Granulocyte colony-stimulating factor therapy for cardiac repair after acute myocardial infarction: A systematic review and meta-analysis of randomized controlled trials

Article Outline

• Abstract
• Methods
  • Study selection and data collection
  • Data analysis
    • Meta-analyses
    • Stratified analyses
• Results
  • Study quality
  • Meta-analyses
    • Efficacy
    • Stratified analysis
    • Safety
• Discussion
  • Limitations
• Conclusions
• Appendix A. Supplemental methods
  • Study selection and data collection
  • Data analysis
    • Meta-analyses
    • Stratified analyses
• Appendix B. Supplemental Table
• Appendix C. Supplemental Figures
• References
• Copyright

Background

Small clinical studies of granulocyte colony-stimulating factor (G-CSF) therapy for cardiac repair after acute myocardial infarction (MI) have yielded divergent results. The effect of G-CSF therapy on left ventricular (LV) function and structure in these patients remains unclear.

Methods

We searched MEDLINE, EMBASE, Science Citation Index, CINAHL, and the Cochrane CENTRAL database of controlled clinical trials (July 2007) for randomized controlled trials of G-CSF therapy in patients with acute MI. We conducted a fixed-effects meta-analysis across 8 eligible studies (n = 385 patients).

Results

Compared with controls, G-CSF therapy increased LV ejection fraction (EF) by 1.09%, increased LV scar size by 0.22%, decreased LV end-diastolic volume by 4.26 mL, and decreased LV end-systolic volume by 2.50 mL. None of these effects were statistically significant. The risk of death, recurrent MI, and in-stent restenosis was similar in G-CSF–treated patients and controls. Subgroup analysis revealed a modest but statistically significant increase in EF (4.73%, P < .0001) with G-CSF therapy in studies that enrolled patients with mean EF <50% at baseline. Subgroup analysis also showed a significant increase in EF (4.65%, P < .0001) when G-CSF was administered relatively early (≤37 hours) after the acute event.

Conclusions

Granulocyte colony-stimulating factor therapy in unselected patients with acute MI appears safe but does not provide an overall benefit. Subgroup analyses suggest that G-CSF therapy may be salutary in acute MI patients with LV dysfunction and when started early. Larger randomized studies may be conducted to evaluate the potential benefits of early G-CSF therapy in acute MI patients with LV dysfunction.

Recent evidence from small clinical trials indicates that therapy with bone marrow cells (BMCs) affords modest benefits in patients with acute myocardial infarction (MI).¹ Because of promising results from animal studies,², ³, ⁴, ⁵, ⁶ and because BMC mobilization using granulocyte colony-stimulating factor (G-CSF) obviates bone marrow aspiration and repeated cardiac catheterization, the feasibility, safety, and efficacy of G-CSF therapy for cardiac repair in humans are being actively investigated. However, the small clinical trials completed thus far have yielded disparate results, and the impact of G-CSF therapy in patients with acute MI remains unclear. To our knowledge, there are no comprehensive analyses of these data. Therefore, we performed a meta-analysis of the results of the randomized controlled trials (RCTs) investigating the potential therapeutic benefits of G-CSF therapy for cardiac repair in patients with acute MI.

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Methods 

A detailed description of methods is provided in the Supplemental Methods available online.

Study selection and data collection 

The review question was: to what extent does therapy with G-CSF affect cardiovascular outcomes in patients with acute MI? This protocol-driven meta-analysis was performed according to the Quality of Reporting of Meta-analysis⁷ statement.

The complete search strategy is available upon request from the authors. We searched MEDLINE, the Cochrane databases, EMBASE, CINAHL, the US FDA Web site (http://www.fda.gov) and BIOSIS Previews (all until July 2007) using database-appropriate terms. One reviewer (A.A.L.) judged eligibility of studies. Because of the fundamentally different approach, we excluded studies that injected G-CSF–mobilized BMCs via the intracoronary route. We also identified 2 RCTs⁸, ⁹ that included patients with chronic ischemic cardiomyopathy (ICM). Given the major differences in cardiac milieu between acute MI and chronic ICM, which may profoundly influence homing of stem/progenitor cells, we performed separate meta-analyses of RCTs without (Table I) as well as with (Supplemental Table 1 available online) patients with ICM. Thus, the primary meta-analysis examining the effects of G-CSF therapy on cardiovascular outcomes in patients with acute MI alone was limited to 8 eligible RCTs. Two reviewers (A.A.L. and B.D.) working in duplicate and independently used a standardized form to abstract data from each study. When data were available from more than 1 follow-up time points,¹⁰, ¹¹ the longest follow-up data were used. We used the criteria of Juni et al¹² to ascertain the methodological quality of included RCTs.¹² The authors' statements regarding blinding and other methods in the original manuscripts were accepted verbatim. In addition, we applied the Jadad scale¹³ for quantifying the study quality.

Table I. Characteristics of studies included in the meta-analysis

Data are expressed as mean ± SD. AMI, Acute MI; NR, not reported.

