receptor modulator / ― / Unpublished data / s31
Sipatrigine (BW619C89) / Sodium channel antagonist
Glutamate release inhibitor / ― / 2000 / Sipatrigine
versus
placebo / 27 / No significant difference in neurological recovery / s32
YM872 / AMPA antagonist / ARTIST / 2006 / YM872 + Alteplase
versus
placebo + Alteplase / Unpublished data / Study was abandoned after failing an interim futility analysis / s33
ARTIST MRI / 2006 / YM872
versus
placebo / Unpublished data / Study was abandoned after failing an interim futility analysis / s34
YM90K / AMPA antagonist / ― / 1997 / Unpublished data / s29
ZK200775 (MPQX) / AMPA antagonist / ― / 2002 / ZK200775
versus
placebo / 61 / Neurological deterioration / s35
Anti-inflammatory
Cyclosporin A / Immunosuppressant / CsAStroke / On-going / Cyclosporin A
versus
Saline / 126 / Unpublished data / s36
Dapsone
(diamino-diphenyl sulfone, DDS) / Antibacterial / DAISY / 2010 / Dapsone
versus
placebo / 300 / Unpublished data / s37
― / 2007 / Dapsone
versus
placebo / 30 / Improvement in neurological recovery / s38
Dexamethasone / Glucocorticoid, anti-inflammatory / ― / 2011 / Dexamethasone
versus
placebo / 60 / No significant difference in neurological recovery / s39
― / 2001 / Dexamethasone
versus
placebo / 40 / No significant difference in neurological recovery / s40
Dexamethasone and dextran 40 / Glucocorticoid, anti-inflammatory, intravascular volume replacement / ― / 1976 / Tapering dose of intramuscular dexamethasone with 3.5 L dextran 40 over approximately 73–74 h versus placebo / 40 / No significant difference in neurological recovery / s41
Enlimomab (anti–
ICAM-1 antibody) / Leukocyte migration and adhesion inhibitor / EAST / 2001 / Enlimomab
versus
placebo / 625 / Neurological deterioration / s42
FK506 (Tacrolimus) / Immunosuppressant / ― / 2004 / Unpublished data / s29
Fludrocortisone / Mineralocorticoid / ― / 1989 / Fludrocortisone
versus
none / 91 / No significant difference in neurological recovery / s43
Ganglioside GM1 / Metabolism, growth / SASS / 1994 / Ganglioside GM1
versus
placebo / 287 / No significant difference in neurological recovery / s44
IASS-H / 1989 / Ganglioside GM1
versus
placebo / 502 / No significant difference in neurological recovery / s45
BRX-345 (arimoclomol) / Heat shock protein inducer / ― / Unpublished data / s31
Hu23F2G (LeukArrest) / Leukocyte adhesion inhibitor / ― / 2000 / LeukArrest + Alteplase
versus
placebo + alteplase / Unpublished data / Trial was terminated after interim analysis / s46
Insulin / Lowers glucose / SHINE / On-going / Insulin (suitable dose)
versus
insulin (lower dose) / 1,400 / Unpublished data / s47
GIST-UK / 2007 / Glucose-potassium-insulin
versus
saline / 933 / No significant difference in neurological recovery / s48
Interleukin-1 receptor antagonist (IL-1 RA) / IL-1 inhibitor / ― / 2005 / IL-1 RA
versus
placebo / 34 / No significant difference in neurological recovery / s49
LDP-01 (Anti-2-integrin antibody) / Leukocyte adhesion and migration inhibitor / ― / 1998 / Unpublished data / s50
Minocycline / Antibacterial
Anti-apoptotic
5-lipoxygenase inhibitor / WAIMATSS / On-going / Minocycline + alteplase
versus
alteplase / Unpublished data / s51
2013 / Minocycline
+ routine care
versus
routine care / 95 / No significant difference in neurological recovery / s52
― / 2012 / Minocycline
versus
placebo / 50 / Improvement in neurological recovery / s53
MINOS / 2010 / Minocycline / 60 / Confirmation of safety / s54
― / 2007 / Minocycline
versus
placebo / 152 / Improvement in neurological recovery / s55
MC-1 / Vitamin B derivative / ― / Unpublished data / s31
Neutrophil inhibitory factor
(rNIF, UK-279.276) / Neutrophil inhibitor / ASTIN / 2003 / UK-279.276
versus
placebo / 966 / No significant difference in neurological recovery / s56
