Table 1.
Overview of neuroprotective trials using reperfusion therapy.
| Study | Year | Agent | Mechanism of action | Reperfusion therapy | Patients (controls) | Mean age (control) | Female % (control) | Median baseline NIHSS (controls) | % LVO/TACS (controls) | Median time to treatment in hr (controls) | Median time to IVT/EVT in hr (controls) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Ogawa et al. (12) | 1999 | Ebselen | Antioxidant, anti-inflammatory | IVT (73%) | 99 (56) | 66.6 (65.6) | 33% (32%) | unknown | MCA 100% | 8.8 (8.4) | IVT 4.6 (6.2) |
| Clark et al. (13) | 2000 | Nalmefene | K-receptor opiate antagonist | IVT (9%) | 368 (182) | 69.8 (70.5) | 49.7% (48.5%) | 12.2 (12.4) | No LVO reported | 4.8 (4.2) | unknown |
| Sacco et al. (14) | 2001 | Gavestinel | Glycine antagonist | IVT (24%) | 1376 (666) | 70 (70) | 47.8% (47.4%) | 12 (12) | TACS 37.7% | 5.2 (5.2) | unknown |
| Lyden et al. (15) | 2001 | Clomethiazole | GABA enhancer | IVT (100%) | 190 (93) | 68 (67.6) | 44% (46%) | 14 (13) | TACS 53% (41%) | 5.4 (5.3) | unknown, all but 2 IVT <3 h |
| Krams et al. (16) | 2003 | UK 279,276 | Anti-inflammatory | IVT (21%) | 966 (248) | 72 (total) | 43% (total) | 13 (unknown) | No LVO reported | 3.1 (unknown) | IVT 2.3 (unknown) |
| Amaro et al. (17) | 2007 | Uric acid | Antioxidant | IVT (100%) | 24 (8) | 70.2 (70.2, 72.9) | 0% (38%, 50%) | 11.8 (8.5) | No LVO reported | 3.6 (3.5) | IVT 2.3 2.3 (2.1) |
| Diener et al. (18) | 2008 | NXY-059 | Antioxidant | IVT (39%) | 4946 (2478) | 71 (71)** | 44.4% (45.8%) | 12 (12) | No LVO reported | 3.45 (3.45) | unknown |
| Ehrenreich et al. (19) | 2009 | Erythropoietin | Antioxidant, anti-inflammatory | IVT (63%) | 522 (266) | 68.6 (68.2) | 45% (47%) | 13 (12) | LVO 22.7% (25.4%) | 4.4 (4.5) | unknown |
| Teal et al. (20) | 2009 | Repinotan | Serotonin receptor agonist | IVT (61%) | 681 (337) | 70.3 (69.7) | 48% (47%) | 15 (14) | No LVO reported | unknown | unknown |
| Hemmen et al. (21) | 2010 | Hypothermia | Hypothermia | IVT (79%) | 58 (30) | 68.9 (62.3) | 43.3% (46.2%) | 14.3 (13.7)* | No LVO reported | 1.1 (N/A) | unknown |
| Heiss et al. (22) | 2012 | Cerebrolysin | Antioxidant, anti-inflammatory | IVT (9%) | 1067 (540) | 65 (65.5) | 40.4% (39.6%) | 9 (9) | No LVO reported | 7.7 (7.6)* | unknown |
| Ginsberg et al. (23) | 2013 | Albumin | Antioxidant, anti-inflammatory, hemodilution | IVT (68%) EVT (4%) IVT + EVT (16%) |
841 (419) | 63.4 (64.8) | 48% (44%) | 11 (11) | TACS 24% (23%) | 3.3 (3.3) | IVT 2.1 (2.2) |
| Lang et al. (24) | 2013 | Cerebrolysin | Antioxidant, anti-inflammatory | IVT (100%) | 119 (59) | 65.5 (67) | 33.3% (37.3%) | 12.3 (11.0)* | No LVO reported | unknown, all 1 h after IVT |
IVT 2.4 (2.2)* |
| Hougaard et al. (25) | 2014 | Remote ischemic perconditioning | Antioxidant, anti-inflammatory | IVT (100%) IVT + EVT (unknown) |
443 (196) | 66 (68)** | 43% (41%) | 4 (5) | No LVO reported | unknown, pre-hospital |
unknown |
| Saver et al. (26) | 2015 | Magnesium | Calcium-channel blocker, NMDA antagonist, vasodilatation | IVT (36%) | 1700 (843) | 69 (69) | 43.5% (41.8%) | 11.5 (11.2) | No LVO reported | 0.75 (0.75) | unknown |
| Woodhouse et al. (27) | 2015 | Transdermal Glyceryl Trinitrate | Nitric oxide donor | IVT (34%) | 273 (139) | 69 (70.8) | 47.9% (38.8%) | 11.4 (12.4) | TACS 29.9% (33.3%) LVO | unknown | unknown |
