This article reviews the risk equations recommended for use in international cardiovascular disease (CVD) primary prevention guidelines and assesses their suitability for use in Australia against a set of a priori defined selection criteria. The review and assessment were commissioned by the National Heart Foundation of Australia on behalf of the Australian Chronic Disease Prevention Alliance to inform recommendations on CVD risk estimation as part of the 2023 update of the Australian CVD risk assessment and management guidelines. Selected international risk equations were assessed against eight selection criteria: development using contemporary data; inclusion of established cardiovascular risk factors; inclusion of ethnicity and deprivation measures; prediction of a broad selection of fatal and non-fatal CVD outcomes; population representativeness; model performance; external validation in an Australian dataset; and the ability to be recalibrated or modified. Of the ten risk prediction equations reviewed, the New Zealand PREDICT equation met seven of the eight selection criteria, and met additional usability criteria aimed at assessing the ability to apply the risk equation in practice in Australia.
Objectives Cardiovascular disease (CVD) is highly preventable and optimal treatments based on absolute risk can halve risk of future events. Compared with women, men have higher risks of developing CVD. However, women can experience suboptimal treatment. We aimed to quantify sex differences in CVD risk, assessment and treatment in Australian adults. Design, participants, setting Cross-sectional analysis of nationally representative data from interview, physical measures, medication review and blood and urine samples, from 2011 to 2012 Australian Health Survey participants aged 45–74 (n=11 518). Outcome measures CVD risk factors, absolute 5-year risk of a primary CVD event, blood pressure and cholesterol assessment in the previous 2 and 5 years and use of recommended CVD preventive medications were compared using Poisson regression to estimate age-adjusted male versus female prevalence ratios (PRs). Results Women had a generally more favourable CVD risk factor profile than men, including lower: current smoking prevalence (women=14.5%; men=18.4%, PR=0.78, 95% CI=0.70 to 0.88); body mass index (women (mean)=28.3 kg/m 2 ; men (mean)=28.8 kg/m 2 , p<0.01); systolic and diastolic blood pressure (systolic: women (mean)=127.1 mm Hg; men (mean)=130.5 mm Hg, p<0.001); blood glucose (women (mean)=5.2 mmol/L; men (mean)=5.5 mmol/L); diabetes prevalence (women=6.8%; men=12.5%, PR=0.55, 95% CI=0.44 to 0.67); prior CVD (women=7.9%; men=11.3%) and absolute primary CVD risk (absolute 5-year CVD risk >15%: women=6.6%, 95% CI=5.4 to 7.8; men=15.4%, 95% CI=13.9% to 16.9%). Compared with men, women had higher low-density lipoprotein, high-density lipoprotein and total cholesterol and sedentary behaviour and lower physical activity. Blood pressure and cholesterol assessment were common in both sexes. Among those at high absolute risk, age-adjusted proportions receiving recommended CVD medications were low, without sex differences (women=21.3%; men=23.8%, PR=0.93, 95% CI=0.49 to 1.78). Fewer women than men with prior atherosclerotic CVD were receiving recommended treatment (women=21.8%, men=41.4%, PR=0.55, 95% CI=0.31 to 0.96). Conclusion Women have a more favourable CVD risk factor profile than men. Preventive treatment is uncommon and women with prior atherosclerotic CVD are around half as likely as men to be receiving recommended treatment.
