PCSK9 Antibodies for the Treatment of Hypercholesterolemia

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomes for intracellular degradation. This results in decreased numbers of LDLR available on the hepatic cell surface to bind LDL particles and remove them from the circulation and therefore to a subsequent increase in circulating LDL-cholesterol (LDL-C) plasma levels. Since 2003, when the role of PCSK9 in LDL-C metabolism was discovered, there have been major efforts to develop efficient and safe methods to inhibit it. Amongst those, monoclonal antibodies against PCSK9 are the furthest in development, with multiple phase 3 trials already published and with cardiovascular endpoint trials currently underway. Two fully human monoclonal antibodies, evolocumab (AMG 145) and alirocumab (REGN727/SAR236553), have been extensively studied in a wide range of subjects, such as those with statin intolerance, as an add-on to statin therapy, as a monotherapy and in patients with familial hypercholesterolemia. PCSK9 antibodies result in a consistent and robust decrease in LDL-C plasma levels ranging from 40% to 70%, either on top of statins or as a monotherapy. If the safety data from the on-going phase 3 trials remain as reassuring as the data available till now, PCSK9 antibodies will offer a novel, powerful therapeutic option to decrease LDL-C plasma levels and, hopefully, cardiovascular risk.     

The PCSK9 Inhibitors: A Novel Therapeutic Target Enters Clinical Practice

There is a critical need for alternative, potent agents that can reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with heterozygous familial hyperlipidemia and statin intolerance and those not reaching lipid-lowering treatment goals who are at high risk for cardiovascular (CV) events. The first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved in July 2015 by the US Food and Drug Administration as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hyperlipidemia or clinical atherosclerotic CV disease, who require additional lowering of LDL-C levels. In clinical trials, PCSK9 inhibitors have been shown to reduce LDL-C levels by as much as 60% to 70% when administered as monotherapy or as an add-on treatment to statins and other lipid-lowering therapies. In studies of PCSK9 genetic mutations, loss of function in the PCSK9 allele was associated with a relative decrease of 88% in the risk for atherosclerotic CV events during 15 years of patient follow-up. The use of PCSK9 inhibitors may eventually support the LDL-C hypothesis that the lower the LDL-C level, the lower the CV risk. Although some recent clinical practice guidelines have deemphasized the importance of numeric LDL-C targets, many clinicians are reluctant to discard them, and this position is supported by recent clinical evidence. We eagerly await the results of the ODYSSEY, FOURIER, and SPIRE clinical outcome trials, which we anticipate will provide further validation that “lower is better” with respect to reducing LDL-C levels and improving clinical outcomes.     

How Do PCSK9 Inhibitors Stack Up to Statins for Low-Density Lipoprotein Cholesterol Control?

Despite advances in the approach toward treating hypercholesterolemia and widespread access to statin medications, not all people are able to reach target low-density lipoprotein cholesterol (LDL-C) levels to reduce their cardiovascular risk. Some of the reasons include the inability to tolerate statin therapy, LDL-C levels that remain high even in the presence of statin therapy, and a familial disorder that is characterized by extremely high levels of LDL-C. A new therapeutic class, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, represents a novel and promising approach to reducing LDL-C levels using a mechanism at the LDL receptor level. The recent approval of the first 2 PCSK9 inhibitors and the anticipated approval of the third agent in this class within approximately 1 year may provide clinicians powerful new weapons to lower LDL-C levels in patients who are not satisfactorily managed with statins. However, the results of long-term studies of the ability of these new medications to influence cardiovascular outcomes will not be known for several years.     

Supplementation with Octacosanol Affects the Level of PCSK9 and Restore Its Physiologic Relation with LDL-C in Patients on Chronic Statin Therapy

Dietary supplementation with sugar cane derivates may modulate low-density lipoprotein cholesterol (LDL-C) and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. The purpose of this study was to determine if dietary supplement (DS), containing Octacosanol (20 mg) and vitamin K2 (45 µg), could restore the disrupted physiologic relation between LDL-C and serum PCSK9. Double-blind, randomized, placebo-controlled, single-center study including 87 patients on chronic atorvastatin therapy was conducted. Eighty-seven patients were randomized to receive DS (n = 42) or placebo (n = 45), and followed for 13 weeks. Serum PCSK9 levels, lipid parameters and their relationship were the main efficacy endpoints. The absolute levels of PCSK9 and LDL-C were not significantly different from baseline to 13 weeks. However, physiologic correlation between % change of PCSK9 and % change of LDL-C levels was normalized only in the group of patients treated with DS (r = 0.409, p = 0.012). This study shows that DS can restore statin disrupted physiologic positive correlation between PCSK9 and LDL-C. Elevated PCSK9 level is an independent risk factor so controlling its rise by statins may be important in prevention of cardiovascular events.     

