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.

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research.

Gender differences in the impact of metabolic syndrome components on mortality in older people: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The influence of metabolic syndrome (MetS) on mortality may be influenced by age- and gender-related changes affecting the impact of individual MetS components. We investigated gender differences in the association between MetS components and mortality in community-dwelling older adults. METHODS AND RESULTS: Prospective studies were identified through a systematic literature review up to June 2019. Random-effect meta-analyses were run to estimate the pooled relative risk (RR) and 95% confidence intervals (95% CI) of all-cause and cardiovascular (CV) mortality associated with the presence of MetS components (abdominal obesity, high triglycerides, low HDL cholesterol, high fasting glycemia, and high blood pressure) in older men and women. Meta-analyses considering all-cause (103,859 individuals, 48,830 men, 55,029 women; 10 studies) and CV mortality (94,965 individuals, 44,699 men, 50,266 women; 8 studies) did not reveal any significant association for abdominal obesity and high triglycerides in either gender. Low HDL was associated with increased all-cause (RR = 1.16, 95% CI: 1.02-1.32) and CV mortality (RR = 1.34, 95% CI: 1.03-1.74) among women, while weaker results were found for men. High fasting glycemia was associated with higher all-cause mortality in older women (RR = 1.35, 95% CI: 1.22-1.50) more than in older men (RR = 1.21, 95% CI: 1.13-1.30), and CV mortality only in the former (RR = 1.36, 95% CI: 1.04-1.78). Elevated blood pressure was associated with increased all-cause mortality (RR = 1.16, 95% CI: 1.03-1.32) and showed marginal significant results for CV death only among women. CONCLUSIONS: The impact of MetS components on mortality in older people present some gender differences, with low HDL cholesterol, hyperglycemia, and elevated blood pressure being more strongly associated to all-cause and CV mortality in women.

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.

An updated review of lipid-modifying therapy.

Statin drugs reduce low-density lipoprotein (LDL)-cholesterol (LDL-C) and cardiovascular risk. Ezetimibe may be used to supplement statin therapy, or used alone in cases of statin intolerance. Statin-associated side effects do occur, especially muscle symptoms and new onset diabetes, but they do not detract from the benefits of statin therapy. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce LDL-C and cardiovascular risk. Evolocumab is subsidised in Australia for patients with familial hypercholesterolaemia when LDL-C is not adequately controlled with maximum doses of statin or ezetimibe or when statin therapy is contraindicated. Fenofibrate reduces triglycerides and cardiovascular risk in patients with type 2 diabetes when triglycerides are elevated and high-density lipoprotein (HDL) is low. A role for dietary omega-3 fatty acids and esters in reducing cardiovascular risk remains controversial. All cases of secondary cardiovascular disease prevention merit intensive lipid therapy, unless a contraindication exists. Lipid therapy is justified in cases of primary prevention when absolute risk is high, especially when lipids are highly elevated or when multiple risk factors are present. Clinical management requires a focus on the predominant lipid disorder present, namely hypercholesterolaemia, hypertriglyceridaemia or combined hyperlipidaemia. There is an ongoing problem of poor long term persistence on lipid therapy, as well as reduced awareness by practitioners of poor risk factor control.

LDL-cholesterol Predicts a First CHD Event in Senior Citizens, Especially So in Those With Elevated Lipoprotein(a): Dubbo Study of the Elderly.

OBJECTIVE: The analysis was designed to explore the combined effects of LDL-cholesterol and lipoprotein(a) (Lp(a)) in predicting incident coronary heart disease (CHD) in senior citizens without prior CHD. 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. Subjects with prior CHD (n=607) were excluded from this analysis. Incident CHD events were identified by hospital record linkage. The contributions of LDL and Lp(a) to CHD events and their combined effects were evaluated in proportional hazards regression models. RESULTS: There were 689 CHD events over 16 years in a cohort of 2198 men and women without prior CHD. LDL-cholesterol (corrected for cholesterol content of Lp(a)) and Lp(a) modelled in quartile categories each independently predicted CHD, but exclusively in Quartile 4 (Q4) for each parameter. Using the combination of LDL Q1 and Lp(a) Q1 as a reference group, LDL Q4 (>4.90mmol/L) most clearly predicted CHD in combination with Lp(a) Q4 (>276mg/L), hazard ratio 1.95 (95%CI 1.31-2.90). CONCLUSION: The present findings may have important practical implications in clinical management. If Lp(a) is assessed in senior citizens without prior CHD and found to be genuinely low, elevated LDL-cholesterol may not require active intervention.

