Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.

CONTEXT: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. OBJECTIVES: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. DESIGN, SETTING, AND PATIENTS: A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. INTERVENTIONS: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. MAIN OUTCOME MEASURES: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. RESULTS: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI, −6.6% to 4.9%], P = .76) or day 7 (1.1% [95% CI, −4.7% to 6.9%], P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. CONCLUSION: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684021.

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT: Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE: To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION: Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES: Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS: Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION: Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00824005.

Cell therapy and satellite centers: the Cardiovascular Cell Therapy Research Network experience.

Due to the changing population in patients with myocardial infarction, recruiting patients in clinical trials continues to challenge clinical investigators. The Cardiovascular Cell Therapy Research Network (CCTRN) chose to expand the reach and power of its recruitment effort by incorporating both referral and treatment satellite centers. Eight treatment satellites were successfully identified and they screened patients over a two year period. The result of this effort was an increase in recruitment, with these treatment satellites contributing 30% of the patients to two of the three Network studies. The hurdles that these satellite treatment centers faced and how they surmounted them provide instruction to clinical research groups eager to expand to satellite systems and to health care practitioners who are interested in taking part in multicenter clinical trials.

A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF).

BACKGROUND: Autologous bone marrow mononuclear cell (ABMMNC) therapy has shown promise in patients with heart failure (HF). Cell function analysis may be important in interpreting trial results. METHODS: In this prospective study, we evaluated the safety and efficacy of the transendocardial delivery of ABMMNCs in no-option patients with chronic HF. Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment (Minnesota Living with Heart Failure and Short Form 36). We also characterized patients' bone marrow cells by flow cytometry, colony-forming unit, and proliferative assays. RESULTS: Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly (P = .001) in cell-treated patients, but function was not affected. Quality-of-life scores improved significantly at 6 months (P = .009 Minnesota Living with Heart Failure and P = .002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control (P = .02) but not in treated patients (P = .16). Function of patients' bone marrow mononuclear cells was severely impaired. Stratifying cell results by age showed that younger patients (≤60 years) had significantly more mesenchymal progenitor cells (colony-forming unit fibroblasts) than patients >60 years (20.16 ± 14.6 vs 10.92 ± 7.8, P = .04). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 mL/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 mL/kg per minute, P = .04). CONCLUSIONS: ABMMNC therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF.

Oversight and management of a cell therapy clinical trial network: experience and lessons learned.

The Cardiovascular Cell Therapy Research Network (CCTRN), sponsored by the National Heart, Lung, and Blood Institute (NHLBI), was established to develop, coordinate, and conduct multiple collaborative protocols testing the effects of cell therapy on cardiovascular diseases. The Network was born into a difficult political and ethical climate created by the recent removal of a dozen drugs from the US formulary and the temporary halting of 27 gene therapy trials due to safety concerns. This article describes the Network's challenges as it initiated three protocols in a polarized cultural atmosphere at a time when oversight bodies were positioning themselves for the tightest vigilance of promising new therapies. Effective strategies involving ongoing education, open communication, and relationship building with the oversight community are discussed.

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design.

BACKGROUND: The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide. TRIAL DESIGN: The Cardiovascular Cell Therapy Research Network (CCTRN) was established by the National Institutes of Health to investigate the role of cell therapy in the treatment of chronic cardiovascular disease. FOCUS is a CCTRN-designed randomized, phase II, placebo-controlled clinical trial that will assess the effect of autologous bone marrow mononuclear cells delivered transendocardially to patients with left ventricular (LV) dysfunction and symptomatic heart failure or angina. All patients need to have limiting ischemia by reversible ischemia on single-photon emission computed tomography assessment. RESULTS: After thoughtful consideration of both statistical and clinical principles, we will recruit 87 patients (58 cell treated and 29 placebo) to receive either bone marrow-derived stem cells or placebo. Myocardial perfusion, LV contractile performance, and maximal oxygen consumption are the primary outcome measures. CONCLUSIONS: The designed clinical trial will provide a sound assessment of the effect of autologous bone marrow mononuclear cells in improving blood flow and contractile function of the heart. The target population is patients with CAD and LV dysfunction with limiting angina or symptomatic heat failure. Patient safety is a central concern of the CCTRN, and patients will be followed for at least 5 years.