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Table 1 Overview of included randomized clinical trials per compound and per category. Trial compounds showing a positive treatment effect over control groups are highlighted (bold)

From: Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review

Compound

Mechanism of action

Year

Blinding\(^{\infty }\)

N\(^{\omega }\)

IVT/EVT\(^{\dagger }\)

Age\(^{\lambda }\)

NIHSS\(^{\rho }\)

T-t-T\(^{\xi }\)

Main outcome parameter

Effect size\(^{\pi }\)

P or ratio [CI]\(^{\ddagger }\)

Safety concern

      

(y)

 

(h)

(time point)

   

Systemic heamodynamics

 Atenolo [13]

\({\beta }_{1}\)-blocking agent

1988

++

201

+/−

69

?

24

Mortality (30 d)

14 \({\text{vs}}\) 25

?

Yes

 Candesartan [14]

AngII-R antagonist

2003

++

339

?

68

?

30

BI (30 d)

89 \({\text{vs}}\) 87

ns

No

 Candesartan [16]

 

2011

++

2029

+/−

71

?

18

mRS (6 mo)

2.0 \({\text{vs}}\) 2.1

1.13 (OR) [0.97–1.32]\(^{a}\)

No

 DCLHb [18]

Increase blood oxygen level

1999

+

85

+/−

66

?

?

mRS \(\ge\)3 (90 d)

51% \({\text{vs}}\) 85%

0.002

Yes

 Irbesartan [19]

AngII-R antagonist

2011

++

43

+/−

69

7

53

Infarct volume (30 d)

280 \({\text{vs}}\) 822

0.63\(^{a}\)

No

 Lifarizine [20]

Sodium and calcium antagonist

1996

++

117

?

69

?

?

Independent mRS (90 d)

\(\Delta\)placebo-drug = 16%

0.522

No

 Lisinopri [21]

ACE inhibitor

2007

++

40

?

74

11

19

mRS \(\le\)2 (90 d)

63% \({\text{vs}}\) 60%

0.56\(^{a}\)

No

 Magnesium sulfate [22]

Multiple action sides resulting in vasodilatation and increased CBF

2004

++

2386

+/−

70

?

7

mRS \(\ge\)2 (90 d)

72% \({\text{vs}}\) 70%

0.95 (OR) [0.80–1.13]

Yes

 Magnesium sulfate [23]

 

2015

++

1700

+/−

69

11

45 min

mRS (90 d)

2.7 \({\text{vs}}\) 2.7

1\(^{a}\)

No

 Nimodipine [24]

Calcium antagonist

1988

++

186

69

?

?

Mortality (6 mo)

28% \({\text{vs}}\) 17%

0.046

No

 Nimodipine [24]

 

1989

++

41

63

?

?

mMS (28 d)

78 \({\text{vs}}\) 89

<0.04

No

 Nimodipine [195]

 

1990

++

52

?

65

?

19

MS improvement (4 mo)

86% \({\text{vs}}\) 75%

ns

No

 Nimodipine [196]

 

1990

++

1215

?

73

?

?

BI \(\ge\)60 (6 mo)

58% \({\text{vs}}\) 55%

0.31

No

 Nimodipine [197]

 

1992

++

1064

?

66

?

28

Mortality (6 mo)

16% \({\text{vs}}\) 14%

ns

No

 Nimodipine [198]

 

1993

++

164

?

72

?

?

Mortality (28 d)

15% \({\text{vs}}\) 10%

ns

No

 Nimodipine [27]

 

1994

++

350

?

58

?

20

mRS \(\le\)2 (12 mo)

64% \({\text{vs}}\) 66%

ns

Yes

 Nimodipine [26]

 

1994

++

295

?

72

?

11

BI (21 d)

22 \({\text{vs}}\) 10

0.003\(^{a}\)

No

 Nimodipine [199]

 

2000

++

153

?

59

?

?

Infarct volume (90 d)

10.2 \({\text{vs}}\) 4.4

ns

?

 Nimodipine [200]

 

2001

++

454

?

71

?

?

mRS >3 (90 d)

27% \({\text{vs}}\) 32%

1.2 (RR) [0.9−1.6]

No

 Piracetam [28]

Positive allosteric AMPA-R modulator

1997

++

927

70

?

7

BI (90 d)

53 \({\text{vs}}\) 56

0.33

No

 Propranolol [13]

\(\beta\)-blocking agent

1988

++

201

+/−

68

?

