Objectives

To assess the feasibility, safety, and efficacy of autologous mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), alone or in combination, in patients with ischemic heart failure.

Background

The prognosis of heart failure (HF) caused by chronic ischemic cardiomyopathy (coronary artery disease and prior myocardial infarction), hereby referred to as “ischemic HF”, remains poor. Many studies have explored the use of various types of stem or progenitor cells in patients with chronic ischemic HF, with encouraging results. Several clinical trials have suggested that MSCs and CPCs are both safe and beneficial in patients with ischemic HF. At the time of this study, no information was available on the efficacy of MSCs and CPCs in humans, however, both cell types have been shown to attenuate left ventricle (LV) dysfunction in animal models. Preclinical models indicate that combining MSCs and CPCs increases the therapeutic effects, but this had not yet been tested in humans.

The CONCERT-HF study was initiated to assess whether autologous MSCs and CPCs, alone or in combination, can be manufactured and delivered to patients with ischemic HF; are well-tolerated; and improve LV function, quality of life, and functional capacity, and/or reduce scar size.

Participants

Eligible participants were aged 21 to 79 years old with documented coronary artery disease, evidence of myocardial scar involving ≥5% of the LV mass by MRI, LV systolic dysfunction (LV ejection fraction [LVEF] ≤40% by MRI), symptoms of HF (NYHA class II-III), and were receiving guideline-driven medical therapy at stable and tolerated doses for ≥1 month before consent.

A total of 125 participants were randomized with 33 participants randomized to the MSCs and CPCs group, 29 patients to the MSCs alone group, 31 patients to the CPCs alone group, and 32 patients to the placebo group.

Design

The CONCERT-HF study was a multi-center Phase II, double-blind, randomized, placebo-controlled trial designed to evaluate the feasibility, safety, and efficacy of MSCs alone, CPCs alone, and their combination compared with placebo as well as each other in patients with ischemic HF. In Stage 1 (open label, lead-in study) participants were randomized 1:1 to either a standard-of-care control group (i.e., they did not undergo harvest, mapping, or injection procedures) or combination therapy (MSCs + CPCs, as described for Stage 2) to complete safety assessments. Once approval was granted for Stage 2, participants were randomized (1:1:1:1) to one of four treatments: placebo, autologous MSCs (target dose, 150 × 10⁶ cells), autologous CPCs (target dose, 5 × 10⁶ cells), or a combination of autologous MSCs and CPCs. At the harvest visit, right ventricular endocardial biopsy (EMB) was performed in participants randomized to receive CPCs alone or a combination of MSCs and CPCs. Participants randomized to receive MSCs alone or placebo had a sham procedure (right heart catheterization without EMB). All participants underwent a bone marrow aspiration and approximately 14 weeks later had transendocardial, electromechanically-guided injections of study product.

Visits occurred at 1 day, 1 week, and 1, 3, 6, and 12 months after study product injection. A telephone contact took place at 24 months to assess the participant’s current medications, as well as morbidity and mortality.

Study endpoints included measures of safety, feasibility, and efficacy. Safety outcomes included all adverse events grade 2 and higher, including major adverse cardiac events (MACE) related to HF (death, hospitalization for worsening HF, and HF exacerbation not requiring hospitalization). Efficacy endpoints included quality of life, MRI measures of LV function and structure, functional capacity, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels.

Conclusions

In patients with ischemic HF, autologous MSCs and CPCs, alone or in combination, are safe and feasible; CPCs were associated with a reduction in the incidence of MACE related to HF compared to placebo; MSCs, either alone or in combination with CPCs, were associated with improved quality of life; these seemingly beneficial effects of CPCs and MSCs on clinical outcome were not associated with changes in LV function or structure; and combination therapy with MSCs and CPCs was associated with the best clinical outcomes with respect to both MACE related to HF and quality of life.

Bolli R, Hare JM, March KL, et al. Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure). Circ Res. 2018;122(12):1703-1715. doi:10.1161/CIRCRESAHA.118.312978

Bolli R, Mitrani RD, Hare JM, et al. A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. Eur J Heart Fail. 2021;23(4):661-674. doi:10.1002/ejhf.2178

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