Repeat Cell Therapy for Chronic Heart Failure Being Tested in Randomized Trials

NEW YORK, NY—Preliminary data suggesting an incremental benefit of repeated—vs single—administration of cell therapy in patients with chronic heart failure have inspired initiation of 2 large randomized clinical trials. The strategy addresses evidence that the myocardial environment changes over time after an acute myocardial infarction (AMI), according to investigators who outlined the trials’ rationale and design January 23, 2014, at the Ninth International Conference on Cell Therapy for Cardiovascular Disease.

Will REPEAT Therapy Make a Difference?

In the first presentation, Birgit Assmus, MD, of Goethe University (Frankfurt, Germany), reviewed previous research demonstrating that retention of infused progenitor cells in the myocardium decreases as the time from an AMI increases. Cell homing may be impaired by ‘healed’ infarction with an established scar, lack of inflammation, and reverse remodeling of the left ventricle, she said. Nonetheless, Dr. Assmus and colleagues earlier showed that in this population, bone marrow stem cell (BMC) infusion has small but significant positive effects on LV function and the heart failure marker NT pro-BNP (Assmus B, et al. N Engl J Med. 2006;355:1222-1232 and Assmus B, et al. Circ Res. 2007;100:1234-1241).

Based on this evidence, an ongoing registry was initiated offering repeat BMC treatment 4 months after initial therapy.

This repeat-therapy approach also yielded improvements in LV function and NT pro-BNP levels, she reported, and observed mortality was consistently—albeit not significantly—lower than that predicted by the Seattle Heart Failure Model (SHFM). In addition, in the total cohort over 3 years, estimated rates of survival and event-free survival were substantially higher among patients who received repeat BMC treatment (both P = 0.02).

Against this encouraging background, the randomized phase II/III REPEAT trial, now under way, will test the hypothesis that initial BMC treatment preconditions the cardiac niche in the LV target area, thereby increasing the efficacy of subsequent cell therapy, Dr. Assmus said.

With a planned enrollment of 668 patients, the trial will include only those who have experienced an AMI at least 3 months earlier and now have an open or bypassed infarct vessel, an LVEF of no more than 45% on echocardiography, and stable chronic heart failure (NYHA class II or III) on optimal medical therapy. Participants will be randomized to a single intracoronary infusion of BMC (n = 334) or an initial BMC infusion followed by a second infusion 4 months later (n = 334).

The primary endpoint is mortality at 2 years. Secondary endpoints include cardiac mortality, rehospitalization for heart failure/heart transplantation/LVAD implantation, NYHA status, NT pro-BNP serum levels, and observed vs SHFM-predicted mortality. Safety assessments include in-hospital events as well as life-threatening arrhythmias and serious adverse events at 4 months after each cell infusion.

An interim analysis will be performed after 25% of patients have completed 1 year of follow-up, which will continue for 4 more years.

RIPASSA: Same Strategy, Different Cells

Henricus J. Duckers, MD, PhD, of University Medical Center Utrecht (Utrecht, The Netherlands), described a similar approach for the ongoing RIPASSA trial. As a rationale, he cited evidence that repeat cell administration may enhance engraftment, and that stem cell populations with different mechanisms of action may be better suited to treating later post-MI biological processes. 

Other researchers have shown that in a preclinical model, animals administered mesenchymal stromal cells (MSCs) reaped a 13.1% improvement in LVEF over controls at 1 week (P < 0.01), Dr. Duckers noted, and those that received a second dose 1 week later experienced an additional 3.3% increase at 4 weeks, which was higher than that of the single-therapy group (P < 0.05). Importantly, repeat MSC treatment improved LVEF predominantly in tissue remote from the infarct area and resulted in greater myocardial mass, superior contractility, and higher arteriolar density in both remote and infarcted segments. 

In a small prospective trial of patients at least 4 months post-MI, 2 intracoronary BMC infusions given 4 months apart failed to increase LV function, although the therapy was safe and all patients improved clinically (Diederichsen ACP, et al. Eur J. Heart Fail. 2008;10:661-667). 

The multicenter randomized, placebo-controlled RIPASSA trial, which is enrolling up to 210 patients, aims to evaluate more definitively whether repeat intracoronary infusion of autologous MSCs provides a better outcome than single therapy. Participants must have stable CAD with refractory angina (Canadian Cardiovascular Score ≥ II) on optimal medical therapy and an LVEF of 35% or less.

 The primary safety endpoint is serious adverse events at 30 days after the second infusion, while the primary efficacy endpoint is the absolute change in VO2 max exercise test from baseline to 12 months. 



1. Assmus B. Repetitive BMC therapy in chronic heart failure: Rationale and design of the REPEAT trial. Presented at: Ninth International Conference on Cell Therapy for Cardiovascular Disease; January 23, 2014; New York, NY.

2. Duckers HJ. Rationale for repeated treatment with mesenchymal stem cells in ischemic heart disease: The RIPASSA trial. Presented at: Ninth International Conference on Cell Therapy for Cardiovascular Disease; January 23, 2014; New York, NY.



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  • Dr. Duckers reports no relevant conflicts of interest.
  • Dr. Assmus makes no statement regarding conflicts of interest.

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