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

Abstract

Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy.

Methods and results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups.

Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Keywords: Cell-based therapy; Clinical trial; Heart failure.

Figure 1

CONCERT-HF CONSORT diagram. CONSORT diagram shows patients screened, enrolled, and treated in the CONCERT-HF trial, as well as number of patients that completed follow-up for each endpoint, along with reasons for non-completion. 6MWT, 6-min walk test; ACT, anticoagulation therapy; BMA, bone marrow aspiration; CPC, c-kit positive cardiac cell; EF, ejection fraction; eGFR, estimated glomerular filtration rate; EMB, endomyocardial biopsy; FU, follow-up; HbA1C, glycated haemoglobin; LV, left ventricular; MLHFQ, Minnesota Living with Heart Failure Questionnaire; MRI, magnetic resonance imaging; MSC, mesenchymal stromal cell; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; VO₂, oxygen consumption.

Figure 2

Heart failure-related major adverse cardiac events (MACE)–time to event. Cumulative (Kaplan–Meier) incidence of heart failure-related MACE. Events occurring between randomization and 30 days past the 12-month follow-up visit were adjudicated as endpoints. Some participants had extended 12-month visit windows due to the COVID-19 pandemic. Log rank P = 0.0364 is based on the entire follow-up of all participants. CPC, c-kit positive cardiac cell; MSC, mesenchymal stromal cell.

Figure 3

Clinical outcome findings. (A) Proportion of first heart failure-related major adverse cardiac events (HF-MACE) by treatment group. Percentage of participants experiencing HF-MACE (first event) during the trial displayed by treatment group. (B) Quality of life results at baseline and follow-up by treatment group. Change in Minnesota Living with Heart Failure Questionnaire scores from baseline to 6 months and from baseline to 12 months by treatment group. Data are mean± standard deviation. CPC, c-kit positive cardiac cell; MSC, mesenchymal stromal cell.