Development of an Australian cardiovascular disease mortality risk score using multiple imputation and recalibration from national statistics.

OBJECTIVE: To develop and recalibrate an Australian 5-year cardiovascular disease (CVD) mortality risk score to produce contemporary predictions of risk. METHODS: Data were pooled from six Australian cohort studies (n = 54,829), with baseline data collected between 1989 and 2003. Participants included were aged 40-74 years and free of CVD at baseline. Variables were harmonised across studies and missing data were imputed using multiple imputation. Cox proportional hazards models were used to estimate the risk of CVD mortality associated with factors mutually independently predictive (p < 0.05) and a 5-year risk prediction algorithm was constructed. This algorithm was recalibrated to reflect contemporary national levels of CVD mortality and risk factors using national statistics. RESULTS: Over a mean 16.6 years follow-up, 1375 participants in the six studies died from CVD. The prediction model included age, sex, smoking, diabetes, systolic blood pressure, total and high-density lipoprotein cholesterol (HDLC), a social deprivation score, estimated glomerular filtration rate and its square and interactions of sex with diabetes, HDLC and deprivation score, and of age with systolic blood pressure and smoking. This model discriminated well when applied to a Scottish study population (c-statistic (95% confidence interval): 0.751 (0.709, 0.793)). Recalibration generally increased estimated risks, but well below those predicted by the European SCORE models. CONCLUSIONS: The resulting risk score, which includes markers of both chronic kidney disease and socioeconomic deprivation, is the first CVD mortality risk prediction tool for Australia to be derived using Australian data. The primary model, and the method of recalibration, is applicable elsewhere.

Comparison of anthropometric measures as predictors of cancer incidence: A pooled collaborative analysis of 11 Australian cohorts.

Obesity is a risk factor for cancer. However, it is not known if general adiposity, as measured by body mass index (BMI) or central adiposity [e.g., waist circumference (WC)] have stronger associations with cancer, or which anthropometric measure best predicts cancer risk. We included 79,458 men and women from the Australian and New Zealand Diabetes and Cancer Collaboration with complete data on anthropometry [BMI, WC, Hip Circumference (HC), WHR, waist to height ratio (WtHR), A Body Shape Index (ABSI)], linked to the Australian Cancer Database. Cox proportional hazards models assessed the association between each anthropometric marker, per standard deviation and the risk of overall, colorectal, post-menopausal (PM) breast, prostate and obesity-related cancers. We assessed the discriminative ability of models using Harrell's c-statistic. All anthropometric markers were associated with overall, colorectal and obesity-related cancers. BMI, WC and HC were associated with PM breast cancer and no significant associations were seen for prostate cancer. Strongest associations were observed for WC across all outcomes, excluding PM breast cancer for which HC was strongest. WC had greater discrimination compared to BMI for overall and colorectal cancer in men and women with c-statistics ranging from 0.70 to 0.71. We show all anthropometric measures are associated with the overall, colorectal, PM breast and obesity-related cancer in men and women, but not prostate cancer. WC discriminated marginally better than BMI. However, all anthropometric measures were similarly moderately predictive of cancer risk. We do not recommend one anthropometric marker over another for assessing an individuals' risk of cancer.

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.

Are high coronary risk patients missing out on lipid-lowering drugs in Australia?

OBJECTIVE: To examine whether high coronary risk patients in Australia, where use of lipid-lowering drugs (LLD) is very high by international standards, are receiving LLD. DESIGN, SETTING AND PATIENTS: Assessment of Pharmaceutical Benefits Scheme pharmacy payment claim records between January 2006 and May 2013 for a 10% random sample of Australian concession card holders. Co-prescriptions were used as a surrogate for high coronary risk groups - coronary heart disease (CHD): antiplatelet drugs (not including solo aspirin) and anti-anginal drugs; diabetes: all standard drugs; hypertension: all standard drugs (not including solo diuretics). MAIN OUTCOME MEASURE: Proportions of patients in high-risk groups not receiving LLD (statins, fibrates or ezetimibe). RESULTS: The database yielded information on 276,212 patients defined as being at high coronary risk (mean age, 66.1 [SD, 14.8] years; 44% male). Of this group, 115,477 patients (42%) had not received any LLD during the study period. For patients in the risk group for CHD in combination with diabetes and hypertension, only 8% (1111/14,257) were not receiving LLD. Across all risk groups, the proportions not receiving LLD were generally highest in those aged ≥ 81 years and, to a lesser extent, < 41 years, and were lowest in those aged 51-70 years. CONCLUSION: A large proportion of concession card holders at high coronary risk, especially those in middle age with CHD and multiple risk factors, are being appropriately prescribed LLD in Australia.

