Publications by authors named "Andrew Tonkin"

236 Publications

Cost-effectiveness of dapagliflozin in chronic heart failure: an analysis from the Australian healthcare perspective.

Eur J Prev Cardiol 2021 Aug;28(9):975-982

School of Public Health and Preventive Medicine, Monash University, Australia.

Aim: To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure and reduced ejection fraction.

Methods: A Markov model was constructed based on the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial to assess the clinical outcomes and costs of 1000 hypothetical subjects with established heart failure and reduced ejection fraction. The model consisted of three health states: 'alive and event-free', 'alive after non-fatal hospitalisation for heart failure' and 'dead'. Costs and utilities were estimated from published sources. The main outcome was the incremental cost-effectiveness ratio per quality-adjusted life-year gained. An Australian public healthcare perspective was employed. All outcomes and costs were discounted at a rate of 5% annually.

Results: Over a lifetime horizon, the addition of dapagliflozin to standard care in patients with heart failure and reduced ejection fraction prevented 88 acute heart failure hospitalisations (including readmissions) and yielded an additional 416 years of life and 288 quality-adjusted life-years (discounted) at an additional cost of A$3,692,440 (discounted). This equated to an incremental cost-effectiveness ratio of A$12,482 per quality-adjusted life-year gained, well below the Australian willingness-to-pay threshold of A$50,000 per quality-adjusted life-year gained. Subanalyses in subjects with and without diabetes resulted in similar incremental cost-effectiveness ratios of A$13,234 and A$12,386 per quality-adjusted life-year gained, respectively.

Conclusion: Dapagliflozin is likely to be cost-effective when used as an adjunct therapy to standard care compared with standard care alone for the treatment of chronic heart failure and reduced ejection fraction.
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http://dx.doi.org/10.1177/2047487320938272DOI Listing
August 2021

Protective lipid-lowering variants in healthy older individuals without coronary heart disease.

Open Heart 2021 Jul;8(2)

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Objective: Genetic variants that disrupt the function of the (proprotein convertase subtilisin kexin type 9) and (apolipoprotein B)genes result in lower serum low-density lipoprotein cholesterol (LDL-C) levels and subsequently confer protection against coronary heart disease (CHD). The objective of this study was to measure the prevalence and selective advantage of such variants among healthy older individuals without a history of CHD.

Methods: We performed targeted sequencing of the and genes in 13 131 healthy individuals without CHD aged 70 years or older enrolled into the ASPirin in Reducing Events in the Elderly trial. We detected variants in the and genes with predicted loss-of-function. We associated variant carrier status with serum LDL-C and total cholesterol (TC) levels at the time of study enrolment, adjusting for statin use.

Results: We detected 22 different rare candidate variants with putative lipid-lowering effect, carried by 104 participants (carrier rate 1 in 126). Serum LDL-C and TC concentrations for rare PCSK9/APOB variant carriers were consistently lower than non-carriers. Rare variant carrier status was associated with 19.4 mg/dL (14.6%) lower LDL-C, compared with non-carriers (p≤0.001, adjusted for statin use). Statin prescriptions were less prevalent in rare variant carriers (16%) than non-carriers (35%). The more common R46L variant (rs11591147-T) was associated with 15.5 mg/dL (11.8%) lower LDL-C in heterozygotes, and 25.2 mg/dL (19.2%) lower LDL-C in homozygotes (both p≤0.001).

Conclusions: Lipid-lowering genetic variants are carried by healthy older individuals and contribute to CHD-free survival.

Trial Registration Number: NCT01038583.
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http://dx.doi.org/10.1136/openhrt-2021-001710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330577PMC
July 2021

Health-related quality of life and incident cardiovascular disease events in community-dwelling older people: A prospective cohort study.

Int J Cardiol 2021 Sep 7;339:170-178. Epub 2021 Jul 7.

School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia; Department of Epidemiology, Erasmus Medical Centre, 3015 GD Rotterdam, The Netherlands. Electronic address:

Background: Lower health-related quality of life (HRQoL) has been shown to predict a higher risk of hospital readmission and mortality in patients with cardiovascular disease (CVD). Few studies have explored the associations between HRQoL and incident CVD. We explored the associations between baseline HRQoL and incident and fatal CVD in community-dwelling older people in Australia and the United States.

Methods: Longitudinal study using ASPirin in Reducing Events in the Elderly (ASPREE) trial data. This includes 19,106 individuals aged 65-98 years, initially free of CVD, dementia, or disability, and followed between March 2010 and June 2017. The physical (PCS) and mental component scores (MCS) of HRQoL were assessed using the SF-12 questionnaire. Incident major adverse CVD events included fatal CVD (death due to atherothrombotic CVD), hospitalizations for heart failure, myocardial infarction or stroke. Analyses were performed using Cox proportional-hazard regression.

Results: Over a median 4.7 follow-up years, there were 922 incident CVD events, 203 fatal CVD events, 171 hospitalizations for heart failure, 355 fatal or nonfatal myocardial infarction and 403 fatal or nonfatal strokes. After adjustment for sociodemographic, health-related behaviours and clinical measures, a 10-unit higher PCS, but not MCS, was associated with a 14% lower risk of incident CVD, 28% lower risk of hospitalization for heart failure and 15% lower risk of myocardial infarction. Neither PCS nor MCS was associated with fatal CVD events or stroke.

Conclusion: Physical HRQoL can be used in combination with clinical data to identify the incident CVD risk among older individuals.
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http://dx.doi.org/10.1016/j.ijcard.2021.07.004DOI Listing
September 2021

Long-Term Blood Pressure Variability and Risk of Cognitive Decline and Dementia Among Older Adults.

