Intracoronary Cardiosphere-Derived Cells After Myocardial Infarction

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Convalescent myocardial infarction with left ventricular dysfunction (n=25). Intervention: Intracoronary autologous cardiosphere-derived cells (CDCs) vs. Routine standard care alone. Primary outcome: Safety endpoints (serious adverse events within 12 months of infusion) and exploratory 1-year MRI scar size reduction (p=0.36).

Q: What does this research mean for the field?

Intracoronary administration of autologous cardiosphere-derived cells reduces myocardial scar size, increases viable mass, and improves regional function at 1 year after myocardial infarction without significant safety concerns. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Konstantinos G. Malliaras; Raj Makkar; Rachel Ruckdeschel Smith; Ke Cheng; Edwin Wu; Robert O. Bonow; Linda Marbán; Adam M. Mendizabal; Eugenio Cingolani; Peter V. Johnston; Gary Gerstenblith; Karl H. Schuleri; Albert C. Lardo; Eduardo Marbán

doi:10.1016/j.jacc.2013.08.724

September 12, 2013Journal of the American College of CardiologyOpen Access

Intracoronary Cardiosphere-Derived Cells After Myocardial Infarction

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Key result

Cardiosphere-derived cells reduce post-MI scar size by ~9 percentage points vs routine care.

P=0.36
n=25

Why the study?

Cardiosphere-derived cells showed regenerative effects at 6 months in the CADUCEUS trial, but complete results, detailed magnetic resonance imaging analysis, and determinants of efficacy at the final 1-year endpoint were unknown.

Does intracoronary administration of autologous cardiosphere-derived cells safely reduce scar size and increase viable myocardium at 1 year in patients with left ventricular dysfunction after myocardial infarction?

Key Points

To report the full 1-year safety, efficacy, and cardiac magnetic resonance imaging outcomes of intracoronary autologous cardiosphere-derived cell infusion in patients with post-infarction left ventricular dysfunction.
Prospective, randomized, controlled CADUCEUS trial conducted across 2 centers in the United States, enrolling 31 participants with recent reperfused myocardial infarction and left ventricular ejection fraction between 25% and 45% randomly assigned 2:1 to cell therapy or standard care.
Autologous cardiosphere-derived cells (12.5 to 25 × 106) derived from endomyocardial biopsies were infused into the infarct-related artery 1.5 to 3 months post-infarction (n=17, plus 1 treated off-protocol at 14 months) versus routine-care control (n=8).
Patients underwent contrast-enhanced cardiac magnetic resonance imaging at baseline, 6 months, and 12 months to quantify left ventricular scar mass, scar size, viable mass, and regional wall thickening.
Over 13.4 months of follow-up, safety endpoints were equivalent between groups, and intracoronary cell infusion raised no significant safety concerns.
At 1 year, cardiac magnetic resonance imaging showed that cell-treated patients experienced reduced scar mass, smaller scar size, increased viable mass, and improved regional function in infarcted segments compared with controls.
Scar shrinkage significantly correlated with increased myocardial viability, improved regional systolic thickening, and baseline scar size, but did not correlate with time from infarction to infusion.

Study Design

Type

RCT (n=25)

Blinding

Blinded core laboratory observer for MRI analysis (no placebo control group)

Randomization

2:1 ratio

Multicenter

Yes

Structured PICO

Does intracoronary administration of autologous cardiosphere-derived cells safely reduce scar size and increase viable myocardium at 1 year in patients with left ventricular dysfunction after myocardial infarction?

P

Population

25 patients (31 randomized) in the United States with moderate left ventricular dysfunction (LVEF 25-45%) 1.5 to 3 months after a reperfused myocardial infarction, followed for 13.4 months.

I

Intervention

Intracoronary infusion of autologous cardiosphere-derived cells (CDCs) at a dose of 12.5 to 25 × 10^6 cells grown from endomyocardial biopsy specimens, delivered via stop-flow technique using an over-the-wire balloon angioplasty catheter in the infarct-related coronary artery, plus standard care.

C

Comparator

Routine standard care alone (no placebo infusion or biopsy).

O

Outcome

Safety endpoints (serious adverse events, death, major adverse cardiac events [composite of death and hospital admission for heart failure or nonfatal recurrent MI], ventricular arrhythmias on 48-h Holter monitoring, and tumor formation on MRI) over 12 months post-infusion (13.4 months follow-up).safety

Main Result

Absolute Event Rate: 35.3% vs 12.5%

p-value: p=0.36

Limitations

Two patients (1 treated and 1 control) were lost to follow-up and did not complete their 1-year visits.
Small phase 1 study not powered to assess efficacy in a definitive manner.
No placebo control group to assess with certainty whether mild troponin elevations were due to cells or transient vessel occlusion.
Two patients (1 treated and 1 control) were lost to follow-up and did not complete their 1-year visits
Small phase 1 study with low statistical power, not powered to assess functional efficacy in a definitive manner
Lack of a placebo control group

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Implication

Final 1-year results of the phase 1 CADUCEUS trial demonstrate that intracoronary autologous cardiosphere-derived cell therapy post-MI is safe and produces sustained reductions in scar mass alongside increases in viable myocardial mass and regional contractility, though global LVEF was unchanged.

Abstract

Objectives This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial. Background Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown. Methods Autologous CDCs (12.5 to 25 × 106) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients. Results In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI. Conclusions Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials.

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Cite This Study

Malliaras et al. (2013) conducted an RCT in Convalescent myocardial infarction with left ventricular dysfunction (n=25). Intracoronary autologous cardiosphere-derived cells (CDCs) vs. Routine standard care alone was evaluated on Safety endpoints (serious adverse events within 12 months of infusion) and exploratory 1-year MRI scar size reduction (p=0.36). Intracoronary autologous cardiosphere-derived cells were safe and reduced scar size at 1 year compared to routine care post-MI.

synapsesocial.com/papers/6af7d257dabe3aae4aca1d65 https://doi.org/10.1016/j.jacc.2013.08.724

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Intracoronary Cardiosphere-Derived Cells After Myocardial Infarction

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Intracoronary Cardiosphere-Derived Cells After Myocardial Infarction

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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