Safety and Efficacy of Bone Marrow Derived Progenitor Cells in Patients with Chronic Ischaemic Heart Failure

MD (res)Bone marrow stem/progenitor cell (BMSC) therapy for cardiac repair in humans is yet to fulfil the exciting potential demonstrated in preclinical experiments. This thesis presents three clinical studies addressing some of the unresolved issues regarding the ideal delivery method, the effect of patient-related factors on progenitor cell concentration/function and the possible biological mechanism(s) of action. The first study describes the intramyocardial arm of the REGENERATE-IHD trial- a randomised controlled trial assessing the efficacy of mobilised BMSCs in patients with ischaemic heart failure. In summary, 30 patients were randomised 1:1 to receive injection of BMSCs suspended in autologous serum or serum alone (control group). All patients received a 5-day course of G-CSF prior to bone marrow harvest and intramyocardial injection. At 1-year, there was a significant increase in ejection fraction, the primary end-point, in patients treated with BMSCs. There were also significant improvements in the secondary end-points of NT-proBNP and symptoms. In the second study, progenitor cell concentration and function were assessed in patients with ischaemic heart failure (IHD), dilated cardiomyopathy (DCM) and acute myocardial infarction (AMI). Findings include ageing having an inverse association with circulating CD34+ cell concentration as well as blunting the effects of G-CSF on BMSC mobilisation. DCM patients had 2 3 significantly higher baseline circulating progenitor cell concentrations compared to IHD/AMI. The final study presents preliminary data regarding a novel imaging technique to detect angiogenesis which is recognised as a potential therapeutic effect of BMSCs. Nine patients with heart failure underwent nuclear imaging using a radio-tracer peptide with a high affinity for v 3, an angiogenesis-related integrin, before and after intracoronary infusion of BMSCs/serum. Preliminary results showed detectable baseline uptake of the radio-tracer suggesting a novel finding of persistent angiogenesis following remote myocardial infarction and also hint at a tantalising possibility that BMSC infusion may lead to therapeutic angiogenesis.Heart Cells Foundation, Barts & The London Charity, Chugai Pharma UK and Cordis Corporation

British Cardiovascular Interventional Society Consensus Position Statement on Out-of-Hospital Cardiac Arrest 1: Pathway of Care

Out-of-hospital cardiac arrest (OHCA) affects 80,000 patients per year in the UK; despite improvements in care, survival to discharge remains lower than 10%. NHS England and several societies recommend all resuscitated OHCA patients be directly transferred to a cardiac arrest centre (CAC). However, evidence is limited that all patients benefit from transfer to a CAC, and there are significant organisational, logistic and financial implications associated with such change in policies. Furthermore, there is significant variability in interventional cardiovascular practices for OHCA. Accordingly, the British Cardiovascular Interventional Society established a multidisciplinary group to address variability in practice and provide recommendations for the development of cardiac networks. In this position statement, we recommend: the formal establishment of dedicated CACs; a pathway of conveyance to CACs; and interventional practice to standardise our approach. Further research is needed to understand the role of CACs and which interventions benefit patients with OHCA to support wide-scale changes in networks of care across the U

British Cardiovascular Intervention Society Consensus Position Statement on Out-of-hospital Cardiac Arrest 2: Post-discharge Rehabilitation

Out-of-hospital cardiac arrest (OHCA) is a major public health issue that poses significant challenges both in immediate management and long-term follow-up. Survivors of OHCA often experience a combination of complex medical, physical and psychological needs that have a significant impact on quality of life. Guidelines suggest a multi-dimensional follow-up to address both physical and non-physical domains for survivors. However, it is likely that there is substantial unwarranted variation in provision of services throughout the UK. Currently, there is no nationally agreed model for the follow-up of OHCA survivors and there is an urgent need for a set of standards and guidelines in order to ensure equal access for all. Accordingly, the British Cardiovascular Interventional Society established a multi-disciplinary working group to develop a position statement that summarises the most up-to-date evidence and provides guidance on essential and desirable services for a dedicated follow-up pathway for survivors of OHC

An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial

This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute of Health Research. This work was funded by unrestricted grants from the Heart Cells Foundation, Barts, and the London Charity and Chugai Pharmaceuticals

Percutaneous revascularization for ischemic left ventricular dysfunction: Cost-effectiveness analysis of the REVIVED-BCIS2 trial

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: −0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom

Arrhythmia and death following percutaneous revascularization in ischemic left ventricular dysfunction: Prespecified analyses from the REVIVED-BCIS2 trial

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82–1.30]; P =0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920048