• Coronary Artery Disease
• Clinical Trials Genomics

Cell therapy has emerged as an exciting and innovative approach for treating patients with advanced ischemic heart disease, including those with refractory angina and/or heart failure [Perin EC et al. JAMA 2012]. The FOCUS–CCTRN trial [NCT00824005] was designed to evaluate the safety and efficacy of bone marrow mononuclear cells (BMCs) in patients with chronic ischemic heart disease and left ventricular (LV) dysfunction with no other revascularization options. Emerson Perin, MD, PhD, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, Texas, USA, presented data from the study, the largest to date on autologous bone marrow therapy in patients with chronic ischemic heart disease.

Prior smaller studies had suggested that BMCs would provide benefit for patients with ischemic cardiomyopathy. The primary objective of FOCUS–CCTRN was to determine if transendocardial administration of 100 × 10⁶ total BMCs improved measures of LV performance and perfusion at 6 months compared with baseline levels. Coprimary endpoints included left ventricular end systolic volume (LVESV), maximal oxygen consumption (MVO₂), and change in ischemic (reversible) defect size.

The study enrolled symptomatic patients (NYHA classification III or Canadian Cardiovascular Society classification II–IV) with a LV ejection fraction (LVEF) ≤45% a perfusion defect by SPECT, and coronary artery disease that was not amenable to revascularization. All were receiving maximal medical therapy at five National Heart, Lung, and Blood Institute–sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009 and April 18, 2011.

A total of 92 patients (82 men; average age 63 years) were randomized (n=61 in the BMC group and n=31 in the placebo group) to receive bone marrow aspiration and transendocardial injection of 100 × 10⁶ bone marrow cells or placebo.

Changes in LV end systolic volume index (−0.9 mL/m² [95% CI, −6.1 to 4.3]; p=0.73), maximal oxygen consumption (1.0 [95% CI, −0.42 to 2.34]; p=0.17), and the difference in the change for percent reversible defect (−1.2 [95% CI, −12.5 to 10.12]; p=0.84) were not statistically significant. No differences were observed in any of the secondary outcomes, including percent myocardial defect, total defect size, regional wall motion, and clinical improvement.

An exploratory analyses revealed that LVEF improved in the BMC group compared with the placebo group (+1.4 vs −1.3; p=0.030). LVEF improvement was observed in patients who were younger than the median study population age and correlated with the percentage of CD34+ and CD133+ cells in bone marrow samples. A prespecified analysis of cell function (ECFC) also showed significant improvement in MV0₂ in patients with higher–than–median ECFC values.

Dr. Perin concluded that evaluation of the inherent variability in the cell product may provide mechanistic insights and help select patients who are likely to benefit from autologous cell therapy. He said that additional analyses of cell function will be forthcoming from the CCTRN biorepository and should help guide the design of future clinical trials in patients with ischemic heart disease and LV dysfunction.

The lack of efficacy that was observed in the primary and secondary results is disappointing for this highly anticipated therapy. It is possible that prior smaller studies overestimated the efficacy or that the characteristics of the cell population or delivery system were not optimal in FOCUS–CCTRN. Additional analyses from this study will be helpful in guiding future trials of cell therapy.

• © 2012 MD Conference Express®