Table 3.
Clinical trials of G-CSF therapy for cardiac repair
| Study/name of the trial |
Trial design | Number of patients |
Duration of therapy | Dose | End-point evaluation method |
Follow-up period |
Outcomes | Side effects in G-CSF-treated patients |
|---|---|---|---|---|---|---|---|---|
| Patients with acute myocardial infarction | ||||||||
| Kang et al. [76] (MAGIC cell trial) | Randomized | Cell infusion = 10 G-CSF = 10, control = 7 | >48 h after AMI for 4 days | 10 μg/kg per day, s.c. | SPECT | 6 months | ↑ Exercise capacity ↑ Myocardial perfusion ↑ LVEF angiogenesis + |
2/3 surviving patients developed in-stent restenosis |
| Suarez de Lezo et al. [142] | Observational | G-CSF = 13 | 5 days after MI for 10 days | 10 μg/kg per day, s.c. | Angiography | 3 months | ↑ LVEF; BMC mobilization + | Spontaneous spleen rupture in 1 patient |
| Ince et al. [70, 71] (FIRSTLINE- AMI) | Randomized | G-CSF = 25, control = 25 | For 6 days | 10 μg/kg per day, s.c. | Angiography, echocardiography | 4 and 12 months | ↑ Regional wall motion in infarct zone ↑ Metabolic activity in infarct zone at 4 months ↑ Resting LVEF Improved remodeling |
Comparable rate of restenosis in G-CSF-treated and control groups |
| Valgimigli et al. [160] | Randomized, placebo- controlled | G-CSF = 10, control = 10 | For 4 days | 5 μg/kg per day, s.c. | SPECT | 6 months | ↑ LVEF ↓ LVEDV EPC mobilization + |
No clinical or angiographic adverse effect |
| Kuethe et al. [86] | Nonrandomized, open-label | G-CSF = 14, control = 9 | 48 h after stent implantation, for mean duration of 7±1 days | 10 μg/kg per day, s.c. | SPECT | 3 months | ↑ Regional wall motion and perfusion ↑ LVEF |
In-stent restenosis in 1 patient |
| Leone et al. [89] (RIGENERA) | Randomized | G-CSF = 14, control = 27 | Starting ≥5 days after AMI for 5 days | 10 μg/kg per day, s.c. | Echocardiography | 4–6 months | ↑ LVEF ↓ LVEDV ↓ LVESV |
No adverse effect |
| Suzuki et al. [145] | Randomized | G-CSF = 12 (AMI), control = 12 (AMI) | For 10 days | 2 μg/kg per day, s.c. titrated to WBC count of 30,000/μl | SPECT, angiography | 1 months | ↑ LVEF ↑ Regional wall motion; CD34 + BMC mobilization + |
No clinical and angiographic adverse effect |
| Ellis et al. [35] | Pilot, dose-escalation randomized | G-CSF = 12, control = 6 | For 5 days | 5-10 μg/kg per day, s.c. | Echocardiography | 1 months | ↔ LV function BMC mobilization + | No serious adverse effect |
| Ripa et al. [133] (STEMMI) | Randomized, double-blind, placebo- controlled | G-CSF = 39, control = 39 | <12 h after MI for 6 days | 10 μg/kg per day, s.c. | MRI | 6 months | ↔ LVEF BMC mobilization + | 8/39 patients developed musculoskeletal pain |
| Zohlnhofer et al. [174] (REVIVAL-2) | Randomized, double-blind, placebo- controlled | G-CSF = 56, control = 58 | For 5 days | 10 μg/kg per day, s.c. | MRI, SPECT, angiography | 4–6 months | ↔ LVEF ↔ Infarct size BMC mobilization + |
7/56 patients developed musculoskeletal pain |
| Engelmann et al. [36, 37] (G-CSF- STEMI) | Randomized, double-blind, placebo-controlled | G-CSF = 23, control = 21 | For 5 days after PCI | 10 μg/kg per day, s.c. | MRI, angiography | 12 months | ↔ LVEF ↔ LV size BMC mobilization + ↑ Myocardial perfusion (early) |
Bone/muscle pain in 2 patients |
| Takano et al. [148] | Randomized, placebo-controlled | G-CSF = 18, control = 22 | Within 24 h after PCI for 5 days | 2.5 μg/kg per day, s.c. | SPECT, angiography | 6 months | ↑ LVEF ↔ LVEDV BMC mobilization + |
In-stent restenosis in 1 patient |
| Achilli et al. (STEM-AMI) [4] | Randomized, placebo-controlled | G-CSF = 24, control = 25 | For 5 days, starting within 12 h after PCI | 5 μg/kg per day b.i.d., s.c. | MRI, echocardiography, SPECT, angiography | 6 months | ↓ Infarct size Improved remodeling ↔ LVEF |
Adverse effects were similar in G-CSF-treated and control groups |
| Patients with chronic myocardial ischemia | ||||||||
| Hill et al. [59] | Non-randomized | G-CSF = 16, control = 15 | For 5 days | 10 μg/kg per day, s.c. | MRI | 3 months | ↔ LVEF ↔ Regional wall motion; BMC mobilization + |
One patient had MI 8 h after the fifth G-CSF dose; one had MI and died 17 days after G-CSF therapy |
| Wang et al. [163] | Non-randomized | G-CSF = 13, control = 16 | For 6 days | 5 μg/kg per day, s.c. | SPECT, MRI and echocardiography | 2 months | Improved clinical symptoms ↓ LVEF ↔ Myocardial perfusion |
No major side effect |
| Ripa et al. [134] | Non-randomized | G-CSF+VEGF = 16 VEGF = 16 Placebo = 16 |
1 week after ischemia for 6 days | 10 μg/kg per day, s.c. | SPECT, MRI and echocardiography | 3 months | ↔ LVEF ↔ Myocardial perfusion ↔ LVEDV |
No major side effect |
| Huttmann et al. [67] | Non-randomized | G-CSF = 16, control = 8 | Four G-CSF treatment periods of 10 days off and 10 days on | 480 μg b.i.d, s.c. (titrated) for 4 × 10 days courses | Echocardiography | 6 months | ↓ NYHA class ↑ 6-min walk distance; BMC mobilization + |
Moderate to severe bone pain |
AMI acute myocardial infarction, BMC bone marrow cell, EPC endothelial progenitor cell, G-CSF granulocyte colony-stimulating factor, LV left ventricular, LVEDD LV end-diastolic diameter, LVEDV LV end-diastolic volume, LVESV LV end-systolic volume, LVEF LV ejection fraction, LVFS LV fractional shortening, MI myocardial infarction, MRI magnetic resonance imaging, NYHA New York Heart Association, RV right ventricular, S.C. subcutaneous, SPECT single photon emission computed tomography, VEGF vascular endothelial growth factor, WBC white blood cell, ↑ increased, ↓ decreased, ↔ no change