European Heart Journal最新文献

Background and aims: Frailty is increasingly prevalent in people presenting with acute coronary syndrome (ACS). This high-risk group is typically excluded from trials of interventions in ACS, and there is uncertainty about the risks and benefits of invasive management.

Methods: Patients with an ACS diagnosis between 2010 and 2015 in England were identified from Hospital Episode Statistics, with linked Office for National Statistics mortality data. Frailty was defined by the Hospital Frailty Risk Score. Causal inference analysis used regional variation in revascularization as an instrumental variable to estimate average treatment effects of revascularization on cardiovascular mortality up to 5 years in people presenting with ACS and low-, intermediate-, or high-risk frailty.

Results: The analysis included 565 378 ACS patients, of whom 11.6% (n = 65 522) were at intermediate risk and 4.7% (n = 26 504) were at high risk of frailty. Intermediate and high frailty risks were associated with reduced likelihood of echocardiography, invasive angiography, or revascularization and increased likelihood of mortality and major adverse cardiovascular events compared with low frailty risk. Cardiovascular death at 5 years was 78.6%, 77.3%, and 75.7% in people at low, intermediate, and high frailty risk, respectively. Instrumental variable analysis suggested that revascularization resulted in a higher absolute reduction in cardiovascular mortality in high and intermediate frail risk patients compared with low risk at 1-year post-ACS.

Conclusions: Frailty is common in people presenting with ACS, where cardiovascular causes are the principal mode of death. Revascularization is associated with short- and long-term survival benefits in people at intermediate and high risk of frailty after adjustment for measured and unmeasured confounders.

Background and aims: Standardized definitions for outcome measures in randomized clinical trials and observational studies are essential for robust and valid evaluation of medical products, interventions, care, and outcomes. The European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) project of the European Society of Cardiology aimed to create international data standards for cardiovascular clinical study outcome measures.

Methods: The EuroHeart methods for data standard development were used. From a Global Cardiovascular Outcomes Consortium of 82 experts, five Working Groups were formed to identify and define key outcome measures for: cardiovascular disease (generic outcomes), acute coronary syndrome and percutaneous coronary intervention (ACS/PCI), atrial fibrillation (AF), heart failure (HF) and transcatheter aortic valve implantation (TAVI). A systematic review of the literature informed a modified Delphi method to reach consensus on a final set of variables. For each variable, the Working Group provided a definition and categorized the variable as mandatory (Level 1) or optional (Level 2) based on its clinical importance and feasibility.

Results: Across the five domains, 24 Level 1 (generic: 5, ACS/PCI: 8, AF: 2; HF: 5, TAVI: 4) and 48 Level 2 (generic: 18, ACS-PCI: 7, AF: 6, HF: 2, TAVI: 15) outcome measures were defined.

Conclusions: Internationally derived and endorsed definitions for outcome measures for a range of common cardiovascular diseases and interventions are presented. These may be used for data alignment to enable high-quality observational and randomized clinical research, audit, and quality improvement for patient benefit.

Background and aims: Glycoprotein VI (GPVI) is a platelet collagen/fibrin(ogen) receptor and an emerging pharmacological target for the treatment of thrombotic and thrombo-inflammatory diseases, notably ischaemic stroke. A first anti-human GPVI (hGPVI) antibody Fab-fragment (ACT017/glenzocimab, KD: 4.1 nM) recently passed a clinical phase 1b/2a study in patients with acute ischaemic stroke and was found to be well tolerated, safe, and potentially beneficial. In this study, a novel humanized anti-GPVI antibody Fab-fragment (EMA601; KD: 0.195 nM) was developed that inhibits hGPVI function with very high potency in vitro and in vivo.

Methods: Fab-fragments of the mouse anti-hGPVI IgG Emf6.1 were tested for functional GPVI inhibition in human platelets and in hGPVI expressing (hGP6tg/tg) mouse platelets. The in vivo effect of Emf6.1Fab was assessed in a tail bleeding assay, an arterial thrombosis model and the transient middle cerebral artery occlusion (tMCAO) model of ischaemic stroke. Using complementary-determining region grafting, a humanized version of Emf6.1Fab (EMA601) was generated. Emf6.1Fab/EMA601 interaction with hGPVI was mapped in array format and kinetics and quantified by bio-layer interferometry.

Results: Emf6.1Fab (KD: 0.427 nM) blocked GPVI function in human and hGP6tg/tg mouse platelets in multiple assays in vitro at concentrations ≥5 µg/mL. Emf6.1Fab (4 mg/kg)-treated hGP6tg/tg mice showed potent hGPVI inhibition ex vivo and were profoundly protected from arterial thrombosis as well as from cerebral infarct growth after tMCAO, whereas tail-bleeding times remained unaffected. Emf6.1Fab binds to a so far undescribed membrane proximal epitope in GPVI. The humanized variant EMA601 displayed further increased affinity for hGPVI (KD: 0.195 nM) and fully inhibited the receptor at 0.5 µg/mL, corresponding to a >50-fold potency compared with ACT017.

Conclusions: EMA601 is a conceptually novel and promising anti-platelet agent to efficiently prevent or treat arterial thrombosis and thrombo-inflammatory pathologies in humans at risk.