Niacin / Vitamin B(3):
metabolic enhancer / ― / 1980 / Xanthinol nicotinate
versus
pentoxifylline / 58 / Xanthinol nicotinate
was inferior to pentoxifylline in neurological recovery / s57
Paracetamol (Acetaminophen) / Analgesic/antipyretic COX inhibitor / PAIS / 2009 / Paracetamol
versus
placebo / 1,400 / Improvement in neurological recovery / s58
RP-1127 / NCCA-ATP channel inhibitor / GAMES-RP / On-going / RP-1127
versus
placebo / 240 / Unpublished data / s59
Antioxidant
AEOL-10150 / Antioxidant / ― / Unpublished data / s31
Albumin / Antioxidant
Improvement of microcirculation / ALIAS-2 / 2011 / Albumin
versus
placebo / 316 / No significant difference in neurological recovery / s60
Deferoxamine / Iron chelator / TANDEM-1 / 2012 / Deferoxamine + alteplase
versus
placebo + alteplase / 62 / Unpublished data / s61
Ebselen (Harmokisane) / Free radical scavenger / ― / 2009 / Ebselen
versus
placebo / 394 / Unpublished data / s62
― / 1998 / Ebselen
versus
placebo / 302 / Early treatment improved neurological recovery / s63
Edaravone / Free radical scavenger / CER / On-going / Edaravone
versus
butylphthalide
versus
cerebrolysin
versus
citicoline
versus
piracetam / 20,000 / Unpublished data / s64
YAMATO / On-going / Edaravone (pre-administration) + alteplase (0.6 mg/kg)
versus
Edaravone (post-administration) + alteplase (0.6 mg/kg) / 200 / Unpublished data / s65
PROTECT4.5 / On-going / Edaravone (pre-administration)
+ alteplase (0.6 mg/kg)
versus
Edaravone (post-administration) + alteplase (0.6 mg/kg)
versus
Edaravone + argatroban
versus
Edaravone + sodium ozagrel / 10,000 / Unpublished data / s66
2013 / Edaravone (high-dose short-term continuous infusion)
versus
placebo / 36 / Confirmation of safety / s67
― / 2012 / Edaravone (pre-administration)
+ alteplase (0.6 mg/kg)
versus
Edaravone (post-administration) + alteplase (0.6 mg/kg) / 40 / Improvement in neurological recovery / s68
― / 2010 / Edaravone (long-term administration)
versus
edaravone (short-term administration) / 40 / Improvement in neurological recovery / s69
― / 2010 / Edaravone (long-term administration)
versus
edaravone (short-term administration) / 72 / Improvement in neurological recovery / s70
EDO / 2009 / Edaravone
versus
sodium ozagrel / 401 / No significant difference in neurological recovery / s71
EAIS / 2003 / Edaravone
versus
placebo / 250 / Improvement in neurological recovery / s72
― / 2003 / Edaravone + sodium ozagrel
versus
sodium ozagrel / 138 / Improvement in neurological recovery / s73
N-acetylcysteine (NAC) / Free radical scavenger / ― / 2009 / N-acetylcysteine
versus
acetaminophen
versus
N-acetylcysteine + acetaminophen
versus
placebo / 120 / Unpublished data / s74
Nicaraven (Antevas) / Free radical scavenger / ― / 1996 / Nicaraven
versus
placebo / 162 / No significant difference in neurological recovery / s75
NXY-059 / Free radical scavenger / SAINT II / 2007 / NXY-059
versus
placebo / 3,306 / No significant difference in neurological recovery / s76
SAINT I / 2006 / NXY-059
versus
placebo / 1,722 / Improvement of neurological recovery / s77
PG2
(Polysaccharides of Astragalus
membranaceus) / Chinese herb anti-inflammatory / Pass / On-going / PG2
versus
placebo / 300 / Unpublished data / s78
Tirilazad (U74006F) / Free radical scavenger / RANTTAS / 1996 / Tirilazad
versus
placebo / 660 / No significant difference in neurological recovery / s79
Uric acid / Free radical scavenger / URICO-ICTUS / 2014 / Uric acid+ alteplase
versus
placebo + alteplase / 411 / No significant difference in neurological recovery / s80
― / 2007 / Uric acid+ alteplase
versus
placebo + alteplase / 24 / Confirmation of safety / s81
Anti-apoptotic/regenerative
ALD-401
(bone marrow-derived adult stem cell therapy) / Regeneration / ― / On-going / ALD-401