J Am Heart Assoc 2021 Jul 26;10(13):e019613. Epub 2021 Jun 26.

Berman Center for Outcomes and Clinical Research Hennepin-Health Research InstituteHennepin Healthcare Minneapolis MN.

Background Blood pressure variability (BPV) in midlife increases risk of late-life dementia, but the impact of BPV on the cognition of adults who have already reached older ages free of major cognitive deficits is unknown. We examined the risk of incident dementia and cognitive decline associated with long-term, visit-to-visit BPV in a post hoc analysis of the ASPREE (Aspirin in Reducing Events in the Elderly) trial. Methods and Results ASPREE participants (N=19 114) were free of dementia and significant cognitive impairment at enrollment. Measurement of BP and administration of a standardized cognitive battery evaluating global cognition, delayed episodic memory, verbal fluency, and processing speed and attention occurred at baseline and follow-up visits. Time-to-event analysis using Cox proportional hazards regression models were used to calculate hazard ratios (HR) and corresponding 95% CI for incident dementia and cognitive decline, according to tertile of SD of systolic BPV. Individuals in the highest BPV tertile compared with the lowest had an increased risk of incident dementia and cognitive decline, independent of average BP and use of antihypertensive drugs. There was evidence that sex modified the association with incident dementia (interaction =0.02), with increased risk in men (HR, 1.68; 95% CI, 1.19-2.39) but not women (HR, 1.01; 95% CI, 0.72-1.42). For cognitive decline, similar increased risks were observed for men and women (interaction =0.15; men: HR, 1.36; 95% CI, 1.16-1.59; women: HR, 1.14; 95% CI, 0.98-1.32). Conclusions High BPV in older adults without major cognitive impairment, particularly men, is associated with increased risks of dementia and cognitive decline. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583; isrctn.com. Identifier: ISRCTN83772183.
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http://dx.doi.org/10.1161/JAHA.120.019613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403315PMC
July 2021

Effect of Statin Therapy on Cognitive Decline and Incident Dementia in Older Adults.

J Am Coll Cardiol 2021 Jun;77(25):3145-3156

Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.

Background: The neurocognitive effect of statins in older adults remain uncertain.

Objectives: The aim of this study was to investigate the associations of statin use with cognitive decline and incident dementia among older adults.

Methods: This analysis included 18,846 participants ≥65 years of age in a randomized trial of aspirin, who had no prior cardiovascular events, major physical disability, or dementia initially and were followed for 4.7 years. Outcome measures included incident dementia and its subclassifications (probable Alzheimer's disease, mixed presentations); mild cognitive impairment (MCI) and its subclassifications (MCI consistent with Alzheimer's disease, other MCI); and changes in domain-specific cognition, including global cognition, memory, language and executive function, psychomotor speed, and the composite of these domains. Associations of baseline statin use versus nonuse with dementia and MCI outcomes were examined using Cox proportional hazards models and with cognitive change using linear mixed-effects models, adjusting for potential confounders. The impact of statin lipophilicity on these associations was further examined, and effect modifiers were identified.

Results: Statin use versus nonuse was not associated with dementia, MCI, or their subclassifications or with changes in cognitive function scores over time (p > 0.05 for all). No differences were found in any outcomes between hydrophilic and lipophilic statin users. Baseline neurocognitive ability was an effect modifier for the associations of statins with dementia (p for interaction < 0.001) and memory change (p for interaction = 0.02).

Conclusions: In adults ≥65 years of age, statin therapy was not associated with incident dementia, MCI, or declines in individual cognition domains. These findings await confirmation from ongoing randomized trials.
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http://dx.doi.org/10.1016/j.jacc.2021.04.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091356PMC
June 2021

Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent.

NPJ Genom Med 2021 Jun 16;6(1):51. Epub 2021 Jun 16.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype-phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older individuals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy (N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy (N = 22), catecholaminergic polymorphic ventricular tachycardia (N = 4), aortopathies (N = 1), and long-QT syndrome (N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%); both with pathogenic variants in long-QT syndrome genes (KCNQ1, SCN5A). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p < 0.001). Variants associated with inherited cardiovascular disorders are found in asymptomatic individuals aged 70 years and older without a history of cardiovascular disease.
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http://dx.doi.org/10.1038/s41525-021-00211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209162PMC
June 2021

Predictive Performance of a Polygenic Risk Score for Incident Ischemic Stroke in a Healthy Older Population.

Stroke 2021 Aug 27;52(9):2882-2891. Epub 2021 May 27.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine (J.T.N., M.R., A. Bakshi, G.P., L.T.P.T., M.R.N., R.L.W., C.M.R., A.M.T., J.J.M., P.L.), Monash University, Melbourne, Australia.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.033670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384668PMC
August 2021

Risk stratification of cardiovascular complications using CHADS-VASc and CHADS scores in chronic atherosclerotic cardiovascular disease.

Int J Cardiol 2021 Aug 3;337:9-15. Epub 2021 May 3.

Cardiology Research Unit, University Hospital Geelong, Barwon Health, Geelong, Australia.