Data analysis 

The main outcomes of our analyses were change from baseline in mean left ventricular ejection fraction (LVEF), infarct scar size, LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and the relative risk (RR) for adverse events, including death, recurrent MI, and in-stent restenosis. We conducted meta-analyses using both “fixed-effects” and “random-effects” models, and the results were similar with respect to the major outcomes. Since we excluded studies that included patients with chronic ICM, we felt that the use of the fixed-effects model was justified.

For data regarding clinical outcome variables, the effect measures estimated were the RR for dichotomous data, which we report with 95% CI. The RR indicates the risk of death, recurrent MI, or in-stent restenosis in an individual receiving G-CSF compared with the respective risk in an individual not receiving G-CSF. We also calculated the absolute risk reduction, that is, risk difference, and the “numbers needed to harm” to assess the clinical significance of the outcome. The RRs from separate studies were combined according to a fixed-effects model (Mantel-Haenszel method¹⁴, ¹⁵).

The Review Manager software (RevMan version 4.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2006, Copenhagen, Denmark) was used for all of the analyses. The proportion of between-study inconsistency due to true differences between studies (rather than differences due to random error or chance) was estimated using the I² statistic.¹⁶ Funnel plots were used to explore any publication bias.

We conducted planned subgroup analyses and examined potential treatment-subgroup interactions. Planned subgroups comprised the mean LVEF at baseline (using LVEF of 50% as cutoff¹⁷, ¹⁸), the average time between the acute event (acute MI or percutaneous coronary intervention [PCI]) and the first dose of G-CSF (using the median initiation time of 37 hours as cutoff), the dose of G-CSF (using the median of 10 μg/kg per day as cutoff), and the peak white blood cell (WBC) and CD34+ cell counts as indicators of BMC mobilization efficacy with G-CSF therapy.

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Results 

Of the 112 articles retrieved during the initial search (Figure 1), 29 were not reports of original investigations (reviews and editorials), 41 were conducted in animals, 4 were cohort studies, 7 injected mobilized BMCs, 4 lacked a control group, 6 used G-CSF for indications other than treatment of AMI, 3 did not report the end points, 2 included ICM patients, and 8 were performed in vitro or without transplantation. Eight RCTs¹⁰, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵ with a total of 385 patients were eligible for review.

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• Figure 1. 

  Selection of trials for inclusion in meta-analysis. mPBCs, Mobilized peripheral blood cells.

Table I summarizes the characteristics of all studies included in our meta-analysis. Notably, the sample size in each study was relatively small (range 18-114 patients, median 40 patients), and the follow-up duration was relatively short (range 1-12 months, median 6 months). Although most studies used 10 μg/kg per day of G-CSF for 5 to 6 days, a few studies used as low as 2.5 μg/kg per day (median 10 μg/kg per day for 5 days). Consequently, the peak WBC count varied from 29.4 × 10³ to 55.0 × 10³ WBCs/μL of blood (median 42.0 × 10³ WBCs/μL). The time of initiation of G-CSF therapy also varied from 1.4 to 120 hours after acute MI (median 37 hours).

Study quality 

Table II describes the methodological quality of the included studies. At least 4 of the included studies failed to blind the participants and caregivers to study allocation. Importantly, in all studies, the outcome ascertainment was performed in a blinded fashion. The interreviewer agreement on these quality domains was greater than 90%.

Table II. Quality assessment scale for RCTs included in the meta-analysis

Source of bias	Ellis et al19	Engelmann et al20	Ince et al10	Leone et al21	Ripa et al22	Takano et al23	Valgimigli et al24	Zohlnhöfer et al25
Selection
Was allocation adequate?	Y	Y	Y	Y	Y	Y	Y	Y
Was an adequate method of randomization described?⁎	Y	N	Y	N	Y	Y	Y	Y
Were groups similar at the start of the study?	Y	Y	Y	Y	Y	Y	Y	Y
Performance
Were the patients/caregivers blinded to the intervention?	Y	Y	N	N	Y	N	N	Y
Detection
Was the outcome ascertained blindly?	Y	Y	Y	Y	Y	Y	Y	Y
Attrition
What percentage was lost to follow-up?	0%	16%	0%	2%	10%	12.5%	0%	3%
Were all patients analyzed in the group to which they were assigned (intention-to-treat analysis)?	Y	Y	Y	Y	Y	Y	Y	Y

Meta-analyses 

Compared with controls, in G-CSF–treated patients, the LVEF increased by 1.09% (95% CI: −0.21 to 2.38, P = .10) (Figure 2), infarct size increased by 0.22% (95% CI: −1.34 to 1.78, P = .78) (Figure 3), LVEDV decreased by 4.26 mL (95% CI: −9.73 to 1.21, P = .13) (Figure 4), and LVESV decreased by 2.50 mL (95% CI: −7.81 to 2.81, P = .36) (Figure 5). Thus, G-CSF therapy failed to significantly improve any of the primary surrogate end points.