| Montaner et al. (28) | 2016 | Simvastatin | Antioxidant, anti-inflammatory | IVT (53%) | 104 (54) | 73.5 (75)** | 52% (40.7%) | 7 (7) | TACS 22% (22.2%) | 7.4 | unknown |
| Wahlgren et al. (29) | 2017 | Imatinib | Tyrosine kinase inhibitor | IVT (100%) EVT (42%) |
60 (17) | 76/73/72 (70)**† | 57%/27%/47% (35%)† | 12 (13) | No LVO reported | 4.0 (unknown) | IVT 1.4 (all patients) EVT unknown |
| Wang et al. (30) | 2017 | Epigallocatechin gallate | Antioxidant | IVT (100%) | 371 (186) | 62.7 (65.1)/67.4 (64.9)† | 49% (46%)/45% (49%)† | 13 (15) | No LVO reported | unknown | unknown |
| Chamorro et al. (31) | 2017 | Uric acid | Antioxidant | IVT + EVT (100%) | 45 (21) | 78 (68)** | 46% (33%) | 17 (15) | IC/T 17% (25%) M1 67% (55%) M2 13% (20%) | 2.3 (2.5) | IVT 1.9 (1.8) |
| Lyden et al. (32) | 2019 | 3K3A-APC | Anti-inflammatory, anti-thrombotic | IVT 54% EVT 5% IVT + EVT 42% |
110 (44) | 64 (64) | 56% (45%) | 13 (13.5) | No LVO reported | unknown | 2.2 (2.1) |
| Culp et al. (33) | 2019 | Dodecafluor- opentane | Improved oxygen transport | IVT 58% EVT 4% IVT + EVT 25% |
24 (6) | 56.9 (55.8) | 39% (17%) | 6.5 (9.5) | No LVO reported | 6.3 (6.6) | unknown |
| Kim et al. (34) | 2020 | Otaplimastat | Anti-inflammatory | IVT 100% EVT 30% |
69 (24) | 63.5/66 (59)**† | 43%/23% (32%)† | 8 (10) | No LVO reported | 1.8 (2.0) | 1.5 (1.8) |
| Pico et al. (35) | 2020 | Remote ischemic perconditioning | Antioxidant, anti-inflammatory | IVT 57% EVT 4% IVT + EVT 30% |
188 (95) | 67.8 (66.7) | 51.6% (44.2%) | 9 (10) | MCA 48.4% (51.6%) Cervical carotid 6.5% (0%) Carotid tandem 6.5% (5.3%) Other 6.5% (12.6%) | 3.7 (N/A) | IVT 2.6 (2.4) EVT 3.1 (3.0) |
| Hill et al. (36) | 2020 | Nerinetide | Reduction of intracellular endogenous nitric oxide | IVT 60% EVT 100% |
1105 (556) | 71.5 (70.3)** | 48.8% (50.5%) | 17 (17) | ICA 20% (18.5%) MCA 80.7% | 3.1 (3.1) | unknown |
| An et al. (37) | 2020 | Remote ischemic perconditioning | Antioxidant, anti-inflammatory | IVT 100% | 68 (34) | 62.1 (67.1) | 35.3% (26.5%) | 6.5 (4.5) | No LVO reported | 3.0 (3.0) | unknown |
| Modrau et al. (38) | 2020 | Theophylline | Redistribution of blood | IVT 100% EVT 14% |
64 (31) | 68 (71)** | 39% (39%) | 8 (6) | LVO 42% (39%) ACA 0% (3% M1 22% (17%) M2 19% (17%) PCA 3% (3%) | unknown | unknown |
| He et al. (39) | 2020 | Remote ischemic perconditioning | Antioxidant, anti-inflammatory | IVT 100% | 49 (25) | 59.5 (61.3) | 16.7% (28%) | 7 (9) | No LVO reported | 3.0 (3.2) | unknown |
| Cheng et al. (40) | 2021 | Normobaric oxygen | Antioxidant | IVT 45% EVT 100% |
175 (87) | 63.8 (65.9) | 36.4% (41.4%) | 17 (16) | MCA 56.8% (66.7%) ICA 21.6% (17.2%) | unknown | unknown |
| Pruvost-Robieux et al. (41) | 2021 | Transcranial direct current stimulation | modulates excitability of neurons | IVT 56% EVT 7% IVT + EVT 38% |
55 (23) | 71.6 (76.2) | 36.4% (56.5%) | 8 (11) | Proximal (ICA, M1, M2) 37% (57%) Distal 18% (13%) None 45% (30%) Prox. ICA 21.6% (16.1%) | 2.8 (2.9) | IVT 2.2. (2.3) EVT 2.6 (2.8) |
*
mean, not median;
**
median, not mean
†
multiple treatment groups.
IVT, intravenous thrombolysis; EVT, endovascular therapy; LVO, large vessel occlusion; NIHSS, National Institutes of Health Stroke Scale; TACS, total anterior circulation syndrome. IC/T, Internal carotid/tandem occlusion; M1, proximal MCA M1 part; M2, proximal MCA M2 part.