Background The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that rivaroxaban plus aspirin reduced major adverse cardiovascular events (MACE) in patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD). We explored whether CHADS-VASc or CHADS scores, well-validated tools for assessing risk of thromboembolic events in atrial fibrillation, can identify vascular patients at highest risk of recurrent events who may derive greatest benefits of treatment. Methods Predictive accuracies of the CHADS-VASc and CHADS scores for MACE, were assessed in this analysis of the COMPASS trial. Kaplan-Meier estimates of cumulative risk were used to compare the effects of rivaroxaban plus aspirin (n = 9152) with aspirin alone (n = 9126) according to risk scores. Results High CHADS-VASc (6-9) or CHADS (3-6) scores were associated with over three times greater absolute risk of MACE compared with CHADS-VASc score of 1-2 or CHADS score of 0. The effects of rivaroxaban plus aspirin compared with aspirin alone were consistent across CHADS-VASc and CHADS score categories for MACE, bleeding and net clinical benefit, with greatest reduction in MACE observed in patients treated for 30 months with highest CHADS score (3-6) (hazard ratio = 0.67, 95% CI: 0.53-0.86, p = 0.0012, 25 events per 1000 patients prevented). Conclusion The CHADS-VASc and CHADS scores can be used in patients with chronic CAD and/or PAD to identify patients who are at highest risk of MACE. Those identified at highest risk by CHADS scores had greatest benefit from dual pathway inhibition with rivaroxaban plus aspirin. Clinical Trial Registration: NCT01776424.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.067DOI Listing
August 2021

Effect of atorvastatin on knee cartilage volume in patients with symptomatic knee osteoarthritis: results from a randomised placebo-controlled trial.

Arthritis Rheumatol 2021 Apr 12. Epub 2021 Apr 12.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia.

Objective: To determine whether atorvastatin compared to placebo slows tibial cartilage volume loss in patients with symptomatic knee osteoarthritis in a multicentre, randomised, double-blind, placebo-controlled trial.

Methods: Participants aged 40-70 years were randomised to oral atorvastatin 40 mg (n=151) or matching placebo (n=153) once daily. Primary endpoint: annual percentage change in tibial cartilage volume assessed using magnetic resonance imaging (MRI) over two years. Pre-specified secondary endpoints: progression of cartilage defects and bone marrow lesions assessed using MRI, and change in Western Ontario and McMaster Universities Osteoarthritis Index pain, stiffness and function over two years.

Results: Of 304 participants (mean age 55.7 years, 55.6% female), 248 (81.6%) completed the trial. Annual change in tibial cartilage volume differed minimally between the atorvastatin and placebo groups (-1.66% vs. -2.17%, difference 0.50%, 95%CI -0.17% to 1.17%). There were no significant differences in progression of cartilage defects (odds ratio 0.86, 95%CI 0.52-1.41) or bone marrow lesions (odds ratio 1.00, 95%CI 0.62-1.63), change in pain [-36.0 vs. -29.5, adjusted difference -2.7, 95%CI -27.1 to 21.7), stiffness (-14.2 vs. -11.8, adjusted difference -0.2, 95%CI -12.2 to 11.8), or function [-89.4 vs. -87.5, adjusted difference 0.3, 95%CI -83.1 to 83.6). Incidence of adverse events was similar in atorvastatin (n=57, 37.7%) and placebo (n=52, 34.0%) groups.

Conclusion: Oral atorvastatin 40 mg once daily, compared with placebo, did not significantly reduce cartilage volume loss over two years in patients with symptomatic knee osteoarthritis. These findings do not support use of atorvastatin in the treatment of knee osteoarthritis.
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http://dx.doi.org/10.1002/art.41760DOI Listing
April 2021

Assessing and modifying cardiovascular risk in people who present to a chest pain clinic with non-cardiac causes.

Med J Aust 2021 04 8;214(6):263-264. Epub 2021 Mar 8.

Monash University, Melbourne, VIC.

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http://dx.doi.org/10.5694/mja2.50984DOI Listing
April 2021

Cost-Effectiveness of Coronary Artery Calcium Scoring in People With a Family History of Coronary Disease.

JACC Cardiovasc Imaging 2021 Jun 13;14(6):1206-1217. Epub 2021 Jan 13.

Baker Heart and Diabetes Research Institute, Melbourne, Australia; Monash University, Melbourne, Australia. Electronic address:

Objectives: To assess the cost effectiveness of coronary artery calcium (CAC) compared with traditional risk factor-based prediction alone in those with an family history of premature coronary artery disease (FHCAD).

Background: The use of CAC scoring to guide primary prevention statin therapy in those with a FHCAD is inconsistently recommended in guidelines, and usually not reimbursed by insurance.

Methods: A microsimulation model was constructed in TreeAge Healthcare Pro using data from 1,083 participants in the CAUGHT-CAD (Coronary Artery Calcium Score: Use to Guide Management of HerediTary Coronary Artery Disease) trial. Outcomes assessed were quality-adjusted life years (QALYs): cost-effectiveness was assessed over a 15-year time horizon from the perspective of the US health care sector using real-world statin prescribing, accounting for the effect of knowledge of subclinical disease on adherence to guideline-directed therapies. Costs were assessed in 2020 USD, with discounting undertaken at 3%.

Results: Statins were indicated in 45% of the cohort using the CAC strategy and 27% using American College of Cardiology/American Heart Association (2019) treatment strategies. Compared with applying a statin treatment threshold of 7.5%, the CAC strategy was more costly ($145) and more effective (0.0097 QALY) with an incremental cost-effective ratio (ICER) of $15,014/QALY. CAC ICER was driven by CAC acquisition and statin prescription cost and improved with certain patient subgroups: male, age >60 years, and 10-year risk pooled cohort equation risk ≥7.5%. CAC scanning of low-risk patients (10-year risk <5%) or those 40 to 50 years of age was not cost-effective.

Conclusions: Systematic CAC screening and treatment of those with FHCAD and subclinical disease was more cost-effective than management using statin treatment thresholds, in the US health care system.
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http://dx.doi.org/10.1016/j.jcmg.2020.11.008DOI Listing
June 2021

Role of Cardiac Biomarkers in Epidemiology and Risk Outcomes.

