Gaps in the Care of Familial Hypercholesterolaemia in Australia: First Report From the National Registry.

BACKGROUND: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients. METHODS: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics. RESULTS: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD. CONCLUSION: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.

Association Between Depressive Symptoms and Incident Cardiovascular Diseases.

Importance: It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVDs). Objective: To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood. Design, Setting, and Participants: A pooled analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 162 036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and the UK Biobank (401 219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline. Exposures: Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Center for Epidemiological Studies Depression (CES-D) scale (range, 0-60; ≥16 indicates possible depressive disorder). The UK Biobank recorded the 2-item Patient Health Questionnaire 2 (PHQ-2; range, 0-6; ≥3 indicates possible depressive disorder). Main Outcomes and Measures: Primary outcomes were incident fatal or nonfatal coronary heart disease (CHD), stroke, and CVD (composite of the 2). Hazard ratios (HRs) per 1-SD higher log CES-D or PHQ-2 adjusted for age, sex, smoking, and diabetes were reported. Results: Among 162 036 participants from the ERFC (73%, women; mean age at baseline, 63 years [SD, 9 years]), 5078 CHD and 3932 stroke events were recorded (median follow-up, 9.5 years). Associations with CHD, stroke, and CVD were log linear. The HR per 1-SD higher depression score for CHD was 1.07 (95% CI, 1.03-1.11); stroke, 1.05 (95% CI, 1.01-1.10); and CVD, 1.06 (95% CI, 1.04-1.08). The corresponding incidence rates per 10 000 person-years of follow-up in the highest vs the lowest quintile of CES-D score (geometric mean CES-D score, 19 vs 1) were 36.3 vs 29.0 for CHD events, 28.0 vs 24.7 for stroke events, and 62.8 vs 53.5 for CVD events. Among 401 219 participants from the UK Biobank (55% were women, mean age at baseline, 56 years [SD, 8 years]), 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1 years). The HR per 1-SD higher depression score for CHD was 1.11 (95% CI, 1.08-1.14); stroke, 1.10 (95% CI, 1.06-1.14); and CVD, 1.10 (95% CI, 1.08-1.13). The corresponding incidence rates per 10 000 person-years of follow-up among individuals with PHQ-2 scores of 4 or higher vs 0 were 20.9 vs 14.2 for CHD events, 15.3 vs 10.2 for stroke events, and 36.2 vs 24.5 for CVD events. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors. Conclusions and Relevance: In a pooled analysis of 563 255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels lower than the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Hypertension, antihypertensive treatment and cancer incidence and mortality: a pooled collaborative analysis of 12 Australian and New Zealand cohorts.

BACKGROUND: Observational studies examining associations between hypertension and cancer are inconsistent. We explored the association of hypertension, graded hypertension and antihypertensive treatment with cancer incidence and mortality. METHOD: Eighty-six thousand five hundred and ninety-three participants from the Australian and New Zealand Diabetes and Cancer Collaboration were linked to the National Death Index and Australian Cancer Database. Cox proportional hazards models estimated hazard ratios and 95% confidence intervals (95% CI) for the association of treated and untreated hypertension with cancer incidence and mortality. RESULTS: Over a median follow-up of 15.1 years, 12 070 incident and 4350 fatal cancers were identified. Untreated and treated hypertension, compared with normotension, were associated with an increased risk for cancer incidence [hazard ratio 1.06, 95% CI (1.00-1.11) and 1.09 (1.02-1.16) respectively], and cancer mortality (1.07, 0.98-1.18) and (1.15, 1.03-1.28), respectively. When compared with untreated hypertension, treated hypertension did not have a significantly greater risk for cancer incidence (1.03, 0.97-1.10) or mortality (1.07, 0.97-1.19). A significant dose-response relationship was observed between graded hypertension and cancer incidence and mortality; Ptrend = 0.053 and Ptrend = 0.001, respectively. When stratified by treatment status, these relationships remained significant in untreated, but not in treated, hypertension. CONCLUSION: Hypertension, both treated and untreated, is associated with a modest increased risk for cancer incidence and mortality. Similar risks in treated and untreated hypertension suggest that the increased cancer risk is not explained by the use of antihypertensive treatment.

Association of Cardiometabolic Multimorbidity With Mortality.

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Prediction of cardiovascular and all-cause mortality at 10 years in the hypertensive aged population.

