Higher testosterone is associated with higher HDL-cholesterol and lower triglyceride concentrations in older women: an observational study.

OBJECTIVE: This study aimed to determine whether concentrations of testosterone and its main precursor after menopause, dehydroepiandrosterone (DHEA), are associated with lipoproteins and other lipids in community-dwelling older women. METHODS: The Sex Hormones in Older Women (SHOW) study was an observational study of 6358 Australian women, aged at least 70 years, with no prior major adverse cardiovascular event who had sex hormones measured by liquid chromatography-tandem mass spectrometry. Associations between hormones and lipids were examined using multilinear regression adjusted for potential confounders. RESULTS: The cross-sectional analyses included 3231 participants, median age 74.0 (interquartile range 71.7-77.9) years. Compared with concentrations in the lowest quartile (Q1), testosterone concentrations in the highest quartiles (Q3 and Q4) were positively associated with high-density lipoprotein cholesterol (HDL-C) (p = 0.002 and p < 0.001, respectively) while Q4 testosterone concentrations were positively associated with total cholesterol (p = 0.038). Q2, Q3 and Q4 testosterone concentrations were significantly inversely associated with triglycerides (TG) (p = 0.024, p = 0.003 and p < 0.001, respectively). For DHEA, Q4 concentrations was positively associated with non-HDL-C (p = 0.024). CONCLUSIONS: In older women, higher endogenous testosterone concentrations are significantly associated with higher HDL-C and lower TG, indicating a less atherogenic profile. These findings suggest a neutral, or potentially protective, cardiovascular disease effect of testosterone in older women.

Compliance-Adjusted Estimates of Aspirin Effects Among Older Persons in the ASPREE Randomized Trial.

The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.

Estrone, sex hormone binding globulin and lipid profiles in older women: an observational study.

OBJECTIVE: We investigated whether estrone and sex hormone binding globulin (SHBG) concentrations are associated with lipid concentrations in older postmenopausal women. METHODS: This was a cross-sectional study of 6358 Australian women, aged 70-95 years, recruited between 2010 and 2014. Associations between estrone and SHBG and lipid concentrations were examined in participants not using medications that influence estrogen concentrations or lipid-lowering therapy. Linear regression models included age, body mass index, smoking, alcohol consumption, renal function and diabetes, with the lowest quartile (Q1) as the reference for estrone and SHBG. RESULTS: The study included 3231 participants with median age of 74.0 (interquartile range 71.7-77.9) years. Estrone concentration Q3 and Q4 were positively associated with high-density lipoprotein cholesterol (HDL-C) (p = 0.017 and p = 0.046, respectively). Inverse associations were seen for estrone Q4 with total cholesterol (p = 0.018), Q2 and Q4 with non-HDL-C (p = 0.045 and p = 0.002, respectively) and Q3 and Q4 with triglycerides (p = 0.030 and p = 0.001, respectively). For SHBG, Q2, Q3 and Q4 were positively associated with HDL-C (all p < 0.001), and inversely with non-HDL-C (all p = 0.001) and triglycerides (all p < 0.001). CONCLUSIONS: Estrone and SHBG are associated with lipid concentrations in older women. SHBG, but not estrone, may provide additional clinical predictive utility for the assessment of cardiometabolic disease risk in older women.

Common genetic variants do not predict recurrent events in coronary heart disease patients.

BACKGROUND: It is unclear whether genetic variants identified from single nucleotide polymorphisms (SNPs) strongly associated with coronary heart disease (CHD) in genome-wide association studies (GWAS), or a genetic risk score (GRS) derived from them, can help stratify risk of recurrent events in patients with CHD. METHODS: Study subjects were enrolled at the close-out of the LIPID randomised controlled trial of pravastatin vs placebo. Entry to the trial had required a history of acute coronary syndrome 3-36 months previously, and patients were in the trial for a mean of 36 months. Patients who consented to a blood sample were genotyped with a custom designed array chip with SNPs chosen from known CHD-associated loci identified in previous GWAS. We evaluated outcomes in these patients over the following 10 years. RESULTS: Over the 10-year follow-up of the cohort of 4932 patients, 1558 deaths, 898 cardiovascular deaths, 727 CHD deaths and 375 cancer deaths occurred. There were no significant associations between individual SNPs and outcomes before or after adjustment for confounding variables and for multiple testing. A previously validated 27 SNP GRS derived from SNPs with the strongest associations with CHD also did not show any independent association with recurrent major cardiovascular events. CONCLUSIONS: Genetic variants based on individual single nucleotide polymorphisms strongly associated with coronary heart disease in genome wide association studies or an abbreviated genetic risk score derived from them did not help risk profiling in this well-characterised cohort with 10-year follow-up. Other approaches will be needed to incorporate genetic profiling into clinically relevant stratification of long-term risk of recurrent events in CHD patients.