Clin Chem 2021 01;67(1):96-106

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany.

Background: The use of biomarkers associated with cardiovascular disease (CVD) is established for diagnostic purposes. Cardiac troponins, as specific markers of myocardial injury, and natriuretic peptides, reflecting myocardial dilation, are routinely used for diagnosis in clinical practice. In addition, a substantial body of research has shed light on the ability of biomarkers to reflect the risk of future major cardiovascular events. Among biomarkers, troponin and members of the natriuretic peptide family have been investigated extensively in the general population, in those at higher risk, and in patients with known CVD. Both biomarkers have been shown to contribute substantially to statistical models describing cardiovascular risk, in addition to and independently of important clinical characteristics. The more precise identification of individuals at risk by appropriate use of biomarkers might lead to an earlier initiation of preventive therapies and potentially avoid significant events.

Content: We summarize the current evidence concerning risk prediction using cardiac biomarkers at different stages in the development of CVD and provide examples of observational studies and large-scale clinical trials testing such application. Beyond the focus on troponin and natriuretic peptides, we also discuss other important and emerging biomarkers in the field with potential for such application, including growth differentiation factor-15, soluble ST2 (alias for IL1RL1 [interleukin 1 receptor like 1), and galectin-3.

Summary: Incorporating biomarkers in risk prediction models might allow more precise identification of individuals at risk. Among the various biomarkers, cardiac troponin appears to be the most promising for prediction of future cardiovascular events in a wide variety of patient populations.
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http://dx.doi.org/10.1093/clinchem/hvaa228DOI Listing
January 2021

Long-Term Blood Pressure Variability and Risk of Cardiovascular Disease Events Among Community-Dwelling Elderly.

Hypertension 2020 12 2;76(6):1945-1952. Epub 2020 Nov 2.

Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia (E.K.C., R.W., A.M.T., J.R., R.L.W., J.J.M., C.M.R.).

High office blood pressure variability (OBPV) in midlife increases the risk of cardiovascular disease (CVD), but the impact of OBPV in older adults without previous CVD is unknown. We conducted a post hoc analysis of ASPREE trial (Aspirin in Reducing Events in the Elderly) participants aged 70-years and older (65 for US minorities) without history of CVD events at baseline, to examine risk of incident CVD associated with long-term, visit-to-visit OBPV. CVD was a prespecified, adjudicated secondary end point in ASPREE. We estimated OBPV using within-individual SD of mean systolic BP from baseline and first 2 annual visits. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% CI for associations with CVD events. In 16 475 participants who survived to year 2 without events, those in the highest tertile of OBPV had increased risk of CVD events after adjustment for multiple covariates, when compared with participants in the lowest tertile (HR, 1.36 [95% CI, 1.08-1.70]; =0.01). Similar increased risk was observed for ischemic stroke (HR, 1.56 [95% CI, 1.04-2.33]; =0.03), heart failure hospitalization, or death (HR, 1.73 [95% CI, 1.07-2.79]; =0.02), and all-cause mortality (HR, 1.27 [95% CI, 1.04-1.54]; =0.02). Findings were consistent when stratifying participants by use of antihypertensive drugs, while sensitivity analyses suggested the increased risk was especially for individuals whose BP was uncontrolled during the OBPV estimation period. Our findings support increased OBPV as a risk factor for CVD events in healthy older adults with, or without hypertension, who have not had such events previously. Registration- URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01038583; URL: https://www.isrctn.com; Unique identifiers: ISRCTN83772183.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666049PMC
December 2020

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

Stroke 2020 10 21;51(10):2901-2909. Epub 2020 Sep 21.

ANMCO Research Center, Florence, Italy (A.P.M.).

Background And Purpose: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities.

Methods: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities.

Results: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests.

Conclusions: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.
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http://dx.doi.org/10.1161/STROKEAHA.120.029762DOI Listing
October 2020

Subgroup analysis of the ASPirin in Reducing Events in the Elderly randomized clinical trial suggests aspirin did not improve outcomes in older adults with chronic kidney disease.

Kidney Int 2021 02 10;99(2):466-474. Epub 2020 Sep 10.

Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; Department of Nephrology, Monash Medical Centre, Monash Health, Melbourne, Victoria, Australia. Electronic address:

The role of aspirin for primary prevention in older adults with chronic kidney disease (CKD) is unclear. Therefore, post hoc analysis of the randomized controlled trial ASPirin in Reducing Events in the Elderly (ASPREE) was undertaken comparing 100 mg of enteric-coated aspirin daily against matching placebo. Participants were community dwelling adults aged 70 years and older in Australia, 65 years and older in the United States, all free of a history of dementia or cardiovascular disease and of any disease expected to lead to death within five years. CKD was defined as present at baseline if either eGFR under 60mL/min/1.73m or urine albumin to creatinine ratio 3 mg/mmol or more. In 4758 participants with and 13004 without CKD, the rates of a composite endpoint (dementia, persistent physical disability or death), major adverse cardiovascular events and clinically significant bleeding in the CKD participants were almost double those without CKD. Aspirin's effects as estimated by hazard ratios were generally similar between CKD and non-CKD groups for dementia, persistent physical disability or death, major adverse cardiovascular events and clinically significant bleeding. Thus, in our analysis aspirin did not improve outcomes in older people while increasing the risk of bleeding, with mostly consistent effects in participants with and without CKD.
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http://dx.doi.org/10.1016/j.kint.2020.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957958PMC
February 2021

Impact of the 2017 American Heart Association and American College of Cardiology hypertension guideline in aged individuals.

J Hypertens 2020 12;38(12):2527-2536

Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Victoria.

