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Previous Volume 355:1210-1221 September 21, 2006 Number 12 Next

Abstract PDF PDA Full Text PowerPoint Slide Set Supplementary Material Perspective by Schwartz, R. S. Editorial by Rosenzweig, A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Pilot trials suggest that the intracoronary administration of autologous progenitor cells may improve left ventricular function after acute myocardial infarction.

Methods In a multicenter trial, we randomly assigned 204 patients with acute myocardial infarction to receive an intracoronary infusion of progenitor cells derived from bone marrow (BMC) or placebo medium into the infarct artery 3 to 7 days after successful reperfusion therapy.

Results At 4 months, the absolute improvement in the global left ventricular ejection fraction (LVEF) was significantly greater in the BMC group than in the placebo group (mean [±SD] increase, 5.5±7.3% vs. 3.0±6.5%; P=0.01). Patients with a baseline LVEF at or below the median value of 48.9% derived the most benefit (absolute improvement in LVEF, 5.0%; 95% confidence interval, 2.0 to 8.1). At 1 year, intracoronary infusion of BMC was associated with a reduction in the prespecified combined clinical end point of death, recurrence of myocardial infarction, and any revascularization procedure (P=0.01).

Conclusions Intracoronary administration of BMC is associated with improved recovery of left ventricular contractile function in patients with acute myocardial infarction. Large-scale studies are warranted to examine the potential effects of progenitor-cell administration on morbidity and mortality. (ClinicalTrials.gov number, NCT00279175 [ClinicalTrials.gov] .)

Experimental studies suggested that intravascular or intramyocardial administration of progenitor cells derived from bone marrow (BMC) or blood may contribute to functional regeneration of infarcted myocardium and enhance neovascularization of ischemic myocardium.^7,8,9,10 Moreover, clinical pilot studies demonstrated that intracoronary infusion of progenitor cells is feasible and may improve the recovery of left ventricular contractility in patients with acute myocardial infarction.^{11,12,13,14,15,16} We therefore designed a double-blind, placebo-controlled, randomized multicenter trial — the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial — to determine whether intracoronary infusion of enriched BMC is associated with improved global left ventricular function in patients with myocardial infarction treated with state-of-the-art methods.

Methods

Study Population and Protocol

We enrolled the first patient in the study on April 16, 2004, and the last 4-month angiographic follow-up was performed on October 31, 2005. The definition of primary and secondary end points, as well as the prespecified subgroup analyses, have been published previously.¹⁷ In brief, patients 18 to 80 years of age were eligible for the study if they had had an acute ST-elevation myocardial infarction that had been successfully reperfused by means of stent implantation and had a substantial residual left ventricular regional wall-motion abnormality (as defined by an ejection fraction 45% according to a visual estimate). Written informed consent was obtained within 3 days after the reperfusion therapy if the patients no longer required intravenous pressor substances or mechanical hemodynamic support. The ethics review board at each participating center approved the protocol, and the study was conducted in accordance with the Declaration of Helsinki. A total of 16 centers in Germany and 1 in Switzerland participated in this investigator-initiated trial.

All patients underwent bone marrow aspiration 3 to 6 days after receiving reperfusion therapy for acute myocardial infarction. The bone marrow aspirate was sent by courier to the central cell-processing laboratory (Institute for Transfusion Medicine, Frankfurt, Germany), where patients were randomly assigned to receive placebo medium or BMC, and the study medication was sent back to the centers. Temperature-registering isolation boxes were used for the shipment of bone marrow aspirates and the study medication to monitor the quality of the materials during transportation. Baseline left ventricular angiography was performed at the time of intracoronary infusion of study medication and was repeated in identical projections at 4 months of follow-up (Figure 1). All patients undergoing bone marrow aspiration underwent randomization, and clinical follow-up started at the time of bone marrow aspiration.

