Efficacy of stem cell in improvement of left ventricular function in acute myocardial infarction--MI3 Trial

Abstract

Background & objectives: Acute myocardial infarction (AMI) is characterized by irreparable and irreversible loss of cardiac myocytes. Despite major advances in the management of AMI, a large number of patients are left with reduced left ventricular ejection fraction (LVEF), which is a major determinant of short and long term morbidity and mortality. A review of 33 randomized control trials has shown varying improvement in left ventricular (LV) function in patients receiving stem cells compared to standard medical therapy. Most trials had small sample size and were underpowered. This phase III prospective, open labelled, randomized multicenteric trial was undertaken to evaluate the efficacy in improving the LVEF over a period of six months, after injecting a predefined dose of 5-10 × 10 [8] autologous mononuclear cells (MNC) by intra-coronary route, in patients, one to three weeks post ST elevation AMI, in addition to the standard medical therapy.

Methods: In this phase III prospective, multicentric trial 250 patients with AMI were included and randomized into stem cell therapy (SCT) and non SCT groups. All patients were followed up for six months. Patients with AMI having left ventricular ejection fraction (LVEF) of 20-50 per cent were included and were randomized to receive intracoronary stem cell infusion after successfully completing percutaneous coronary intervention (PCI).

Results: On intention-to-treat analysis the infusion of MNCs had no positive impact on LVEF improvement of ≥ 5 per cent. The improvement in LVEF after six months was 5.17 ± 8.90 per cent in non SCT group and 4.82 ± 10.32 per cent in SCT group. The adverse effects were comparable in both the groups. On post hoc analysis it was noted that the cell dose had a positive impact when infused in the dose of ≥ 5 X 10 [8] (n=71). This benefit was noted upto three weeks post AMI. There were 38 trial deviates in the SCT group which was a limitation of the study.

Interpretation & conclusions: Infusion of stem cells was found to have no benefit in ST elevation AMI. However, the procedure was safe. A possible benefit was seen when the predefined cell dose was administered which was noted upto three weeks post AMI, but this was not significant and needs confirmation by larger trials.

Fig. 1

Flow chart depicting patients’ enrollment and follow up. SAE, serious adverse event; LFU, lost to follow up; MNC, mononuclear cells.

Fig. 2A

Stratified analysis of SCT group with nested cohort: Effect on primary outcome. Box and whisker plot showing primary outcome at 6 months in 2 groups. Group 1, SCT (n=71) and Group 2 Nested cohort from non SCT group (n=71). Actual increase in EF at 6 months between SCT group (7.03 ± 10.33 %, Median 6, IQR 0-14) and nested cohort from non SCT arm (4.1 ± 9.1%, Median 3.01, -2.15-10.45) was not significantly different.

Fig. 2B

Stratified analysis of Trial deviates with nested cohort: Effect on primary outcome. Box and whisker plot showing primary outcome at 6 months in 2 groups. Group 1,Trial deviates (n=38) and Group 2, Nested cohort from non SCT arm (n=38). Actual increase in EF at 6 months between trial deviates group (2.75 ± 9.6%, Median 3.25, IQR -3.91-9.49) and nested cohort from non SCT arm (4.37 ± 8.87% Median 3.5, -0.75-8.86) was not significantly different.

Fig. 2C

Impact of cell dose administered on primary outcome. Box and whisker plot showing primary outcome at 6 months in 2 groups. Group 1, SCT (n=71) and Group 2, Trial deviates (n=38). Actual increase in EF at 6 months between SCT group (7.03 ± 10.33%, Median 6, IQR 0-14) and Trial deviates (2.75 ± 9.6%, Median 3.25, IQR -3.91-9.49) was significant (P<0.05).

Fig. 2D

Impact of timing of infusion in SCT arm on primary outcome. Box and whisker plot showing primary outcome at 6 months in 2 groups. Group 1, early (infusion given in < 10 days, n=21) and Group 2, late (infusion given between day 10 to day 21, n=50). : Actual increase in EF at 6 months between the early group (6 ± 10.45 %, Median 7.5, IQR 0.49-14) and late group (7.47 ± 10.97, Median 4, IQR -2 - 14) was not significant.