Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

AIMS: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. METHODS AND RESULTS: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. CONCLUSION: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01458405.

Effects of estrogen replacement with and without medroxyprogesterone acetate on brachial flow-mediated vasodilator responses in postmenopausal women with coronary artery disease.

BACKGROUND: Hormone therapy has been shown to have no cardioprotective effect and may, in fact, be harmful in older postmenopausal women. Estrogen has been shown to enhance endothelial-dependent flow-mediated vasodilation (FMD) in healthy and younger women. The effect of estrogen on older and less healthy postmenopausal women with atherosclerosis is unclear. METHODS: The Estrogen Replacement and Atherosclerosis trial randomized 309 postmenopausal women with established coronary atherosclerosis (mean, 65.8 years) to unopposed estrogen (conjugated estrogen, 0.625 mg), estrogen plus 2.5 mg medroxyprogesterone actate (MPA), or placebo. After mean of 3.2 years of follow-up, brachial FMD was measured using 2-dimensional ultrasound in women available for follow-up at 4 of the 5 clinic sites (n = 198). RESULTS: The %FMD of the brachial artery was not statistically different in the placebo arm compared with either unopposed estrogen or estrogen + MPA arm in both the adjusted and the unadjusted models. Subsequent analysis combining the estrogen arm with the estrogen + MPA arm and comparing with the placebo arm was also not significant in both the adjusted and the unadjusted models. Similar results were obtained when analyses were limited to women who took >80% of the study medication over the course of the trial (n = 133). CONCLUSION: An average of 3.2 years of treatment with unopposed estrogen or estrogen plus progestins did not result in significant improvements in endothelial vasodilation compared with placebo. This apparent absence of an effect on brachial artery endothelial function in older postmenopausal women with established coronary heart disease may help explain the lack of benefit of estrogen for secondary prevention of coronary heart disease.