REVIVE Trial: Retrograde Delivery of Autologous Bone Marrow in Patients With Heart Failure

Abstract

Cell therapy is an evolving option for patients with end-stage heart failure and ongoing symptoms despite optimal medical therapy. Our goal was to evaluate retrograde bone marrow cell delivery in patients with either ischemic heart failure (IHF) or nonischemic heart failure (NIHF). This was a prospective randomized, multicenter, open-label study of the safety and feasibility of bone marrow aspirate concentrate (BMAC) infused retrograde into the coronary sinus. Sixty patients were stratified by IHF and NIHF and randomized to receive either BMAC infusion or control (standard heart failure care) in a 4:1 ratio. Accordingly, 24 subjects were randomized to the ischemic BMAC group and 6 to the ischemic control group. Similarly, 24 subjects were randomized to the nonischemic BMAC group and 6 to the nonischemic control group. All 60 patients were successfully enrolled in the study. The treatment groups received BMAC infusion without complications. The left ventricular ejection fraction in the patients receiving BMAC demonstrated significant improvement compared with baseline, from 25.1% at screening to 31.1% at 12 months (p = .007) in the NIHF group and from 26.3% to 31.1% in the IHF group (p = .035). The end-systolic diameter decreased significantly in the nonischemic BMAC group from 55.6 to 50.9 mm (p = .020). Retrograde BMAC delivery is safe. All patients receiving BMAC experienced improvements in left ventricular ejection fraction, but only those with NIHF showed improvements in left ventricular endsystolic diameter and B-type natriuretic peptide. These results provide the basis for a larger clinical trial in HF patients. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1021-1027 SIGNIFICANCEThis work is the first prospective randomized clinical trial using high-dose cell therapy delivered via a retrograde coronary sinus infusion in patients with heart failure. This was a multinational, multicenter study, and it is novel, translatable, and scalable. On the basis of this trial and the safety of retrograde coronary sinus infusion, there are three other trials under way using this route of delivery.

Catheter‐based retrograde coronary sinus infusion is a practical delivery technique for introducing biological molecules into the cardiac system

“…Several clinical studies have been published that examined the safety and efficacy of retrograde infusion therapies. The retrograde delivery techniques employed in these studies included (a) fixed infusion volume and fixed plasmid concentration, (b) fixed infusion volume with variable plasmid concentration, and (c) variable infusion volume with fixed plasmid concentration . However, none of these studies included a characterization of the global cardiac distribution of the biological molecules after infusion.…”

“…The secondary objective of this study was to evaluate the Advance® CS Coronary Sinus Infusion Catheter . The Advance® CS Coronary Sinus Infusion Catheter was used in the REVIVE and RESCUE‐HF human clinical trials, wherein autologous bone marrow cell concentrate and allogeneic umbilical cord sub‐epithelial cells, respectively, were successfully delivered via a retrograde approach through the CS. The catheter has 510(k) clearance and CE mark for “temporary occlusion of the coronary sinus for delivery of contrast media, drugs, therapeutic agents, or for possible introduction of devices into the coronary venous system.” The catheter is currently available in shaft lengths of 80 and 135 cm.…”

“…With coronary sinus (CS) occlusion or a disruption in venous return through the coronary veins, the Thebesian system facilitates the drainage of myocardial venous blood. Preclinical testing has shown that the CS could be occluded for up to 1 hr without detrimental effects . In general, the high volume capacity and low pressure environment of the coronary venous system are features conducive to retrograde infusion therapies, as demonstrated in recent human clinical studies …”

“…Preclinical testing has shown that the CS could be occluded for up to 1 hr without detrimental effects. 6 In general, the high volume capacity and low pressure environment of the coronary venous system are features conducive to retrograde infusion therapies, as demonstrated in recent human clinical studies. [6][7][8][9] The primary objective of this study was to characterize in a porcine model the cardiac biodistribution and functional protein expression of luciferase plasmid 24-hr after catheter-based balloon occlusion of the CS and retrograde infusion into the cardiac venous system.…”

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

“…Even in clinical trials, structural and functional parameters, carried out by several imaging techniques, remain as conventional endpoints. A significant part of the clinical trials do not resort to any kind of molecular monitoring [81][82][83][84]88,89,92,94] and when they do, they are limited to some conventional cardiac markers (Table 1), mainly BNP [90,96], NT-proBNP [77][78][79][80]86,87,91,93], in addition to creatine kinase [77,86,87,90,[95][96][97], troponins I [90,96,97] and T [77,80,86,87] and some inflammation markers, such as TNF-α, IL-6 [79] and C-reactive protein [77,86]. Therefore, we suggest to screen biofluids (Box 5, Fig.…”