Abstract Circulating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p<4.9×10 -10 ) at 144 (94 novel) genomic regions. We show that inheritance of blood metabolite levels in the general population is characterized by pleiotropy, allelic heterogeneity, rare and common variants with large effects, non-linear associations, and enrichment for nonsynonymous variation in transporter and enzyme encoding genes. The majority of identified genes are known to be involved in biochemical processes regulating metabolite levels and to cause monogenic inborn errors of metabolism linked to specific metabolites, such as ASNS (rs17345286, MAF=0.27) and asparagine levels. We illustrate the influence of metabolite-associated variants on human health including a shared signal at GLP2R (p.Asp470Asn) associated with higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes risk, and demonstrate beta-arrestin signalling as the underlying mechanism in cellular models. We link genetically-higher serine levels to a 95% reduction in the likelihood of developing macular telangiectasia type 2 [odds ratio (95% confidence interval) per standard deviation higher levels 0.05 (0.03-0.08; p=9.5×10 -30 )]. We further demonstrate the predictive value of genetic variants identified for serine or glycine levels for this rare and difficult to diagnose degenerative retinal disease [area under the receiver operating characteristic curve: 0.73 (95% confidence interval: 0.70-0.75)], for which low serine availability, through generation of deoxysphingolipids, has recently been shown to be causally relevant. These results show that integration of human genomic variation with circulating small molecule data obtained across different measurement platforms enables efficient discovery of genetic regulators of human metabolism and translation into clinical insights.
Data on the expected effectiveness of a formal cardiovascular risk screening program are needed Population-based screening programs for early disease detection are important for preventing morbidity, disability, and premature death. Australia has five structured population-based health screening programs for cancer and for newborn conditions.1 Australia's current guidelines for cardiovascular disease (CVD) prevention recommend risk assessment for the general population aged 45–74 years using a validated risk equation.2 Yet, recent data show that less than 50% of eligible Australians have relevant risk factor data recorded in primary care to enable risk assessment,3 and there are huge shortfalls and inequities in treatment for individuals at high risk.4-6 Although enhancement of chronic disease risk assessment is identified as a priority in the 2021 Australian National Preventive Health Strategy,7 no formal structured population screening programs are currently in place for CVD or related chronic diseases, such as chronic kidney disease (CKD) and diabetes. The Population Based Screening Framework sets out criteria to inform decision making on screening programs.1 We outline the evidence and data gaps for a formal CVD risk screening program in Australia, including elements relating to diabetes and CKD, against key criteria of the Framework (Box). CVD is a leading cause of death and morbidity in Australia and globally.8 In 2019, CVD accounted for a quarter of deaths in Australia9 and is estimated to cost the Australian economy around $5 billion annually.10 Around 80% of CVD events are preventable through early detection of risk and treatment.11, 12 CVD typically develops slowly over many decades before acute events occur. The risk factors for CVD, many of which are shared with diabetes and CKD, are well established and there is direct evidence that addressing these factors leads to a reduced probability of developing CVD. A range of predictive scores are available to quantify an individual's future risk of experiencing CVD events, including myocardial infarction, stroke, and death from CVD. These risk equations can be used in asymptomatic individuals. There are also measures of atherosclerosis for subclinical disease detection including coronary artery calcium scoring, intima-media thickness measurement, and ankle brachial index,13 but their validity varies and these measures are not broadly recommended in Australia.2 CVD risk can be assessed in primary care settings using predictive equations with information on risk factors, including age, sex, smoking, diabetes, blood pressure and cholesterol. The Framingham risk equation, recommended for use in Australia's soon to be updated 2012 guidelines,2 has been validated in several populations, including Australia.14 CVD risk assessment is non-invasive and considered safe and acceptable, although it may raise anxiety in some patients. In certain circumstances, additional testing with coronary calcium scoring may also be used to target preventive treatments. Sensitivity and specificity measures rely on being able to dichotomise outcomes based on people truly having or not having a disease and this being reflected in the screening test. Rather than diagnosing CVD, absolute CVD risk assessment quantifies the likelihood that an individual will experience a primary CVD event in given period of time. People above a specific threshold are considered at high risk and may be offered treatment. Risk treatment thresholds can change over time; if risk thresholds decrease (as has been typically observed around the world), then more people would be treated and more CVD events would be prevented. Thus, sensitivity and specificity are difficult to determine for absolute CVD risk assessment. In terms of the population that would be potentially