Treatment of dyslipidemia and cardiovascular outcomes: the journey so far--is this the end for statins?

Dyslipidemia is common and is associated with the highest population-attributable risk for cardiovascular disease. Of various cardiovascular preventive therapies, the evidence from randomized controlled trials supporting the importance of aggressive lipid lowering is the most robust, particularly for statins. Despite the use of proven therapies, cardiovascular disease event rates remain relatively high, underpinning the development of novel therapies. In addition to testing new drugs to reduce low-density-lipoprotein cholesterol, there has been a major focus on treatments that can favorably influence high-density-lipoprotein cholesterol and triglyceride levels. This review provides an overview of the important relationship between lipids and cardiovascular disease, the lipid-modifying therapeutic approaches to reducing cardiovascular disease, new guidelines and recommendations, and the challenges ahead for the treatment of dyslipidemia, particularly whether statins will remain at the forefront of recommended therapies.

Maximizing efficiency and cost-effectiveness of Type 2 diabetes screening: the AusDiab study.

AIMS: To evaluate how to most efficiently screen populations to detect people at high risk of incident Type 2 diabetes and those with prevalent, but undiagnosed, Type 2 diabetes. METHODS: Data from 5814 adults in the Australian Diabetes, Obesity and Lifestyle study were used to examine four different types of screening strategies. The strategies incorporated various combinations of cut-points of fasting plasma glucose, the non-invasive Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK1) and a modified version of the tool incorporating fasting plasma glucose (AUSDRISK2). Sensitivity, specificity, positive predictive value, screening costs per case of incident or prevalent undiagnosed diabetes identified and intervention costs per case of diabetes prevented or reverted were compared. RESULTS: Of the four strategies that maximized sensitivity and specificity, use of the non-invasive AUSDRISK1, followed by AUSDRISK2 in those found to be at increased risk on AUSDRISK1, had the highest sensitivity (80.3%; 95% confidence interval 76.6-84.1%), specificity (78.1%; 95% confidence interval 76.9-79.2%) and positive predictive value (22.3%; 95% confidence interval 20.2-24.4%) for identifying people with either prevalent undiagnosed diabetes or future incident diabetes. It required the fewest people (24.1%; 95% confidence interval 23.0-25.2%) to enter lifestyle modification programmes, and also had the lowest intervention costs and combined costs of running screening and intervention programmes per case of diabetes prevented or reverted. CONCLUSIONS: Using a self-assessed diabetes risk score as an initial screening step, followed by a second risk score incorporating fasting plasma glucose, would maximize efficiency of identifying people with undiagnosed Type 2 diabetes and those at high risk of future diabetes.

Clinical effectiveness in everyday practice: improving outcomes for all patients through a national acute coronary syndrome data collaborative.

The management of acute coronary syndromes (ACS) has an extensive and impressive evidence-base with which to guide clinical practice. Despite this, translation to the clinical environment has proved to be challenging and incomplete and can be attributed to patient, provider and system factors. Causes of suboptimal guideline adherence relate to diverse issues, including patient complexity, barriers in knowledge translation of guideline recommendations and a limited capacity within health services. Addressing these factors may enable more effective guideline implementation. In Australia, the infrastructure for clinical data management is fragmented, uncoordinated and often administratively driven, compromising access to important information, which might improve clinical effectiveness. An integrated approach is required to improve clinical effectiveness in ACS care in Australia. Greater access to information both to assist in clinical decision-making and monitoring outcomes may help direct the focus towards understudied populations and improve performance and clinically relevant outcomes. A peer-led initiative based on common datasets, providing rapid feedback, while developing and disseminating a 'toolbox' of proven and sustainable interventions, could improve clinical effectiveness in the Australian management of ACS and provides a rationale for a national ACS registry.

