Lack of beneficial effects of granulocyte colony-stimulating factor in ...

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Acta Cardiol 2011; 66(2): 219-224

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doi: 10.2143/AC.66.2.2071254

Lack of beneficial effects of granulocyte colony-stimulating factor in patients with subacute myocardial infarction undergoing late revascularization: a double-blind, randomized, placebo-controlled clinical trial Hossein MEHDIKHANI KARIMABAD1, MD; Mahmood SHABESTARI1, MD; Hossein BAHARVAND2,3,4, PhD; Ahmad VOSOUGH2, PhD; Hamid GOURABI2, PhD; Abdolhossein SHAHVERDI2, PhD; Aliakbar SHAMSIAN5, MD; Saeid ABDOLHOSEINI1, MD; Kasra MOAZZAMI2, MD; Mehdi MORADI MARJANIMEHR5, MD; Farhad EMAMI1, MD; Hamid Reza BIDKHORI5, MD; Ali HAMEDANCHI1, MD; Soheila TALEBI1, MD; Farid FARROKHI1, MD; Farhad JABBARIAZAD1, MD; Mahsa FADAVI1, MD; Uousef GARIVANI1, MD; Mahmood MAHMOODI1, MD; Nasser AGHDAMI2, MD, PhD 1

Razavi Hospital, Mashhad; 2Department of Regenerative Medicine, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran; Department of Stem Cells and Developmental Biology, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran; 4 Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, 5ACECR, Mashhad Branch, Iran. 3

Background Early clinical studies have suggested that administration of granulocyte-colony stimulating factor (G-CSF) may improve the clinical condition of patients suffering from myocardial infarction (MI). This prospective, randomized, double-blind, placebo-controlled single-centre trial aims to assess the safety and clinical efficacy of G-CSF administration in patients with subacute MI and impaired LV function undergoing delayed primary percutaneous coronary intervention (PCI).

Methods A total of 16 patients (13 men, mean age 51 years) with subacute ST-segment elevation MI and a left ventricular (LV) ejection fraction (EF) of less than 45% at baseline who underwent late revascularization, were included in the study. Patients were randomized in a double-blind fashion to receive either G-CSF (at a dose of 10 μg/kg body weight) or placebo for five consecutive days. End points consisted of assessment of safety parameters as well as changes of global and regional myocardial function from baseline until six months following PCI. Results G-CSF administration resulted in a significant mobilization of different cell populations (four-fold increase in WBC count and a six-fold increase in CD34+ cells). G-CSF treatment was well tolerated in most patients and no major adverse cardiac events or severe G-CSF-related side effects were identified during hospitalization and at follow-up. No significant differences were observed between the G-CSF and placebo groups regarding global and regional myocardial function parameters.

Conclusion G-CSF administration is safe, but not effective, in improving impaired LV functional parameters in patients with subacute MI who had an impaired baseline EF of less than 45%.

Keywords Granulocyte colony – stimulating factor – myocardial infarction – percutaneous coronary intervention.

INTRODUCTION Address for correspondence: Nasser Aghdami, MD, PhD, Department of Regenerative Medicine, Royan Institute for Stem Cell Biology and Technology, ACECR, P.O. Box 19395-4644, Tehran, Iran. E-mail: [email protected] Received 7 June 2010; second revision accepted for publication 21 September 2010.

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Congestive heart failure following myocardial infarction (MI) continues to be a major worldwide medical problem1. While the effectiveness of current pharmacological and interventional strategies in terms of improved survival has been established in these patients, such modalities have failed to regenerate dead myocardium resulting from ischaemic damage2. As a consequence,

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progressive myocardial dysfunction is unavoidable and these patients are prone to manifest adverse left ventricular remodelling, resulting in heart failure and eventually death. The increased understanding of the regenerative capacity of pluripotent stem cells has made these cells highly attractive for repopulating damaged myocardium in order to improve cardiac muscle function3,4. It has been shown that these cell populations may enhance myocardial restoration whether by direct administration into the myocardium or through mobilization with cytokines using granulocyte colony stimulating factor (G-CSF)5,6. Mobilization of pluripotent cells with G-CSF is an interesting concept7 since it obviates the need for bone marrow aspiration and repeated cardiac catheterization and has therefore been actively investigated by several groups. While most studies have addressed the safety and efficacy of G-CSF administration in patients with acute MI, studies investigating patients suffering from subacute myocardial infarction undergoing delayed revascularization are few. Therefore in the present study, we undertook a singlecentre, randomized, double-blind trial in patients with subacute MI and impaired LV function who underwent delayed primary percutaneous coronary intervention (PCI).