versus
sham bone marrow harvest and sham dosing procedure / 100 / Unpublished data / s82
Allogeneic mesenchymal
bone marrow cell therapy / Regeneration / ― / On-going / Allogeneic mesenchymal
bone marrow cell therapy / 35 / Unpublished data / s83
Basic fibroblast growth factor
(Trafermin, Fiblast) / Growth factor / ― / 2002 / Trafermin
versus
placebo / 286 / No significant difference in neurological recovery / s84
CNTO-0007 (Cell therapy) / Regeneration / ― / On-going / CNTO-0007
versus
placebo / 13 / Unpublished data / s85
Erythropoietin
(EPO) / Anti-apoptosis
Oxygen delivery / ― / 2009 / Erythropoietin versus
placebo / 522 / No significant difference in neurological recovery / s86
GM602 / Anti-apoptosis
Anti-inflammatory / GMAIS / On-going / GM602
versus
placebo / 36 / Unpublished data / s87
Granulocyte-colony stimulating factor
(G-CSF) / Regeneration / AXIS-2 / 2012 / AX200
versus
placebo / 328 / No significant difference in neurological recovery / s88
Lu AA24493 (carbamylated erythropoietin) / Anti-apoptosis
Oxygen delivery / ― / 2011 / Lu AA24493
versus
placebo / 24 / Unpublished data / s89
MP-124 / PARP inhibitor / ― / Unpublished data / s26
MultiStem®
(Stem cell therapy) / Regeneration / ― / 2011 / MultiStem®
versus
placebo / 140 / Unpublished data / s90
NTx®-265 / Regeneration / REGENESIS / 2009 / NTx®-265
versus
placebo / 134 / Unpublished data / s91
ONO-2231 / PARP inhibitor / ― / Unpublished data / s31
PF-03049423 / Neurogenesis
Augmentation of cerebral blood flow / ― / On-going / PF-03049423
versus
placebo / 240 / Unpublished data / s92
PS519/MLN519 / Proteasome inhibitor / ― / 2000 / Unpublished data / s29
SB623
(Stem cell therapy) / Regeneration / ― / On-going / SB623 / 18 / Unpublished data / s93
Calcium/adrenergic modulating/antihypertensive
Antihypertensive treatment / Several antihypertensive agents / CATIS / 2014 / Antihypertensive treatment
versus
no antihypertensive treatment / 4,071 / No significant difference in neurological recovery / s94
Atenolol (Tenormin) / -blocker / ― / 1993 / Atenolol + aspirin
versus
placebo + aspirin / 1,473 / No significant difference in occurrence of stroke events / s95
Candesartan cilexetil (TCV-116, Blopress, CV-11974) / AT1 receptor antagonist Antihypertensive / SCAST / 2012 / Candesartan cilexetil
versus
placebo / 2,029 / No significant difference in neurological recovery / s96
Cyclandelate / Vasodilator
(calcium modulator) / ― / 1987 / Cyclandelate / 303 / Improvement in neurological recovery / s97
DP-b99 (DP-BAPA) / Calcium chelator / MACSI / On-going / DP-b99
versus
placebo / 770 / Unpublished data / s98
― / 2008 / DP-b99
versus
placebo / 150 / Improvement in neurological recovery / s99
Encadin (NS-7) / Calcium channel blocker / ― / Unpublished data / s31
Flunarizine / Calcium channel blocker / FIST / 1996 / Flunarizine
versus
placebo / 331 / Improvement in neurological recovery / s100
Ginsenoside-Rd / Calcium channel blocker / ― / 2009 / Ginsenoside-Rd versus placebo / 199 / Improvement in early neurological recovery / s101
― / 2012 / Ginsenoside-Rd versus placebo / 386 / Improvement in neurological recovery / s102
ILS-920 / Calcium channel blocker / ― / 2009 / ILS-920 / 16 / Unpublished data / s103
Irbesartan / AT1 receptor antagonist Antihypertensive / ― / 2012 / Irbesartan
versus
placebo / 43 / No significant difference in neurological recovery / s104
Nicardipine / Calcium antagonist / ― / 2001 / Nicardipine + aspirin
versus
aspirin / 264 / No significant difference in neurological recovery / s105
Nimodipine / Calcium channel blocker / NICE / On-going / Nimodipine
versus
placebo / 665 / Unpublished data / s106
INWEST / 2003 / Nimodipine
versus
placebo / 295 / No significant difference in neurological recovery / s107
