Author + information
- Received January 20, 2006
- Revision received June 29, 2006
- Accepted July 3, 2006
- Published online October 17, 2006.
- Markus G. Engelmann, MD⁎,
- Hans D. Theiss, MD⁎,
- Christine Hennig-Theiss⁎,
- Armin Huber, MD†,
- Bernd J. Wintersperger, MD†,
- Anja-Eva Werle-Ruedinger†,
- Stefan O. Schoenberg, MD†,
- Gerhard Steinbeck, MD⁎ and
- Wolfgang-M. Franz, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Prof. Dr. med. Wolfgang-M. Franz, Ludwig Maximilians University, Medical Clinic I—Department of Cardiology Klinikum Grosshadern, Marchioninistr. 15, D-81377 Munich, Germany.
Objectives The purpose of this investigator-driven, prospective, randomized, double-blinded, placebo-controlled phase II study was to compare the effects of granulocyte colony-stimulating factor (G-CSF) on the improvement of myocardial function in patients undergoing delayed percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).
Background Experimental and early clinical studies suggest that transplantation of stem cells improves cardiac regeneration and neovascularization after acute myocardial infarction. Most investigators have utilized either a direct injection or intracoronary infusion of bone marrow–derived cells, but early cytokine-mediated mobilization of stem cells has been reported to show similar improvement in cardiac function.
Methods Forty-four patients with late revascularized subacute STEMI were treated either with G-CSF or placebo over 5 days after successful PCI. Primary end points were change of global and regional myocardial function from baseline (1 week after PCI) to 3 months after PCI assessed by magnetic resonance imaging (MRI). Secondary end points consisted of characterization of mobilized stem cell populations, assessment of safety parameters up to 12 months including 6-month angiography, as well as myocardial perfusion assessed by MRI.
Results Global myocardial function from baseline (1 week after PCI) to 3 months improved in both groups, but G-CSF was not superior to placebo (Δejection fraction6.2 ± 9.0 vs. 5.3 ± 9.8%, p = 0.77). A slight but non-significant improvement of regional function occurred in both groups. Granulocyte colony-stimulating factor resulted in mobilization of endothelial progenitor cell populations and was well tolerated with a similar rate of target lesion revascularization from in-stent restenosis. In both groups major adverse cardiovascular events occurred in a comparable frequency. Granulocyte colony-stimulating factor resulted in significant improvement of myocardial perfusion 1 week and 1 month after PCI.
Conclusions Granulocyte colony-stimulating factor treatment after PCI in subacute STEMI is feasible and relatively safe. However, patients do not benefit from G-CSF when PCI is performed late. Granulocyte colony-stimulating factor results in improved myocardial perfusion of the infarcted area, which may reflect enhanced neovascularization.
Late coronary reperfusion is frequently associated with left ventricular remodeling leading to sudden cardiac death or progressive heart failure. The outcome of patients suffering from subacute myocardial infarction (MI) is considered to be serious; patients are threatened by progressive myocardial dysfunction and increased mortality resulting from the long time interval between onset of infarction to revascularization (1). Animal experiments have shown that application of granulocyte colony-stimulating factor (G-CSF) after MI can improve mortality and ameliorate myocardial damage (2). Early non-placebo controlled human trials report safety of G-CSF administration after immediate percutaneous coronary intervention (PCI) and improvement of global left ventricular function (3,4). However, the use of G-CSF was made uncertain by a report of increased rate of in-stent restenosis (ISR) when G-CSF was administered before PCI (5).
The aim of this investigator-driven, prospective, randomized, double-blinded clinical study was to investigate safety and efficacy of G-CSF in patients undergoing delayed revascularization after subacute ST-segment elevation myocardial infarction (STEMI).
Materials and methods
Starting in December 2002, we prospectively enrolled patients suffering from subacute STEMI with late revascularization achieved by PCI. Inclusion criteria were subacute STEMI, onset of pain more than 6 h and up to 7 days, akinesia of at least 1 myocardial segment demonstrated by echocardiography at admission, suitable for PCI of the infarct-related artery, and no contraindications against electrocardiogram (ECG)-triggered magnetic resonance imaging (MRI) (Fig. 1).Patients who were clinically unstable, had other severe underlying illnesses, or contraindications against G-CSF were excluded. Patients having aspirin intolerance or currently receiving steroids, immunosuppressants, or cytostatics were also excluded. None of the patients had a history of MI.
