Elsevier

The Lancet

Volume 379, Issue 9819, 10–16 March 2012, Pages 895-904
The Lancet

Articles
Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial

https://doi.org/10.1016/S0140-6736(12)60195-0Get rights and content

Summary

Background

Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction.

Methods

In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2–4 weeks after myocardial infarction (with left ventricular ejection fraction of 25–45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5–3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360.

Findings

Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months.

Interpretation

We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes.

Funding

US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.

Introduction

Myocardial infarction is common, and many patients develop substantial scarring despite optimum treatment.1 The presence and extent of myocardial scarring predisposes to progressive unfavourable left ventricular remodelling, heart failure, and sudden death.2, 3 Present treatment approaches seek to limit the initial injury and block secondary maladaptive pathways. Conversely, regenerative therapy seeks to shrink scar and regrow healthy heart muscle. Despite more than a decade of clinical trials of cardiac regenerative therapy, this ambitious goal remains elusive. Trials with bone marrow mononuclear cells4, 5, 6, 7 or mesenchymal stem cells in patients after myocardial infarction have shown an excellent safety profile,8 but efficacy is inconsistent5, 7 and sometimes transient.6 Most studies have assessed global functional endpoints such as ejection fraction. However, the actual targets of regeneration—scar mass and viable myocardial mass—can be measured rigorously by contrast-enhanced MRI. In the few controlled studies of stem cells that used MRI to assess outcomes, scar size (ie, scar mass normalised by total left ventricular mass) did not change substantially, if at all, after cell therapy, with little or no relation to ejection fraction.4, 5, 6, 9, 10, 11 Even positive studies have failed to show increases in viable myocardium in addition to shrinkage of scar tissue.4

The notion of endogenous mammalian heart regeneration, which has traditionally been viewed as heretical, has gained support recently.12 Various populations of putative endogenous cardiac progenitor cells have been identified, with widespread preclinical evidence for efficacy in cardiac repair and functional improvement after myocardial infarction.13 The present study uses a straightforward approach for generation of heart-derived cells as therapeutic candidates. Percutaneous endomyocardial biopsies are used to obtain source tissue and the cardiosphere culture method14 to yield tens of millions of cardiosphere-derived cells (CDCs) in a timely manner.15 CDCs are clonogenic, have multilineage potential, can be safely delivered via the intracoronary route, and mediate reductions in scar size in preclinical models of myocardial infarction.16, 17, 18, 19

In the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) study, we aimed to assess safety of autologous intracoronary CDCs administered to patients 1·5–3 months after myocardial infarction, and test the hypothesis that CDCs convert scar tissue to viable myocardium.

Section snippets

Study design and participants

An investigator-sponsored Investigational New Drug Application (number 13930) was granted by the US Food and Drug Administration (FDA) for the CADUCEUS protocol, which involved two sites: the Cedars-Sinai Heart Institute (CA, USA) and The Johns Hopkins Hospital (MD, USA).

Patients with a recent myocardial infarction (≤4 weeks previously) and left ventricular dysfunction (ejection fraction 25–45% by clinically indicated imaging after infarction) were eligible for inclusion if they were aged 18

Results

Between May 5, 2009, and Dec 16, 2010, we screened 436 patients and randomly allocated 31 eligible patients to treatment groups (figure 2). Two patients allocated to receive CDCs withdrew consent before first biopsy sampling and another became ineligible for infusion because of occlusion of the infarct-related artery detected at the time of intended infusion. Four patients received a low cell dose (12·5 million cells), one received an intermediary cell dose (17·3 million cells), and 12 received

Discussion

Regeneration is defined as regrowth of lost or destroyed parts or organs.26 Although nature provides numerous examples of spontaneous regeneration after injury, we have, as physicians, thus far failed in our efforts to achieve therapeutic regeneration. Our study provides an initial indication that therapeutic regeneration might indeed be possible in cardiac tissue.

We report a phase 1 clinical trial of heart-derived cells that reached its prespecified primary endpoints: the controlled

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