BACKGROUND: We have previously developed a score for predicting cardiovascular events in the intermediate term in an elderly hypertensive population. In this study, we aimed to extend this work to predict 10-year cardiovascular and all-cause mortality in the hypertensive aged population. METHODS: Ten-year follow-up data of 5,378 hypertensive participants in the Second Australian National Blood Pressure study who were aged 65-84 years at baseline (1995-2001) and without prior cardiovascular events were analyzed. By using bootstrap resampling variable selection methods and comparing the Akaike and Bayesian information criterion and C-indices of the potential models, optimal and parsimonious multivariable Cox proportional hazards models were developed to predict 10-year cardiovascular and all-cause mortality. The models were validated using bootstrap validation method internally and using the Dubbo Study dataset externally. RESULTS: The final model for cardiovascular mortality included detrimental (age, smoking, diabetes, waist-hip ratio, and disadvantaged socioeconomic status) and protective factors (female sex, alcohol consumption, and physical activity). The final model for all-cause mortality also included detrimental (age, smoking, random blood glucose, and disadvantaged socioeconomic status) and protective factors (female sex, alcohol consumption, body mass index, and statin use). Blood pressure did not appear in either model in this patient group. The C-statistics for internal validation were 0.707 (cardiovascular mortality) and 0.678 (all-cause mortality), and for external validation were 0.729 (cardiovascular mortality) and 0.772 (all-cause mortality). CONCLUSIONS: These algorithms allow reliable estimation of 10-year risk of cardiovascular and all-cause mortality for hypertensive aged individuals.

Seasonality of cardiovascular risk factors: an analysis including over 230†000 participants in 15 countries.

OBJECTIVE: To assess the seasonality of cardiovascular risk factors (CVRF) in a large set of population-based studies. METHODS: Cross-sectional data from 24 population-based studies from 15 countries, with a total sample size of 237 979 subjects. CVRFs included Body Mass Index (BMI) and waist circumference; systolic (SBP) and diastolic (DBP) blood pressure; total, high (HDL) and low (LDL) density lipoprotein cholesterol; triglycerides and glucose levels. Within each study, all data were adjusted for age, gender and current smoking. For blood pressure, lipids and glucose levels, further adjustments on BMI and drug treatment were performed. RESULTS: In the Northern and Southern Hemispheres, CVRFs levels tended to be higher in winter and lower in summer months. These patterns were observed for most studies. In the Northern Hemisphere, the estimated seasonal variations were 0.26 kg/m(2) for BMI, 0.6 cm for waist circumference, 2.9 mm Hg for SBP, 1.4 mm Hg for DBP, 0.02 mmol/L for triglycerides, 0.10 mmol/L for total cholesterol, 0.01 mmol/L for HDL cholesterol, 0.11 mmol/L for LDL cholesterol, and 0.07 mmol/L for glycaemia. Similar results were obtained when the analysis was restricted to studies collecting fasting blood samples. Similar seasonal variations were found for most CVRFs in the Southern Hemisphere, with the exception of waist circumference, HDL, and LDL cholesterol. CONCLUSIONS: CVRFs show a seasonal pattern characterised by higher levels in winter, and lower levels in summer. This pattern could contribute to the seasonality of CV mortality.

Childbearing history and late-life mortality: the Dubbo study of Australian elderly.

OBJECTIVE: to examine the association of parity with mortality in later life. DESIGN: a longitudinal, community-based study. SETTING: semi-rural town of Dubbo, NSW, Australia. SUBJECTS: a total of 1,571 women and 1,233 men 60 years and older first examined in 1988-89. OUTCOME MEASURES: all-cause and cause-specific mortality rates analysed over 16-year follow-up. Hazard ratios obtained from proportional hazards models employing conventional predictors, potential confounders and measure of parity. RESULTS: increasing parity in women was weakly associated with overweight, diabetes and hypertension. All-cause mortality fell progressively with increasing parity in women (hazard ratio and 95% confidence intervals): childless, 1.00; 1 child, 1.03 (0.75-1.43); 2 children, 0.83 (0.61-1.11); 3 children, 0.80 (0.60-1.08); 4 children, 0.91 (0.66-1.25); 5 children, 0.70 (0.49-1.01); 6+ children, 0.60 (0.43-0.85) (trend for parity P<0.002). This result was similar whether or not hypertension, diabetes and overweight were included in multivariate models adjusting for social variables and other confounders. The reduction in all-cause mortality was accompanied by a parallel reduction in deaths from cancer and respiratory conditions, while coronary heart disease mortality increased 60-111% in all parous women. CONCLUSION: there was increased all-cause mortality in later life in childless women, accompanied by reduced mortality as parity increased. Underlying mechanisms are unclear but findings may have public health importance.

Recalibration and validation of the SCORE risk chart in the Australian population: the AusSCORE chart.