After acute PCI of the infarct-related artery using bare metal stents, patients were treated with clopidogrel for at least 4 weeks. Patients were randomized to receive either G-CSF (Filgrastim, Amgen GmbH, Munich, Germany) at a dose of 10 μg/kg body weight/day subcutaneously or placebo (saline). Randomization and preparation of the study medication using neutral syringes were independently performed by the department of pharmacy of our institution. Follow-up visits were performed at 1 and 3 months and included clinical status, laboratory examinations, ECG, echocardiography, safety, adverse events, and medications. All patients received aspirin, clopidogrel, angiotensin-converting enzyme inhibitors, beta-blockers, and statins at discharge. The use of clopidogrel was mandatory for 4 weeks after PCI, and a recommendation to the general practitioner/cardiologist was given by our institution regarding continuation of clopidogrel for 3 to 6 months. After completion of the 3-month follow-up visit, patients entered an observational study in order to assess long-term safety and clinical outcome of treatment up to 1 year. To assess occurrence of ISR, coronary angiography was performed 6 months after enrollment (Fig. 1).
The study was conducted according to the national and international regulations and was approved by the university’s ethics committee. All patients gave their written informed consent.
Primary end points
The primary end points were changes of global and regional cardiac function using MRI from baseline (1 week after PCI) to 3 months of follow-up. Global function was determined by left ventricular ejection fraction (EF). Regional myocardial function was assessed as segmental systolic wall thickening of the infarct area.
Secondary end points
Secondary end points comprised changes of end-diastolic and end-systolic myocardial thickness, end-diastolic volume, end-systolic volume, and infarct volume using MRI from baseline (1 week after PCI) to 3 months of follow-up. Furthermore, change of myocardial perfusion parameters were assessed from baseline to 3 months. Occurrence of major adverse cardiac events (MACE), such as death, repeat MI or acute coronary syndromes, coronary artery bypass grafting, and reintervention, as well as spontaneously reported adverse events were followed up to 1 year after PCI. Changes of blood count and liver enzymes, number and characterization of mobilized stem cells (CD34+/c-kit+, CD34+/CD31+, CD34+/CD133+), and changes of inflammatory parameters were analyzed.
The sample size was determined to assess efficacy of G-CSF with regard to improvement of segmental systolic wall thickening and left ventricular EF. Detection of a difference of 1 mm in systolic wall thickening, and 8% in left ventricular EF, respectively, with an 80% power and an α error of 5%, would require 36 patients (18 patients for each treatment group). We adjusted the sample size for an estimated 10% loss of follow-up, which resulted in 20 patients in each group and a total sample size of 40 patients.
Complete blood count was routinely assessed using automated laboratory cell counter. C-reactive protein analysis was performed using turbidometry. Cytokine level of interleukin-6 was assessed using enzyme-linked immunoadsorbent assay. Liver enzymes measurement was performed in a standard automated analyzer.
Cytometric analysis was performed using a flow cytometer (FACScan, Becton Dickinson, Heidelberg, Germany). Each analysis included 100,000 events. For immunophenotyping, we used the monoclonal antibodies against CD31, CD34, CD45, CD117 (c-kit), CD133, CXCR4 (Clone 12G5, R&D Systems, Minneapolis, Minnesota), conjugated with fluorescein isothiocyanate, phycoerythrin, or phycoerythrin cyanine-5 (BD PharMingen/Coulter Immunotech, Hamburg, Germany).