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• Figure 2. 

  Mean change in LVEF. Forest plot of unadjusted difference in mean (with 95% CIs): G-CSF therapy resulted in a 1.09% (95% CI: −0.21 to 2.38, P = .10) increase in mean LVEF. The imaging modality is specified within parentheses. FU, Follow-up; WMD, weighted mean difference.

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• Figure 3. 

  Mean change in infarct scar size. Forest plot of unadjusted difference in mean (with 95% CIs): G-CSF therapy resulted in a 0.22% (95% CI: −1.34 to 1.78, P = .78) increase in mean infarct scar size. The imaging modality is specified within parentheses.

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• Figure 4. 

  Mean change in LVEDV. Forest plot of unadjusted difference in mean (with 95% CIs): G-CSF therapy resulted in a 4.26-mL (95% CI: −9.73 to 1.21, P = .13) reduction in mean LVEDV. The imaging modality is specified within parentheses.

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• Figure 5. 

  Mean change in LVESV. Forest plot of unadjusted difference in mean (with 95% CIs): G-CSF therapy resulted in a 2.50-mL (95% CI: −7.81 to 2.81, P = .36) reduction in LVESV. The imaging modality is specified within parentheses.

Because the variability in G-CSF dosage might have influenced the outcomes of our analysis, in a separate meta-analysis we examined the pooled outcomes of studies that used a uniform G-CSF dose of 10 μg/kg per day. However, the outcomes (Supplemental Figures 1-5 available online) were similar to those derived from the analysis that included all G-CSF dosages. Furthermore, when data from all studies (a total of 10 RCTs, including patients with acute MI as well as chronic ICM [451 patients]) were analyzed using a random-effects model, the outcomes (Supplemental Figures 6-10 available online) did not differ from those obtained with an analysis restricted to acute MI patients alone. We drew funnel plots (Supplemental Figure 11 available online) to seek evidence of publication bias; where inconsistency was high, the funnel plots were not interpretable; where inconsistency was low, the funnel plots were inconclusive.

A statistically significant and clinically relevant improvement in LVEF (mean increase of 4.73% [95% CI: 2.67 to 6.79, P < .0001]) was noted in G-CSF–treated patients in studies that included patients with mean LVEF of <50% at baseline (Table III and Figure 6). Significant improvements were observed in other surrogate parameters, including LVEDV (mean decrease by 7.82 mL [95% CI: −14.68 to −0.96, P < .03]) and LVESV (mean decrease by 10.07 [95% CI: −18.88 to −1.26, P < .04]) (Table III). On the other hand, G-CSF therapy failed to halt the deterioration in LVEF as well as other functional parameters when given to patients with normal LVEF (>50%) at baseline (Table III and Figure 6). The treatment-subgroup interaction was also statistically significant (P < .0001) (Table III). In addition, we observed a statistically significant and clinically relevant improvement in LVEF (mean increase of 4.65% [95% CI: 2.51 to 6.80, P < .0001]) in G-CSF–treated patients when G-CSF therapy was started early after acute MI or PCI (≤37 hours) as compared with later initiation (Table III and Figure 7). The treatment-subgroup interaction was also statistically significant (P < .0001) (Table III). However, in 4 studies¹⁰, ²¹, ²³, ²⁴ that included patients with low LVEF and in 3 studies¹⁰, ²³, ²⁴ in which G-CSF therapy was started early after the acute event, the patients and/or the caregivers were apparently not blinded (Table II). Therefore, despite the large observed benefits, we cannot entirely exclude the role of performance bias influencing the results.

Table III. Subgroup analysis examining the impact of baseline LVEF, duration between acute event/PCI and the start of G-CSF therapy, G-CSF dose, and peak white blood and CD34⁺ cell counts on outcome variables

ISR, In-stent restenosis.

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• Figure 6. 

  Mean change in LVEF according to baseline LVEF. Forest plots of unadjusted difference in mean (with 95% CIs) change in LVEF in G-CSF–treated patients compared with controls stratified by the mean LVEF in G-CSF–treated groups at baseline. The interaction between the baseline LVEF and the change in LVEF was also statistically significant (P < .0001).

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• Figure 7. 

  Mean change in LVEF according to onset of G-CSF therapy. Forest plots of unadjusted difference in mean (with 95% CIs) change in LVEF in G-CSF–treated patients compared with controls stratified by the timing of G-CSF therapy. The interaction between the timing of G-CSF therapy and the change in LVEF was also statistically significant (P < .0001).

No significant differences in the incidence of death (RR 1.08, 95% CI: 0.34 to 3.43) or recurrent MI (RR 1.49, 95% CI: 0.36 to 6.12) between G-CSF–treated patients and controls were observed (Figure 8). The crude rate of in-stent restenosis was also not different between the 2 groups (23% in both G-CSF–treated and placebo groups). The pooled analysis of 328 patients demonstrated no difference in the in-stent restenosis risk (RR 0.92, 95% CI: 0.62 to 1.37).