View larger version (23K): [in this window] [in a new window]   Figure 1. Enrollment and Outcomes. LVEF denotes left ventricular ejection fraction, CRP C-reactive protein, and LV left ventricular.

 
Cell Preparation and Administration

A total of 50 ml of bone marrow was aspirated into heparin-treated syringes from the iliac crest with the use of local anesthesia. The bone marrow aspirate was shipped at room temperature together with 20 ml of venous blood used to produce patients' own serum to the central cell-processing laboratory. Progenitor cells were isolated and enriched with the use of Ficoll–Hypaque centrifugation procedures.¹⁴ The cell suspension consisted of a heterogeneous cell population including hematopoietic, mesenchymal, and other progenitor cells, as well as mononuclear cells. The cells were suspended in 10 ml of X VIVO 10 medium (a serum-free medium containing pharmaceutical-grade human components, Cambrex), including 2 ml of the patient's own serum. The placebo medium consisted of the 10 ml of X VIVO 10 medium, including 2 ml of the patient's own serum (without BMC). Frequencies of BMC were assessed according to the guideline of the International Society of Hematotherapy and Graft Engineering.¹⁸

After undergoing arterial puncture, all patients received 7500 to 10,000 U of heparin, and the first 85 patients received a bolus of abciximab (0.25 mg per kilogram of body weight). Cells were infused with the use of a stop-flow technique through an over-the-wire balloon catheter (Opensail, Guidant) positioned within the segment containing the stent, as described previously.¹²

Left Ventricular Angiography

Left ventricular angiograms were obtained in identical standard projections at the time of the baseline procedure (immediately before intracoronary cell infusion) and at 4 months. An experienced investigator in a central core laboratory who was unaware of the patient's treatment assignment quantitatively analyzed the left ventricular angiograms from individual patients with the use of CMS software (version 6.0, Medis), as previously described.¹² Left ventricular ejection fraction (LVEF) and left ventricular volumes were calculated with the use of the area–length method, and regional wall motion in the infarcted zone was determined with the use of the center-line chord method.¹²

End Points

The primary end point was the absolute change in global LVEF from baseline to 4 months, as measured by quantitative left ventricular angiography.¹⁷ Secondary end points included changes in left ventricular end-diastolic and end-systolic volume and changes in regional wall motion. Prespecified subgroup analyses were conducted to determine whether there was an interaction of the primary end point with baseline LVEF and the time to intracoronary-infusion therapy. Prespecified clinical end points included major adverse events (defined as death, recurrence of myocardial infarction, or any revascularization procedure) and rehospitalization for heart failure. Other clinical events or combined end points were assessed as a post hoc analysis. Only the first event for each patient was included in the analysis. As of June 16, 2006, 1-year clinical follow-up data were available for 168 patients.

Statistical Analysis

Continuous variables are presented as means ±SD (unless stated otherwise). Analysis-of-variance testing was used to compare the incidence of the primary end point — the change in LVEF — between the groups. For subgroup analyses, subgroup variables were entered as effects into the univariate analysis-of-variance model to determine whether there was an interaction with the treatment assignment. An analysis-of-variance model was used to adjust for effects, and an analysis-of-covariance model was used to adjust for covariates. To estimate the treatment effect, differences in least-square means and corresponding 95% confidence intervals (CIs) were calculated on the basis of the analysis-of-variance model. All other analyses were performed in a nonparametric paired fashion with the use of the Wilcoxon signed-rank test, if not stated otherwise. Nonparametric Mann–Whitney U and Kruskal–Wallis tests were used to compare continuous with categorical variables. Categorical variables were compared with the chi-square test or Fisher's exact test, as appropriate. Spearman's correlation coefficient was used to correlate continuous data. A P value of less than 0.05 was considered to indicate statistical significance. All reported P values are two-sided. Statistical analyses were performed with SPSS software (version 13.0, SPSS).

