Responder Definition in Clinical Stem Cell Trials in Cardiology: Will the Real Responder Please Stand Up?

Defining responders to cell treatment based on functional measurements in cardiac stem cell trials has been troublesome, and it may be considered as the Holy Grail. The functional recovery after myocardial infarction (MI) can range from only mild impairments and recovery to progression into heart failure at the next clinical visit regardless of the therapy given. In a clinical trial with adequate randomization, this will not pose an issue on the overall outcome of the trial. However, subgroup analyses become difficult, as the whimsical course of the disease influences the end result on top of the effect of the cell treatment. In other words, even patients who have suffered significant loss of functional cardiac capacity may still have benefited from cell therapy compared with the potential reference point of the same patient in the placebo group. Among other reasons, this can make subgroup analyses hard to interpret and potentially less informative. Proper subgroup analyses are ideally addressing true response, based on (pre)clinical hints, and are prospectively declared. Furthermore, the power needed to show specific responding groups might be beyond the number of participants included in hitherto conducted cell therapy trials.