HOMA insulin sensitivity index and the risk of all-cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study.

AIMS/HYPOTHESIS: We assessed whether the relationships between insulin sensitivity and all-cause mortality as well as fatal or non-fatal cardiovascular disease (CVD) events are independent of elevated blood glucose, high blood pressure, dyslipidaemia and body composition in individuals without diagnosed diabetes. METHODS: Between 1999 and 2000, baseline fasting insulin, glucose and lipids, 2 h plasma glucose, HbA(1c), anthropometrics, blood pressure, medication use, smoking and history of CVD were collected from 8,533 adults aged >35 years from the population-based Australian Diabetes, Obesity and Lifestyle study. Insulin sensitivity was estimated by HOMA of insulin sensitivity (HOMA-%S). Deaths and fatal or non-fatal CVD events were ascertained through linkage to the National Death Index and medical records adjudication. RESULTS: After a median of 5.0 years there were 277 deaths and 225 CVD events. HOMA-%S was not associated with all-cause mortality. Compared with the most insulin-sensitive quintile, the combined fatal or non-fatal CVD HR (95% CI) for quintiles of decreasing HOMA-%S were 1.1 (0.6-1.9), 1.4 (0.9-2.3), 1.6 (1.0-2.5) and 2.0 (1.3-3.1), adjusting for age and sex. Smoking, CVD history, hypertension, lipid-lowering medication, total cholesterol and waist-to-hip ratio moderately attenuated this relationship. However, the association was rendered non-significant by adding HDL. Fasting plasma glucose, but not HOMA-%S significantly improved the prediction of CVD, beyond that seen with other risk factors. CONCLUSIONS/INTERPRETATION: In this cohort, HOMA-%S showed no association with all-cause mortality and only a modest association with CVD events, largely explained by its association with HDL. Fasting plasma glucose was a better predictor of CVD than HOMA-%S.

Validity of self-reported cardiovascular disease events in comparison to medical record adjudication and a statewide hospital morbidity database: the AusDiab study.

Epidemiological studies often rely on self-reported cardiovascular disease (CVD) information, but this may be inaccurate. We investigated the accuracy of self-reported CVD (myocardial infarction, stroke, coronary artery bypass surgery and coronary artery angioplasty) during the follow up of the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Self-reported CVD events, including the date of the event and hospital admission details, were collected with an interviewer-administered questionnaire. Of the 276 self-reported CVD events, 188 (68.1%) were verified by adjudication of medical records. Furthermore, linkage to the statewide Western Australian Hospital Morbidity Database (WAHMD) showed that CVD events were unlikely to be missed, with only 0.2% of those denying any CVD event being recorded as having had an event on the WAHMD. The adjudication of medical records was as accurate as record linkage to the WAHMD for validation of self-reported CVD, but combining the results from both methods of ascertainment improved CVD event identification.

Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study.

AIMS/HYPOTHESIS: Hyperglycaemia is a risk factor for cardiovascular disease (CVD) and all-cause mortality in individuals without diabetes. We investigated: (1) whether the risk of all-cause and CVD mortality extended continuously throughout the range of fasting plasma glucose (FPG), 2 h plasma glucose (2hPG) and HbA(1c) values; and (2) the ability of these measures to improve risk prediction for mortality. METHODS: Data on 10,026 people aged >or=25 years without diagnosed diabetes were obtained from the population-based Australian Diabetes, Obesity and Lifestyle study. Between 1999 and 2000, FPG, 2hPG and HbA(1c) were assessed and all-cause (332 deaths) and CVD (88 deaths) mortality were obtained after 7 years. RESULTS: Both 2hPG and HbA(1c) exhibited linear relationships with all-cause and CVD mortality, whereas FPG showed J-shaped relationships. The adjusted HR (95% CI) for all-cause mortality per SD increase was 1.2 (1.1-1.3) for 2hPG and 1.1 (1.0-1.2) for HbA(1c). The HR for FPG <5.1 mmol/l (per SD decrease) was 2.0 (1.3-3.0); for FPG >or=5.1 mmol/l (per SD increase) the HR was 1.1 (1.0-1.2). Corresponding HRs for CVD mortality were 1.2 (1.0-1.4), 1.2 (1.0-1.3), 4.0 (2.1-7.6) and 1.3 (1.1-1.4). The discriminative ability of each measure was similar; no measure substantially improved individual risk identification over traditional risk factors. CONCLUSIONS/INTERPRETATION: In individuals without diagnosed diabetes, 2hPG and FPG, but not HbA(1c) were significant predictors of all-cause mortality, whereas all measures were significant predictors of CVD mortality. However, these glucose measures did not substantially improve individual risk identification.

