AIMS:Haptoglobin (HP) 2-2 phenotype has been suggested as a risk factor for cardiovascular disease (CVD) and to modulate fenofibrate benefit on CVD risk in Type 2 diabetes. However, little is known as to whether HP levels modulate CVD risk and fenofibrate response. METHODS AND RESULTS:Haptoglobin phenotype and levels were determined in 8047 Fenofibrate Intervention and Event Lowering in Diabetes trial participants at baseline and randomization (after a 16 week run-in period, including a 6 week fenofibrate therapy) and their association with new on-trial total CVD events over 5 years was assessed. Higher baseline HP levels were associated with total CVD events in the placebo group {n = 4030, hazard ratio [95% confidence interval (CI)] = 1.30 [1.02-1.66] for HP level Tertile 3 vs. Tertile 1, P = 0.035}. This was driven by participants with HP 1-1 phenotype (P for interaction = 0.011). Participants with the lowest baseline HP level tertile and HP 1-1 phenotype tended to have the lowest CVD risk, whereas CVD risk was similar in other participants, regardless of HP phenotype and levels. Fenofibrate benefit on total CVD events did not differ significantly by HP phenotypes, baseline HP level tertiles, or tertiles of change in HP levels by fenofibrate during active run-in. CONCLUSION:Higher baseline HP levels were associated with a higher CVD risk, especially in participants with HP 1-1 phenotype. A lower CVD risk is found only in Type 2 diabetes participants with both the HP 1-1 phenotype and low baseline HP levels. Fenofibrate benefits on CVD risk reduction did not differ by HP levels or phenotype. LAY SUMMARY:We evaluated the relationship of different forms or phenotypes of the blood protein, haptoglobin, and its circulating levels with the risk of developing CVD and fenofibrate benefit in patients with Type 2 diabetes, and showed that both HP phenotype and levels are important to assess CVD risk in patients with Type 2 diabetes, although fenofibrate did not modulate CVD risk via HP phenotype or level.Higher baseline HP levels were associated with higher CVD risk, especially in participants with HP 1-1 phenotype.Fenofibrate benefit on CVD did not differ by HP phenotype and baseline or change in HP levels.

AIMS:Colchicine has recently been approved for the treatment of atherosclerotic cardiovascular disease (ASCVD). Since then, three large trials of colchicine in ASCVD have failed to reach their primary endpoints. METHODS AND RESULTS:A systematic search of PubMed, Embase and Cochrane Central Register of Controlled Trials was performed (PROSPERO registration: CRD42024616378). The primary endpoint of major adverse cardiovascular events (MACE) was defined as a composite of myocardial infarction (MI), stroke and cardiovascular death. The key secondary endpoint of extended MACE (eMACE) was defined as MACE plus coronary revascularisation. Pooled estimates were calculated using a random-effects model and are presented as risk ratio [95% confidence interval (CI)]. 1624 articles were screened. 12 met inclusion criteria, yet one trial reported zero endpoint events in both arms. As such, 11 trials were included in the meta-analysis, with a total of 1983 primary endpoint events across 30 808 participants. Colchicine was associated with a 17% reduction in the incidence of MACE [0.83 (0.73, 0.95); P = 0.006] and 23% reduction in the incidence of eMACE [0.77 (0.63, 0.94); P = 0.01]. This reduction was driven by a lower rate of MI [0.78 (0.63, 0.95); P = 0.02] and coronary revascularisation [0.73 (0.55, 0.97); P = 0.03]. There were also numerically fewer strokes in the colchicine-treated population [0.81 (0.63, 1.04); P = 0.11]. Colchicine had no effect on cardiovascular [0.96 (0.79, 1.15); P = 0.64] or non-cardiovascular mortality [1.04 (0.76, 1.41); P = 0.81]. CONCLUSION:Colchicine reduces the risk of non-fatal ischaemic events in patients with ASCVD. Further studies are required to identify a population(s) who stands to benefit most from this promising therapy.