The MRI examinations were carried out on a 1.5-T whole-body scanner (Magnetom Sonata, Siemens Medical Solutions, Erlangen, Germany) at 3 time points; the first examination was performed 1 week after successful PCI (baseline, 1 week after PCI) to avoid overestimation of myocardial impairment resulting from stunning (6). Follow-up MRI was performed at 1 and 3 months. Cardiac functional imaging was based on a segmented CINE TrueFISP pulse sequence using a shared echo technique (temporal resolution: 42 ms, voxel size: in-plane resolution 1.3 × 1.5 mm2, slice thickness: 8 mm). Functional assessment was performed with a stack of slices with 1-cm distance in a double oblique short-axis orientation (7). Regional systolic myocardial thickening was assessed on a segmental base (16-segement model) as absolute and relative values determined in areas of infarction, border zone, and remote areas not affected by infarction. Myocardial segments that were related to the infarct artery and presented with loss of function as well as demonstrated late enhancement were judged to be infarct segments. Border zone segments were defined as the 2 segments adjacent to the infarct region located in the same slice; diastolic and end-systolic thickness were added and divided by 2. Remote segments were those related to a non-infarct artery, had preserved function, and did not show late enhancement. The myocardial viability was assessed using inversion recovery T1w contrast-enhanced MRI using the late enhancement technique using gadobenate dimeglumine (Multihance, Altana, Konstanz, Germany, 0.1 mmol/kg bodyweight), as previously described (8).
Myocardial perfusion was assessed using a T1-weighted saturation recovery gradient echo sequence with prospective ECG triggering during the first path of contrast agent. Three slices with a thickness of 10 mm were acquired in a basal, mid-papillary, and apical position in a short-axis view every heart beat while breath holding (field-of-view 340 × 265 mm2, in-plane spatial resolution 2.7 × 2.1 mm). Hyperemia was induced with a continuous intravenous infusion of 140 μg/kg · min−1adenosine (Adenoscan, Sanofi, Munich, Germany, bolus 0.05 mmol/kg gadobenate dimeglumine, flow rate 5 ml/s). For perfusion analysis, the left ventricular myocardium was divided into 6 equiangular segments per slice, and signal intensity time curves were obtained. The upslope value of the line from the foot point to the signal maximum was used for further calculations. The myocardial perfusion reserve index was calculated by division of the corrected upslope of the stress examination by the corresponding segment’s corrected upslope value of the rest examination. Microvascular obstruction was identified as described previously (9). All MR analyses were performed in consensus by 3 independent experienced radiologists (B.J.W., A.H., A.W.) (8) who were unaware of study treatment, clinical, or laboratory data of study subjects.
Results are expressed in mean values ± SD, or median (range) as indicated. Parametrical tests included paired ttesting; categoric variables were assessed using chi-square or Fisher exact test where appropriate. For perfusion analysis, non-parametrical tests (Mann-Whitney Utest, Wilcoxon test) were used. A level of p < 0.05 was taken to indicate statistical significance (SPSS release 13.0, SPSS Inc., Chicago, Illinois).
The baseline characteristics were comparable in both groups (Table 1).All patients suffered from a partial or complete proximal occlusion (Thrombolysis In Myocardial Infarction [TIMI] flow grade 0/1) of at least 1 coronary artery resulting in extensive MIs. Percutaneous coronary intervention was successfully achieved in all patients resulting in TIMI flow grade 2/3. The time from PCI to onset of stem cell mobilization or placebo treatment was comparable. There was no significant difference between the groups regarding cardiovascular risk factors, thrombolysis before PCI, or use of glycoprotein IIb/IIIa antagonists. We used stent sizes from 2.5 mm to 3.5 mm. Mean stent diameters, or number of implanted stents, were comparable (data not shown).
Stem cell mobilization and laboratory parameters
Granulocyte colony-stimulating factor treatment resulted in a significant mobilization of different stem cell populations (Table 2,Fig. 2).Granulocyte colony-stimulating factor resulted in a transiently 4-fold increase of leukocytes when compared with placebo. The number of endothelial precursors increased 23- to 29-fold after G-CSF but not after placebo treatment. Both groups presented moderately elevated inflammatory parameters before treatment, which decreased during treatment (Table 2).
Safety of G-CSF administration
Granulocyte colony-stimulating factor was well tolerated in most patients. During the application of either G-CSF or placebo, no MACE were observed. In 2 patients, G-CSF was discontinued at day 3 because of occurrence of bone pain and pericardial effusion, respectively. The patient presenting moderate to severe bone pain during application of G-CSF suffered from a common cold. Pericardial effusion after MI was also documented in 1 case treated with placebo.