Glycated hemoglobin measurement and prediction of cardiovascular disease.

IMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk. RESULTS: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

Persistence on warfarin in patients with atrial fibrillation: experience in Australia 2006-2009.

BACKGROUND: Long-term persistence on warfarin in patients with non-valvular atrial fibrillation is essential to minimise thromboembolic complications, especially ischaemic stroke. This study examines persistence in Australian patients with presumed atrial fibrillation newly prescribed warfarin. METHODS: Longitudinal assessment of Pharmaceutical Benefit Scheme payment claim records from October 2006 through September 2009 in a 10% random sample of the Australian population holding long-term concession cards. MAIN OUTCOME MEASURES: proportion not filling first repeat prescription, median persistence time on medication, long-term persistence at 33 months. RESULTS: A total of 1 108 patients (representative of 11 080 nationally) were newly prescribed warfarin; mean age 74 years, 50% were females. Fifteen percent (95% CI: 13-17) failed to collect the first repeat prescription, median persistence time on medication was only 12 months (95% CI: 10-13), long-term persistence at 33 months was 26% (95% CI: 23-27). DISCUSSION: There is significant discontinuation of warfarin therapy. When due to non-compliance, an opportunity for stroke prevention is being lost.

Lipoprotein(a) and the risk of recurrent coronary heart disease: the Dubbo Study.

OBJECTIVE: Elevated Lipoprotein(a) [Lp(a)] has not been firmly established as a risk factor for recurrent coronary heart disease (CHD). The present analysis explored this relationship in senior citizens. METHODS: This was a longitudinal study in 607 subjects, all with prevalent CHD, mean age 71 years, followed for 16 years. Baseline examinations of lipids and other CHD risk factors were conducted in 1988-89 in Dubbo, Australia. The independent contribution of Lp(a) to a further CHD event was examined in proportional hazards regression models. RESULTS: There were 399 incident CHD cases. Median Lp(a) in CHD cases was 130 mg/L (Interquartile range 60-315) and in non-cases 105 mg/L (45-250) (p < .07, U-Test). 26% of CHD cases and 19% of non-cases had Lp(a) 300 + mg/L; 18% of CHD cases and 8% of non-cases had Lp(a) 500 + mg/L. Lp(a) in Quintile 5 of its distribution (355 + mg/L), using Lp(a) Quintile 1 (<50mg/L) as reference, significantly predicted recurrent CHD with Hazard Ratio 1.53 (95% CI 1.11-2.11, p = .01). Prediction was independent of other risk factors. Lp(a) 500 + mg/L versus lower, significantly predicted recurrent CHD with Hazard Ratio 1.59 (1.16-2.17, p < .01). Prediction was similarly significant for Lp(a) 300 + mg/L versus lower, with Hazard Ratio 1.37 (1.09-1.73, p < .01). CONCLUSION: Elevated Lp(a) is an independent and significant predictor of recurrent CHD in senior citizens. Upper reference Lp(a) levels of 500 mg/L (≈125nmol/L) or 300 mg/L (≈75nmol/L) both appear to be appropriate. The clinical benefit of therapy to reduce elevated Lp(a) remains to be confirmed.

Lipoprotein(a) [Lp(a)], a type of "bad cholesterol", has been shown to be an important cause of coronary artery disease (CAD). In the long-term Dubbo Study of senior citizens in Australia, Professor Simons' team have previously shown that citizens with Lp(a) readings greater than 276 mg/L had a 46% greater chance of a first CAD problem (e.g. a heart attack) compared with those having much lower readings. This new study asked whether Lp(a) might also increase the chance of a second or repeat episode of CAD in citizens who had already manifested CAD. In 607 senior citizens with previous CAD followed for 16 years, those with Lp(a) readings greater than 355 mg/L had a 53% greater chance of manifesting another CAD problem compared with those having much lower readings. The team concluded that Lp(a) remains an important cause of repeat CAD in senior citizens. The benefit of emerging treatments to lower Lp(a) remains to be confirmed in ongoing research.

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.

Lipid-related markers and cardiovascular disease prediction.

CONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk. RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

Persistence with a single pill versus two pills of amlodipine and atorvastatin: the Australian experience, 2006-2010.

OBJECTIVE: To study patient persistence on therapy for hypertension and dyslipidaemia using a single-pill combination compared with a two-pill approach. DESIGN AND SETTING: Post-hoc observational assessment of Pharmaceutical Benefits Scheme claim records covering the period April 2005 to March 2010. PARTICIPANTS: A 10% random sample of Australian long-term concession card holders was analysed. The patients studied had commenced on either amlodipine and atorvastatin as two individual pills, or a single pill containing both amlodipine and atorvastatin (AA), with neither combined approach having been dispensed to them in the previous 6 months. MAIN OUTCOME MEASURES: The proportions of patients failing to fill their first repeat prescription after 1 month or failing to persist with treatment at 12 months, and the median persistence time (MPT) were measured. RESULTS: Of 4146 patients prescribed the AA single pill, 11% failed to fill the first repeat prescription and 33% had ceased treatment by 12 months (MPT, 35 months). Of 6204 patients prescribed amlodipine and atorvastatin as two pills, 23% failed to fill the first repeat prescriptions and 59% had ceased treatment by 12 months (MPT, 7 months). In a multivariate model, cessation of single-pill therapy increased by 165% if there was no prior therapy, but only increased by 48%-55% if there was no prior therapy with a calcium channel blocker or statin. MPT on the single pill was 8 months in those without prior antihypertensive therapy, but was ≥ 37 months in those with any prior antihypertensive therapy. CONCLUSION: A single-pill combination drug is associated with superior long-term persistence compared with two-pill therapy in the management of hypertension and dyslipidaemia.

Is prediction of cardiovascular disease and all-cause mortality genuinely driven by the metabolic syndrome, and independently from its component variables? The Dubbo study.

BACKGROUND: The Metabolic Syndrome (MetS) predicts an increased risk of cardiovascular disease and all-cause mortality. Is this prediction genuinely driven by the syndrome and independently from its component variables? METHODS: A longitudinal cohort study in Dubbo, Australia of 2805 men and women ≥60 years followed for 16 years from 1988. Cox proportional hazards models were calculated for coronary heart disease (CHD), ischaemic stroke and all-cause mortality with MetS as an independent variable. Separate models included the MetS variable, with or without the presence of one of its five component variables. RESULTS: MetS was present in 33% of subjects. Obesity was present in 43% of those with MetS, high blood pressure in 99%, elevated triglycerides in 83%, low HDL-C in 75% and glycaemia in 48%. With respect to CHD and all-cause mortality, prediction by MetS was similar in the presence or absence of individual component factors (e.g. hazard ratio (95% CI) for CHD by MetS when low HDL-C present 1.60(1.39-1.84) and 1.67(1.37-2.04) when low HDL-C absent). With stroke, prediction by MetS was lost in the absence of elevated triglycerides or glycaemia factors (e.g. hazard ratio for stroke by MetS when glycaemia present 1.59(1.24-2.05) and 1.08(0.82-1.42) when glycaemia absent). CONCLUSIONS: The findings suggest that prediction of CHD and all-cause mortality is genuinely driven by the MetS and independently of its component variables. Prediction of ischaemic stroke is more complex, with some components providing prediction independently from the MetS.

Long term persistence with statin therapy -- experience in Australia 2006-2010.

BACKGROUND: Long term persistence on statin drugs has been shown to be unsatisfactory, however, there is little recent Australian data. This study examines current persistence Australia-wide in patients who have been newly prescribed a statin drug. METHOD: We conducted a longitudinal assessment of Pharmaceutical Benefit Scheme claim records dating from April 2005 to March 2010. Main outcome measures were the proportion of patients who were not filling a first repeat prescription at 1 month, and median persistence time during follow up. RESULTS: For 77,867 patients initiated to statin, 86% of prescriptions came from general practitioners. Forty-three percent of patients discontinued statin within 6 months, 23% failed to collect their first repeat at 1 month, and median persistence time was only 11 months. In those aged 65--74 years, median persistence time was 19 months but only 3--6 months for those less than 55 years. DISCUSSION: Unsatisfactory long term persistence on statin therapy has changed little over the past 10 years. There may be an opportunity for early intervention within 3--4 weeks of initiation to improve persistence, as valuable resources are being wasted and an opportunity for disease prevention missed.

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.