Leptin, but not adiponectin, is a predictor of recurrent cardiovascular events in men: results from the LIPID study.

OBJECTIVE: To investigate the relationships between plasma leptin and adiponectin levels and recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes. DESIGN, SUBJECTS AND MEASUREMENTS: A nested case-control study examined circulating leptin and adiponectin levels in plasma obtained 4-6 years after entry into the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial. Plasma was assayed from 184 men who suffered recurrent events within 4.4 years after blood collection and 184 matched controls who remained free of further events. The association between cardiovascular events and the explanatory variables was examined by conditional logistic regression analysis. RESULTS: Relative risk (RR) increased across increasing leptin quartiles; the highest quartile compared with the lowest quartile was related to the highest risk (P for trend=0.002); the increased risk remained after adjustment for risk factors (P=0.018) or for obesity (P=0.038), but in the final model (adjusted for randomized treatment, other drugs, LIPID risk score, age and body mass index), the risk was attenuated (RR=1.61, 95% CI: 0.72-3.57, P for trend=0.34). Adiponectin did not predict cardiovascular events. Subjects randomly allocated to pravastatin had 6% lower leptin levels (P=0.04) than those allocated to placebo. CONCLUSION: Plasma leptin was a significant and independent predictor of recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes.

The metabolic syndrome as a tool for predicting future diabetes: the AusDiab study.

OBJECTIVE: To compare the ability of the metabolic syndrome (MetS), a diabetes prediction model (DPM), a noninvasive risk questionnaire and individual glucose measurements to predict future diabetes. DESIGN: Five-year longitudinal cohort study. Tools tested included MetS definitions [World Health Organization, International Diabetes Federation, ATPIII and European Group for the study of Insulin Resistance (EGIR)], the FINnish Diabetes RIsk SCore risk questionnaire, the DPM, fasting and 2-h post load plasma glucose. SETTING: Adult Australian population. SUBJECTS: A total of 5842 men and women without diabetes > or =25 years. Response 58%. A total of 224 incident cases of diabetes. RESULTS: In receiver operating characteristic curve analysis, the MetS was not a better predictor of incident diabetes than the DPM or measurement of glucose. The risk for diabetes among those with prediabetes but not MetS was almost triple that of those with MetS but not prediabetes (9.0% vs. 3.4%). Adjusted for component parts, the MetS was not a significant predictor of incident diabetes, except for EGIR in men [OR 2.1 (95% CI 1.2-3.7)]. CONCLUSIONS: A single fasting glucose measurement may be more effective and efficient than published definitions of the MetS or other risk constructs in predicting incident diabetes. Diagnosis of the MetS did not confer increased risk for incident diabetes independent of its individual components, with an exception for EGIR in men. Given these results, debate surrounding the public health utility of a MetS diagnosis, at least for identification of incident diabetes, is required.

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Failure of current public educational campaigns to impact on the initial response of patients with possible heart attack.

AIMS: The National Heart Foundation of Australia recognizes that the risk of lethal arrhythmias is greater very early after the onset of myocardial infarction and that the more promptly flow can be restored in the infarct-related artery the greater will be the benefits for survival and preservation of heart function. The Heart Foundation has therefore conducted several public media campaigns to encourage patients to seek help more promptly and evaluated their impact. METHODS: Since 1996, we have conducted four surveys of delays preceding admission of patients to coronary care units throughout Australia to assess the impact of the Heart Foundation's media campaigns. Data were collected on 1665 patients who presented to 73 hospitals; information on patient delay was available for 1178 of them. RESULTS: There were no significant differences in patient delay (median 1.5-2.0 h) in the four surveys from 1996 to 2002, nor when patients were categorized by age, sex, presenting diagnosis or history of previous myocardial infarction or coronary revascularization by percutaneous or surgical techniques. CONCLUSION: New approaches are needed to reduce patient-related delay after the onset of symptoms suggesting possible myocardial infarction.