VENUS / 2001 / Nimodipine
versus
placebo / 454 / No significant difference in neurological recovery / s108
― / 1994 / Nimodipine
versus
placebo / 350 / No significant difference in neurological recovery / s109
ANS / 1992 / Nimodipine
versus
placebo / 1,064 / No significant difference in neurological recovery / s110
TRUST / 1990 / Nimodipine
versus
placebo / 1,215 / No significant difference in neurological recovery / s111
― / 1990 / Nimodipine
versus
placebo / 60 / No significant difference in neurological recovery / s112
Papaverine / Calcium channel blocker / ― / 1979 / Papaverine
versus
vincamine / 263 / Papaverine was inferior to vincamine in neurological recovery / s113
Propranolol / -adrenergic blockade
Membrane stabilization / BEST / 1988 / Propranolol
versus
atenolol
versus
placebo / 302 / No significant difference in neurological recovery / s114
PY 108-068 / Calcium antagonist / ― / 1989 / PY 108-068
versus
placebo / 19 / No significant difference in neurological recovery / s115
SUN-N8075 / Na+/Ca2+ channel blocker / ― / Unpublished data / s31
S-0139 (SB-737004) / Endothelin antagonist / ― / 2002 / Unpublished data / s116
TS011 / 20-Hydroxyeicosatetraenoic acid synthesis inhibitor / ― / Unpublished data / s31
Vinpocetine
(ethyl apovincaminate) / Calcium inhibitor
Vasodilator
Sodium blocker / CAVIN / On-going / Vinpocetine +
citicoline +
aspirin or clopidogrel
versus
Citicoline +
aspirin or clopidogrel / 610 / Unpublished data / s117
― / 2001 / Vinpocetine + dextran
versus
dextran / 30 / Improvement in neurological recovery / s118
Thrombolytic
3K3A-APC
(recombinant human activated protein C) / Anticoagulant / ― / 2013 / Unpublished data / Confirmation of safety / s119
Abciximab
(reopro, c7E 3Fab) / Antiplatelet: glycoprotein inhibitor / AbESTT-II / 2008 / Abciximab
versus
placebo / 1,800 / No significant difference in neurological recovery / s120
Alfimeprase / Thrombolytic / ― / 2008 / Alfimeprase / 7 / Unpublished data / s121
Alteplase / Antithrombotic / ATLANTIS A / 2000 / Intravenous alteplase (0.9 mg/kg) within 6 h of AIS
versus
placebo / 142 / No significant difference in neurological recovery, increased risk of intracerebral hemorrhage / s122
ATLANTIS B / 1999 / Intravenous alteplase (0.9 mg/kg) within 3–5 h of AIS
versus
placebo / 547 / No significant difference in neurological recovery, increased risk of intracerebral hemorrhage / s123
EXTEND / On-going / Intravenous alteplase (0.9 mg/kg) 3–9 h after AIS
versus
placebo / 400 / Unpublished data / s124
IST-3 / 2012 / Intravenous alteplase (0.9 mg/kg) within 6 h after AIS
versus
placebo / 3,035 / Improvement in neurological recovery / s125
J-MARS / 2010 / Intravenous alteplase (0.6 mg/kg) / 7,492 / Confirmation of safety and effectiveness / s126
J-ACT II / 2010 / Intravenous alteplase (0.6 mg/kg) / 58 / Confirmation of safety and effectiveness / s127
ECASS / 1995 / Intravenous alteplase (1.1 mg/kg) within 6 h of AIS versus placebo / 620 / Improvement in neurological recovery only in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan / s128
ECASS II / 1998 / Intravenous alteplase (0.9 mg/kg) within 3 h or 3–6 h of AIS versus placebo / 800 / No statistical benefit for alteplase, increased risk of intracranial hemorrhage in treatment group / s129
ECASS III / 2008 / Intravenous alteplase (0.9 mg/kg) 3.0–4.5 h after AIS
versus
placebo / 821 / Improvement in neurological recovery / s130
NINDS Stroke Study / 1995 / Intravenous alteplase (0.9 mg/kg) within 3 h of AIS versus placebo / 624 / Post hoc analysis showed improvement in neurological outcome at 3 months / s131
SITS-ISTR / 2008 / Intravenous alteplase (0.9 mg/kg) 3.0–4.5 h after AIS
versus
