IxCELL-DCM: rejuvenation for cardiac regenerative therapy?

The possibility of tissue rejuvenation through regenerative therapies has generated great excitement among both the scientific community and the public, especially for conditions with perceived irreversible tissue loss such as myocardial injury. Groundbreaking approaches have experimentally identified reparative capacity in the human heart, suggesting that if this process could be harnessed, the treatment of conditions such as acute myocardial infarction and chronic congestive heart failure might be revolutionised. A series of studies first presented a decade ago showed that administration of various selected and unselected bone marrow preparations were associated with improvement, albeit relatively modest, in left ventricular function. Individually not powered to detect improvements in cardiac events, in aggregate, these studies suggest that, despite the rather modest improvement in left ventricular function, a reduction in clinical events might be attained if adequately powered clinical trials could be done. Nonetheless, the field has generated some scepticism for several reasons including individual, poorly conducted and reported studies, and discordant findings among trials, including several National Institutes of Health-sponsored trials, one of which showed no benefit of unselected bone marrow cells on a series of surrogate markers in congestive heart failure. In The Lancet, Amit Patel and colleagues present the results of the IxCELL-DCM trial, a randomised, rigorously conducted double-blind study comparing intramyocardial injection of Ixmyelocel-T with intramyocardial placebo injections. Ixmyelocel-T is an expanded multicellular therapeutic product produced from a patient’s own bone marrow by selectively expanding bone marrow mononuclear cells for 2 weeks. The expanded cell product enriched for mesenchymal and macrophage lineages might enhance potency. In the per-protocol population encompassing all patients with adequate intramyocardial delivery of the investigational product (defined as at least 50% of the prepared product), the authors showed an improvement in the prespecified composite primary endpoint of total deaths, cardiovascular admissions to hospital, and outpatient visits requiring treatment for congestive heart failure. The results were robust for a variety of analyses, including analysis of a modified intention-totreat population of all patients receiving any injections, conventional Kaplan-Meier analysis, total mortality (eight in the placebo group vs four in the Ixmyelocel-T group), and number of serious adverse events, which all favoured patients given Ixmyelocel-T. Importantly, the improved clinical outcome was noted despite only marginal changes in left ventricular functional parameters. These results substantiate the aggregate findings of previous studies. Nevertheless, the modest size of IxCELL-DCM affects several aspects of trial interpretation. First, the population analysed included only those who received therapy, and an intention-to-treat analysis was not the predefined analysis population; thus, the results do not capture three deaths and nine patients who were removed from all of the analysis populations due to inadequate cell product or adverse events. It is unlikely that a trial of this design would meet regulatory requirements for approval. Second, the primary endpoint could have been driven by two patients receiving placebo who each experienced five and seven admissions, to hospital for congestive heart failure, a limitation of an analysis dependent on total number of events. The consistency of trends among the modified intentionto-treat and Kaplan-Meier analyses are reassuring in this regard, and novel approaches to clinical endpoint trials such as this are urgently needed if outcome studies are Published Online April 4, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)30138-6