During the observational period, several MACE were documented in both treatment groups. One patient of the G-CSF group presented with a recurrent MI resulting from in-stent thrombosis 14 days after initial stent procedure, although the patient actually had taken aspirin and clopidogrel. Initially, this patient had received 3 stents with a cumulative length of approximately 45 mm. The occlusion could be successfully re-opened. One patient of the G-CSF treatment group died 3 weeks after the 6-month angiography; autopsy examination was refused by the relatives. Two patients of the placebo group, but none of the G-CSF group, received coronary bypass grafts. Four of 19 patients (21%) from the G-CSF group had an ISR of the infarct-related artery and required target lesion revascularization (TLR). Six of 21 patients (29%, p = 0.721 when compared with G-CSF group) from the placebo group presented with ISR, and subsequent TLR was performed (Table 3).Four patients from the G-CSF group refused to undergo follow-up angiography. None of them suffered from recurrent angina in the long term. When compared with placebo, neither cumulative incidences of MACE nor occurrence of restenosis differed significantly from the G-CSF group.
One patient of the G-CSF group presented stool abnormalities and malaise at 3 months of follow-up. We found a colon carcinoma that was treated using chemotherapy. The comparison of the observed serious adverse events demonstrated no significant difference of clinical events in both treatment groups (Table 3).
Myocardial function and perfusion assessed by MRI
Baseline, 1-month, and 3-month follow-up MRI were performed 7.9 ± 2.7 days, 41.0 ± 17.2 days, and 108.6 ± 23.4 days after PCI, respectively. Magnetic resonance imaging of 37 patients who completed 3-month follow-up (G-CSF group: n = 19, placebo: n = 18) demonstrated that left ventricular EF was comparable at baseline (1 week after PCI) in both groups. Ejection fraction improved by 6.2 ± 9.0% from baseline to 3 months of follow-up in G-CSF-treated patients and by 5.3 ± 9.8% after placebo treatment (p = 0.77) (Fig. 3,Table 4).Other global and regional myocardial function parameters are shown in Table 4. Infarct volumes were comparable and decreased significantly from baseline to 3 months of follow-up in the G-CSF treatment group. The infarct volume in the placebo group was reduced by trend. Microvascular obstruction was observed in 33% (G-CSF) and 29% (placebo) of cases (p = 1.0).
Granulocyte colony-stimulating factor resulted in a significantly increased resting perfusion in the area of infarction at baseline, and at 1 month of follow-up (Table 5).Resting perfusion at 3 months was slightly increased in G-CSF-treated patients. Adenosine-induced hyperemia resulted in a significant increase of perfusion in both G-CSF- and placebo-treated subjects in infarct as well as in remote areas. The myocardial perfusion reserve index was slightly increased in infarct and remote areas in placebo-treated patients compared with the G-CSF group.
The present findings demonstrate, for the first time, safety and feasibility of G-CSF treatment in patients suffering from late revascularized STEMI in a prospective, randomized, placebo-controlled analysis. Granulocyte colony-stimulating factor was not superior to placebo regarding improvement of global as well as regional myocardial function. As a secondary finding, the trial demonstrates significant increase of myocardial perfusion in the short term. Several stem-cell populations, which are considered to improve myocardial regeneration or neovascularization, are significantly mobilized by G-CSF. This cytokine was generally well tolerated, with no significantly higher rate of ISR or MACE when compared with placebo.
The novel therapeutic concept of stem-cell mobilization using G-CSF in MI was made uncertain by Kang et al. (5), who described ISR to be a major adverse event. In contrast with this report, the present study and 4 recent publications of clinical trials report rare occurrences of ISR or TLR (3,4,10,11). In addition, intravascular ultrasound in humans demonstrated no increased neointima formation in G-CSF-treated subjects (12). The lower rate of ISR in our study patients may be influenced by the time point of G-CSF administration after establishment of complete revascularization. Complete stem-cell mobilization in the MAGIC cell trial (effects of intracoronary infusion of peripheral blood stem-cells mobilized with G-CSF on left ventricular systolic function and restenosis after coronary stenting in MI) was achieved 4 days before elective PCI of the infarct-related artery (5) at the time of highest leukocyte count, which may have resulted in proangiogenic and proinflammatory processes within the culprit lesion. Hill et al. (13) recently reported another clinical study of 16 patients suffering from reproducible myocardial ischemia in whom coronary revascularization had not been performed before G-CSF administration. In this trial, 2 cases of MI were observed, and 1 patient died 17 days after G-CSF treatment (13). In contrast with our trial and the more recent studies (12,14), Hill et al. (13) did not administer clopidogrel or glycoprotein IIb/IIIa antagonists during G-CSF treatment.
