Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.Keywords Low-density lipoprotein Á Proprotein convertase subtilisin kexin type 9 (PCSK9) Á Prevention Á Monoclonal antibody Á Evolocumab Á Alirocumab
BackgroundAs a consequence of population ageing, the number of older patients presenting with acute coronary syndrome (ACS) is increasing. The historical underrepresentation of older patients in many pivotal ACS clinical trials undermines the practice of evidence-based medicine in this high-risk cohort. This study evaluates the feasibility of recruitment of older patients to a longitudinal, clinical study.MethodsThe study to Improve Cardiovascular Outcomes in high-risk patieNts with ACS (ICON-1) is an observational, prospective cohort study investigating predictors of poor outcome in older patients with ACS. All patients aged ≥75 years, referred to a tertiary cardiovascular centre in the North East of England for coronary angiography with a view to urgent percutaneous coronary intervention, were screened for inclusion. A screening log was prospectively maintained, and a detailed analysis was performed to identify the factors associated with recruitment and non-recruitment to ICON-1.ResultsOf the 629 patients screened over 34 months, 457 (72.7%) satisfied the a priori-defined study inclusion/exclusion criteria. Of those eligible to participate, 300 (68.5%) provided informed consent and were recruited to the study; 59 (13.5%) were unable to consent due to a lack of capacity or limitations in communication, and 79 patients (18.0%) declined to participate in the study. Those lacking adequate capacity to consent were older than those able to provide informed consent (83.0±4.7 vs 81.0±4.7 years, p=0.002). Women were more likely to decline than men (25.1% vs 10.0%, p<0.001).ConclusionsThe recruitment of patients was robust, comparing favourably to previous longitudinal studies within this age group. Although enrolling older people to research remains challenging, this cohort is enthusiastic to participate. The contribution of older patients must not be ignored, particularly in the setting of an ever-ageing population, in whom cardiovascular disease burden is high.Trial registration numberNCT01933581; Pre-results.
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A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: 'in patients undergoing oesophagectomy, does a minimally invasive approach convey a benefit in hospital length of stay (LOS), when compared to an open approach?' A total of 647 papers were identified, using an a priori defined search strategy; 24 papers represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group, study type, relevant outcomes and key results are tabulated. Of the studies identified, data from two randomized controlled trials were available. The first randomized study compared the use of open thoracotomy and laparotomy versus thoracoscopy and laparoscopy. Those undergoing minimally invasive oesophagectomy (MIO) left hospital on average 3 days earlier than those treated with the open oesophagectomy (OO) technique (P = 0.044). The other randomized trial, which compared thoracotomy with thoracoscopy and laparoscopy, demonstrated a reduction of 1.8 days in the LOS when employing the MIO technique (P < 0.001). With the addition of the remaining 22 non-randomized studies, comprising 3 prospective and 19 retrospective cohort studies, which are heterogeneous with regard to their design, study populations and outcomes; data are available representing 3173 MIO and 25 691 OO procedures. In total, 13 studies (including the randomized trials) demonstrate a significant reduction in hospital LOS associated with MIO; 10 suggest no significant difference between techniques; and only 1 suggests a significantly greater length of stay associated with MIO. The only two randomized trials comparing MIO and OO demonstrated a reduction in length of stay in the MIO group, without compromising survival or increasing complication rates. All bar one of the non-randomized studies demonstrated either a significant reduction in length of stay with MIO or no difference. The benefit in reduced length of stay was not at the cost of worsened survival or increased complications, and conversion rates in all studies were low.
Despite rapid advances in cardiovascular research and therapeutic strategies, ischemic heart disease (IHD) remains the leading cause of mortality worldwide. MicroRNAs (miRNAs) are small, noncoding RNAs which post transcriptionally regulate gene expression. In the past few years, miRNAs have emerged as key tools for the understanding of the pathophysiology of IHD, with potential uses as new biomarkers and therapeutic targets. Several studies report a regulatory role of miRNAs, with regard to fundamental components of IHD pathogenesis and progression, such as lipoprotein metabolism, atherogenesis, vascular calcification, platelet function, and angiogenesis. Due to their high stability in biofluids, circulating miRNAs have attracted attention as promising biomarkers of IHD, especially in cardiovascular risk prediction and the diagnosis of myocardial infarction. Furthermore, experimental studies have demonstrated the potential of miRNA-targeted therapy in improving hyperlipidemia, atherosclerosis, and angiogenesis. In this review, the current knowledge on the role of miRNAs in IHD and translational perspectives of their use is discussed.
Coronary artery disease is the result of atherosclerotic changes to the coronary arterial wall, comprising endothelial dysfunction, vascular inflammation and deposition of lipid-rich macrophage foam cells. Certain high-risk atherosclerotic plaques are vulnerable to disruption, leading to rupture, thrombosis and the clinical sequelae of acute coronary syndrome. Though recognised as the gold standard for evaluating the presence, distribution and severity of atherosclerotic lesions, invasive coronary angiography is incapable of identifying non-stenotic, vulnerable plaques that are responsible for adverse cardiovascular events. The recognition of such limitations has impelled the development of intracoronary imaging technologies, including intravascular ultrasound, optical coherence tomography and near-infrared spectroscopy, which enable the detailed evaluation of the coronary wall and atherosclerotic plaques in clinical practice. This review discusses the present status of invasive imaging technologies; summarises up-to-date, evidence-based clinical guidelines; and addresses questions that remain unanswered with regard to the future of intracoronary plaque imaging.
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