Comparative Effect of Bergamot Polyphenolic Fraction and Red Yeast Rice Extract in Rats Fed a Hyperlipidemic Diet: Role of Antioxidant Properties and PCSK9 Expression

Elevated serum cholesterol levels, either associated or not with increased triglycerides, represent a risk of developing vascular injury, mostly leading to atherothrombosis-related diseases including myocardial infarction and stroke. Natural products have been investigated in the last few decades as they are seen to offer an alternative solution to counteract cardiometabolic risk, due to the occurrence of side effects with the use of statins, the leading drugs for treating hyperlipidemias. Red yeast rice (RYR), a monacolin K-rich natural extract, has been found to be effective in counteracting high cholesterol, being its use accompanied by consistent warnings by regulatory authorities based on the potential detrimental responses accompanying its statin-like chemical charcateristics. Here we compared the effects of RYR with those produced by bergamot polyphenolic fraction (BPF), a well-known natural extract proven to be effective in lowering both serum cholesterol and triglycerides in animals fed a hyperlipidemic diet. In particular, BPF at doses of 10 mg/Kg given orally for 30 consecutive days, counteracted the elevation of both serum LDL cholesterol (LDL-C) and triglycerides induced by the hyperlipidemic diet, an effect which was accompanied by significant reductions of malondialdehyde (MDA) and glutathione peroxidase serum levels, two biomarkers of oxidative stress. Furthermore, the activity of BPF was associated to increased HDL cholesterol (HDL-C) levels and to strong reduction of Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels which were found increased in hyperlipidemic rats. In contrast, RYR at doses of 1 and 3 mg/Kg, produced only significant reduction of LDL-C with very poor effects on triglycerides, HDL-C, glutathione peroxidase, MDA and PCSK9 expression. This indicates that while BPF and RYR both produce serum cholesterol-lowering benefits, BPF produces additional effects on triglycerides and HDL cholesterol compared to RYR at the doses used throughout the study. These additional effects of BPF appear to be related to the reduction of PCSK9 expression and to the antioxidant properties of this extract compared to RYR, thereby suggesting a more complete protection from cardiometabolic risk.     

An Economic Evaluation of Valsartan for Post-MI Patients in the UK Who Are Not Suitable for Treatment with ACE Inhibitors

Objectives:  The overall objective of this study was to estimate the costs and outcomes associated with treatment with valsartan for post-myocardial infarction (post-MI) patients with left ventricular systolic dysfunction, heart failure, or both, who are not suitable for treatment with angiotensin-converting enzyme (ACE) inhibitors, compared to placebo.
Methods:  A Markov model, using data drawn from the Valsartan in Acute Myocardial Infarction (VALIANT) trial and other trials, was developed to predict the future health pathways, resource use, and costs for patients who have recently experienced an MI. Patients received either valsartan (mean dose 247 mg) or placebo. Cost data were drawn from national databases and published literature, although health outcome utility weights were derived from existing studies. Patient outcomes were modeled for 10 years, and incremental cost-effective ratios were calculated for valsartan compared with placebo.
Results:  Over a period of 10 years, a cohort of 1000 patients treated with valsartan experienced 147 fewer cardiovascular deaths, 37 fewer nonfatal MIs, and 95 fewer cases of heart failure than a cohort who received placebo. The incremental cost of valsartan, compared with placebo, was £2680 per patient, although the incremental effectiveness of valsartan was 0.5021 quality-adjusted life-years (QALYs) gained per patient. Therefore, the incremental cost per QALY for treatment with valsartan was £5338. When analysis was undertaken using life-years rather than QALYs, the cost per life-year gained was £4672.
Conclusions:  For patients who are not suitable for treatment with ACE inhibitors, valsartan is a viable and cost-effective treatment for their management after an MI.     