Objectives: The AHA/ACC-2017 hypertension guideline recommends an age-independent target blood pressure (BP) of less than 130/80 mmHg. In an elderly cohort without established cardiovascular disease (CVD) at baseline, we determined the impact of this guideline on the prevalence of hypertension and associated CVD risk.

Methods: Nineteen thousand, one hundred and fourteen participants aged at least 65 years from the ASPirin in Reducing Events in the Elderly (ASPREE) study were grouped by baseline BP: 'pre-2017 hypertensive' (BP ≥140/90 mmHg and/or on antihypertensive drugs); 'reclassified hypertensive' (normotensive by pre-2017 guidelines; hypertensive by AHA/ACC-2017 guideline), and 'normotensive' (BP <130 and <80 mmHg). For each group, we evaluated CVD risk factors, predicted 10-year CVD risk using the Atherosclerotic Cardiovascular Disease (ASCVD) risk equation, and reported observed CVD event rates during a median 4.7-year follow-up.

Results: Overall, 74.4% (14 213/19 114) were 'pre-2017 hypertensive'; an additional 12.3% (2354/19 114) were 'reclassified hypertensive' by the AHA/ACC-2017 guideline. Of those 'reclassified hypertensive', the majority (94.5%) met criteria for antihypertensive treatment although 29% had no other traditional CVD risk factors other than age. Further, a relatively lower mean 10-year predicted CVD risk (18% versus 26%, P < 0.001) and lower CVD rates (8.9 versus 12.1/1000 person-years, P = 0.01) were observed in 'reclassified hypertensive' compared with 'pre-2017 hypertensive'. Compared with 'normotensive', a hazard ratio (95% confidence interval) for CVD events of 1.60 (1.26-2.02) for 'pre-2017 hypertensive' and 1.26 (0.93-1.71) for 'reclassified hypertensive' was observed.

Conclusion: Applying current CVD risk calculators in the elderly 'reclassified hypertensive', as a result of shifting the BP threshold lower, increases eligibility for antihypertensive treatment but documented CVD rates remain lower than hypertensive patients defined by pre2017 BP thresholds.
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http://dx.doi.org/10.1097/HJH.0000000000002582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218338PMC
December 2020

Coronary artery calcium scoring in cardiovascular risk assessment of people with family histories of early onset coronary artery disease.

Med J Aust 2020 08 30;213(4):170-177. Epub 2020 Jul 30.

Baker IDI Heart and Diabetes Institute, Melbourne, VIC.

Objectives: To assess the predictive value of the Australian absolute cardiovascular disease risk (ACVDR) calculator and other assessment tools for identifying Australians with family histories of early onset coronary artery disease (CAD) who have coronary artery calcification.

Design, Setting, Participants: People without known CAD were recruited at seven Australian hospitals, October 2016 - January 2019. Participants were aged 40-70 years, had a family history of early onset CAD, and a 5-year ACVDR of 2-15%.

Main Outcome Measures: CT coronary artery calcium score greater than zero (any coronary calcification) or greater than 100 (calcification warranting lipid therapy).

Results: 1059 participants were recruited; 477 (45%) had non-zero coronary artery calcium scores (median 5-year ACVDR, 4.8% [IQR, 2.9-7.6%]; median coronary artery calcium score, 41.7 [IQR, 8-124]); 582 (55%) did not (median 5-year ACVDR, 3.2% [IQR, 2.0-4.6%]). Of 151 participants with calcium scores of 100 or more, 116 (77%) were deemed to be at low cardiovascular risk by Australian guidelines, while 14 of 75 participants at intermediate risk (19%) had zero calcium scores. The sensitivity of the ACVDR calculator for identifying people with non-zero calcium scores (area under receiver operator curve [AUC], 0.674) was lower than that of the pooled cohort equation (AUC, 0.711; P < 0.001). ACVDR (10-year)- and Multi-Ethnic Study of Atherosclerosis (MESA)-predicted risk categories concurred for 511 participants (48%); classifications were concordant for 925 participants (87%) when the ACVDR was supplemented by calcium scores.

Conclusions: Coronary artery calcium scoring should be considered as part of the heart health check for patients at intermediate ACVDR risk and with family histories of early onset CAD. Alternative risk calculators may better select such patients for further diagnostic testing and primary prevention therapy.

Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN 12614001294640; 11 December 2014 (prospective).
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http://dx.doi.org/10.5694/mja2.50702DOI Listing
August 2020

Cost-effectiveness of dapagliflozin in chronic heart failure: an analysis from the Australian healthcare perspective.

Eur J Prev Cardiol 2020 Jul 14:2047487320938272. Epub 2020 Jul 14.

School of Public Health and Preventive Medicine, Monash University, Australia.

Aim: To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure and reduced ejection fraction.

Methods: A Markov model was constructed based on the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial to assess the clinical outcomes and costs of 1000 hypothetical subjects with established heart failure and reduced ejection fraction. The model consisted of three health states: 'alive and event-free', 'alive after non-fatal hospitalisation for heart failure' and 'dead'. Costs and utilities were estimated from published sources. The main outcome was the incremental cost-effectiveness ratio per quality-adjusted life-year gained. An Australian public healthcare perspective was employed. All outcomes and costs were discounted at a rate of 5% annually.

Results: Over a lifetime horizon, the addition of dapagliflozin to standard care in patients with heart failure and reduced ejection fraction prevented 88 acute heart failure hospitalisations (including readmissions) and yielded an additional 416 years of life and 288 quality-adjusted life-years (discounted) at an additional cost of A$3,692,440 (discounted). This equated to an incremental cost-effectiveness ratio of A$12,482 per quality-adjusted life-year gained, well below the Australian willingness-to-pay threshold of A$50,000 per quality-adjusted life-year gained. Subanalyses in subjects with and without diabetes resulted in similar incremental cost-effectiveness ratios of A$13,234 and A$12,386 per quality-adjusted life-year gained, respectively.