Current guidelines for the management of unstable angina: a new diagnostic and management paradigm.

The new guidelines reflect a worldwide change to more sensitive diagnostic strategies and more aggressive management of unstable angina. Stratification to high risk now includes those patients with only a minor degree of electrocardiographic ST depression (0.5 mm) or a significant elevation of cardiac troponin. High-risk patients are recommended to be treated with intensive medical and invasive management. Intermediate-risk patients may be best evaluated using an accelerated diagnostic strategy over an 8-12 h period before being reclassified as high or low risk.

Chronic heart failure in Australian general practice. The Cardiac Awareness Survey and Evaluation (CASE) Study.

OBJECTIVES: To investigate the frequency and general practitioner awareness of patients with chronic heart failure (CHF), and to evaluate a cardiac algorithm and document cardiac investigations performed in establishing this diagnosis. DESIGN AND SETTING: Between March and August 1998, consecutive patients aged 60 years and older presenting to their GP were assessed. In patients previously diagnosed with CHF, aetiology and diagnostic assessments were documented. In patients with suspected CHF (by a standardised algorithm, based on World Health Organization guidelines), further investigations and GP diagnosis were recorded. PATIENTS: 80 consecutive patients were assessed by each of 341 GPs throughout Australia, reflecting the Australian metropolitan/rural population mix of 1996. This provided a total of 22060 evaluable patients. MAIN OUTCOME MEASURES: Estimated numbers of patients with CHF in general practice (previously and newly diagnosed); major aetiological factors; use of ancillary diagnostic tests; drugs prescribed. RESULTS: CHF was diagnosed in 2905 of 22060 patients (13.2%) (2485 previously diagnosed and 420 newly diagnosed). Major aetiological factors were ischaemic heart disease and hypertension. Echocardiography had been performed in 64% of previously diagnosed patients, but was performed in only 22% of possible CHF patients. Angiotensin-converting enzyme (ACE) inhibitors were prescribed in 58.1% of patients with CHF. Patients with evidence of left ventricular dysfunction were more likely to have received ACE inhibitors. CONCLUSIONS: CHF appears to be very common in the elderly, based on GP diagnosis of the condition. Of 100 patients aged 60 years and over presenting to their GP, two new cases of CHF will be detected using a simple clinical algorithm in conjunction with appropriate diagnostic tests. ACE inhibitors appear to be underutilised.

Clinical relevance of statins: their role in secondary prevention.

Five large randomized clinical trials show the benefits of lipid lowering with statins on cardiac morbidity and mortality. Three of these were secondary-prevention trials--the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, Cholesterol and Recurrent Events (CARE), and Scandinavian Simvastatin Survival Study (4S). The CARE and LIPID studies, performed with pravastatin, comprise populations that are representative of the majority of patients with coronary disease in that they included subjects with 'average' cholesterol levels. The 4S study, using simvastatin, comprised a patient population with elevated lipid levels. Pooled data from three trials, CARE, LIPID, and the West of Scotland Coronary Prevention Study (WOSCOPS), were examined in the Pravastatin Pooling Project (PPP). Individual patient data from these three event trials were pooled into a single database, permitting subgroup analyses and providing increased power. In the PPP, pravastatin-treated patients had significantly lower all-cause mortality (7.9, vs. 9.8% in those receiving placebo, a relative risk reduction of 20%). Pravastatin treatment was associated with a significant 24% reduction in CHD mortality and a nonsignificant difference in other vascular deaths (17%) and noncardiovascular deaths (12%). However, the reductions in absolute risk were much larger in those with a history of coronary heart disease than in those without. In the combined analysis of CARE and LIPID, there was also a uniform relative risk reduction in both men and women. In high-risk groups such as diabetics, smokers, hypertensives, and the elderly, there were also significant risk reductions in clinical end points. Finally, in the 598 participants, who had a stroke (90% of which were non-fatal), CARE and LIPID individually demonstrated reductions in non-fatal and total stroke. These data confirm that benefits of treatment in secondary prevention of coronary heart disease encompasses prevention of stroke as well as coronary heart disease events. The benefits are found in those who have had unstable angina as well as myocardial infarction. These findings strengthen even further the case for much more widespread use of statins in secondary prevention.