Timothy R. Bates

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.

Non-adherence to statin therapy : a major challenge for preventive cardiology

Background: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular disease, the leading cause of death worldwide. In the last twenty years, effective lipid-lowering therapies, particularly statins, have become widely available to prevent and reverse the progression of disease. However, there is a significant gap between expected and actual benefits; this may be attributed to poor adherence to statin therapy. Objective: To define the extent, causes (including psychological aspects), consequences and management of non-adherence to statins. Methods: Literature using PubMed and Medline up to and including 30 July 2009. Results: Adherence to statin therapy is suboptimal in both primary and secondary prevention of cardiovascular disease. Causes vary, and include patient factors (e.g., comorbidities, financial constraints, psychological issues), practitioner factors (e.g., poor knowledge of adherence, time constraints, poor communication skills and patient–doctor working alliance) and system factors (e.g., medication costs, lack of clinical monitoring, drug side effects). Non-adherence is associated with adverse health outcomes and increased costs of healthcare. A framework, based on a multidisciplinary approach, for addressing non-adherence, including managing the statin-intolerant patient, is presented. Conclusions: Non-adherence to statins is a significant issue for the prevention and treatment of cardiovascular disease. Increased awareness of the causes and solutions for overcoming non-adherence, including safer prescribing, improvement in physician–patient alliance and reduction in drug costs, will enhance the cost-effectiveness of the use of statins and significantly improve patient care and outcomes.

Intravenous Minocycline in Acute Stroke A Randomized, Controlled Pilot Study and Meta-analysis

Background and Purpose— Minocycline, in animal models and 2 small randomized controlled human trials, is a promising neuroprotective agent in acute stroke. We analyzed the efficacy and safety of intravenous minocycline in acute ischemic and hemorrhagic stroke. Methods— A multicenter prospective randomized open-label blinded end point evaluation pilot study of minocycline 100 mg administered intravenously, commenced within 24 hours of onset of stroke, and continued 12 hourly for a total of 5 doses, versus no minocycline. All participants received routine stroke care. Primary end point was survival free of handicap (modified Rankin Scale, ⩽2) at day 90. Results— Ninety-five participants were randomized; 47 to minocycline and 48 to no minocycline. In the intention-to-treat population, 29 of 47 (65.9%) allocated minocycline survived free of handicap compared with 33 of 48 (70.2%) allocated no minocycline (rate ratio, 0.94; 95% confidence interval, 0.71–1.25 and odds ratio, 0.73; 95% CI, 0.31–1.71). A meta-analysis of the 3 human trials suggests minocycline may increase the odds of handicap-free survival by 3-fold (odds ratio, 2.99; 95% CI, 1.74–5.16) but there was substantial heterogeneity among the trials. Conclusions— In this pilot study of a small sample of acute stroke patients, intravenous minocycline was safe but not efficacious. The study was not powered to identify reliably or exclude a modest but clinically important treatment effect of minocycline. Larger trials would improve the precision of the estimates of any treatment effect of minocycline. Clinical Trial Registration— URL: http://www.anzctr.org.au. Unique identifier: ACTRN12612000237886.

Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit

BACKGROUND Familial hypercholesterolemia (FH) is the most common dominantly inherited cause of premature coronary artery disease (CAD). However, the diagnosis of FH in patients who have premature CAD in hospital settings is under-recognized, this also represents a missed opportunity for screening their close family members and implementing primary prevention. OBJECTIVE To investigate the point prevalence of FH in a coronary care unit (CCU) among patients with early-onset CAD. METHODS The prevalence of FH, based on modified phenotypic Dutch Lipid Clinic Network Criteria, and the spectrum of associated CAD risk factors, were investigated in a CCU setting. Data were collected on 175 coronary care patients with onset of CAD at age <60 years. RESULTS The prevalence of probable/definite FH was 14.3% (95% confidence interval, 9.0%-19.5%); 46.3% of the patients gave a family history of premature CAD and 20.6% had an untreated low-density lipoprotein cholesterol >5.0 mmol/L. Diabetes, hypertension, obesity, and smoking were common and equally prevalent in patients with and without FH. CONCLUSIONS FH is relatively frequent among patients with a history of early-onset CAD in the CCU. Every effort should be made to detect FH in these patients and to initiate cascade testing of available family members to prevent the development of CAD in those who may be unaware that they also have the condition.