Conclusion: Dapagliflozin is likely to be cost-effective when used as an adjunct therapy to standard care compared with standard care alone for the treatment of chronic heart failure and reduced ejection fraction.
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http://dx.doi.org/10.1177/2047487320938272DOI Listing
July 2020

Association of Statin Use With Disability-Free Survival and Cardiovascular Disease Among Healthy Older Adults.

J Am Coll Cardiol 2020 07;76(1):17-27

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Background: There is clinical uncertainty regarding the benefits and harms of prescribing statins in healthy subjects ≥70 years of age.

Objectives: The aim of this study was to examine the association among statins, dementia-free and disability-free survival, and cardiovascular disease (CVD) among healthy older adults using data from the ASPREE (Aspirin in Reducing Events in the Elderly) trial.

Methods: ASPREE was a randomized trial of 19,114 community-dwelling persons in Australia and the United States ≥65 years of age and free of documented CVD, dementia, and disability. Data were collected for those ≥70 years of age, and participants who took statins at baseline were compared with those who did not using Cox proportional hazards regression with inverse probability weighting. The primary outcome, referred to as "disability-free survival," was a composite of all-cause mortality, dementia, or persistent physical disability. Other outcomes included the individual components of the composite outcome, major adverse cardiovascular events, fatal CVD, myocardial infarction, and stroke.

Results: Of the 18,096 included participants (median age 74.2 years, 56.0% women), 5,629 took statins at baseline. Over a median follow-up period of 4.7 years, baseline statin use was not associated with disability-free survival or with the risk for all-cause mortality or dementia. However, it was associated with lower risks for physical disability and all cardiovascular outcomes.

Conclusions: Among healthy community-dwelling adults ≥70 years of age, statin use may be beneficial for preventing physical disability and CVD but not beneficial for prolonging disability-free survival or avoiding death or dementia. Future clinical trials are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.jacc.2020.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967891PMC
July 2020

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals.

Genet Med 2020 11 1;22(11):1883-1886. Epub 2020 Jul 1.

Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals.

Methods: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards.

Results: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders.

Conclusion: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.
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http://dx.doi.org/10.1038/s41436-020-0881-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606791PMC
November 2020

Genetic Variation in PEAR1, Cardiovascular Outcomes and Effects of Aspirin in a Healthy Elderly Population.

Clin Pharmacol Ther 2020 12 20;108(6):1289-1298. Epub 2020 Jul 20.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

The platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 variant has been identified as a genetic determinant of platelet aggregation in response to antiplatelet therapies, including aspirin. However, association with atherothrombotic cardiovascular events is less clear, with limited evidence from large trials. Here, we tested association of rs12041331 with cardiovascular events and aspirin use in a randomized trial population of healthy older individuals. We undertook post hoc analysis of 13,547 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial, median age 74 years. Participants had no previous diagnosis of atherothrombotic cardiovascular disease at enrollment, and were randomized to either 100 mg daily low-dose aspirin or placebo for median 4.7 years follow-up. We used Cox proportional hazard regression to model the relationship between rs12041331 and the ASPREE primary cardiovascular disease (CVD) end point, and composites of major adverse cardiovascular events (MACE) and ischemic stroke (STROKE); and bleeding events; major hemorrhage (MHEM) and intracranial bleeding (ICB). We performed whole-population analysis using additive and dominant inheritance models, then stratified by treatment group. Interaction effects between genotypes and treatment group were examined. We observed no statistically significant association (P < 0.05) in the population, or by treatment group, between rs12041331 and cardiovascular or bleeding events in either model. We also found no significant interaction effects between rs12041331-A and treatment group, for CVD (P = 0.65), MACE (P = 0.32), STROKE (P = 0.56), MHEM (P = 0.59), or ICB (P = 0.56). The genetic variant PEAR1 rs12041331 is not associated with cardiovascular events in response to low-dose aspirin in a healthy elderly population.
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http://dx.doi.org/10.1002/cpt.1959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959328PMC
December 2020

Familial Hypercholesterolemia in a Healthy Elderly Population.

Circ Genom Precis Med 2020 08 10;13(4):e002938. Epub 2020 Jun 10.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.).

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http://dx.doi.org/10.1161/CIRCGEN.120.002938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442644PMC
August 2020

Patterns of Association between Depressive Symptoms and Chronic Medical Morbidities in Older Adults.

J Am Geriatr Soc 2020 08 13;68(8):1834-1841. Epub 2020 May 13.

School of Medicine, IMPACT the Institute for Mental and Physical Health and Clinical Translation, Barwon Health, Deakin University, Geelong, Victoria, Australia.

Objectives: To investigate the association between depressive symptoms and several medical morbidities, and their combination, in a large older population.

Design: Cross-sectional study of baseline data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial.

Setting: Multicentric study conducted in Australia and the United States.

Participants: A total of 19,110 older adults (mean age = 75 years [standard deviation = ±4.5]).

Measurements: Depressive symptoms were measured using the Center for Epidemiological Studies Depression (CES-D 10) scale. Medical morbidities were defined according to condition-specific methods. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to test associations before and after accounting for possible confounders.