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• Figure 8. 

  Relative risk of adverse clinical outcomes. Forest plot of unadjusted risk ratio (RR, with 95% CIs) for major reported adverse effects, namely, death, recurrent MI, and in-stent restenosis in G-CSF–treated patients compared with controls. None of these end points were significantly different between groups.

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Discussion 

Despite the completion of several relatively small clinical trials, the effect of G-CSF therapy on cardiac repair remains controversial. The overall results of our meta-analysis indicate that administration of G-CSF in unselected patients with acute MI fails to improve any of the clinically relevant primary end-points examined. The observed differences achieved neither statistical nor clinical significance. Although the results of subgroup analysis should be interpreted with caution, they suggest that G-CSF may be potentially beneficial in patients with lower LVEF (<50%) at baseline and if given earlier (≤37 hours) after acute MI/PCI. Importantly, the pooled estimates of potential side effects demonstrate that G-CSF therapy is relatively safe. The results presented herein may be useful for the design of future clinical trials of G-CSF therapy for cardiac repair.

The overall outcome showing no beneficial effect of G-CSF therapy in unselected patients with acute MI is somewhat incongruent with the modest salutary effects of BMC transplantation in humans.¹ In animal models, G-CSF or combinatorial cytokine therapies have been found to result in myocardial homing of mobilized BMCs, repair of the infarcted myocardium, and improvement in LV structural and functional parameters as well as survival.², ³, ⁴, ⁵, ⁶ The homing of c-kit–positive cells in the myocardium was found to be increased when G-CSF was combined with stromal-derived factor 1 (SDF-1),²⁶ emphasizing the well-known role of the SDF-1/CXC-chemokine-receptor4 axis in homing of pluripotent cells. The addition of stem cell factor or Flt-3 ligand to G-CSF therapy also resulted in improved outcomes.⁶ Although G-CSF therapy effectively mobilizes BMCs, it is plausible that the lack of benefit in the clinical trials may be due, at least in part, to myocardial homing of relatively small number of stem/progenitor cells. Indeed, it has been reported that the expression of surface markers responsible for homing on mobilized cells varies depending on the cytokine regimen.⁶ Moreover, different cytokines are known to preferentially mobilize somewhat different subsets of BMCs.²⁷, ²⁸ Future studies investigating the characteristics of G-CSF–mobilized cells will be necessary to glean additional mechanistic insights in this regard.

The variable dose/duration (2.5-10 μg/kg per day) of G-CSF therapy and the consequent variability in CD34+ cell count (15 ± 19 to 72 ± 154 cells/μL) and the peak WBC count (29.4 ± 9 × 10³ to 55 ± 8 × 10³ cells/μL) (Table I) might also have influenced the overall results. In a dose-escalating study, Ellis et al¹⁹ did not observe differences between the effects of low- and high-dose G-CSF therapy. Also, Takano et al²³ did not find a correlation between the peak CD34+ cell count and improvement in LVEF after G-CSF therapy. However, in an observational nonblinded study, a correlation between the spontaneously mobilized CD34+ cell count and the improvement in regional as well as global LV function after acute MI was noted.²⁹ When we separately analyzed data from RCTs that used a uniform G-CSF dose of 10 μg/kg per day (Supplemental Figures 1-5), the outcomes were similar to those from the analysis that included all G-CSF dosages. Consistent with these observations, in subgroup analyses, we did not observe any correlation between the G-CSF dose or the peak WBC/CD34+ cell counts and the change in any of the examined parameters.

The lack of overall efficacy of G-CSF therapy might also have resulted from the differences in methodology and patient characteristics in these trials. In the study by Kang et al,⁸ the authors found an initial correlation between the baseline LVEF and subsequent improvement with G-CSF therapy at 6- and 12-month follow-up. After correction for the variable baseline data, this continued to be the only independent correlation. It is quite conceivable that G-CSF therapy will fail to improve an LVEF that is already normal or near normal (>50%). Indeed, in the subgroup analysis based on baseline LVEF (using a cutoff of 50%), we found that G-CSF therapy improved LVEF in studies of patients with worse LV function (mean LVEF <50%) (Table III and Figure 6). The interaction between baseline LVEF and subsequent improvement with G-CSF therapy was statistically significant. These observations are consonant with the results obtained with BMC transplantation in the REPAIR-AMI study.³⁰ However, because these are post hoc analyses of published data rather than individual patient data, and because the influence of performance bias on the interaction cannot be entirely excluded, larger double-blind RCTs specifically designed to address this question will be necessary.