BACKGROUND: Development of a validated risk prediction model for future cardiovascular disease (CVD) in Australians is a high priority for cardiovascular health strategies. DESIGN: Recalibration of the SCORE (Systematic COronary Risk Evaluation) risk chart based on Australian national mortality data and average major CVD risk factor levels. METHODS: Australian national mortality data (2003-2005) were used to estimate 10-year cumulative CVD mortality rates for people aged 40-74 years. Average age-specific and sex-specific levels of systolic blood pressure, total cholesterol and prevalence of current smoking were generated from data obtained in eight Australian large-scale population-based surveys undertaken from the late 1980s. The SCORE risk chart was then recalibrated by applying hazard ratios for 10-year CVD mortality obtained in the SCORE project. Discrimination and calibration of the recalibrated model was evaluated and compared with that of the original SCORE and Framingham equations in the Blue Mountains Eye Study in Australia using Harrell's c and Hosmer-Lemeshow chi statistics, respectively. RESULTS: An Australian risk prediction chart for CVD mortality was derived. Among 1998 Blue Mountains Eye Study participants aged 49-74 years with neither CVD nor diabetes at baseline, the Harrell's c statistics for the Australian risk prediction chart for CVD mortality were 0.76 (95% confidence interval: 0.69-0.84) and 0.71 (confidence interval: 0.62-0.80) in men and women, respectively. The corresponding Hosmer-Lemeshow chi statistics, the measure of calibration, were 2.32 (P = 0.68) and 7.43 (P = 0.11), which were superior to both the SCORE and Framingham equations. CONCLUSION: This new tool provides a valid and reliable method to predict risk of CVD mortality in the general Australian population.

A comparison of risk factors for coronary heart disease and ischaemic stroke: the Dubbo study of Australian elderly.

BACKGROUND: Conventional risk factors for coronary heart disease (CHD) and ischaemic stroke (IS) have been well documented. This study examines whether there is a unique pattern of risk factors for each disease. METHODS: This is a prospective cohort study in Dubbo NSW which has followed 2805 men and women 60 years and older for 16 years since 1988-1989. CHD and IS events were identified by hospital record linkage. The independent contributions of risk factors to these events were evaluated in proportional hazards regression models. RESULTS: CHD events (without stroke) occurred in 853 subjects (30.4/100). IS events (without CHD) occurred in 185 subjects (6.6/100). Some risk factors produced broadly similar prediction of CHD and IS events (male sex, current smoking, diabetes, LDL cholesterol, reduced peak expiratory flow, physical disability). Other factors potentially produced unique prediction of CHD (CHD at baseline, family history of CHD, HDL cholesterol, ApoB/ApoA1 ratio) or IS (stroke at baseline), or stronger prediction of IS compared with CHD (age, hypertension, atrial fibrillation). CONCLUSIONS: CHD and IS may each have some unique predictors, but treatable risk factors have been demonstrated for both cardiovascular outcomes.

Impact of smoking, diabetes and hypertension on survival time in the elderly: the Dubbo Study.

OBJECTIVE: To study the impact of various risk factors on survival time in a cohort of elderly Australians. DESIGN, SETTING AND PARTICIPANTS: A longitudinal, prospective cohort study conducted in Dubbo, NSW. Participants were men and women aged 60 years or over living in the community, first assessed in 1988-1989 and followed for 15 years. MAIN OUTCOME MEASURES: Mortality rates; risk factors; survival times. RESULTS: There were 668 deaths in 1233 men (54%) and 625 deaths in 1572 women (40%). Coronary heart disease was the major cause of death, rates being higher in men than women until age group 80+ years; stroke death rates were similar in both sexes; cancer and respiratory death rates were higher in men than women across all ages. In a proportional hazards model, the independent predictors of mortality were cigarette smoking, diabetes, very high blood pressure (BP), impaired peak expiratory flow (PEF), physical disability, and zero intake of alcohol. Over 15 years, the average reductions in survival time associated with various risk factors, in men and women respectively, were smoking, 22 and 15 months; diabetes, 18 and 18 months; very high BP, 16 and 9 months; impaired PEF, 14 and 17 months; physical disability, 16 and 12 months; zero alcohol intake, 9 and 5 months. Combinations of selected risk factors were associated with a multiplier effect. CONCLUSION: The reduction in survival time in elderly citizens demonstrated in the presence of smoking, diabetes and hypertension highlights a potential benefit to healthy ageing to be gained from prevention and intervention.

Risk functions for prediction of cardiovascular disease in elderly Australians: the Dubbo Study.

OBJECTIVES: To evaluate a Framingham risk function for coronary heart disease in an elderly Australian cohort and to derive a risk function for cardiovascular disease (CVD) in elderly Australians. DESIGN AND SETTING: Analysis of data from a prospective cohort study (the Dubbo Study) in a semi-urban town (population, 34 000). PARTICIPANTS: 2805 men and women 60 years and older living in the community, first assessed in 1988, and a subcohort of 2102 free of CVD at study entry. MAIN OUTCOME MEASURES: Incidence of CVD (myocardial infarction, coronary death or stroke) over 5 and 10 years. RESULTS: A Framingham risk function assessing "hard" coronary heart disease (ie, myocardial infarction or coronary death) accurately predicted 10-year incidence in men and women aged 60-79 years who were free of prevalent CVD or diabetes at study entry. In a multiple logistic model, CVD incidence was significantly predicted by age, sex, taking antihypertensive medication, blood pressure, smoking, total cholesterol level and diabetes. For a given age and cholesterol level, CVD risk over 5 years was doubled in the presence of antihypertensive medication or diabetes, increased by 50% with cigarette smoking, and halved in women compared with men. CONCLUSIONS: We have derived a simple CVD risk function specifically for elderly Australians that employs risk factors readily accessible to all medical practitioners.