METHODS Patients

In the present study, from 2006 to 2008, we prospectively enrolled 16 patients with subacute ST-segment elevation MI with late revascularization achieved by PCI. Inclusion criteria were the presence of a first large anterior MI, onset of pain of more than six hours and up to seven days, total occlusion of LAD alone, and LV ejection fraction less than 45% despite successful percutaneous revascularization of the infarct-related artery. Patients who had a previous MI, angiographically significant lesions in the right coronary artery and/or left circumflex coronary artery, who were clinically unstable (defined as systolic blood pressure < 80 mm Hg requiring intravenous pressors or intra-aortic balloon counterpulsation), older than 80 years, as well as those who had a history of leucopenia, thrombocytopenia, hepatic or renal dysfunction, malignancy, sepsis, or contraindications against G-CSF, were excluded. The study was conducted according to national and international regulations and was approved by the university’s ethics committee. All patients gave their written informed consent after an explanation of the procedure and potential risks.

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Treatment protocol

The study was a prospective, randomized, doubleblind, placebo-controlled single-centre trial. Following successful PCI, patients were randomly assigned by a blinded independent coordinator with the use of a computer based 1:1 randomization scheme to either the G-CSF or control group. In the G-CSF group, patients were subcutaneously injected with G-CSF (Kirin Brewery Co., Ltd., Japan) at a dose of 10 μg/kg body weight over 24 hours after PCI for five consecutive days. In the control group, patients were subcutaneously injected with saline. Double blinding was achieved by the use of identical-appearing injection syringes containing either G-CSF or placebo as provided by the hospital pharmacy with the contents masked to the patient, treating physicians, and nurses. In addition, all patients received standard care which included aspirin, clopidogrel, angiotensin-converting enzyme inhibitors, beta blockers, and statins in appropriate doses. The use of clopidogrel was mandatory for four weeks following PCI. Echocardiography

In all patients, two-dimensional echocardiography (2D echo) (Vivide 7 dimension, VingMed, GE) was performed at baseline, three and six months after PCI. Global and regional contractility studies were performed using a sonar 5500 ultrasound system (Philips) and analyzed according to the Standards of the American Society of Echocardiography in four standard views (parasternal long-axis, short-axis, apical 4- and 2-chamber views). LV end-diastolic and end-systolic volumes, LV ejection fraction, and wall motion score index (WMSI) were independently evaluated with echocardiography by two experienced blinded observers according to the recommendations of the American Society of Echocardiography. Accordingly, regional wall motion was scored as: 1, normal; 2, hypokinetic; 3, akinetic; 4, dyskinetic and 5, aneurysm for each segment and a WMSI was calculated as the sum of the score of all segments divided by the total number of segments. Myocardial perfusion assessment

In the present study, assessment of myocardial perfusion was performed using ECG-gated dipyridamole stress 99mTc-tetrofosmin SPECT at baseline and six months follow-up for all patients. Following dipyridamole infusion, 99mTc-tetrofosmin was administered and the resulting SPECT image was divided into 20 segments and each segment was graded with 4 scores between 0 and 3 (0 = normal uptake; 1 = mildly reduced uptake; 2 = moderately reduced uptake; 3 = defective) to assess the

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G-CSF therapy for patients with myocardial infarction

severity of myocardial perfusion abnormalities. The defect scores were defined as the summation of the scores for the LAD-related portion of the LV in both the rest and stress images (DSL-rest and DSL-stress). SPECT data analysis was performed in a blinded fashion by two independent observers with no knowledge of the clinical status and medical therapy of patients.