Intravenous alteplase (0.9 mg/kg) within 3 h after AIS / 12,529 / No significant difference in neurological recovery / s132
SITS-MOST / 2007 / Intravenous alteplase (0.9 mg/kg) within 3 h after AIS
versus
Intravenous alteplase (0.9 mg/kg) within 3 h after AIS
(relevant pooled results from five previously conducted randomized controlled trials) / 6,483 / No significant difference in neurological recovery / s133
J-ACT / 2006 / Intravenous alteplase (0.6 mg/kg) / 103 / Confirmation of safety and effectiveness / s134
Aminophylline / Phosphodiesterase inhibitor / ― / 1980 / Aminophylline
versus
placebo / 46 / No significant difference in neurological recovery / s135
Ancrod / Fibrinogen-depleting / ESTAT / 2006 / Ancrod
versus
placebo / 1,222 / No significant difference in neurological recovery / s136
STAT / 2000 / Ancrod
versus
placebo / 500 / Improvement in neurological recovery / s137
Argatroban / Anticoagulant / ARTSS-2 / On-going / Argatroban + alteplase
versus
alteplase / 105 / Unpublished data / s138
ARTSS / 2012 / Argatroban + alteplase / 65 / Confirmation of safety / s139
2007 / Argatroban
versus
heparin
versus
no anticoagulation treatment / 3,113 / Argatroban was inferior to heparin in neurological recovery / s140
ARGIS-1 / 2004 / Argatroban
versus
placebo / 171 / Confirmation of safety / s141
Aspirin / Antiplatelet / CAST-IST / 2000 / Aspirin
versus
placebo (CAST),
Open (IST) / 40,000 / Secondary prevention of stroke / s142
Batroxobin
(Defibrase, DF-521) / Fibrinogen-depleting / 2005 / Defibrase
versus
placebo / 1,053 / Improvement in neurological recovery / s143
Certoparin / Anticoagulant / PROTECT / 2006 / Certoparin
versus
unfractionated heparin / 545 / Confirmation of safety / s144
Cilostazol / Antiplatelet / ― / 2013 / Cilostazol + aspirin
versus
aspirin / 510 / No significant difference in neurological recovery / s145
― / 2012 / Cilostazol + aspirin
versus
aspirin / 76 / Improvement in neurological recovery / s146
Clopidogrel / Antiplatelet / CHANCE / 2013 / Clopidogrel + aspirin
versus
aspirin / 5,170 / Secondary prevention of stroke / s147
― / 2012 / Clopidogrel + aspirin
versus
aspirin / 3,200 / No significant difference in secondary prevention of stroke / s148
Defibrotide (polydeoxyribonucleotide) / Antiplatelet: glycoprotein inhibitor / ― / 1989 / Unpublished data / s29
Dalteparin / Anticoagulant / HAEST / 2000 / Dalteparin
versus
aspirin / 449 / No significant difference in neurological recovery / s149
Desmoteplase / Antithrombotic / DIAS-4 / On-
going / Desmoteplase
versus
placebo / 400 / Unpublished data / s150
DIAS-3 / On-going / Desmoteplase
versus
placebo / 480 / Unpublished data / s151
DIAS-2 / 2009 / Desmoteplase
versus
placebo / 193 / No significant difference in neurological recovery / s152
Enoxaparin / Antithrombotic / PREVAIL / 2009 / Enoxaparin
versus
unfractionated heparin / 1,762 / No significant difference in neurological recovery / s153
Eptifibatide (cromafiban; Integrilin) / Antiplatelet: glycoprotein inhibitor / CLEAR-ER / On-going / Eptifibatide + alteplase (0.6 mg/kg)
versus
alteplase (0.9 mg/kg) / 126 / Confirmation of safety / s154
CLEAR / 2008 / Eptifibatide + alteplase
versus
alteplase / 94 / Confirmation of safety / s155
Heparin / Anticoagulant / IST / 1997 / Heparin
versus
no heparin / 19,435 / No significant difference in neurological recovery / s156
HF-0420 / Heparinoid
Anticoagulant / ― / Unpublished data / s31
Microplasmin / Thrombolytic / ― / 2009 / Microplasmin
versus
placebo / 40 / No significant difference in neurological recovery / s157
MRX-801 / Sonolysis / TUCSON / 2009 / MRX-801 + alteplase
versus
placebo + alteplase / 72 / Confirmation of safety / s158
Nadroparin / Antithrombotic / FISS-tris / 2007 / Nadroparin
versus
aspirin / 353 / No significant difference in neurological recovery / s159
