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
acute myocardial-infarction; cells; coronary-artery-disease; f-18; fluorodeoxyglucose; General & Internal Medicine; intramyocardial injection; metabolic-activity; progenitor; randomized controlled-trial; research network cctrn; stem-cells; transcoronary transplantation
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 Aphase 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.
Perin E C; Willerson J T; Pepine C J; Henry T D; Ellis S G; Zhao D X M; Silva G V; Lai D J; Thomas J D; Kronenberg M W; Martin A D; Anderson R D; Traverse J H; Penn M S; Anwaruddin S; Hatzopoulos A K; Gee A P; Taylor D A; Cogle C R; Smith D; Westbrook L; Chen J; Handberg E; Olson R E; Geither C; Bowman S; Francescon J; Baraniuk S; Piller L B; Simpson L M; Loghin C; Aguilar D; Richman S; Zierold C; Bettencourt J; Sayre S L; Vojvodic R W; Skarlatos S I; Gordon D J; Ebert R F; Kwak M; Moye L A; Simari R D; Cardiovasc Cell Therapy Res Networ
Jama-Journal of the American Medical Association
2012
2012-04
Journal Article
<a href="http://doi.org/10.1001/jama.2012.418" target="_blank" rel="noreferrer noopener">10.1001/jama.2012.418</a>
Effect of the Use and Timing of Bone Marrow Mononuclear Cell Delivery on Left Ventricular Function After Acute Myocardial Infarction The TIME Randomized Trial
cardiosphere-derived cells; double-blind; General & Internal Medicine; intracoronary infusion; ischemic-heart-disease; progenitor cells; reduced neovascularization capacity; regeneration; repair; research network; stem-cells; therapy
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 x 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 x 10(6) 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.
Traverse J H; Henry T D; Pepine C J; Willerson J T; Zhao D X M; Ellis S G; Forder J R; Anderson R D; Hatzopoulos A K; Penn M S; Perin E C; Chambers J; Baran K W; Raveendran G; Lambert C; Lerman A; Simon D I; Vaughan D E; Lai D J; Gee A P; Taylor D A; Cogle C R; Thomas J D; Olson R E; Bowman S; Francescon J; Geither C; Handberg E; Kappenman C; Westbrook L; Piller L B; Simpson L M; Baraniuk S; Loghin C; Aguilar D; Richman S; Zierold C; Spoon D B; Bettencourt J; Sayre S L; Vojvodic R W; Skarlatos S I; Gordon D J; Ebert R F; Kwak M; Moye L A; Simari R D; Cctrn
Jama-Journal of the American Medical Association
2012
2012-12
Journal Article
<a href="http://doi.org/10.1001/jama.2012.28726" target="_blank" rel="noreferrer noopener">10.1001/jama.2012.28726</a>