We also observed a statistically significant and clinically relevant improvement in LVEF in treated patients when G-CSF administration was initiated early (≤37 hours after the acute event) (Table III and Figure 7). The subgroup-treatment interaction was also statistically significant. However, these results could also be biased by the apparent lack of blinding the patients/caregivers in 3 of the included studies. In animal studies, the beneficial effects of G-CSF were observed when therapy was started before² or shortly after³, ⁶ ischemic injury, and early initiation of G-CSF therapy resulted in better outcomes.⁵ Myocardial expression of chemoattractants, such as SDF-1, leukemia inhibitory factor, and hepatocyte growth factor, peaks at 24 to 72 hours after acute MI.³¹, ³², ³³ Therefore, greater myocardial homing of mobilized BMCs would be expected when the peak BMC mobilization coincides temporally with the peak expression of myocardial homing factors. However, since G-CSF therapy also up-regulates Akt,³⁴ resulting in a significant reduction in apoptosis, and activates the myocardial JAK/STAT pathway,⁵ the overall effects of G-CSF therapy may depend not only on the mobilization of BMCs but also on the influence of these signaling events in the infarcted myocardium. The optimal timing of G-CSF therapy remains to be determined in future basic as well as clinical studies.

An increased albeit statistically insignificant risk of in-stent restenosis has been reported with G-CSF therapy.⁸ In contrast, G-CSF therapy was not associated with increased in-stent restenosis in 41 patients in the STEMMI trial,²² which carefully evaluated neointimal hyperplasia at 5 months using angiography and intravascular ultrasound.³⁵ Furthermore, an individual patient-data meta-analysis of the adverse effects of G-CSF in the setting of acute MI including 106 patients showed no increased risk of in-stent restenosis, reduction in minimal luminal diameter, stent thrombosis, or reinfarction.³⁶ Importantly, the development of in-stent restenosis is influenced by multiple factors, such as the patient population, lesion type, and technical competency. When we analyzed the reported risk of in-stent restenosis across the included studies, totaling 284 patients, we found no difference in in-stent restenosis risk between the treatment and the placebo/control arms. Moreover, the incidence of in-stent restenosis in this setting decreases considerably after a few months. In our meta-analysis, none of the included studies reported an increased incidence of serious side effects beyond minor systemic side effects, such as bone ache and malaise. However, the risk of side-effects associated with G-CSF therapy needs to be evaluated during longer follow-up periods.

Limitations 

Although the total number of patients in the meta-analysis is relatively small, our analysis effectively summarizes the available data, reaches valid conclusions regarding the efficacy of G-CSF therapy, and provides important insights. Despite the significant interaction between baseline LVEF and timing of therapy with the observed benefits, we cannot entirely exclude the role of performance bias in influencing the results. Also, because our meta-analysis was based on published data rather than on individual patient data, in subgroup analyses, the ability to precisely identify the best time to initiate G-CSF therapy and the LVEF cutoff was limited. Finally, the duration of the follow-up in the studies included in this meta-analysis was relatively short.

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Conclusions 

The results of this meta-analysis suggest that G-CSF therapy does not improve LV function and structure in unselected patients with acute MI. However, G-CSF may potentially benefit acute MI patients with impaired LVEF at baseline and when therapy is initiated early. Granulocyte colony-stimulating factor therapy appears to be safe. The results presented herein may be useful for the design of future clinical trials of G-CSF therapy for cardiac repair.

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Appendix A. Supplemental methods 

Study selection and data collection 

The review question was: To what extent does therapy with G-CSF affect cardiovascular outcomes in patients with acute MI? This protocol-driven meta-analysis was performed according to the Quality of Reporting of Meta-analysis (QUOROM)³⁷ statement.

One reviewer (A.A.L.) judged eligibility of studies. The vast majority of studies that investigated the efficacy of G-CSF therapy for myocardial repair utilized the ability of this agent to mobilize bone marrow cells. In 3 RCTs,³⁸, ³⁹, ⁴⁰ bone marrow cells were mobilized via G-CSF therapy followed by harvest and intracoronary injection of mobilized cells. Since the use of intracoronary cell injection represents a fundamentally different approach compared with s.c. G-CSF therapy, and since recent data have demonstrated variable degrees of cardiac engraftment between progenitor cells mobilized with G-CSF and non-mobilized cells injected via the intracoronary route,⁴¹ we excluded studies that injected G-CSF-mobilized BMCs via the intracoronary route.³⁸, ³⁹, ⁴⁰ We also identified 2 RCTs⁴², ⁴³ that included patients with chronic ischemic cardiomyopathy (ICM). Given the major differences in cardiac milieu between acute MI and chronic ICM, which may profoundly influence homing of stem/progenitor cells, we performed separate meta-analyses of RCTs without (Table I) as well as with (supplemental Table 1) patients with ICM. Thus, the primary meta-analysis examining the effects of G-CSF therapy on cardiovascular outcomes in patients with acute MI alone was limited to 8 eligible RCTs.

We searched MEDLINE (January 1980 to July 2007), the Cochrane databases (July 2007), EMBASE (January 1980 to July 2007), CINAHL (January 1982 to July 2007), the US Food and Drug Administration Web site (http://www.fda.gov) and BIOSIS Previews (January 1980 to July 2007) using database-appropriate terms for the following: coronary artery disease, cytokines, G-CSF, myocardial infarction, mobilized progenitor cells, circulating progenitor cells, myocardial regeneration, and cardiac repair. We sought additional studies by reviewing the reference lists of eligible studies and relevant review articles. The complete search strategy is available upon request from the authors.

