Related Study

See also the companion CCTRN-TIME study.

Objectives

To determine if intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) improves global and regional left-ventricular (LV) function when delivered 2-3 weeks following first myocardial infarction (MI).

Background

Several randomized trials have demonstrated that administration of autologous BMCs following acute MI may result in improvement in left-ventricular ejection fraction (LVEF) or regional LV function and may be associated with decreased clinical adverse events. However, the majority of trials have administered BMCs within the first week following primary percutaneous coronary intervention (PCI). To determine the optimal time to administer BMCs, the NHLBI-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) developed two prospective clinical trials, TIME and LateTIME. TIME was designed to compare the effects of BMC delivery in patients with predominantly ST segment MIs at 3 versus 7 days post-MI, while LateTIME was designed to explore whether delayed BMC delivery 2-3 weeks following MI could improve global and regional LV function. The time frame of 2-3 weeks post-MI may be particularly important for those patients who present to centers that lack expertise in cell therapy or those patients initially too sick as a result of cardiogenic shock or other medical issues. These patients may particularly benefit from cell therapy given that several trials have demonstrated that those patients with the most depressed LV function appear to derive the most improvement from BMC delivery.

Participants

87 adult patients with LVEF ≤ 45% by echocardiography following successful primary PCI with stenting of the infarct-related coronary artery were enrolled. 58 patients were randomized to the active intervention and 29 were randomized to placebo.

Design

LateTIME was a phase-II, randomized, double-blinded, placebo-controlled trial developed to determine if delayed (2-3 weeks) intracoronary administration of BMCs to patients with predominantly anterior MIs, can safely produce a measurable improvement in global and regional LV function. All patients underwent bone marrow aspiration on the morning of their treatment day and BMCs were isolated using a closed, automated Ficoll cell processing system to ensure a uniform cellular product. After the cells passed stipulated lot release criteria, including viability (>70%) and sterility, patients were randomized in a 2:1 ratio to cell therapy or placebo. The target dose for the treatment group was 150 × 106 total nucleated cells. Patients randomized to placebo received 5% HSA/saline to which 100 microliters of autologous blood was added to ensure that the color and consistency of the solution matched that of the BMC product. Within 12 hours of aspiration, the BMCs or placebo was delivered to the infarct-related artery via a percutaneous transluminal coronary angioplasty catheter in six aliquots of five ml each using stop-flow technique. All patients were treated with aspirin and 75 mg of clopidogrel in addition to guideline recommended post-MI medications. All patients were to be followed for two years to assess clinical events.

The primary endpoints were changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone from baseline to 6 months as measured by cardiac MRI. Secondary endpoints included changes in LV volumes and infarct size.

Conclusions

Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs compared to intracoronary placebo infusion, 2-3 weeks after PCI did not improve global or regional function at 6 months.

Traverse JH, Henry TD, Ellis SG, et al. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA. 2011;306(19):2110–2119. doi:10.1001/jama.2011.1670

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