Ian Hamilton-Craig

A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients witb hypercholesterolemia☆

We directly compared the safety and efficacy of atorvastatin and simvastatin in hypercholesterolemic patients. This 1-year, randomized, double-blind study was performed at 9 community- and university-based research hospitals in Australia. One-hundred seventy-seven patients between the ages of 18 and 80 years with baseline low-density-lipoprotein (LDL) cholesterol ≤4.14 and ≤7.76 mmol/L (160 and 300 mg/dl, respectively) and triglycerides ≤4.52 mmol/L (400 mg/dl) received once-daily dosing with atorvastatin (Lipitor) 10 mg or simvastatin (Zocor) 10 mg. At week 16, the dose of medication was titrated to atorvastatin 20 mg or simvastatin 20 mg if patients did not meet LDL cholesterol target of ≤ 3.36 mmol/L (130 mg/dl). Efficacy was reported as percent change from baseline in LDL cholesterol, total cholesterol, very low density lipoprotein cholesterol, total triglycerides, high-density lipoprotein cholesterol, apolipoproteins Al and B, and lipoprotein(a). Atorvastatin caused significantly greater reductions from baseline than did simvastatin for LDL cholesterol, total cholesterol, very low density lipoprotein cholesterol, triglycerides, and apolipoprotein B (p <0.05). No patient in either treatment group had clinically important elevations in creatine phosphokinase, alanine amino-transaminase, or aspartate aminotransaminase. No serious adverse events were considered associated with treatment. With atorvastatin 10 mg, 46% of the patients achieved LDL cholesterol target goal by week 16, whereas only 27% of the simvastatin patients achieved the target goal at the 10-mg dose. This cholesterol-lowering profile affords utility in many patient types.

Familial hypercholesterolaemia: A model of care for Australasia

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated. To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described. This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification.

A topographical map of the causal network of mechanisms underlying the relationship between major depressive disorder and coronary heart disease

Objective: Major depressive disorder (MDD) and coronary heart disease (CHD) are both clinically important public health problems. Depression is linked with a higher incidence of ischaemic cardiac events and MDD is more prevalent in patients with CHD. No single comprehensive model has yet described the causal mechanisms linking MDD to CHD. Several key mechanisms have been put forward, comprising behavioural mechanisms, genetic mechanisms, dysregulation of immune mechanisms, coagulation abnormalities and vascular endothelial dysfunction, polyunsaturated omega-3 free fatty acid deficiency, and autonomic mechanisms. It has been suggested that these mechanisms form a network, which links MDD and CHD. The aim of this review is to examine the causal mechanisms underlying the relationship between MDD and CHD, with the aim of constructing a topological map of the causal network which describes the relationship between MDD and CHD. Methods: The search term ‘depression and heart disease’ was entered into an electronic multiple database search engine. Abstracts were screened for relevance and individually selected articles were collated. Results: This review introduces the first topological map of the causal network which describes the relationship between MDD and CHD. Conclusions: Viewing the causal pathways as an interdependent network presents a new paradigm in this field and provides fertile ground for further research. The causal network can be studied using the methodology of systems biology, which is briefly introduced. Future research should focus on the creation of a more comprehensive topological map of the causal network and the quantification of the activity between each node of the causal network.

Mind and Heart: Heart Rate Variability in Major Depressive Disorder and Coronary Heart Disease − a Review and Recommendations