Health and Economic Consequences of Sevelamer Use for Hyperphosphatemia in Patients on Hemodialysis

OBJECTIVES: The safety and efficacy of sevelamer hydrochloride in binding phosphate in patients with end-stage renal disease and its ability to attenuate the progression of cardiac calcification have been well documented but not the longer-term health and economic implications. Thus, a model of the predicted long-term consequences of sevelamer compared with calcium-based binders (acetate and carbonate) was developed. METHODS: Long-term cardiovascular implications of 1 year of treatment with phosphate binders in patients on hemodialysis are estimated based on the patient's demographics, comorbidities, and physiologic and renal parameters. The initial calcification score and expected changes over 1 year are derived using regression equations developed from the Treat-to-Goal study and translated to cardiovascular disease risk based on equations developed from a long-term cohort study. In this article, the implications of cardiovascular disease for life expectancy and medical costs are accounted for from a US payer perspective. RESULTS: The cardioprotective effect of sevelamer over 1 year is estimated to result in a 12% reduction in cardiovascular events compared with calcium acetate. In a population of 100 patients, the savings of 205,600 dollars accrued due to avoiding nine cardiovascular events with sevelamer, largely offset the increased binder costs, leading to a favorable cost-effectiveness ratio of about 2200 dollars per (discounted) life-year gained. CONCLUSIONS: Although both binders provide equivalent phosphate binding capacity, the results indicate that the advantage of 1 year of treatment with sevelamer in attenuating the progression of calcification has important clinical and economic consequences, suggesting that this provides good value for money.     

心血管疾病患者连续护理认知水平测评量表的构建

目的研制心血管疾病患者连续护理认知水平测评量表,并检验其信效度。方珐在参阅大量国内外文献的基础上．针对心血管疾病患者的连续护理需求．经咨询专家。编制了包括4个维度、62个条目的心血管疾病患者连续护理认知水平测评量表。请5位专家评阅,测算量表的效度;选取200名心血管疾病患者进行预试验调查,检验其信度。结果形成心血管疾病患者连续护理认知水平测评量表,量表内容效度系数为0．8418,所有条目均与其所属维度相关：各维度与总分的相关系数r=-0．873～0．968：各维度及总量表内部一致性信度Cranl）aeth’sa=0．9020～0．9838。结论该量表具有良好的可信度、稳定性和准确性．可作为心血管疾病患者连续性护理知识掌握程度的测评量表。     

Medicalisation,risk and the use of statins for primary prevention of cardiovascular disease: a scoping review of the literature

Primary prevention of cardiovascular disease has been a site of medicalisation, as demonstrated by the significant increase in the use of cholesterol-lowering drugs, statins, over the last thirty years. While this is welcomed by many in the medical community, others have criticised the expansion of statin use to low-risk people. In the context of this debate, the aim of this article is to present a broad scoping review of the literature on how preventative health, risk and ‘candidacy’ for statin treatment are perceived and negotiated by clinicians and patients. We examine how evidence and knowledge about cardiovascular risk reduction is produced, interpreted and communicated and how patients’ gender, socio-demographic and cultural differences may impact patterns of statin use. We found that few studies differentiated between the use of statins in those with and those without established cardiovascular disease, despite the fact that the majority of statin users, and women in particular, fall into the primary prevention category. In this context, the process of medicalisation is predicated on healthy individuals being subject to medical surveillance of risk factors, which have acquired the status of disease in their own right. Central to this process has been the heuristic that identifies elevated cholesterol as a medical problem warranting statin treatment, as well as the difficulties encountered by doctors and patients in understanding, interpreting and communicating risk. This individualised construction of risk and disease has largely ignored the supposedly widely recognised social and political determinants of health and illness.     

The Structure of Relationships between the Human Exposome and Cardiometabolic Health: The Million Veteran Program