25

Mortality (30 d)

14 \({\text{vs}}\) 27

?

Yes

Excitotoxicity

 Aptiganel HCl [34]

NMDA-R antagonist

2001

++

628

72

12

?

Phase II part: \(\Delta\)NIHSS (7 d)

− 4 \({\text{vs}}\)− 3.5

0.41

Yes

         

Phase III part: mRS (90 d)

3.1 \({\text{vs}}\) 3.3

0.44

 

 Clomethiazole [35]

GABA-R agonist

1999

++

1360

71

?

?

BI \(\ge\)60 (90 d)

55% \({\text{vs}}\) 56%

0.649

No

 Clomethiazole [37]

 

2001

++

190

+

67

14

5.4

BI \(\ge\)60 (90 d)

67% \({\text{vs}}\) 66%

0.94 (OR) [0.51–1.72]

No

 Clomethiazole [36]

 

2002

++

1198

72

17

?

BI \(\ge\)60 (90 d)

46% \({\text{vs}}\) 42%

0.11

No

 Diazepam [38]

GABA-R agonist

2006

++

849

?

72

?

?

mRS <3 (90 d)

49% \({\text{vs}}\) 52%

1.14 (OR) [0.87−1.49]

No

 Fanapanel [39]

AMPA-R antagonist

2002

++

61

67

6

17

NIHSS (30 d)

?

0.07

Yes

 Gavestinel (GV150526) [40]

NMDA-R antagonist

2001

++

1367

?

72

12

5.2

mRS \(\le\)1 (90 d)

26% \({\text{vs}}\) 29%

0.3

No

 Lanicemine HCl [41]

NMDA-R antagonist

2002

++

103

67

9

?

\(\Delta\)NIHSS \(\ge\)4 (30 d)

?

0.563 (OR) [0.24−1.31]

Yes

 Lithium [42]

NMDA-R antagonist

2014

++

66

+/–

62

7

?

\(\Delta\)NIHSS (30 d)

− 1.64 \({\text{vs}}\) − 2.34

0.402

No

 Lubeluzole [45]

Indirect NMDA-R antagonist

1996

++

193

?

71

15

4.3

\(\Delta\)NIHSS (28 d)

− 5.8 \({\text{vs}}\) − 6.4

ns

Yes

 Lubeluzole [43]

 

1997

++

700

+/−

71

15

4.6

mRS \(\ge\)3 (90 d)

44% \({\text{vs}}\) 42%

0.04

No

 Lubeluzole [44]

 

1998

++

725

70

?

4.4

mRS 3−5 (90 d)

48% \({\text{vs}}\) 52%

ns

No

 Nalmefene [46]

Opioid-R antagonist

2000

++

330

+/–

70

12

4.4

\(\Delta\)NIHSS \(\ge\)4 (90 d)

65% \({\text{vs}}\) 64%

0.88

No

 Selfotel [48]

NMDA-R antagonist

2000

++

567

?

69

14

4.5

BI \(\ge\)60 (90 d)

61% \({\text{vs}}\) 58%

0.49

Yes

Oxidative and nitrosative stress

 Disufenton sodium [50]

Free radical scavenger

2001

++

147

68

8

15

\(\Delta\)NIHSS (30 d)

− 3 \({\text{vs}}\) − 3

ns

No

 Disufenton sodium [53]

 

2006

++

1699

+/−

68

13

3.8

mRS (90 d)

\(\le\)1: 31% \({\text{vs}}\) 33%

1.20 (OR) [1.01−1.42]

No

 Disufenton sodium [54]

 

2007

++

3195

+/–

69

13

3.8

mRS (90 d)

\(\le\)1: 29% \({\text{vs}}\) 27%

0.94 (OR) [0.83−1.06]\(^{a}\)

No

 Disufenton sodium [51]

 

2008

++

5028

+/−

71

13

3.8

mRS (90 d)

\(\le\)1: 29% \({\text{vs}}\) 29%

1.02 (OR) [0.92−1.13]\(^{a}\)

No

 Ebselen [58]

Free radical scavenger

1998

++

300

65

?

29

BI \(\ge\)75 (90 d)

50% \({\text{vs}}\) 64%

0.012

No

 Ebselen [57]

 

1999

++

99

+/−

99

?