Objective: There is a reciprocal association between major depressive disorder (MDD) and coronary heart disease (CHD). These conditions are linked by a causal network of mechanisms. This causal network should be quantitatively studied and it is hypothesised that the investigation of vagal function represents a promising starting point. Heart rate variability (HRV) has been used to investigate cardiac vagal control in the context of MDD and CHD. This review aims to examine the relationship of HRV to both MDD and CHD in the context of vagal function and to make recommendations for clinical practice and research. Methods: The search terms ‘heart rate variability’, ‘depression’ and ‘heart disease’ were entered into an electronic multiple database search engine. Abstracts were screened for their relevance and articles were individually selected and collated. Results: Decreased HRV is found in both MDD and CHD. Both diseases are theorised to disrupt autonomic control feedback loops on the heart and are linked to vagal function. Existing theories link vagal function to both mood and emotion as well as cardiac function. However, several factors can potentially confound HRV measures and would thus impact on a complete understanding of vagal mechanisms in the link between MDD and CHD. Conclusions: The quantitative investigation of vagal function using HRV represents a reasonable starting point in the study of the relationship between MDD and CHD. Many psychotropic and cardiac medications have effects on HRV, which may have clinical importance. Future studies of HRV in MDD and CHD should consider antidepressant medication, as well as anxiety, as potential confounders.

Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia.

High-dose potent statin therapy in combination with ezetimibe is now standard practice for the treatment of adult patients with heterozygous familial hypercholesterolemia (heFH), as the result of numerous studies in patients with primary hypercholesterolemia or heFH. These studies have shown the combination to be both effective and safe in the short to medium term. Recently, short-term ezetimibe therapy has also been shown to be effective and safe in combination with statin therapy for children and adolescents with heFH. Effective statin–ezetimibe combination therapy is capable of achieving near-normal lipid profiles in heFH patients, with expected improvement in risk for cardiovascular disease (CVD) and improved life expectancy resulting predominantly from reduction in levels of low-density lipoprotein cholesterol. There are few data to support a pleiotropic action of ezetimibe with regard to CVD benefit, unlike therapy with statins. No serious and unexpected clinical adverse effects of combination statin–ezetimibe therapy have emerged till date, although data are limited in children and adolescents, for whom longer-term studies are required. Recent data suggesting possible proatherogenic effects of ezetimibe require confirmation. One large long-term randomized controlled clinical outcomes trial is in progress in non-FH patients to determine the efficacy and safety of ezetimibe therapy; it is unlikely that such a trial will ever be performed in patients with FH.

At Sea with SEAS: The First Clinical Endpoint Trial for Ezetimibe, Treatment of Patients with Mild to Moderate Aortic Stenosis, Ends with Mixed Results and More Controversy ☆ ☆☆

SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) hypothesised that aggressive lipid lowering with simvastatin/ezetimibe reduced cardiovascular disease (CVD) risk and the need for aortic valve replacement (AVR) in patients with asymptomatic aortic stenosis (AS). The study enrolled from 173 centres in seven European countries 1873 elderly non-diabetics with mild to moderate AS (mean aortic-valve area 1.28+/-0.47 cm(2)), who had no indication for lipid-lowering therapy. Patients were randomised to treatment with either simvastatin/ezetimibe 40/10mg daily or matching placebo after a four-week diet/placebo run-in period. Compared with placebo, LDL cholesterol was reduced by 61% (2.0 mmol/l). There was no difference in the primary endpoint (a combination of AVR, CV death, non-fatal MI, congestive heart failure from AS progression, coronary revascularisation, hospitalised unstable angina and non-haemorrhagic stroke). Compared with placebo, CVD events were reduced by 4.4% from 20.1% to 15.7% in the simvastatin/ezetimibe group (p=0.02). Cancer incidence and cancer deaths were more frequent in the simvastatin/ezetimibe group (9.9% vs. 7.0%, p=0.03 and 4.1% vs. 2.5%, p=0.05, respectively). These differences were not related to any form of cancer and did not increase with increased duration of therapy.

Clinical features and genetic analysis of three patients with severe hypertriglyceridaemia

Hypertriglyceridaemia is a common biochemical abnormality that can be due to primary causes or, more commonly, secondary causes. Moderate hypertriglyceridaemia is a risk factor for cardiovascular disease and can develop into severe hypertriglyceridaemia which is a risk factor for acute pancreatitis. Familial chylomicronaemia is a rare autosomal recessive disorder, usually diagnosed in childhood and is characterized by marked hypertriglyceridaemia and biochemical deficiency of lipoprotein lipase (LPL), apolipoprotein (apo) C-II, homozygous (or compound heterozygous) gene mutations in LPL or more rarely, APOC2. Recently, loss-of-function mutations in the APOA5 gene have been reported in patients with severe hypertriglyceridaemia in whom LPL or APOC2 mutations were not found. We describe the clinical features and genetic analysis of three patients with severe hypertriglyceridaemia including novel mutations LPL c.464T>C (p.Leu155Pro) and APOA5 c.823C>T (p.Gln275*).