Results: Depressive symptoms were significantly associated with obesity (OR = 1.19; 95% CI = 1.07-1.32), diabetes (OR = 1.22; 95% CI = 1.05-1.42), gastroesophageal reflux disease (GERD) (OR = 1.41; 95% CI = 1.28-1.57), metabolic syndrome (OR = 1.16; 95% CI = 1.03-1.29), osteoarthritis (OR = 1.41; 95% CI = 1.27-1.57), respiratory conditions (OR = 1.25; 95% CI = 1.10-1.42), history of cancer (OR = 1.19; 95% CI = 1.05-1.34), Parkinson's disease (OR = 2.56; 95% CI = 1.83-3.56), polypharmacy (OR = 1.60; 95% CI = 1.44-1.79), and multimorbidity (OR = 1.29; 95% CI = 1.12-1.49). No significant association was observed between depressive symptoms and hypertension, chronic kidney disease, dyslipidemia, and gout (P > .05). A significant dose-response relationship was evident between the number of medical comorbidities and the prevalence of depression (OR = 1.18; 95% CI = 1.13-1.22).

Conclusion: Late-life depressive symptoms are significantly associated with several medical morbidities, and there appears to be a cumulative effect of the number of somatic diseases on the prevalence of depression. These findings augment the evidence for a complex relationship between mental and physical health in an otherwise healthy older population and might guide clinicians toward early recognition of high-risk individuals. J Am Geriatr Soc 68:1834-1841, 2020.
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http://dx.doi.org/10.1111/jgs.16468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879564PMC
August 2020

The association of antihypertensive use and depressive symptoms in a large older population with hypertension living in Australia and the United States: a cross-sectional study.

J Hum Hypertens 2020 11 30;34(11):787-794. Epub 2020 Jan 30.

School of Medicine, IMPACT Strategic Research Centre, Barwon Health, Deakin University, Geelong, VIC, Australia.

Cardiovascular drugs impact many pathways involved in depression pathophysiology and treatment. However, their distinct impact on mood is underrecognized and the literature is conflicting. Therefore, using a very large and well-characterised sample of older adults with hypertension, we aimed to investigate the prevalence of depressive symptoms in users of different antihypertensive classes. We analysed baseline data from 14,195 older individuals with hypertension enroled in a large clinical trial. Median age was 75 years. The association of antihypertensive use by class and depression prevalence, as measured by a validated depression scale, was determined using logistic regression models. Multivariable logistic models were implemented to account for important confounding factors. Our analyses showed a positive association between depressive symptoms and the use of beta blockers (BB) (OR: 1.37; 95% CI: 1.17-1.60, p < 0.01), compared with users of other antihypertensive classes. All other classes of antihypertensives (including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and calcium channel blockers) were not significantly associated with depressive symptoms. In secondary analysis, this relationship was stronger for lipophilic (39%) and nonselective BB (52%) compared with hydrophilic (26%) and selective medications (31%), respectively. This study adds further evidence for a probable association between BB and depression in a large sample of older adults with hypertension and no history of cardiovascular disease or heart failure. These findings should regenerate interest and increase awareness of clinicians about the possible adverse effects of these medications in an otherwise healthy older population.
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http://dx.doi.org/10.1038/s41371-020-0303-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390661PMC
November 2020

Hypertension prevalence in patients attending tertiary pain management services, a registry-based Australian cohort study.

PLoS One 2020 24;15(1):e0228173. Epub 2020 Jan 24.

Caulfield Pain Management and Research Centre, Caulfield Hospital, Caulfield, Victoria, Australia.

Persistent pain and hypertension often co-occur, and share several biological and lifestyle risk factors. The present study aimed to provide insight into the prevalence of, and factors associated with, hypertension in the largest cohort of patients seeking treatment in 43 tertiary pain clinics in Australia. Adults aged > = 18 years registered to the electronic Persistent Pain Outcomes Collaboration registry between 2013 and 2018 were included if they had persistent non-cancer pain (N = 43,789). Risk Ratios (RRs) compared prevalence of self-reported hypertension with the general and primary care Australian populations, and logistic regression examined factors associated with hypertension. One in four (23.9%) patients had hypertension, which was higher than the Australian adult population (2014-15: RR = 5.86, 95%CI: 5.66, 6.06; 2017-18: RR = 9.40, 95%CI: 9.01, 9.80), and in primary care patients (2011-13: RR = 1.17, 95%CI: 1.15, 1.20). Adjusting for covariates, patients with higher odds of hypertension were older, lived in regions with higher socioeconomic disadvantage, had higher levels of BMI, were born outside the Oceania/Australasia region, and had comorbid arthritis, diabetes, or severe-extremely severe anxiety symptoms. Female patients and those with depression symptoms had lower adjusted odds. Unadjusted analyses showed an association between widespread pain, pain duration, pain severity and interference, and lower pain self-efficacy with hypertension; however, only pain severity remained significant in adjusted analyses. Hypertension was more prevalent in people with persistent pain than in the general community, was associated with more severe pain, and commonly co-occurred with pain-related impairments. Routine hypertension screening and treatment targeting shared mechanisms of hypertension and pain may improve treatment outcomes in the pain clinic setting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980551PMC
April 2020

Factors Associated With Treatment and Control of Hypertension in a Healthy Elderly Population Free of Cardiovascular Disease: A Cross-sectional Study.

Am J Hypertens 2020 04;33(4):350-361

Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Background: Despite readily available treatments, control of blood pressure (BP) with population aging remains suboptimal. Further, there are gaps in the understanding of the management of high BP in the aged. We explored antihypertensive treatment and control among elderly hypertensive participants free from overt cardiovascular disease (CVD), and identified factors related to both "untreated" and "treated but uncontrolled" high BP.