Org 10172 (Danaparoid, Orgaran) / Antithrombotic / TOAST / 1998 / Org 10172
versus
placebo / 1,281 / No significant difference in neurological recovery / s160
Pentoxifylline / Improve capillary flow / ― / 1988 / Pentoxifylline
versus
placebo / 297 / No significant difference in neurological recovery / s161
Propentofylline
(HWA 285) / Phosphodiesterase inhibitor / ― / 1993 / Propentofylline
versus
placebo / 27 / No significant difference in neurological recovery / s162
Prostacyclin / Antiplatelet: eicosanoid vasodilator / ― / 1987 / Prostacyclin
versus
placebo / 80 / No significant difference in neurological recovery / s163
Prourokinase / Antithrombotic / PROACT II / 1999 / Prourokinase + heparin
versus
heparin / 180 / Improvement in neurological recovery / s164
Reteplase / Thrombolytic / ― / 2011 / Reteplase + alteplase
versus
Urokinase + alteplase / 197 / No significant difference in neurological recovery / s165
RPR 109891 / Antiplatelet glycoprotein inhibitor / ― / 1998 / Unpublished data / s29
SAR126119 (TAFIa inhibitor) / Thrombolytic / ― / Unpublished data / s26
Solulin / Neuroprotective
Thrombolytic / ― / 2011 / Solulin
versus
placebo / 42 / Confirmation of safety / s166
Streptokinase / Thrombolytic / ASK / 1996 / Streptokinase
versus
placebo / 340 / No significant difference in neurological recovery / s167
MAST-E / 1996 / Streptokinase
versus
placebo / 310 / No significant difference in neurological recovery / s168
MAST-I / 1995 / Streptokinase
versus
Aspirin
versus
Streptokinase + aspirin
versus
neither / 622 / No significant difference in neurological recovery / s169
TAL-05-00018
(human plasma-
derived fibrinolysin) / Thrombolytic / ― / On-going / TAL-05-00018 / 61 / Unpublished data / s170
THR-18 / Antithrombotic / ― / 2010 / THR-18 + alteplase
versus
placebo+ alteplase / 22 / Unpublished data / s171
Tinzaparin / Anticoagulant / TAIST / 2001 / Tinzaparin
versus
aspirin / 1,486 / No significant difference in neurological recovery / s172
Tirofiban
(MK-383, aggrastat) / Antiplatelet: glycoprotein inhibitor / SaTIS / 2011 / Tirofiban
versus
placebo / 260 / No significant difference in neurological recovery / s173
Tenecteplase / Thrombolytic / ― / 2012 / Tenecteplase
versus
alteplase / 75 / Improvement in neurological recovery / s174
Triflusal
(2-acetoxy-4-
trifluoromethylbenzonic acid) / Arachidonic acid metabolism
inhibitor (antiplatelet) / MAESTRO / On-going / Triflusal
versus
clopidogrel / 795 / Unpublished data / s175
TAPIRSS / 2004 / Triflusal
versus
aspirin / 431 / No significant difference in prevention of stroke / s176
TACIP / 2003 / Triflusal
versus
aspirin / 2,113 / No significant difference in prevention of stroke / s177
TS01 / Thrombolytic / ― / On-going / Unpublished data / s178
Urokinase / Thrombolytic / SWISS / On-going / Urokinase (intravenous)
versus
urokinase (intra-arterial) / 704 / Unpublished data / s179
― / 2012 / Urokinase
versus
antiplatelet drugs / 143 / Improvement in neurological recovery / s180
― / 2002 / Urokinase
versus
placebo / 511 / Improvement in neurological recovery / s181
V10153 / Thrombolytic / VASST / 2009 / V10153 / 49 / Unpublished data / s182
Nootropic/stimulant
BAY-387271 / Cannabinoid agonist / ― / Unpublished data / s31
Cerebrolysin / Nootropic / CASTA / 2012 / Cerebrolysin
versus
placebo / 1,070 / No significant difference in neurological recovery / s183
Citicoline
(CDP choline) / Membrane precursor, antioxidant
Vascular insufficiency
Immunostimulatory
Nootropic / ICTUS / 2012 / Citicoline
versus
placebo / 2,298 / No significant difference in neurological recovery / s184
Dexamphetamine / Stimulant / ― / 2003 / Dexamphetamine
versus
placebo / 45 / No significant difference in neurological recovery / s185
EGB-761 (Gingko biloba extract) / MAO inhibitor antiplatelet