However, we documented several adverse events in G-CSF-treated subjects. One patient, who suffered from MI owing to an in-stent thrombosis, had received 3 stents with a total length of 45 mm into the left anterior descending coronary artery followed by clopidogrel and tirofiban during the initial procedure. In-stent restenosis and thrombosis are reported to be associated with an increased lesion and stent length (15). One patient of the G-CSF group died 3 weeks after the 6-month follow-up angiography, which had demonstrated a good stent result and a normal myocardial function. Death may have resulted from sudden cardiac death, although ventricular arrhythmias have never been documented in his medical history. One case of colon carcinoma was observed in a patient from the G-CSF group after 3 months. The occurrence of a formerly undiagnosed intestinal tumor may be coincidental, because human bone marrow donors, who receive G-CSF, do not show significant increase of malignancies (16). Granulocyte colony-stimulating factor was shown to have no effect on cancer cell proliferation in mice but promoted tumor growth via enhanced angiogenesis (17).
In the present study, left ventricular function improved significantly in both treatment groups, but G-CSF was not superior to placebo. Most animal studies reported improved hemodynamic and myocardial function when G-CSF was administered before or after establishment of infarction (2,18). One mechanism of repair, by which G-CSF may improve cardiac function after MI, is considered to be the mobilization of bone marrow–derived stem cells homing into the damaged tissue area, where they induce neovascularization (18,19). Homing of the stem cells can be improved by the chemokine stromal cell–derived factor 1 (SDF-1), which is intrinsically produced by the myocardium after MI. As recently shown, the intramyocardial delivery of SDF-1 combined with G-CSF increases homing of c-kit+stem cells (20). On the other hand, direct antiapoptotic effects of G-CSF via activation of the Jak/Stat pathway may contribute to an improved survival of cardiomyocytes preventing left ventricular remodeling after MI (21). Recently, the G-CSF receptor was shown to be up-regulated shortly after MI, indicating a sensitization of the heart to direct influences of this specific cytokine (22).
The application of G-CSF in humans after MI results in a more heterogeneous pattern of effects. The FIRSTLINE-AMI (Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Granulocyte Colony-Stimulating Factor) trial demonstrated in a randomized and controlled, but not blinded, study a beneficial effect of G-CSF on MI (4,14). Treatment of 25 patients with G-CSF first given 85 ± 30 min after immediately performed PCI resulted in a significant improvement of EF of 8% at 12 months, while EF of non-placebo controlled subjects decreased by 5%. Another study observed a tendency of improvement of EF and left ventricular end-diastolic volume in G-CSF-treated subjects (11). In this study, patients with late presentation were not submitted to primary PCI. Granulocyte colony-stimulating factor/placebo was initiated at a lower dose and more rapid than in the present study. Recently, in a prospective, non-randomized, open-label study (3), 14 patients were treated with G-CSF 48 h after PCI for 7 ± 1 days. The EF increased by 8% in the G-CSF group, compared with 3% in the control group. In contrast with the present investigation, these studies may be biased either by the absence of double-blind placebo treatment or the selection of control subjects from patients, who refused G-CSF treatment. More recently, a double-blind, randomized, placebo-controlled trial investigated the use of G-CSF versus placebo after immediately performed PCI in patients suffering from acute MI (n = 87) (10). The time point of G-CSF initiation in this trial was comparable to our study, but PCI was performed earlier. The systolic wall thickening improved by 17% in the infarct area of both G-CSF- and placebo-treated patients. Both groups demonstrated improvement of EF by 8%, but G-CSF was not superior to placebo.