treated, around 11.2% (95% CI, 10.2–12.2%) of the Australian population aged 45–74 years were estimated to be at high risk of a first time CVD event (> 15% risk over five years) in 2012.4 For comparison, 11% of women are recalled after a first mammogram as part of the Australian national BreastScreen program.15 The follow-up care of patients identified at high risk of CVD is embedded in Australian primary care and may include referral to allied health professionals and other specialists, further diagnostic testing and pharmacotherapy. Risk assessment usually occurs in primary care with general practitioners and practice nurses well equipped to conduct the screening activity and associated follow-up. Equity of access to medicines prescribed for the management of high CVD risk is through subsidy under the Pharmaceutical Benefits Scheme (PBS). Evidence-based guidelines for the assessment of CVD risk are available, and the Medicare Benefits Schedule currently supports this activity via items 699 and 177. Preventive treatments for those at high risk of developing CVD are cost-effective, safe, widely available, and acceptable. Evidence from large-scale randomised trials show that lipid- and blood pressure-lowering therapies reduce the risk of CVD events and all-cause mortality by around 25%.16, 17 Lipid- and blood pressure-lowering therapies are listed as a cost-effective intervention for preventing chronic disease in the population in both the Australian Assessing Cost-Effectiveness in Prevention (ACE-Prevention) study18 and the World Health Organization's "Best Buy" interventions.19 Treating CVD risk can also help tackle chronic diseases such as CKD, diabetes and dementia. Statins and blood pressure-lowering medications are readily available and subsidised through the PBS. Acceptability studies that have looked at patient preferences around statins found that people were more worried about clinical outcomes such as myocardial infarction and stroke than potential adverse effects of treatment.20 Like many conditions, including cancer, the disease processes underpinning CVD operate on a continuum, with atherosclerosis typically starting many years before CVD is diagnosed. CVD risk assessment involves using a combination of a person's observable risk factors to identify individuals most likely to have a future event, generally within five to ten years. CVD events will still occur in people assessed as low risk, but treating those identified as high risk is international best practice and more effective than treating individual risk factors, such as high blood pressure. Due to the imperfect nature of risk assessment and the long subclinical disease period, RCTs assessing the clinical impact of CVD risk assessment would need to be large-scale and long term to detect changes in CVD outcomes. A systematic review of systematic reviews found little evidence to support the clinical effectiveness of CVD risk assessment,21 although small reductions in individual risk factor levels (smoking, systolic blood pressure, and cholesterol)21 and predicted risk level22 have been found. Overall, studies have generally been of poor quality, with short follow-up periods (maximum 18 months), and have not assessed CVD events and mortality.21 Absolute CVD risk assessment and treatment meets three, and partly meets a further one, of the five key criteria for disease screening programs in Australia. The key evidence gap for supporting structured population CVD risk screening in Australia is a lack of RCT evidence on the effectiveness of screening programs in reducing CVD events and mortality. However, RCTs of CVD risk screening programs would need to be large-scale and long term to be sufficiently powered to detect a change in clinical outcomes. Other data need to be considered in absence of RCT data for this criterion. There is precedence for this: cervical cancer screening in Australia was recommended based on the effectiveness of the individual components of screening and prevention, despite lacking RCT data on the screening program. A formal CVD risk screening program is likely to reduce the burden of CVD across the population, but we currently lack data to support this. This evidence gap could be bridged with models that combine high quality, large-scale data on components of CVD risk assessment and prevention to assess the expected impact of population-wide screening. Similar modelling provided the evidence to underpin changes in bowel and cervical cancer screening.25, 26 Such models are lacking for CVD in Australia but are currently being developed. In the meantime, interventions that target chronic disease risk factors across the population, and improving systems for embedding CVD risk assessment, management and follow-up within primary care are crucial for continued prevention of CVD in Australia. This work was supported by an Ian Potter Foundation Public Research Project Grant (Ref. 31110715). Ellie Paige was supported by a Postdoctoral Fellowship (Ref. 102131) from the National Heart Foundation of Australia (2018–2022). Emily Banks is supported by the National Health and Medical Research Council of Australia (Ref. 1136128). The funders played no role in the planning or writing of this publication. Emma Lonsdale left her role as Executive Officer at the Australian Chronic Disease Prevention Alliance in October 2022. Open access publishing facilitated by Australian National University, as part of the Wiley - Australian National University agreement via the Council of Australian University Librarians. Natalie Raffoul receives speaker fees from Amgen and Novartis. Not commissioned; externally peer reviewed.