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Table 1 Baseline characteristics of patients Variable Number of patients Age Male sex, % Duration of pain (hours)

G-CSF group

Control group

8

7

P-value NS

48.62 ± 8.71

54.42

NS

7

5

NS

58 ± 38

66 ± 40

NS NS

Cardiovascular risk factors

End points

Hypertension, %

1

0

The primary end point was the change in global cardiac function determined by LVEF from baseline to six months follow-up as measured by echocardiography. Secondary end points comprised changes of LVESV, LVEDV and WMSI assessed from baseline to six months. Safety end points were: (1) death from any cause, reinfarction, and new revascularization; (2) other adverse events; (3) in-stent restenosis; and (4) changes in inflammatory parameters (C-reactive protein and erythrocyte sedimentation rate). Diagnosis of reinfarction was based on the presence of at least two of the following criteria: new ST-segment changes and an increase in creatine kinase and creatine kinase-MB of at least 50% more than the previous level in at least two samples that were three times or more the upper limit of normal. Binary restenosis was defined as a stenosis diameter of more than 50% within the stent or in the 5-mm segments proximal or distal to the stent as assessed by angiographic followup scheduled at six months for all patients.

Dyslipidaemia, %

1

3

NS

Diabetes, %

4

2

NS

Statistical analysis

Continuous variables were expressed as mean values ± SD. Categorical variables were assessed by the use of the chi-square or Fisher exact test where appropriate. Statistical comparisons between treatment groups were made by paired Student’s t test and 2-way analysis of variance (ANOVA) or by their corresponding nonparametric alternatives (Mann-Whitney U test or Wilcoxon test), as appropriate. Statistical significance was assumed at a value of P < 0.05. All analysis was conducted using the SPSS statistical software (version 15; SPSS Inc., Chicago, IL, USA).

RESULTS Patient selection and baseline characteristics

In this study, 311 patients with MI were initially screened. The causes for exclusion were: LVEF > 45% (n = 151), non-ST-segment elevation MI (n = 34), multiple vessel disease (n = 33), history of previous MI (n = 27), systolic blood pressure < 80 mm Hg (n = 23), age > 80 years (n = 17), and patient refusal (n = 10).

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Smoking, %

5

4

NS

Family history of CAD, %

3

3

NS

101.3750 ± 53.377

74.5714 ± 23.789

NS

13.875 ± 2.377

15.1429 ± 3.2877

NS

Creatine kinase max Creatine kinase-MB max Medications at discharge Aspirin, %

8

7

NS

Clopidrogel, %

8

7

NS

Statin, %

2

5

NS

ACE inhibitor

1

1

NS

Beta blocker

4

3

NS

All included patients (n =15) underwent successful percutaneous coronary intervention of the infarctrelated artery, with complete revascularization achieved in all patients. The groups were homogeneous and well balanced with regard to demographics, clinical characteristics and comorbidity profiles (table 1). All patients received optimal medical treatment during the follow-up period (table 1). Cell mobilization

G-CSF treatment resulted in a significant mobilization of different cell populations. G-CSF was associated with an approximate fourfold increase in WBC count and a sixfold increase in CD34+ cells (table 2). However, such increases were not identified in the control group. Left ventricular parameters

At baseline, all parameters of LV function were similar in both the G-CSF-treated and control group. LVEF improved by 6.12 ± 3.72% from baseline to six months follow-up in G-CSF treated patients (P = 0.002), but not in the control group (1.14 ± 5.84%, P = 0.62). There was an increase in LVEF at six months in the G-CSF group when compared with the control group, although it was not significant (P = 0.062). Changes in other myocardial function parameters are shown in table 3. No significant differences were identified between the two groups in

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Table 3 Echocardiographic data

Table 2 Haematologic data Parameter

G-CSF group

Control group

P-value

WBC (103/mm3) Baseline

Control group

P-value

0.31

Baseline (%)

36.5 ± 6.39

37.14 ± 6.36

NS