Antioxidant
Reduces leukocyte activation
Increases cerebral blood flow / ― / 1995 / Gingko biloba extract
versus
placebo / 55 / No significant difference in neurological recovery / s186
Hydergine / Nootropic
Antioxidant / ― / 1978 / Hydergine
versus
dexamethasone
versus
mannitol
versus
placebo / 300 / No significant difference in neurological recovery / s187
Methamphetamine / Stimulant / ― / Unpublished data / s26
Msc-1 (AGY-94806) / Opioid receptor sigma agonist / ― / Unpublished data / s31
Nafronyl oxalate (Naftidrofuryl) / Serotonin antagonist / ― / 1990 / Naftidrofuryl
versus
placebo / 100 / No significant difference in neurological recovery / s188
Piracetam / AMPA (NA+) modulator / PASS / 1997 / Piracetam
versus
placebo / 927 / Improvement in neurological recovery / s189
Semax / Derivative of ACTH-4-10 / ― / 1997 / Semax
versus
conventional therapy / 110 / Confirmation of safety / s190
Fluid-regulative
Glycerol / Hyperosmolar agent / ― / 1993 / Glycerol
versus
placebo / 113 / No significant difference in neurological recovery / s191
Dextran / Hemodilution / ― / 1992 / Hemodilution with dextran
versus
no treatment / 102 / Improvement in neurological recovery / s192
Hydroxyethyl starch pentastarch / Hemodilution / ― / 2002 / Hemodilution with hydroxyethyl starch pentastarch
versus
hemodilution with saline / 106 / No significant difference in neurological recovery / s193
Mannitol / Hyperosmotic agent
Reduces edema and ICP / ― / 2003 / Mannitol
versus
no mannitol / 805 / No significant difference in neurological recovery / s194
Oxygen-delivering (analyzed with other group because of low numbers)
Diaspirin cross-linked hemoglobin / Oxygen delivery
Free radical scavenger / ― / 1999 / Diaspirin cross-linked hemoglobin
versus
placebo / 85 / Significantly worsened neurological recovery / s195
Hyperbaric oxygen treatment / Oxygen delivery / ― / 2003 / Hyperbaric oxygen treatment
versus
sham treatment / 33 / No significant difference in neurological recovery / s196
Normobaric oxygen treatment / Oxygen delivery / ― / 2010 / Normobaric oxygen treatment
versus
control
(room air or oxygen 2 L/min) / 40 / No significant difference in neurological recovery / s197
Oxygenated fluorocarbon nutrient
emulsion / Oxygen delivery / ― / 2006 / Oxygenated fluorocarbon nutrient
emulsion / 4 / Confirmation of safety / s198
Other effects
Atorvastatin / HMGCoA reductase inhibitor
Antioxidant / ― / 2012 / Atorvastatin
versus
placebo / 40 / No significant difference in neurological recovery / s104
― / 2010 / Atorvastatin
versus
simvastatin / 371 / Improvement in neurological recovery / s199
Caffeinol / Stimulant, depressant, diuretic adenosine receptor modulator / ― / 2009 / Caffeinol + alteplase + hypothermia / 20 / Confirmation of safety / s200
Corticotrophin / GABA receptor modulator
Pituitary hormone / ― / 1987 / Unpublished data / s29
Endovascular therapy / Mechanical removal of thrombus
or antithrombotic / MERCI / 2005 / Single arm trial of thrombectomy in patients with AIS after thrombolysis / 164 / No significant difference in neurological recovery / s201
MR RESCUE / 2013 / Embolectomy
versus
intravenous alteplase / 118 / No significant difference in neurological recovery / s202
IMS III / 2013 / Intravenous alteplase + embolectomy
versus
intravenous alteplase / 656 / No significant difference in neurological recovery / s203
SYNTHESIS Expansion / 2013 / Intra-arterial alteplase + embolectomy
versus
intravenous alteplase / 362 / No significant difference in neurological recovery / s204
― / 2013 / Non-randomized comparison of Trevo and Solitaire stent retrievers with Merci devices in patients with large vessel occlusion who had received thrombolysis / 122 / Improvement in neurological outcome and reduction in complication rate compared with Merci system / s205