Abstract Background The Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor ( IL6R ) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R -Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture. Method Using data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R -Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death. Results After adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [−0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05). Conclusions Our proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.
Objectives: We aimed to investigate antidepressant use, including the class of antidepressant, in mid-age and older Australians according to sociodemographic, lifestyle and physical and mental health-related factors. Methods: Baseline questionnaire data on 111,705 concession card holders aged ⩾45 years from the 45 and Up Study—a population-based cohort study from New South Wales, Australia—were linked to administrative pharmaceutical data. Current- and any-antidepressant users were those dispensed medications with Anatomical Therapeutic Chemical classification codes beginning N06A, within ⩽6 months and ⩽19 months before baseline, respectively; non-users had no antidepressants dispensed ⩽19 months before baseline. Multinomial logistic regression was used to calculate adjusted relative risk ratios (aRRRs) for predominantly self-reported factors in relation to antidepressant use. Results: Some 19% of the study population (15% of males and 23% of females) were dispensed at least one antidepressant during the study period; 40% of participants used selective serotonin reuptake inhibitors (SSRIs) only and 32% used tricyclic antidepressants (TCAs) only. Current antidepressant use was markedly higher in those reporting: severe versus no physical impairment (aRRR 3.86(95%CI 3.67–4.06)); fair/poor versus excellent/very good self-rated health (4.04(3.83–4.25)); high/very high versus low psychological distress (7.22(6.81–7.66)); ever- versus never-diagnosis of depression by a doctor (18.85(17.95–19.79)); low-dose antipsychotic use versus no antipsychotic use (12.26(9.85–15.27)); and dispensing of ⩾10 versus <5 other medications (5.97(5.62–6.34)). Sociodemographic and lifestyle factors were also associated with use, although to a lesser extent. Females, older people, those with lower education and those with poorer health were more likely to be current antidepressant users than non-users and were also more likely to use TCAs-only versus SSRIs-only. Conclusions: Use of antidepressants is substantially higher in those with physical ill-health and in those reporting a range of adverse mental health measures. In addition, sociodemographic factors, including sex, age and education were also associated with antidepressant use and the class of antidepressant used.
Sodium is an essential dietary component, but excess sodium intake can lead to high blood pressure and an increased risk of cardiovascular disease. Many national and international bodies, including the World Health Organization, have advocated for population-wide sodium reduction interventions. Most have been unsuccessful due to inadequate sodium reduction by food industry and difficulties in persuading consumers to add less salt to food. Recent research highlights potassium-enriched salt as a new, feasible, acceptable and scalable approach to reducing the harms caused by excess sodium and inadequate potassium consumption. Modelling shows that a global switch from regular salt to potassium-enriched salt has the potential to avert millions of strokes, heart attacks and premature deaths across the globe each year. There will be many challenges to switching the world's salt supply to potassium-enriched salt, but the success of universal salt iodization shows that making a global change to the manufacture and use of salt is a tractable proposition. This in-depth review of universal salt iodization identified the importance of a multi-sectoral effort with strong global leadership, the support of multilateral organizations, engagement with the salt industry, empowered in-country teams, strong participation of national governments, understanding the salt supply chain, and a strategic advocacy and communication plan. Key challenges to the implementation of the iodization program were costs to government, industry and consumers, industry concerns about consumer acceptability, variance in the size and capabilities of salt producers, inconsistent quality control, ineffective regulation, and trade-related regulatory issues. Many of the opportunities and challenges to universal salt iodization will likely also be applicable to switching the global salt supply to iodized and potassium-enriched salt.
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