9

Infarct volume (30 d)

12.74 \({\varvec{{\text{vs}}}}\) 8.30

0.034

No

 Edaravone [59]

Free radical scavenger

2003

++

250

66

7

36

mRS (90 d)

2.2 \({\varvec{{\text{vs}}}}\) 1.8

0.038

No

 Epigallocatechin Gallate [60]

Free radical scavenger

2017

++

71

+

65

15

?

NIHSS \(\le\)10 (7 d)

41% \({\text{vs}}\) 45%

ns

No

 Glyceryl Trinitrate [61]

Free radical scavenger

2015

++

4011

+/−

70

11

26

mRS (90 d)

?

1.01 (OR) [0.91–1.13]\(^{a}\)

No

 Glyceryl Trinitrate [63]

 

2019

+

852

+/−

74

10

1.1

mRS (90 d)

3 \({\text{vs}}\) 3

0.083\(^{a}\)

No

 Uric−acid [68]

Free radical scavenger

2014

++

411

+

77

13

3

mRS (90 d)

3 \({\varvec{{\text{vs}}}}\) 2

0.045\(^{a}\)

No

 Tirilazad mesylate [70]

Free radical scavenger

1994

++

111

+/−

66

8

8.5

NIHSS (90 d)

1 \({\text{vs}}\) 2

0.105

No

 Tirilazad mesylate [71]

 

1996

++

556

69

10

4.3

BI (90 d)

95 \({\text{vs}}\) 95

0.87 (OR) [0.60−1.25]\(^{a}\)

No

 Tirilazad mesylate [72]

 

2002

+

368

?

70

?

?

Infarct volume (8 d)

37mL \({\text{vs}}\) 43mL

0.55

?

Blood–brain barrier and vasogenic edema

 Albumin+Ringers-glucose [10]

Colloid-osmotic pressure modifier

1992

297

+/−

75

?

?

Mortality (90 d)

21% \({\text{vs}}\) 17%

ns

No

 Albumin [80]

 

2011

++

424

+/−

70

11

3.5

Mortality (90 d)

13% \({\text{vs}}\) 21%

1.55 (RR) [1.01−2.39]

Yes

 Albumin [77]

 

2013

++

841

+/−

64

11

?

Good outcome (90 d)

44% \({\text{vs}}\) 44%

0.96 (RR) [0.84−1.10]\(^{a}\)

Yes

 Citicoline [83]

Cell membrane stabilizer

1997

++

259

?

68

13

14.5

mRS (30 d)

3.1 \({\varvec{{\text{vs}}}}\) 2.5

0.03\(^{a}\)

No

 Citicoline [85]

 

2000

++

81

?

70

12

14.3

\(\Delta\)Infarct volume (30 d)

18.9 \({\text{vs}}\) 11.3

0.18

No

 Citicoline [84]

 

2001

++

899

?

68

14

13

Infarct volume (30 d)

58.9 \({\text{vs}}\) 57.7

0.80

No

 Citicoline [86]

 

2012

++

2298

+/−

73

15

6.7

mRS \(\le\)1 (90 d)

18% \({\text{vs}}\) 18%

1.07 (OR) [0.85−1.36]

No

 Fasudil [88]

Rho-kinase inhibitor

2005

++

160

68

?

22

\(\Delta\)mRS \(\le\)− 2 (30 d)

44% \({\varvec{{\text{vs}}}}\) 63%

0.0015

No

 Glyburide [95]

K\(_{ATP}\)/NC\(_{Ca-ATP}\) channel inhibitor

2016

++

77

+/−

60

20

9

mRS \(\le\)3 (90 d)

41% \({\text{vs}}\) 39%

0.87 (OR) [0.32−2.32]\(^{a}\)

No

 Imatinib [96]

Tyrosine kinase inhibitor

2017

+/−

60

+

73

12

4

mRS \(\le\)2 (90 d)

61% \({\text{vs}}\) 78%

0.296\(^{a}\)

No

 Sodium tanshinone IIA sulfonate [98]

Downregulation MMP9

2017

++

42

+

64

8

3.5

mRS \(\le\)1 (90 d)

43% \({\varvec{{\text{vs}}}}\) 76%

0.028

?