Results

Enrollment and Baseline Characteristics

A total of 217 patients with an acute myocardial infarction successfully reperfused by means of stent implantation gave written informed consent to participate in the trial. Of these patients, 13 were excluded before undergoing bone marrow aspiration (Figure 1). Of the remaining 204 patients undergoing bone marrow aspiration, 103 were randomly assigned to receive an infusion of placebo medium and 101 to receive a BMC infusion into the infarct-related coronary artery. The two groups were well matched with respect to baseline characteristics and procedural characteristics of the reperfusion therapy and concomitant pharmacologic therapy during the study (Table 1). The characteristics of the BMC are provided in the Supplementary Appendix (available with the full text of this article at www.nejm.org).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of the Patients and Concomitant Therapy.

 
Procedural Results of Intracoronary Infusion

After bone marrow aspiration, one patient withdrew consent and one patient was excluded owing to fever and an increase in the level of C-reactive protein. No patient had bleeding complications or hematoma formation at the bone marrow puncture site. Intracoronary infusion was successful in all patients in the BMC group. In the placebo group, intracoronary infusion was not performed in three patients: in one the guidewire could not be advanced into the infarct-related artery, one had an air embolism during initial angiography before the guidewire could be advanced, and one had angiographic evidence of a thrombus in a non–infarct-related artery.

Quantitative Variables of Left Ventricular Function

Baseline measurements of left ventricular function and volumes did not differ significantly between the two groups (Table 1). At 4 months, paired left ventricular angiograms with adequate contrast opacification for quantitative analysis were available for 95 patients in the BMC group and 92 patients in the placebo group. Paired left ventricular angiograms were not available for the two patients in each group who died, five patients (three in the placebo group and two in the BMC group) who declined to undergo angiography at follow-up, three patients who missed one angiographic session (two patients in the placebo group and one patient in the BMC group), and one patient with left ventricular thrombus in the placebo group. In addition, in one patient in each group, poor contrast opacification precluded quantitative analysis of the left ventricular angiogram (Figure 1).

Global LVEF increased from a mean of 46.9±10.4% at baseline to 49.9±13.0% at 4 months in the placebo group. In the BMC group, global LVEF increased from 48.3±9.2% to 53.8±10.2% (Table 2). At 4 months, LVEF was significantly higher in the BMC group than in the placebo group (P=0.02). The absolute increase in LVEF was significantly greater in the BMC group than in the placebo group (2.5%; 95% CI, 0.5 to 4.5; P=0.01).

View this table: [in this window] [in a new window]   Table 2. Quantitative Measures of Left Ventricular Function.

 
In order to document that the primary end point of the study was not affected by the subtle, nonsignificant differences in both baseline variables and clinical end points during follow-up between the two groups, we reanalyzed the data after adjustment for a variety of effects or covariates (Figure 2). None of the adjustments altered the primary finding that intracoronary administration of BMC was associated with a significantly greater increase in global LVEF than was placebo.

View larger version (22K): [in this window] [in a new window]   Figure 2. Effect of BMC Therapy as Compared with Placebo on the Primary End Point of the Absolute Change in the Global LVEF from Baseline to 4 Months. The primary end point is shown before and after adjustment for effects according to analysis of variance (ANOVA) or analysis of covariance (ANCOVA). The large diamonds show the absolute change in LVEF, and the small diamonds show the 95% CI.

 
Selective analysis of the infarcted zone revealed a significantly greater improvement in regional contractility in the BMC group than in the placebo group (Table 2). End-diastolic volumes slightly increased in both groups (Table 2). In contrast, left ventricular end-systolic volumes remained constant in the BMC group but increased in the placebo group. The absolute change in left ventricular end-systolic volumes differed significantly between the two groups (Table 2).

