Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Abstract

AimsCardiopoietic cells, produced through cardiogenic conditioning of patients’ mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort.Methods and resultsThis multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann–Whitney estimator 0.54, 95% confidence interval [CI] 0.47–0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200–370 mL (60% of patients) (Mann–Whitney estimator 0.61, 95% CI 0.52–0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death.ConclusionThe primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

“…25–29 The global rank composite score is not a clinical measure but rather an analytic approach that compares every participant in a study with every other participant on the basis of a predefined hierarchy of outcomes — in this case, outcomes specific for severe scleroderma. 1,4,9,12 Objective components (death, event-free survival, and FVC) were scored at a higher priority than more subjective measures (HAQ-DI score and modified Rodnan skin score).…”

Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

“…Furthermore, intracoronary injection requires cells to extravasate and migrate to the areas of injury, which may result in lower engraftment rates than intramyocardial injection, thus requiring higher initial doses. 30 Another trial by Perin et al 24 31 Teerlink et al 23 found that patients who received <20 injections (and therefore fewer cells) had greater reverse remodeling than those receiving >20 injections. However, the total number of injected cells was ≤600 million, a dose that is much higher compared with our and other studies.…”

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

“…Moreover, 21 patients receiving lineage-specified SCs demonstrated improved LVEF and 6-min walk distance when compared to 15 patients receiving standard of care alone [415]. However, in the larger phase III clinical trial CHART-1 (NCT01768702) no difference was found in primary efficacy endpoints between cardiopoietic cell treatment and control group [416] albeit post hoc analysis revealed an cell-mediated reverse remodeling at 1 year follow-up [417].…”