The exposome represents the array of dietary, lifestyle, and demographic factors to which an individual is exposed. Individual components of the exposome, or groups of components, are recognized as influencing many aspects of human physiology, including cardiometabolic health. However, the influence of the whole exposome on health outcomes is poorly understood and may differ substantially from the sum of its individual components. As such, studies of the complete exposome are more biologically representative than fragmented models based on subsets of factors. This study aimed to model the system of relationships underlying the way in which the diet, lifestyle, and demographic components of the overall exposome shapes the cardiometabolic risk profile. The current study included 36,496 US Veterans enrolled in the VA Million Veteran Program (MVP) who had complete assessments of their diet, lifestyle, demography, and markers of cardiometabolic health, including serum lipids, blood pressure, and glycemic control. The cohort was randomly divided into training and validation datasets. In the training dataset, we conducted two separate exploratory factor analyses (EFA) to identify common factors among exposures (diet, demographics, and physical activity) and laboratory measures (lipids, blood pressure, and glycemic control), respectively. In the validation dataset, we used multiple normal regression to examine the combined effects of exposure factors on the clinical factors representing cardiometabolic health. The mean ± SD age of participants was 62.4 ± 13.4 years for both the training and validation datasets. The EFA revealed 19 Exposure Common Factors and 5 Physiology Common Factors that explained the observed (measured) data. Multivariate regression in the validation dataset revealed the structure of associations between the Exposure Common Factors and the Physiology Common Factors. For example, we found that the factor for fruit consumption was inversely associated with the factor summarizing total cholesterol and low-density lipoprotein cholesterol (LDLC, p = 0.008), and the latent construct describing light levels of physical activity was inversely associated with the blood pressure latent construct (p < 0.0001). We also found that a factor summarizing that participants who frequently consume whole milk are less likely to frequently consume skim milk, was positively associated with the latent constructs representing total cholesterol and LDLC as well as systolic and diastolic blood pressure (p = 0.0006 and <0.0001, respectively). Multiple multivariable-adjusted regression analyses of exposome factors allowed us to model the influence of the exposome as a whole. In this metadata-rich, prospective cohort of US Veterans, there was evidence of structural relationships between diet, lifestyle, and demographic exposures and subsequent markers of cardiometabolic health. This methodology could be applied to answer a variety of research questions about human health exposures that utilize electronic health record data and can accommodate continuous, ordinal, and binary data derived from questionnaires. Further work to explore the potential utility of including genetic risk scores and time-varying covariates is warranted.     

电话访视制度在社区慢性病患者护理中的应用

目的探讨电话访视制度在社区慢性病患者护理中的应用。方法以我辖区内2011年1月-2013年1月间收治的80例社区慢性病患者为研究对象,随机分为观察组与对照组,所有患者均积极治疗原发病,观察组患者在此基础上增加电话访视措施,比较两组患者干预后治疗依从度、自我护理能力、生活质量和对护理服务满意度之间的差异。结果观察组患者治疗依从度、自我护理能力、生活质量和对护理服务的满意度均高于对照组,其差异有统计学意义（P〈0．05）。结论电话访视制度可以有效提高社区慢性病患者的治疗依从度,增强其自我护理能力,改善其生活质量,提高其对护理服务的满意度。     

Generational Cohorts Hold the Key to Understanding Patients and Health Care Providers: Coming-of-Age Experiences Influence Health Care Behaviors for a Lifetime

The health care landscape is ever changing. Medical groups are experiencing challenges in recruiting staff, dealing with managing effective clinical teams, and tempering the growing tensions among partnerships and medical groups. Additionally, all clinicians report many patients are now approaching them differently than in the past. They come armed with medical information from the Internet and a more questioning attitude toward the clinician's directive for care. What accounts for these behavioral changes and management challenges within health care organizations? These issues may be best understood and addressed through generational cohort analysis.     

The Use of the International Classification of Diseases,Ninth Revision (ICD-9) Coding in Identifying Chronic Hepatitis B Virus Infection in Health System Data: Implications for Surveillance

Objective

To evaluate the sensitivity, specificity, positive and negative predictive values of the ICD-9 coding system for surveillance of chronic hepatitis B virus infection (HBV) using data from an observational cohort study in which ICD-9-coded HBV cases were validated by chart review.

Introduction

In the United States, 800,000- 1.4 million people are chronically infected with hepatitis B virus (HBV); these persons are at increased risk for chronic liver disease and its sequelae (CDC, 2010; Wasley, 2010). Current national viral hepatitis surveillance is a passive laboratory-initiated reporting system to state or local health departments with only 39 health departments reporting chronic HBV infection in the National Notifiable Disease Surveillance System (NNDSS). Since active HBV surveillance can be expensive and labor-intensive, the ICD-9 coding system has been proposed for surveillance of chronic hepatitis B.

Methods

We examined the electronic health records (EHRs) available as part of an existing cohort study of persons with chronic viral hepatitis. Records from 1.6 million adult patients who had one or more services from 2006–2008 in four integrated health care systems were reviewed. Complex algorithms using laboratory data and/or use of qualifying hepatitis B ICD-9 codes were applied to EHR patient data to create the chronic HBV cohort. Disease status was manually validated by abstractor review of the medical record. Sensitivity, specificity, positive and negative predictive values were calculated based upon presence of either one hepatitis B-specific ICD-9 code or two such ICD-9 codes separated by at least six months.

