NEW ORLEANS (FRONTLINE MEDICAL NEWS) – Longer follow-up has not altered initial negative findings of the randomized phase II TIME trial, which tested the efficacy of early intracoronary stem cell therapy, given on day 3 or 7 after an ST-segment acute MI (STEMI). However, loss of the sickest patients from follow-up may have influenced the findings.

“When TIME (Transplantation in Myocardial Infarction Evaluation) was developed several years ago, the optimal timing for cell delivery following myocardial infarction was not known and had not been directly tested in a prospective clinical trial,” explained lead investigator Jay H. Traverse, MD , director of research at the Minneapolis Heart Institute Foundation and a senior consulting cardiologist at the Abbott Northwestern Hospital, Minneapolis.

Results at 6 months among the 120 randomized patients showed improvements but no significant differences between the trial’s cell therapy and placebo groups with respect to measures of global and regional left ventricular (LV) function on cardiac MRI, he recapped at the American Heart Association scientific sessions.

With the new, additional follow-up out to 2 years in 85 patients, both groups saw further gains in LV ejection fraction and further reductions in LV infarct size, as well as stable LV end-diastolic volume index, but still with no significant differences between them.

Of note, however, 10 of the patients lost to follow-up were lost because they received implantable cardioverter defibrillators (ICDs) and, given technologic limitations at the time, could no longer undergo cardiac MRI, Dr. Traverse noted. “These 10 patients are important as we look at the long-term follow-up of TIME because these patients were more likely to have the most severe LV dysfunction and most remodeled left ventricles. This [subset] represents a limitation to long-term follow-up studies in this population.”

Challenges to research

Two challenging issues seen in many trials of cell therapy for cardiovascular disease are their underpowered nature and the changing natural history of the disease, according to session comoderator Timothy D. Henry, MD , head of cardiology at Cedars-Sinai in Los Angeles.

“One of the things with the TIME trial that’s striking, really, is that even though these are high-risk patients, there was almost no mortality in 2 years,” he commented. “Second of all… there were no differences in ejection fraction, but that’s because you are missing 30% of people. And your missing 30% of people are the sick people, so of course if you are just going to follow normal people for 2 years, you’re going to have normal results.”

“What you are seeing is a little bit illusory because all the sick patients got ICDs and we could no longer image them at that time,” Dr. Traverse agreed. “That will be less of an issue in some of our future trials that we have started now, like CONCERT and SENECA , where we are now able to do MRI analysis of people with devices. So that will certainly help.”

Nonetheless, all trials in similar patient populations are plagued by substantial rates of dropout over time and faced with improving outcomes generally, because of better medical therapy, he acknowledged. “You can see as far as the natural history, even taking into account the ICD changes that would have lowered volumes, people are pretty stable on medical therapy. Their ejection fractions and volumes out to 2 years were really quite stable. We have certainly impacted that.”

That issue raises the question of whether investigators should be using other endpoints going forward, according to session panelist Doris A. Taylor, PhD , director of Regenerative Medicine Research at the Texas Heart Institute in Houston.

“One of the things I’ve seen over and over in this field is constantly evolving questions about which endpoints we should follow and what constitutes positive effects,” she commented. “So given the natural history, what are the endpoints we should be using?”

“Patients don’t care what their ejection fraction is per se. But they want to know if they have to get an ICD or if they will be hospitalized for heart failure, and their family is affected if they die,” Dr. Traverse replied. “We definitely need these hard endpoints. The problem is that you need so many patients with these hard endpoints that [the trials] are just financially not very doable. So that’s a big issue.”

Trial details

Patients enrolled in TIME had a first anterior STEMI, underwent reperfusion by angioplasty and stenting, and had LV dysfunction with an ejection fraction of 45% or lower. They all received either autologous bone marrow mononuclear cells or placebo on day 3 or day 7 after their MI by intracoronary infusion.

Of the initial 120 randomized patients, 10 patients were lost to follow-up because of receipt of an ICD, 3 had died (1 each from cardiovascular causes, pancreatitis, and hemorrhagic stroke), 7 were lost to follow-up for other reasons, and 15 had acquired other contraindications to MRI, according to Dr. Traverse.

At 2 years, the remaining patients in both the cell therapy and placebo groups had roughly 5% absolute increases in LV ejection fraction from baseline and roughly 45% reductions in infarct size from baseline, with no significant differences between groups.

When all patients were combined, about half were determined to have had microvascular obstruction at baseline. This finding was an adverse prognostic factor, associated with poorer recovery of LV function over time, greater adverse LV remodeling, and a higher likelihood of receiving an ICD, Dr. Traverse reported.

He has received a research grant from the National Heart, Lung, and Blood Institute, which sponsored the TIME trial.