Neurogenesis/-regeneration/-recovery

 Cerebrolysin [103]

Multiple neurotrophic factors

2012

++

1067

+/−

65

9

8

mRS (90 d)

2 \({\text{vs}}\) 2

ns

No

 Cerebrolysin [104]

 

2012

++

119

+

66

12

2

mRS \(\le\)1 (90 d)

55% \({\text{vs}}\) 53%

0.13 (OR) [−0.55 to 0.88]

No

 Cerebrolysin [106]

 

2017

++

100

68

10

?

mRS \(\le\)1 (30 d)

26% \({\varvec{{\text{vs}}}}\) 31%

0.01

No

 Cerebrolysin [105]

 

2016

++

40

+/−

67

10

7

NIHSS (21 d)

7.3 \({\varvec{{\text{vs}}}}\) 5.9

<0.05

No

 Choriogonadotropin + epoetin-\(\alpha\)[108]

Neural stem cell proliferation stimulator

2014

++

96

58

13

38

\(\Delta\)NIHSS (90 d)

− 8 \({\text{vs}}\) − 8

0.31\(^{a}\)

No

 Cutamesine [109]

\(\alpha\)-1 receptor (Sig-1R) agonist

2014

++

60

+/−

67

9

59

mRS \(\le\)1 (56 d)

19% \({\text{vs}}\) 42%

2.68 (OR) [0.62−11.49]\(^{a}\)

No

 Dexamphetamine [110]

TAAR1 agonist

2003

++

45

?

67

?

53

BI (90 d)

?

ns

No

 DL-3-n-butylphthalide (NBP) [105]

Multiple neuroprotective effects

2016

++

40

+/−

67

11

7

NIHSS (21 d)

7.3 \({\varvec{{\text{vs}}}}\) 5.5

<0.01

No

 Erythropoietin [111]

Erythropoiesis stimulator

2009

++

460

+/−

68

13

4

Lesion volume (7 d)

91 \({\varvec{{\text{vs}}}}\) 86

0.67

Yes

 Filgrastim [113]

Granulocyte colony stimulating factor

2012

++

60

+/−

72

10

233

Lesion volume (90 d)

5.2 \({\varvec{{\text{vs}}}}\) 27.6

0.51

No

 Filgrastim [112]

 

2013

++

323

+/−

69

12

7

Lesion volume (30 d)

65.9 \({\text{vs}}\) 59.0

0.44\(^{a}\)

No

 GSK-249320 [114]

Blocking Myelin-associated glycoprotein

2017

++

134

+/−

68

10

52

mRS (90 d)

2.8 \({\text{vs}}\) 2.7

ns

No

 Kallikrein [117]

Serine proteinase

2011

++

44

?

68

10

42

\(\Delta\)Lesion volume (14 d)

0 \({\varvec{{\text{vs}}}}\) 81.5

0.009

No

 Neurotropin [120]

Neurotrophic factor

1994

++

144

+/−

72

?

?

\(\Delta\)Lesion volume (11 d)

0.17 \({\varvec{{\text{vs}}}}\) − 1.27

0.02

No

Neuroinflammation

 Atorvastatin [19]

HMG-CoA reductase inhibitor

2011

++

81

+/−

67

6

53

Lesion volume (30 d)

280 \({\text{vs}}\) 462

0.792\(^{a}\)

No

 Atorvastatin [127]

 

2011

++

62

75

13

7

Lesion volume (3 d)

16.2 \({\text{vs}}\) 30.4

0.33

No

 Ceftriaxone [128]

Bacterial cell wall synthesis inhibitor

2015

+

2538

+/−

74

5

?

mRS \(\le\)2 (90 d)

60% \({\text{vs}}\) 62%; 0.94 (OR)

[0.80–1.11]

No

 Cyclosporine [132]

Calcineurin inhibitor

2015

+

110

+

68

13

2.5

\(\Delta\)Lesion volume (30 d)

28.8 \({\text{vs}}\) 21.8

0.18

No

 Enlimomab [136]

ICAM antibody

2001

++

625

69

15

4.5

mRS \(\le\)1 (90 d)

34% \({\text{vs}}\) 27%

0.004\(^{a}\)

Yes

 Fingolimod [137]

S1P-R1 antagonist

2015

+/−

47

+

59

12

3

Lesion volume (7 d)

12.1 \({\varvec{{\text{vs}}}}\) − 2.3

<0.01

No

 Minocycline [139]

Microglia activation inhibiton

2007

+/−

152

+/−

66

8

13

mRS (90 d)

2.1 \({\varvec{{\text{vs}}}}\) 0.9

<0.0001

No

 Minocycline [140]

 

2013

+/−

95

+/−

68

9

11

mRS \(\le\)2 (90 d)

33% \({\text{vs}}\) 29%

0.94 (RR) [0.71–1.25]

No

 Moxifloxacin [141]

Antibiotic

2008

++

79

?