Interaction between Change in LVEF and Both Baseline LVEF and Time to Infusion

There was a significant inverse relation between baseline LVEF and the absolute change in LVEF at 4 months in the BMC group (r=–0.21, P=0.04) but not in the placebo group (r=+0.11, P=0.31). When the total patient population was dichotomized according to the median value of LVEF at baseline, there was a significant interaction between the treatment effect of the BMC infusion and the baseline LVEF (P=0.02). Among patients with a baseline LVEF at or below the median value (48.9%), patients in the BMC group had an absolute increase in LVEF that was three times that in the placebo group (Figure 3A): 7.5±7.1% as compared with 2.5±7.7% (absolute difference, 5.0%; 95% CI, 2.0 to 8.1). Among patients with a baseline LVEF above the median, the absolute difference between groups was 0.3% (95% CI, –2.2 to 2.8), with an absolute improvement in LVEF in the placebo group of 3.7±4.6%, as compared with 4.0±7.1% in the BMC group.

View larger version (29K): [in this window] [in a new window]   Figure 3. Interaction between Baseline LVEF and the Absolute Change in LVEF (Panel A) and between the Timing of Intracoronary Infusion of BMC or Placebo after Reperfusion Therapy and the Absolute Change in LVEF (Panel B). In Panel A, the P value for interaction was determined by analysis of variance. In both panels, the upper and lower edges of each box plot indicate the 25th and 75th percentiles, the "whiskers" the 10th and 90th percentiles, the solid horizontal line the median, and the dotted line the mean. All outliers are shown as individual data points. In Panel B, the P value for interaction was calculated with the use of a general linear model. The solid line in Panel B shows the regression curve for the BMC group, and the dotted line shows the regression curve for the placebo group

 
Correlating the absolute changes in LVEF at 4 months with the time from reperfusion therapy to intracoronary infusion of BMC or placebo medium revealed a significant interaction, with a progressive increase in BMC-associated recovery of contractile function as the interval between reperfusion therapy and BMC infusion increased (P=0.01) (Figure 3B). In fact, the beneficial effects of BMC infusion on the recovery of contractile function were confined to patients who were treated more than 4 days after infarct reperfusion. BMC infusion on day 5 or later was associated with an absolute increase in LVEF of 5.1% (95% CI, 1.7 to 8.5; absolute improvement in LVEF, 1.9±7.6% in the placebo group vs. 7.0±7.7% in the BMC group; P=0.004), whereas no benefit was observed in patients treated up to day 4 after reperfusion (treatment-associated increase in LVEF, 0.6%; 95% CI, –1.8 to 3.0; absolute improvement in LVEF, 3.9±5.4% in the placebo group vs. 4.5±6.8% in the BMC group; P=0.62). The interaction between the BMC treatment effect and the timing of the procedure (4 days vs. 5 days) was significant (P=0.03) and remained significant when baseline LVEF was also entered into the model as a covariate (P=0.04).

Clinical Outcomes

Table 3 summarizes the adverse clinical events during hospitalization for acute myocardial infarction, at 4 months, and at 1 year (data were available for 168 patients as of June 16, 2006). The occurrence of the individual major adverse cardiac events of death, recurrence of myocardial infarction, and rehospitalization for heart failure did not differ significantly between the two groups during follow-up. However, the incidence of the prespecified combined clinical end point of death, recurrence of myocardial infarction, and coronary revascularization was significantly lower in the BMC group than in the placebo group (Table 3). Likewise, the post hoc combined clinical end point of death, recurrence of myocardial infarction, and rehospitalization for heart failure occurred less frequently in the BMC group than in the placebo group.

View this table: [in this window] [in a new window]   Table 3. Clinical Events during Follow-up.