Methods: We analyzed baseline data from 19,114 individuals aged ≥65 years enrolled from Australia and United States (US) in the ASPirin in Reducing Events in the Elderly study. Hypertension was defined as an average systolic/diastolic BP ≥140/90 mm Hg and/or the use of any BP lowering medication. "Controlled hypertension" was defined if participants were receiving antihypertensive medication and BP <140 and 90 mm Hg. Descriptive analyses were used to summarize hypertension control rates; logistic regression was used to investigate relationships with treatment and BP control.

Results: Overall, 74% (14,213/19,114) of participants were hypertensive; and of these 29% (4,151/14,213) were untreated. Among those treated participants, 53% (5,330/10,062) had BP ≥140/90 mm Hg. Participants who were untreated were more likely to be men, have higher educational status, and be in good physical health, and less likely to have significant comorbidities. The factors related to "treated but uncontrolled" BP included older age, male, Black race (vs. White), using antihypertensive monotherapy (vs. multiple) and residing in Australia (vs. US).

Conclusions: High levels of "untreated" and "treated but uncontrolled" BP occur in healthy elderly people without CVD, suggesting there are opportunities for better BP control in the primary prevention of CVD in this population.

Clinical Trials Registration: NCT01038583.
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http://dx.doi.org/10.1093/ajh/hpz192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109352PMC
April 2020

Changes in plasma lipids predict pravastatin efficacy in secondary prevention.

JCI Insight 2019 07 11;4(13). Epub 2019 Jul 11.

Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

BACKGROUNDStatins have pleiotropic effects on lipid metabolism. The relationship between these effects and future cardiovascular events is unknown. We characterized the changes in lipids upon pravastatin treatment and defined the relationship with risk reduction for future cardiovascular events.METHODSPlasma lipids (n = 342) were measured in baseline and 1-year follow-up samples from a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study subcohort (n = 4991). The associations of changes in lipids with treatment and cardiovascular outcomes were investigated using linear and Cox regression. The effect of treatment on future cardiovascular outcomes was examined by the relative risk reduction (RRR).RESULTSPravastatin treatment was associated with changes in 206 lipids. Species containing arachidonic acid were positively associated while phosphatidylinositol species were negatively associated with pravastatin treatment. The RRR from pravastatin treatment for cardiovascular events decreased from 23.5% to 16.6% after adjustment for clinical risk factors and change in LDL-cholesterol (LDL-C) and to 3.0% after further adjustment for the change in the lipid ratio PI(36:2)/PC(38:4). Change in PI(36:2)/PC(38:4) mediated 58% of the treatment effect. Stratification of patients into quartiles of change in PI(36:2)/PC(38:4) indicated no benefit of pravastatin in the fourth quartile.CONCLUSIONThe change in PI(36:2)/PC(38:4) predicted benefit from pravastatin, independent of change in LDL-C, demonstrating its potential as a biomarker for monitoring the clinical benefit of statin treatment in secondary prevention.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry identifier ACTRN12616000535471.FUNDINGBristol-Myers Squibb; NHMRC grants 211086, 358395, and 1029754; NHMRC program grant 1149987; NHMRC fellowship 108026; and the Operational Infrastructure Support Program of the Victorian government of Australia.
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http://dx.doi.org/10.1172/jci.insight.128438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629250PMC
July 2019

Development and validation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients.

Eur Heart J 2020 01;41(3):371-380

Zora Biosciences Oy, Tietotie 2C, 02150 Espoo, Finland.

Aims: Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies.

Methods And Results: Ceramides and PCs were analysed using liquid chromatography-mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28-1.63) in WECAC, 1.47 (1.34-1.61) in the LIPID trial, and 1.69 (1.31-2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44-1.85) and 2.04 (1.57-2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention.

Conclusion: A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.
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http://dx.doi.org/10.1093/eurheartj/ehz387DOI Listing
January 2020

Vascular Pathology and Osteoarthritis: A Systematic Review.

J Rheumatol 2020 05 1;47(5):748-760. Epub 2019 Jun 1.

From the School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, Melbourne; Australian National University (ANU) College of Health and Medicine, Canberra; The Alfred Hospital, Melbourne, Australia.

Objective: Vascular pathology (changes in blood vessels) and osteoarthritis (OA) are both common chronic conditions associated with aging and obesity, but whether vascular pathology is a risk factor for OA is unclear. The aim of this study was to systematically review the evidence for an association between vascular pathology and risk of joint-specific OA.

Methods: Scopus, Ovid Medline, and EMBASE were searched from inception to February 2019. MeSH terms and keywords were used to identify studies examining the association between vascular pathology and OA. Two reviewers independently extracted the data and assessed the methodological quality. Qualitative evidence synthesis was performed.

Results: Fifteen studies with high (n = 3), fair (n = 3), or low (n = 9) quality were included. Features of vascular pathology included atherosclerosis, vascular stiffness, and endothelial dysfunction in different vascular beds. There was evidence for an association between vascular pathology and risk of hand OA in women but not men, and between vascular pathology and risk of knee OA in both men and women. Only 2 studies examined hip OA showing no association between vascular pathology and risk of hip OA.

Conclusion: There is evidence suggesting an association between vascular pathology and risk of hand and knee OA, with a potential causal relationship for knee OA. Based on the limited evidence, it is hard to conclude an association for hip OA. Further stronger evidence is needed to determine whether there is a causal relationship.
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http://dx.doi.org/10.3899/jrheum.181236DOI Listing
May 2020

Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin.

Gastroenterology 2019 09 29;157(3):682-691.e2. Epub 2019 May 29.

University of Washington, Seattle, Washington.

Background & Aims: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.

Methods: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.

Results: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.

Conclusions: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.
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http://dx.doi.org/10.1053/j.gastro.2019.05.056DOI Listing
September 2019
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