72

16

?

BI \(\ge\)60 (6 mo)

55% \({\text{vs}}\) 64%

0.57

No

 Natalizumab [147]

\(\alpha\)4 integrin antagonist

2017

++

161

+/−

70

13

7

\(\Delta\)Lesion volume (30 d)

4 \({\text{vs}}\) 4

0.68

No

 Simvastatin [148]

HMG-CoA reductase inhibitor

2008

++

60

73

12

?

mRS (90 d)

3 \({\text{vs}}\) 3

0.86

Yes

 Simvastatin [149]

 

2016

++

104

+/−

74

7

7

mRS\(\le\)2 (90 d)

70% \({\text{vs}}\) 69%

0.99 (OR) [0.35−2.78]\(^{a}\)

No

 UK-279,276 [151]

Neutrophil inhibitor

2003

++

746

+/−

72

13

4

Mortality (90 d)

15% \({\text{vs}}\) 17%

ns

No

Additional compounds

 Acetaminophen[153]

Inhibit cyclo-oxygenases or serotonerge system

2001

++

42

?

70

5

?

mRS (5 d)

?

ns

No

 Acetaminophen [152]

 

2009

++

1400

+/−

70

7

6

mRS \(\le\)2 (90 d)

50% \({\text{vs}}\) 51%

1.09 (OR) [0.88−1.33]

No

 DP-b99 [154]

Zinc and calcium ion chelator

2008

++

150

73

12

6

mRS \(\le\)1 (90 d)

16% \({\varvec{{\text{vs}}}}\) 31%

0.05

No

 Reptinotan [155]

(5-HT)1A receptor agonist

2009

++

681

+/−

70

15

?

mRS \(\le\)2 (90 d)

38% \({\text{vs}}\) 32%

0.136\(^{a}\)

No

  1. \(^{\infty }\) ++ = double blinded; + = single blinded; +/− = Open-label, blinded analysis; − = no blinding
  2. \(^{\theta }\) Placebo controlled trial, Yes (Y) or No (N)
  3. \(^{\omega }\) Number of included patients (N)
  4. \(^{\dagger }\) + = (r)tPA and/or MT; +/− = “standard treatment” or mixed standard treatment and no treatment; − = No additional treatment; ? = not reported
  5. \(^{\lambda }\) Mean or median age in years (y)
  6. \(^{\rho }\) Mean or median NIHSS at baseline
  7. \(^{\xi }\) Time to treatment: (estimated) mean or median time from symptom onset to treatment (or else inclusion time); in hours (h), unless stated otherwise
  8. \(^{\pi }\) Effect size = Placebo \(versus\) active treatment group (\(^{a}\) = adjusted)
  9. \(^{\ddagger }\) Significance level (P) or confidence interval (CI)
  10. NIHSS = The National Institutes of Health Stroke Scale; mRS = modified Rankin Scale; BI = Barthel Index; (m)MS = (modified) Mathew Sale; Good outcome = mRS \(\le\)1 or NIHSS \(\le\)1; ? = unknown; d = days; mo = months;
  11. \(\Delta\) = difference in outcome measure between baseline and readout timepoint; RR = Risk Ratio; OR = Odds Ratio; IVT = Intravenous trombolyses; EVT = Endovascular thrombectomy; AngII = Angiotensin II;
  12. DCLHb = Diaspirin cross-linked hemoglobin; ACE = angiotensin-converting enzyme; CBF = cerebral blood flow; AMPA = \({\alpha }\)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA = N-Methyl-d-aspartate;
  13. GABA = \({\gamma }\)-aminobutyric acid; K = Potassium; ATP = Adinosine triphosphate; NC\(_{Ca}\) = nonselective cation channel for calcium; MMP9 = Matrix metallopeptidase 9; TAAR1 = Trace amine-associated receptor 1;
  14. ICAM = intercellular adhesion molecules; HMG-CoA = \({\beta }\)-Hydroxy \({\beta }\)-methylglutaryl-Co-enzyme A; S1P = sfingosine 1-fosfaat; 5-HT = 5-hydroxytryptamine (serotonin); LD = low dose; HD = high dose; -R = Receptor