 
Discussion

The principal finding of our study is that intracoronary administration of BMC is associated with a significant increase in the recovery of left ventricular contractile function in patients with optimally treated acute myocardial infarction. Because the results of early pilot studies were promising,^{11,12,13,14,15,16} we designed a placebo-controlled, double-blind, multicenter trial in which patients with acute myocardial infarction were randomly assigned to receive an infusion of either BMC or placebo medium in the infarct-related artery within 3 to 7 days after successful reperfusion therapy and the implantation of a stent. After 4 months, the global LVEF was significantly higher in the BMC group than in the placebo group. The enhanced recovery of global left ventricular contractile function after the intracoronary administration of BMC was due to a significant reduction in the extent and magnitude of regional left ventricular dysfunction within the territory of the infarct. Thus, segments with the most severe impairment in contractility at baseline appear to derive the greatest benefit from BMC administration. Moreover, intracoronary administration of BMC abrogated left ventricular end-systolic volume expansion after the infarction. Taken together, our findings indicate that when combined with optimal reperfusion therapy (stent implantation) and state-of-the-art medical treatment, intracoronary administration of BMC enhances the recovery of global and regional left ventricular function after myocardial infarction.

The results of our predefined subgroup analysis generate some important hypotheses essential for designing trials that address the clinical relevance of BMC administration. The magnitude of left ventricular contractile recovery was inversely related to the baseline LVEF, confirming similar observations in the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) pilot trial.¹⁴ Patients with the most severely depressed left ventricular contractile function had the greatest improvement in contractile function after the intracoronary administration of BMC. A reduced LVEF during the acute phase of myocardial infarction is the most important independent predictor of a poor outcome, even in the era of optimal reperfusion therapy with the use of stenting of the infarct-related artery.¹⁹ Thus, enhanced recovery of contractile function may be beneficial specifically in patients with large infarcts and depressed left ventricular function.

The mechanisms involved in mediating the recovery of contractile function after the intracoronary infusion of BMC are not well understood.²⁰ The microenvironment within the infarct tissue and the timing of cell delivery may be important determinants of the incorporation and effect of BMC.²⁰ We found that an intracoronary infusion of BMC within 4 days after reperfusion therapy for acute myocardial infarction had only marginal effects on the recovery of left ventricular contractile function. This finding is in agreement with the preliminary results of a small, randomized, placebo-controlled trial in which intracoronary infusion of bone marrow–derived mononuclear progenitor cells within 24 hours after reperfusion therapy failed to improve left ventricular function in patients with acute myocardial infarction.²¹

Our study was not powered to assess whether intracoronary infusion of BMC can reduce the risk of complications and death among patients with acute myocardial infarction. However, the incidence of individual adverse clinical end points tended to be lower in the BMC group than in the placebo group. Thus, the intracoronary administration of BMC appears to be safe and feasible.

A major limitation of our study was the exclusive use of left ventricular angiography for the serial assessment of left ventricular function. Although angiography is well suited to delineate regional contractile function, the use of magnetic resonance imaging to assess global left ventricular function would have more precisely depicted changes in the distorted geometry of the infarcted hearts.

In summary, after acute myocardial infarction, the intracoronary administration of BMC enhances left ventricular contractile recovery. Given the safety profile of this treatment and the beneficial effects in patients with the most severely impaired left ventricular function, large-scale studies are warranted to examine the potential effects of this novel approach on the risk of death and complications in patients with large acute myocardial infarctions and depressed left ventricular contractile function.

Supported by an unrestricted research grant from Guidant. Guidant provided balloon catheters, and Eli Lilly provided the abciximab.

Dr. Schächinger reports having received consulting fees from Guidant and AstraZeneca and lecture fees from Pfizer, Novartis, Merck Sharp & Dohme, Lilly, Boehringer Ingelheim, Sanofi-Aventis, and Boston Scientific. Dr. Dimmeler reports having received consulting fees from Guidant and Genzyme and lecture fees from Medtronic. Dr. Zeiher reports having received consulting fees from Guidant. Dr. Haberbosch reports having received lecture fees from Takeda, Merck Sharp & Dohme, Essex, and Pfizer. Drs. Dimmeler and Zeiher report that they are cofounders of t2cure, a for-profit company focused on regenerative therapies for cardiovascular disease. They serve as scientific advisers and are shareholders. No other potential conflict of interest relevant to this article was reported.