Two reviewers (A.A.L. and B.D.) working in duplicate and independently used a standardized form to abstract data from each study. When necessary, LV end-diastolic volume (LVEDV) was estimated from LVEDV index. Ince et al.⁴⁴, ⁴⁵ provided the LV end diastolic diameter and LVEDV was calculated using the Teichholz formula.⁴⁶ Data from echocardiography and cardiac MRI were considered equivalent. When both echocardiographic and cardiac MRI functional data were available, cardiac MRI data were preferentially used. When data were available from more than one follow-up time points,⁴⁴, ⁴⁵ the longest follow-up data were used.

We used the criteria of Juni et al.⁴⁷ to ascertain the methodological quality of included RCTs.⁴⁷ The authors’ statements regarding blinding and other methods in the original manuscripts were accepted verbatim. In addition, we applied the Jadad scale⁴⁸ for quantifying the study quality.

Data analysis 

The main outcomes of our analyses were change from baseline in mean LV ejection fraction (LVEF), infarct scar size, LVEDV, LV end-systolic volume (LVESV), and the relative risk (RR) for adverse events, including death, recurrent MI, and in-stent restenosis. We conducted meta-analyses using both ‘fixed-effects’ and ‘random-effects’ models to pool these outcomes across included studies, estimating weighted mean differences between G-CSF-treated patients and controls and the respective 95% confidence intervals (CI). Results obtained via fixed-and random-effects models were similar with respect to the major outcomes. Since we excluded studies that included chronic ICM patients, we felt that the use of the fixed-effects model was justified.

For data regarding clinical outcome variables, the effect measures estimated were the RR for dichotomous data, which we report with 95% CI. The RR indicates the risk of death, recurrent MI, or in-stent restenosis in an individual receiving G-CSF compared with the respective risk in an individual not receiving G-CSF. We also calculated the absolute risk reduction (ARR), i.e. risk difference (RD), and the ‘numbers needed to harm’ (NNH) to assess the clinical significance of the outcome. ARR signifies the absolute difference in outcome rates between the G-CSF-treated and control groups. The NNH is the reciprocal of the ARR and denotes the number of patients that would need to be treated to develop any of the adverse outcomes. The RRs from separate studies were combined according to a fixed-effects model [Mantel-Haenszel method ⁴⁹, ⁵⁰].

The Review Manager software (RevMan version 4.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2006) was used for all of the analyses. The proportion of between-study inconsistency due to true differences between studies (rather than differences due to random error or chance) was estimated by the I² statistic.⁵¹ Funnel plots were used to explore any publication bias.

We conducted planned subgroup analyses and examined potential treatment-subgroup interactions. Planned subgroups comprised the mean LVEF at baseline [using LVEF of 50% as cut-off ⁵², ⁵³], the average time between the acute event (acute MI or percutaneous coronary intervention [PCI]) and the first dose of G-CSF (using the median initiation time of 37 hours as cut-off), the dose of G-CSF (using the median of 10 μg/kg/day as cut-off), and the peak white blood cell (WBC) and CD34+cell counts as indicators of BMC mobilization efficacy with G-CSF therapy.

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Appendix B. Supplemental Table 

Supplemental Table 1. Characteristics of studies included in the meta-analysis (patients with acute myocardial infarction as well as chronic ischemic cardiomyopathy)

All numbers are presented as mean ± SD. AMI, acute MI; C, control; G-CSF, granulocyte colony-stimulating factor; ICM, ischemic cardiomyopathy; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NR, not reported; OMI, old MI; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; T, G-CSF-treated; WBC, white blood cell.

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Appendix C. Supplemental Figures 

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• Supplemental Figure 1. 

  Forest plot of unadjusted difference in mean (with 95% CIs) change in LVEF in G-CSF-treated patients compared with controls in RCTs that used a uniform G-CSF dose of 10 μg/kg/day. The figure shows the summary of the included RCTs. G-CSF therapy resulted in a 0.72% (95% CI: −2.25 to 0.81; P = .19) decrease in mean LVEF. The imaging modality is specified within parentheses. FU, follow-up; G-CSF, granulocyte colony-stimulating factor; LVEF, left ventricular ejection fraction; WMD, weighted mean difference.

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• Supplemental Figure 2. 

  Forest plot of unadjusted difference in mean (with 95% CIs) change in infarct scar size in G-CSF-treated patients compared with controls in RCTs that used a uniform G-CSF dose of 10 μg/kg/day. The figure shows the summary of the included RCTs. G-CSF therapy resulted in a 0.28% (95% CI: −2.22 to 1.65; P = .77) increase in mean infarct scar size. The imaging modality is specified within parentheses. G-CSF, granulocyte colony-stimulating factor; WMD, weighted mean difference.