Design of the familial hypercholesterolaemia australasia network registry: Creating opportunities for greater international collaboration

Familial Hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipoprotein metabolism that leads to premature coronary heart disease. There are over 65,000 people estimated to have FH in Australia, but many remain undiagnosed. Patients with FH are often undertreated, but with early detection, cascade family testing and adequate treatment, patient outcomes can improve. Patient registries are key tools for providing new information on FH and enhancing care worldwide. The development and design of the FH Australasia Network Registry is a crucial component in the comprehensive model of care for FH, which aims to provide a standardized, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. Informed by stakeholder engagement, the FH Australasia Network Registry was collaboratively developed by government, patient and clinical networks and research groups. The open-source, webbased Rare Disease Registry Framework was the architecture chosen for this registry owing to its open-source standards, modular design, interoperability, scalability and security features; all these are key components required to meet the ever changing clinical demands across regions. This paper provides a high level blueprint for other countries and jurisdictions to help inform and map out the critical features of an FH registry to meet their particular health system needs.

From Physiome to Pathome: A Systems Biology Model of Major Depressive Disorder and the Psycho-Immune-Neuroendocrine Network

This article introduces a systems biology model of the psycho-immune-neuroendocrine (PINE) network. It provides a comprehensive synthesis of the network of biological mechanisms which link major depressive disorder (MDD) with several diseases including hypertension, atherosclerosis, coronary heart disease (CHD), cerebrovascular accident (CVA) and type 2 diabetes. The first part of this article provides an overview of concepts such as the PINE physiome and pathome, as well as the application of a systems biology framework to explain the significant reciprocal associations of MDD with the above named medical illnesses. The second part describes the normal physiological pathways of immune mechanisms, the hypothalamic-pituitary-adrenal (HPA) axis, autonomic pathways and central nervous system function, which form the PINE physiome. The third section describes how homeostasis of the PINE physiome is disrupted by chronic stress, on a background of genetic and developmental diathesis factors, resulting in a network of pathophysiological pathways called the PINE pathome. MDD, CHD, type 2 diabetes, CVA, hypertension and atherosclerosis can act to maintain the PINE network in a stable pathological state. This article presents comprehensive topographical maps of both the PINE physiome and the PINE pathome. Implications of the model and the importance of adopting a systems approach to understanding the relationship between these diseases is discussed in the last section, including the possibility of novel treatments for MDD and areas of future research.

Lipid-modifying therapy in the elderly

Cardiovascular disease (CVD) mortality and morbidity increases with increasing age, largely as a result of increased lifetime exposure as well as increased prevalence of CVD risk factors. Hospitalization for CVD increases by a factor of over 18× for those aged 85+ years versus those aged <30 years. In spite of this, life expectancy continues to increase, and in Australia for people reaching the age of 65 years, it is now 84 years in men and 87 years in women. The number of people for whom lipid management is potentially indicated therefore increases with aging. This is especially the case for secondary prevention and for people aged 65–75 years for whom there is also evidence of benefit from primary prevention. Many people in this age group are not treated with lipid-lowering drugs, however. Even those with CVD may be suboptimally treated, with one study showing treatment rates to fall from ~60% in those aged <50 years to <15% for those aged 85+ years. Treatment of the most elderly patient groups remains controversial partly from the lack of randomized trial intervention data and partly from the potential for adverse effects of lipid therapy. There are many complex issues involved in the decision to introduce effective lipid-lowering therapy and, unfortunately, in many instances there is not adequate data to make evidence-based decisions regarding management. This review summarizes the current state of knowledge of the management of lipid disorders in the elderly and proposes guidelines for management.