Results

Of 1,652,055 adult patients, 2,202 (0.1%) met criteria for inclusion into the chronic HBV cohort. Of the 2,202 confirmed cases, the sensitivity of use of one ICD-9 code was 83.9%, positive predictive value was 61.0%, specificity was 99.9% and the negative predictive value was over 99.9% (ConclusionsOur findings suggest that use of one or two hepatitis B specific ICD 9 codes can identify cases with chronic HBV infection. For health departments with access to electronic medical records, collection of ICD-9 data may be useful for surveillance and potentially improve reporting of chronic HBV infection.Measurement of sensitivity, specificity, and predictive values of using one hepatitis B-specific ICD-9 code among persons receiving services from four health care systems from 2006–2008

	Confirmed HBV case	Not a HBV case	Total
One ICD-9 code	1,847	1,182	3,029
No ICD-9 code	355	1,648,671	1,649,026
Total	2,202	1,649,853	1,652,055

Open in a separate windowSensitivity= 1,847/2,202= 83.9%Specificity= 1,648,671/1,649,853= 99.9%Positive predictive value= 1,847/3,029= 61.0%Negative predictive value= 1,648,671/1,649,026= >99.9%     

美国疾病预防控制中心和世界卫生组织传染病监测系统评价策略分析

目的 对比分析美国疾病预防控制中心(CDC)及WHO的监测系统评价方案,探讨适合中国的传染病监测系统评价策略.方法 系统收集美国CDC及WHO历年来提出的各版本监测系统评价方案,分析其主要思想和对中国的适用性;以现况分析和可行性分析探讨适合中国的传染病监测系统评价策略.结果 美国CDC提出的评价方案适于评价专病监测系统,重在对系统特征进行分析.WHO提出的评价方案适于评价国家或区域的整体监测体系,重在对系统功能进行分析.中国现阶段开展的监测系统评价多应用了特征评价的思想,也已初步具备功能评价的条件.结论 现阶段制定传染病监测系统评价策略时应参考美国CDC及WHO的各版本监测方案,并结合中国国情加以制定.     

Weighted hurdle regression method for joint modeling of cardiovascular events likelihood and rate in the US dialysis population

We propose a new weighted hurdle regression method for modeling count data, with particular interest in modeling cardiovascular events in patients on dialysis. Cardiovascular disease remains one of the leading causes of hospitalization and death in this population. Our aim is to jointly model the relationship/association between covariates and (i) the probability of cardiovascular events, a binary process, and (ii) the rate of events once the realization is positive—when the ‘hurdle’ is crossed—using a zero‐truncated Poisson distribution. When the observation period or follow‐up time, from the start of dialysis, varies among individuals, the estimated probability of positive cardiovascular events during the study period will be biased. Furthermore, when the model contains covariates, then the estimated relationship between the covariates and the probability of cardiovascular events will also be biased. These challenges are addressed with the proposed weighted hurdle regression method. Estimation for the weighted hurdle regression model is a weighted likelihood approach, where standard maximum likelihood estimation can be utilized. The method is illustrated with data from the United States Renal Data System. Simulation studies show the ability of proposed method to successfully adjust for differential follow‐up times and incorporate the effects of covariates in the weighting. Copyright © 2014 John Wiley & Sons, Ltd.     

Survey findings on characteristics and health status of clients treated by the federally funded (US) Health Care for the Homeless Programs

For almost two decades, the US Health Care for the Homeless (HCH) Program has funded clinics across the country for homeless populations. Between October and December 2003, for the first time ever, a nationally representative sample of the almost 200 HCH clinics with a response rate of approximately 71% (the HCH User Visit Survey) was created to examine the health status of its users ( n  = 1017). This study employed the HCH User Visit Survey's cross-sectional data set to evaluate health indicators of individuals using HCH Services with the US population, and compare individuals who reported they routinely used HCH clinics ('usual' HCH users) to those who did not ('non-usual' users). HCH users had poorer health status than the US population (44.0% versus 12.3%, respectively). Usual HCH users had similar healthcare status compared to non-usual users, but were more likely to be uninsured, non-English speakers, and walking or taking public transportation to their medical appointments. Usual versus non-usual HCH users were also more apt to have slept in cars, buses or on the streets in the week prior to the survey (14.8% versus 4.3%, respectively). This study shows that the HCH clinics are serving homeless individuals who have a variety of complex health and psychosocial needs, and its most frequent users are those who experience the most barriers accessing care.