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• Supplemental Figure 3. 

  Forest plot of unadjusted difference in mean (with 95% CIs) change in LVEDV in G-CSF-treated patients compared with controls in RCTs that used a uniform G-CSF dose of 10 μg/kg/day. The figure shows the summary of the included RCTs. G-CSF therapy resulted in a 2.94 mL (95% CI: −11.03 to 5.14; P = .48) increase in mean LVEDV. The imaging modality is specified within parentheses. FU, follow-up; G-CSF, granulocyte colony-stimulating factor; LVEDV, left ventricular end-diastolic volume; WMD, weighted mean difference.

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• Supplemental Figure 4. 

  Forest plot of unadjusted difference in mean (with 95% CIs) change in LVESV in G-CSF-treated patients compared with controls in RCTs that used a uniform G-CSF dose of 10 μg/kg/day. The figure shows the summary of included RCTs. G-CSF therapy resulted in a 1.27 mL (CI: −7.04 to 4.50; P = .67) increase in LVESV. The imaging modality is specified within parentheses. G-CSF, granulocyte colony-stimulating factor; LVESV, left ventricular end-systolic volume; WMD, weighted mean difference.

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• Supplemental Figure 5. 

  Forest plot of unadjusted risk ratio (RR, with 95% CIs) for major reported adverse effects, namely, death, recurrent MI, and in-stent restenosis in G-CSF-treated patients compared with controls in RCTs that used a uniform G-CSF dose of 10 μg/kg/day. The figure shows the summary of included RCTs. The RR of death was 1.32 (CI: 0.27 to 6.48), RR of recurrent MI was 0.97 (CI: 0.14 to 6.48), and RR of in-stent restenosis was 0.97 (CI: 0.63 to 1.51). None of these end-points were significantly different between groups. FU, follow-up; G-CSF, granulocyte colony-stimulating factor; MI, myocardial infarction; RR, risk ratio.

• 
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• Supplemental Figure 6. 

  Forest plot of unadjusted difference in mean (with 95% CIs) change in LVEF in G-CSF-treated patients compared with controls. All eligible RCTs that included patients with acute MI as well as chronic ischemic cardiomyopathy were included. The figure shows the summary of the included RCTs. G-CSF therapy resulted in a 1.62% (95% CI: −1.76 to 5.00; P = .35) increase in mean LVEF. The imaging modality is specified within parentheses. FU, follow-up; G-CSF, granulocyte colony-stimulating factor; LVEF, left ventricular ejection fraction; WMD, weighted mean difference.

• 
  • View Large Image
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• Supplemental Figure 7. 

  Forest plot of unadjusted difference in mean (with 95% CIs) change in infarct scar size in G-CSF-treated patients compared with controls. All eligible RCTs that included patients with acute MI as well as chronic ischemic cardiomyopathy were included. The figure shows the summary of the included RCTs. The imaging modality is specified within parentheses. G-CSF therapy resulted in a 0.25% (95% CI: −1.27 to 1.77; P = .75) increase in mean infarct scar size. G-CSF, granulocyte colony-stimulating factor; WMD, weighted mean difference.

• 
  • View Large Image
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• Supplemental Figure 8. 

  Forest plot of unadjusted difference in mean (with 95% CIs) change in LVEDV in G-CSF-treated patients compared with controls. All eligible RCTs that included patients with acute MI as well as chronic ischemic cardiomyopathy were included. The figure shows the summary of the included RCTs. G-CSF therapy resulted in a 3.22 mL (95% CI: −10.97 to 4.53; P = .42) decrease in mean LVEDV. The imaging modality is specified within parentheses. FU, follow-up; G-CSF, granulocyte colony-stimulating factor; LVEDV, left ventricular end-diastolic volume; WMD, weighted mean difference.

• 
  • View Large Image
  • Download to PowerPoint

• Supplemental Figure 9. 

  Forest plot of unadjusted difference in mean (with 95% CIs) change in LVESV in G-CSF-treated patients compared with controls. All eligible RCTs that included patients with acute MI as well as chronic ischemic cardiomyopathy were included. The figure shows the summary of included RCTs. G-CSF therapy resulted in a 3.07 mL (CI: −11.08 to 4.94; P = .45) decrease in LVESV. The imaging modality is specified within parentheses. G-CSF, granulocyte colony-stimulating factor; LVESV, left ventricular end-systolic volume; WMD, weighted mean difference.

• 
  • View Large Image
  • Download to PowerPoint

• Supplemental Figure 10. 

  Forest plot of unadjusted risk ratio (RR, with 95% CIs) for major reported adverse effects, namely, death, recurrent MI, and in-stent restenosis in G-CSF-treated patients compared with controls. All eligible RCTs that included patients with acute MI as well as chronic ischemic cardiomyopathy were included. The figure shows the summary of included RCTs. The RR of death was 1.08 (CI: 0.27 to 4.40), RR of recurrent MI was 1.54 (CI: 0.32 to 7.37), and RR of in-stent restenosis was 1.02 (CI: 0.70 to 1.47). None of these end-points were significantly different between groups. FU, follow-up; G-CSF, granulocyte colony-stimulating factor; MI, myocardial infarction; RR, risk ratio.