Estradiol / Antioxidant
Anti-inflammatory
Anti-apoptotic / WEST / 2006 / Estradiol
versus
placebo / 664 / Slightly worsened neurological recovery / s206
Glyburide
(RP-1127) / Ca-ATP channel blocker / GAMES-PILOT / On-going / RP-1127 / 10 / Unpublished data / s207
Glyceryl trinitrate (Nitroglycerin, GTN) / NO donor / ENOS / On-going / Glyceryl trinitrate
versus
no glyceryl trinitrate / 3,500 / Unpublished data / s208
HF-0220 / Neuroprotective steroid / ― / Unpublished data / s31
Hypothermia / Reduce cerebral oxygen demand (CMRO2)
Metabolic and synaptic
transmission inhibitor / ICTuS-L / 2010 / Hypothermia
versus
normothermia / 59 / No significant difference in neurological recovery / s209
Reduce CMRO2 / ― / 2014 / Hypothermia (35ºC) versus standard care in patients receiving thrombolysis within 6 h of AIS onset / 36 / Confirmation of safety / s210
Lithium / Stimulation of BDNF secretion / ― / On-going / Lithium / 35 / Unpublished data / s211
Lovastatin / HMGCoA reductase inhibitor
Antioxidant / Neu-START II / On-going / Lovastatin
versus
placebo / 130 / Unpublished data / s212
Neu-START / 2009 / Lovastatin / 33 / Confirmation of safety / s213
NeuroAiD
(MLC601,
Danqi Piantang Jiaonang) / Stimulation of BDNF secretion / CHIMES / On-going / NeuroAiD
versus
placebo / 1,100 / No significant difference in neurological recovery / s214
― / 2011 / MLC601
versus
placebo / 150 / Improvement in neurological recovery / s215
― / 2009 / Danqi Piantang Jiaonang
versus
Buchang Naoxintong Jiaonang / 605 / Improvement in neurological recovery / s216
ONO-2506 / Astrocyte-modulating agent
Attenuates extracellular
monamine / ― / 2012 / ONO-2506
versus
placebo / 1,320 / Unpublished data / s217
Percutaneous transluminal angioplasty and stenting / Vasodilatation / SAMMPRIS / 2013 / Percutaneous
transluminal
angioplasty and
stenting +
medical management (aspirin +
clopidogrel)
versus
medical management / 451 / Stenting group was inferior to medical management group in secondary prevention of stroke / s218
PF-3049423 / Unpublished data / ― / Unpublished data / s26
Radix salviae miltiorrhizae / Antioxidant
Partial endothelin-1 inhibitor / ― / 2000 / Unpublished data / s29
Repinotan
(BAY × 3072) / Serotonin agonist / mRECT / 2009 / Repinotan
versus
placebo / 681 / No significant difference in neurological recovery / s219
Simvastatin / HMGCoA reductase inhibitor
Antioxidant / ― / On-going / Simvastatin
versus
placebo / 340 / Unpublished data / s220
MISTICS / 2008 / Simvastatin
versus
placebo / 60 / Improvement in neurological recovery / s221
Sphenopalatine ganglion (SPG) stimulation / Induction of cerebral vasodilatation / ImpACT-24 / On-going / The Ischemic
Stroke System®
versus
sham control / 450 / Unpublished data / s222
SUN N4057
(Piclozotan) / Serotonin 1A receptor agonist / ― / 2011 / Piclozotan
versus
placebo / 43 / Unpublished data / s223
TAK-218 / Dopamine suppressor
Sodium channel modulator / ― / 2001 / Unpublished data / s29
Tinofedrine
(D 8955, Novocebrin) / Blood flow, increased metabolism / ― / 1978 / Unpublished data / s29
Transcranial laser therapy (TLT) / Mitochondrial stimulation / NEST-3 / On-going / NeuroThera® Laser System
versus
sham treatment / 1,000 / Unpublished data / s224
NEST-2 / 2009 / NeuroThera® Laser System
versus
sham treatment / 660 / No significant difference in neurological recovery / s225
Trazodone (Desyrel) / Serotonin reuptake inhibitor / ― / 1986 / Trazodone
versus
placebo / 49 / No significant difference in neurological recovery / s226
Transcranial ultrasound / Alteplase enhancer / CLOTBUST-HF / 2013 / Intravenous alteplase +
transcranial ultrasound / 20 / Confirmation of safety / s227
SUPPLEMENTAL REFERENCES