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Published on: March 1, 2016
Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized,
Raj R Makkar1, Dean J Kereiakes2, Frank Aguirre3
1Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Insights
Allogeneic cardiosphere-derived cells (CDCs) were safe for patients with myocardial infarction (MI) but did not reduce scar size. However, CDCs did decrease left ventricular volumes and NT-proBNP levels, indicating disease-modifying effects.
Area of Science:
- Cardiovascular Medicine
- Regenerative Medicine
- Cell Therapy
Background:
- Cardiosphere-derived cells (CDCs) are cardiac progenitor cells with demonstrated therapeutic potential in preclinical models and prior clinical studies.
- Previous research suggests CDCs possess disease-modifying bioactivity in conditions such as cardiomyopathy and following acute myocardial infarction (MI).
Purpose of the Study:
- To evaluate the safety and efficacy of intracoronary administration of allogeneic CDCs in patients with post-MI left ventricular (LV) dysfunction.
- The study aimed to assess changes in infarct size and other cardiac parameters following CDC treatment.
Main Methods:
- The ALLSTAR trial was a multicenter, randomized, double-blinded, placebo-controlled study involving patients 4 weeks to 12 months post-MI with LV ejection fraction (LVEF) ≤45% and LV scar size ≥15%.
- Patients received intracoronary CDCs or placebo via a stop-flow technique. Primary safety endpoints included major adverse cardiac events and specific cardiac events within 1 month post-infusion.
- The primary efficacy endpoint was the relative change in infarct size at 12 months, assessed by cardiac MRI. A pre-specified interim analysis at 6 months informed trial continuation.
Main Results:
- A total of 134 patients were treated (90 to CDC group, 44 to placebo group). No primary safety endpoint events occurred.
- At 6 months, there was no significant difference in the percentage change in scar size between the CDC and placebo groups (P=0.51).
- However, CDC treatment resulted in significant reductions in LV end-diastolic volume (P=0.02), LV end-systolic volume (P=0.02), and NT-proBNP levels (P=0.02) compared to placebo.
Conclusions:
- Intracoronary infusion of allogeneic CDCs is safe in patients with post-MI LV dysfunction.
- While CDCs did not significantly reduce infarct scar size at 6 months, observed reductions in LV volumes and NT-proBNP suggest disease-modifying bioactivity.
- Further investigation may be warranted to explore the therapeutic potential of CDCs in cardiovascular regeneration.
Aims:
Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial.
Methods And Results:
We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients.
Conclusion:
Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs.
Trial Registration:
Clinicaltrials.gov identifier: NCT01458405.