• 
  • View Large Image
  • Download to PowerPoint
• 
  • View Large Image
  • Download to PowerPoint

• Supplemental Figure 11. 

  Funnel plot of the included studies showing the publication bias and the consistency of the study results around the mean outcome. The Funnel plots were done for each of the outcomes separately (panels A-E). Where inconsistency was high, the funnel plots were not interpretable; where inconsistency was low, the funnel plots were inconclusive. LV, left ventricular; LVEDV, LV end-diastolic volume; LVEF, LV ejection fraction; LVESV, LV end-systolic volume.

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45. Ince H, Petzsch M, Kleine H, et al. Preservation from left ventricular remodeling by front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by use of granulocyte-colony-stimulating factor (FIRSTLINE-AMI). Circulation. 2005;112:3097–3106
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48. Jadad A, Moore R, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996;17:1–12
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50. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335–371
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    • MEDLINE
    • CrossRef
51. Higgins J, Thompson S, Deeks J, et al. Measuring inconsistency in meta-analysis. BMJ. 2003;327:557–560
    • View In Article
    • CrossRef
52. Ferguson D, White C, Schwartz J, et al. Influence of baseline ejection fraction and success of thrombolysis on mortality and ventricular function after acute myocardial infarction. Am J Cardiol. 1984;54:705–711
    • View In Article
    • MEDLINE
    • CrossRef
53. Little W, Applegate R. Congestive heart failure: systolic and diastolic function. J Cardiothorac Vasc Anesth. 1993;7(4 (Suppl 2)):2–5
    • View In Article
    • MEDLINE
    • CrossRef
54. Ellis SG, Penn MS, Bolwell B, et al. Granulocyte colony stimulating factor in patients with large acute myocardial infarction: results of a pilot dose-escalation randomized trial. Am Heart J. 2006;152:e9–e14
    • View In Article
    • Full Text
    • Full-Text PDF (39 KB)
    • CrossRef
55. Engelmann MG, Theiss HD, Hennig-Theiss C, et al. Autologous bone marrow stem cell mobilization induced by granulocyte colony-stimulating factor after subacute ST-segment elevation myocardial infarction undergoing late revascularization: final results from the G-CSF-STEMI (Granulocyte Colony-Stimulating Factor ST-Segment Elevation Myocardial Infarction) trial. J Am Coll Cardiol. 2006;48:1712–1721
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (387 KB)
    • CrossRef
56. Kang HJ, Kim HS, Koo BK, et al. Intracoronary infusion of the mobilized peripheral blood stem cell by G-CSF is better than mobilization alone by G-CSF for improvement of cardiac function and remodeling: 2-year follow-up results of the Myocardial Regeneration and Angiogenesis in Myocardial Infarction with G-CSF and Intra-Coronary Stem Cell Infusion (MAGIC Cell) 1 trial. Am Heart J. 2007;153:e1–e8
    • View In Article
    • Full Text
    • Full-Text PDF (39 KB)
    • CrossRef
57. Ince H, Petzsch M, Kleine HD, et al. Prevention of left ventricular remodeling with granulocyte colony-stimulating factor after acute myocardial infarction: final 1-year results of the Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Granulocyte Colony-Stimulating Factor (FIRSTLINE-AMI) Trial. Circulation. 2005;112(Suppl):I73–I80
    • View In Article
58. Leone AM, Galiuto L, Garramone B, et al. Usefulness of granulocyte colony-stimulating factor in patients with a large anterior wall acute myocardial infarction to prevent left ventricular remodeling (the rigenera study). Am J Cardiol. 2007;100:397–403
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (179 KB)
    • CrossRef
59. Ripa RS, Jorgensen E, Wang Y, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation. 2006;113:1983–1992
    • View In Article
    • CrossRef
60. Suzuki K, Nagashima K, Arai M, et al. Effect of granulocyte colony-stimulating factor treatment at a low dose but for a long duration in patients with coronary heart disease. Circ J. 2006;70:430–437
    • View In Article
    • MEDLINE
    • CrossRef
61. Takano H, Hasegawa H, Kuwabara Y, et al. Feasibility and safety of granulocyte colony-stimulating factor treatment in patients with acute myocardial infarction. Int J Cardiol. 2007;122:41–47
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (289 KB)
    • CrossRef
62. Valgimigli M, Rigolin GM, Cittanti C, et al. Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile. Eur Heart J. 2005;26:1838–1845
    • View In Article
    • MEDLINE
    • CrossRef
63. Zohlnhofer D, Ott I, Mehilli J, et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. Jama. 2006;295:1003–1010
    • View In Article
    • CrossRef