Elevated lipoprotein(a), hypertension and renal insufficiency as predictors of coronary artery disease in patients with genetically confirmed heterozygous familial hypercholesterolemia ☆

BACKGROUND Familial hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol and increased risk of premature coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] increases CAD in FH, although the independence of this association relative to other CAD risk factors remains unclear. In this study, we examined the association between Lp(a) and other cardiovascular risk factors and prevalent CAD in patients with FH. METHODS A cross-sectional study of 390 patients with genetically confirmed FH were studied. Clinical and biochemical parameters of FH patients with and without CAD were compared. RESULTS FH patients with CAD were older and more often male and had a higher prevalence of hypertension, smoking, diabetes, obesity, reduced eGFR, and elevated plasma Lp(a) and pre-treatment LDL-cholesterol and triglyceride (or low HDL-cholesterol) than FH patients without CAD (P<0.05 for all). In univariate analyses, age, male gender, smoking, hypertension, reduced eGFR, diabetes, obesity, plasma creatinine, Lp(a) and pretreatment LDL-cholesterol, triglycerides and HDL-cholesterol levels were significant predictors of CAD in the FH patients (P<0.05 for all). Elevated LDL-cholesterol, raised Lp(a), hypertension and reduced eGFR remained significant independent predictors of CAD (P<0.05 for all) in FH after adjusting for other modifiable risk factors. CONCLUSIONS Elevated Lp(a), hypertension and renal insufficiency are independent risk factors beyond elevated pretreatment LDL-cholesterol which predict CAD in patients with FH. In spite of the cross-sectional design of our study, we propose the need for identifying and managing these abnormalities to reduce excess CAD risk in FH patients. However, this proposal remains to be formally tested in a prospective study.

Severe HDL deficiency due to novel defects in the ABCA1 transporter.

Objectives.  The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency.

A new model of care for familial hypercholesterolaemia from Western Australia: closing a major gap in preventive cardiology

Familial hypercholesterolaemia (FH) is the most common monogenic cause of premature coronary artery disease. FH remains underdiagnosed and inadequately treated, with no national strategies for dealing with the problem. We report an executive summary of a comprehensive model of care for FH developed in Western Australia.

Statin myopathy: The fly in the ointment for the prevention of cardiovascular disease in the 21st century?

Introduction: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk. Areas covered: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence. Expert opinion: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.

Reducing Haemorrhagic Transformation after Thrombolysis for Stroke: A Strategy Utilising Minocycline

Haemorrhagic transformation (HT) of recently ischaemic brain is a feared complication of thrombolytic therapy that may be caused or compounded by ischaemia-induced activation of matrix metalloproteinases (MMPs). The tetracycline antibiotic minocycline inhibits matrix MMPs and reduces macroscopic HT in rodents with stroke treated with tissue plasminogen activator (tPA). The West Australian Intravenous Minocycline and TPA Stroke Study (WAIMATSS) aims to determine the safety and efficacy of adding minocycline to tPA in acute ischaemic stroke. The WAIMATSS is a multicentre, prospective, and randomised pilot study of intravenous minocycline, 200 mg 12 hourly for 5 doses, compared with standard care, in patients with ischaemic stroke treated with intravenous tPA. The primary endpoint is HT diagnosed by brain CT and MRI. Secondary endpoints include clinical outcome measures. Some illustrative cases from the early recruitment phase of this study will be presented, and future perspectives will be discussed.

Quality of Acute Care and Long-Term Quality of Life and Survival: The Australian Stroke Clinical Registry.

Background and Purpose— Uncertainty exists over whether quality improvement strategies translate into better health-related quality of life (HRQoL) and survival after acute stroke. We aimed to determine the association of best practice recommended interventions and outcomes after stroke. Methods— Data are from the Australian Stroke Clinical Registry during 2010 to 2014. Multivariable regression was used to determine associations between 3 interventions: received acute stroke unit (ASU) care and in various combinations with prescribed antihypertensive medication at discharge, provision of a discharge care plan, and outcomes of survival and HRQoL (EuroQoL 5-dimensional questionnaire visual analogue scale) at 180 days, by stroke type. An assessment was also made of outcomes related to the number of processes patients received. Results— There were 17 585 stroke admissions (median age 77 years, 47% female; 81% managed in ASUs; 80% ischemic stroke) from 42 hospitals (77% metropolitan) assessed. Cumulative benefits on outcomes related to the number of care processes received by patients. ASU care was associated with a reduced likelihood of death (hazard ratio, 0.49; 95% confidence interval, 0.43–0.56) and better HRQoL (coefficient, 21.34; 95% confidence interval, 15.50–27.18) within 180 days. For those discharged from hospital, receiving ASU+antihypertensive medication provided greater 180-day survival (hazard ratio, 0.45; 95% confidence interval, 0.38–0.52) compared with ASU care alone (hazard ratio, 0.64; 95% confidence interval, 0.54–0.76). HRQoL gains were greatest for patients with intracerebral hemorrhage who received care bundles involving discharge processes (range of increase, 11%–19%). Conclusions— Patients with stroke who receive best practice recommended hospital care have improved long-term survival and HRQoL.