We are indebted to Hans Martin (Department of Hematology) for expert advice, to Tina Rasper and Nicola Krzossok for technical assistance in cell processing, to Wilhelm Sauermann for statistical advice, to Tayfun Aybek for database assistance, to Florian Seeger and Jörg Honold for logistic support, and to the following nonprofit research organizations, which supported the research leading to the initiation of the study: Alfried Krupp Stiftung, German Research Foundation, and European Vascular Genomics Network.

^* Members of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) study group are listed in the Appendix.

Source Information

From the Department of Internal Medicine III, Johann Wolfgang Goethe University, Frankfurt (V.S., B.A., S.D., A.M.Z.); the Department of Cardiology, Herzzentrum Leipzig, Leipzig (S.E., R.H.); the Department of Cardiology, Kerckhoff Klinik, Bad Nauheim (A.E., C.W.H.); the Department of Internal Medicine, Zentralklinikum Suhl, Suhl (W.H.); the Department of Cardiology, Universitätsklinikum Giessen, Giessen (H.H.); the Department of Cardiology, Zentralklinikum, Bad Berka (J.Y.); the Hamburg University Cardiovascular Center, Hamburg (D.G.M.); the Department of Cardiology, Universitätsklinikum, Mannheim (T.S.); and the Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service Baden–Württemberg–Hessen, Frankfurt (T.T.) — all in Germany; and the Department of Cardiology, Universitätsspital, Zurich, Switzerland (R.C.).

Address reprint requests to Dr. Zeiher at the Department of Internal Medicine III, J.W. Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany, or at zeiher{at}em.uni-frankfurt.de.

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The following investigators and committee members participated in the REPAIR-AMI study (numbers in parentheses are the numbers of patients enrolled): Germany — Herzzentrum, Leipzig (35) — S. Erbs, R. Hambrecht; J.W. Goethe Universität, Frankfurt (28) — V. Schächinger, A. Zeiher; Kerckhoff Klinik, Bad Nauheim (22) — A. Elsässer, M. Stanisch, C. Hamm; Zentralklinikum, Suhl (18) — W. Haberbosch; Universitätsklinikum, Giessen (15) — H. Hölschermann, H. Tillmanns; Zentralklinikum, Bad Berka (14) — J. Yu, B. Lauer; Hamburg University Cardiovascular Center, Hamburg (13) — D. Mathey, T. Tübler; Universitätsklinikum, Mannheim (11) — T. Süselbeck, M. Brückmann, K. Haase; Universitätsklinikum, Homburg/Saar (9) — G. Nickenig, N. Werner, M. Böhm; Kardiologisches Centrum Rotes Kreuz, Frankfurt (8) — J. Haase; Klinikum, Kassel (5) — C. Hansen, J. Neuzner; Bergmannshaeil Klinik, Universität Bochum, Bochum (4) — A. Germing, A. Mügge; Herzzentrum Ludwigshafen (4) — B. Mark, J. Senges; Herzzentrum Nordrhein Westfalen, Bad Oeynhausen (3) — C. Hoffmann, M. Farr, D. Horstkotte; Klinikum, Lippe (1) — A. Cuneo, U. Tebbe; Universitätsklinik, Mainz (1) — S. Genth-Zotz, T. Münzel; Switzerland — Universitätsspital, Zurich (13) — R. Corti, T. Lüscher; Steering Committee — A.M. Zeiher (principal investigator), S. Dimmeler, V. Schächinger, W. Haberbosch, K.K. Haase, D. Mathey, R. Hambrecht; Study Coordinating Center, Frankfurt, Germany — H. Braun, V. Schächinger; Angiographic Core Laboratory, Frankfurt, Germany — B. Assmus, A.M. Zeiher; Safety Committee — T. Bonzel (Fulda, Germany), W. Kasper (Wiesbaden, Germany).

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