In contrast to the variety of recently published clinical trials, the present study focused on the effects of G-CSF in patients suffering from subacute MI who were admitted late for PCI. The outcome of patients suffering from subacute STEMI is considered to be serious; patients are threatened by progressive myocardial dysfunction resulting from the long time interval between onset of infarction to revascularization (1). The initial EFs were markedly reduced in both study groups reflecting an extended myocardial damage in those patients. Most other trials included patients presenting less severe myocardial dysfunction (4,23). Microvascular obstruction, which may have contributed to the observed myocardial dysfunction, occurred in both treatment groups within a minority of patients in equal measure.
The time point of G-CSF initiation after successful PCI may be an important factor, because G-CSF treatment was started very rapidly in the FIRSTLINE-AMI trial. In our study, G-CSF and placebo treatment were initiated at an average of 31 ± 24 h after successful revascularization. In a larger trial of 114 subjects (G-CSF n = 56) (23), patients received G-CSF 5 days after immediately performed PCI. The very late treatment resulted in a small decrease of infarct size in both groups (G-CSF −6.2 ± 9.1% vs. −4.9 ± 8.9% in placebo control subjects, p = 0.56) and no substantial increase of EF in both groups. This result supports the hypothesis that late administration after PCI may diminish the potential benefit of G-CSF as demonstrated in animal studies (21).
In the current trial, we demonstrate an increased myocardial perfusion at rest in G-CSF-treated patients within 1 month. The reason for elevated perfusion assessed by baseline MR may result from the late time point of examination. Baseline MR was performed an average of 8 days after PCI. At that point, the 5-day course of G-CSF was already administered, and early effects of G-CSF on myocardial perfusion may have occurred. The beneficial effect of G-CSF on myocardial perfusion has not been established in humans. However, increased cardiac blood flow and metabolism after G-CSF treatment was shown in a baboon model of infarction (24). Mechanisms that promote enhanced myocardial perfusion include significant release of endothelial progenitor cells into circulation, as observed in our study. In addition, paracrine angiogenic factors, such as vascular endothelial growth factor, are released by neutrophils after administration of G-CSF and increase neovascularization in ischemic tissue (19). Enhanced neovascularization may serve as one important mechanism facilitating reduction of infarct size after MI. The reduction of infarct size was significant in the G-CSF group, but less so in the control group (p = 0.15 vs. p = 0.08). Interestingly, the absolute infarct size was smaller in G-CSF-treated patients. We recently demonstrated in a murine model of infarction that G-CSF results in a reduced infarct size and an enhanced arteriogenesis in the peri-infarct area mediated by an increased expression of the intracellular adhesion molecule-1 on endothelial cells (25).
In summary, G-CSF treatment appears to be safe in the majority of subjects suffering from MI, when successful PCI was performed. The occurrence of 1 death and 1 MI in the G-CSF group necessitates a careful patient monitoring during further studies. Granulocyte colony-stimulating factor was not superior to placebo regarding improvement of myocardial function in patients with subacute infarctions in whom delayed PCI was performed. Granulocyte colony-stimulating factor resulted in a significant increase of myocardial perfusion within 1 month after PCI. Due to its phase II character, the present study is limited by the relatively low number of patients. We conclude that further research should focus on immediate administration of G-CSF in early revascularized MI and on larger multicenter trials investigating clinical outcome.
The authors thank Dr. H. Diem and Dr. M. Adam, Hematology Laboratory, Institute of Clinical Chemistry, Klinikum Grosshadern, Munich, for their excellent support.
This study was supported by research grants from Amgen GmbH, Munich, Germany; E. Lilly Deutschland GmbH, Bad Homburg, Germany; and Altana, Konstanz, Germany. The Ludwig Maximilians University is the holder of a pending patent (“Uses and methods for treating ischemia,” EP 03 02 4526.0 and US 60/514,474) claiming a second medical use of G-CSF to treat ischemic organ failure. Elements of this study are part of the theses of C.H.T. and A.E.W.R.
- Abbreviations and Acronyms
- ejection fraction
- Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Granulocyte Colony-Stimulating Factor Trial
- granulocyte colony-stimulating factor
- in-stent restenosis
- major adverse cardiovascular events
- myocardial infarction
- magnetic resonance imaging
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- target lesion revascularization
- Received January 20, 2006.
- Revision received June 29, 2006.
- Accepted July 3, 2006.
- American College of Cardiology Foundation
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