BACKGROUND:The use of Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory out-of-hospital cardiac arrest (OHCA) is increasing. The EVIDENCE study of refractory OHCA transportation did not report a survival benefit of expedited transportation to hospital, likely in part owing to a very limited number of patients receiving ECPR. The reasons for this, the total potential numbers of ECPR patients and the effects of different system changes would assist in trial and clinical service planning. METHODS:A pre-specified, post-hoc analysis was performed of the randomised controlled trial (RCT) - EVIDENCE (ACTRN12621000668808) and the contemporaneous EVIDENCE Registry (non-randomised data), which examined assessing ECPR eligibility, why ECPR was not provided and survival to hospital discharge. A truly eligible hospital-based ECPR patient was defined as a patient meeting ECPR criteria and arriving to an ECPR-capable hospital within 1 h of arrest with no sustained ROSC within ECPR service hours (office hours). Potential ECPR patients (meeting ECPR criteria with no ROSC on-scene) were also defined and quantified. RESULTS:Thirty-eight of 1497 (3%) OHCA patients in the combined RCT and Registry were truly eligible for hospital-based ECPR. Main reasons for exclusion of potential ECPR patients were arrival to hospital >1-h post-arrest, arrival to a non-ECPR-capable centre, and/or arrival outside of ECPR-capable hours. Seventy-nine (5%) and 350 (23%) patients were identified as potential hospital-based and pre-hospital ECPR candidates, respectively. Survival to hospital discharge of potential ECPR patients was 5%. CONCLUSION:Only a small percentage of OHCA patients were considered eligible for ECPR, predominantly due to challenges in accessing ECPR therapy. ECPR-eligible patients, not treated with ECPR, have very poor survival outcomes.

INTRODUCTION:We aimed to determine whether health system costs differed between two pre-hospital transportation processes for cardiac arrest; and by the timing of out of hospital cardiac arrest (OHCA): inside or outside business hours when extracorporeal cardio-pulmonary resuscitation (ECPR) was available. METHODS:A prospective costing analysis was undertaken from a health system perspective, alongside the EVIDENCE trial conducted across Greater Sydney, Australia. Healthcare use reflected all medical interventions for patients from paramedic contact to hospital discharge or death. Mean total and per-participant healthcare use and costs were reported by trial allocation, with differences assessed using non-parametric Kruskal-Wallis tests. RESULTS:All 197 randomised participants in EVIDENCE were included in the costing analysis (102 in the expedited arm; 95 patients in the standard care arm; mean age 55 years, 82% males). Mean hospital length of stay from admission to discharge: 15 days (SD: 23) for expedited; 17 days (SD: 26) for standard care; and 17 days (SD: 28) for admissions during ECPR hours, 14 days (SD: 19) outside hours. Mean costs per patient were AUD$60,780 (SD: $122,520) for the expedited group and $67,579 (SD: $135,326) for standard care. The difference in mean costs (-$6799) was not significant (95% CI: -$44,014 to $30,416). Mean costs per participant were $36,182 higher within ECPR hours, compared with outside ECPR hours (95% CI: $1554-72,918). CONCLUSIONS:Health system costs of expedited transport and standard care for patients with OHCA were comparable. Patients transported within, rather than outside, hospital business hours incurred greater healthcare costs. TRIAL REGISTRATION:ACTRN12621000668808.

Importance:The most effective initial fraction of inspired oxygen (Fio2) for resuscitating preterm newborns is unknown. Objective:To compare outcomes of newborns born at 23 to 28 weeks' gestation resuscitated with initial Fio2 of 0.6 vs 0.3. Design, Setting, and Participants:Randomized clinical trial conducted in 31 maternity hospitals in 6 countries. Consent by waiver was obtained in Australia, certain institutions in India, and Malaysia; prospective informed consent was obtained in certain institutions in India and all institutions in Singapore, Spain, and the US. Infants due at 23 to 28 weeks' gestation were randomized shortly before birth. Those with congenital abnormalities affecting oxygenation, neurodevelopment, or survival were excluded. Randomization was conducted from September 2018 to September 2024, with follow-up expected to close in September 2026. Intervention:Infants were randomized (1:1) to receive an initial Fio2 of 0.6 or 0.3; Fio2 was titrated to meet standard targets for oxygen saturation by pulse oximetry in the first 10 minutes or for clinical needs. Clinicians and those assessing outcomes were not blinded to group assignment. Main Outcomes and Measures:The primary outcome was death and brain injury at 36 weeks' corrected gestational age; secondary outcomes were the individual components of the primary outcome. Results:A total of 1641 newborns were randomized. The primary analysis included 728 newborns randomized to receive an Fio2 of 0.6 and 741 to an Fio2 of 0.3 after excluding 172 newborns, mostly for birth after 28 weeks' gestation and transfer to another hospital before birth (54% female). Rates of escalation to Fio2 of 1.0 were similar between the groups (Fio2 of 0.6: 41%; Fio2 of 0.3: 38%). Primary outcome information was ascertained in 1423 newborns (96.9%). Death or brain injury at 36 weeks' corrected gestational age occurred in 330 of 703 newborns (46.9%) assigned to the Fio2 of 0.6 group vs 344 of 720 (47.8%) assigned to the Fio2 of 0.3 group (relative risk, 0.98 [95% CI, 0.89-1.09]). Conclusions and Relevance:Initiating resuscitation of preterm infants with Fio2 of 0.6 vs 0.3 did not affect the risk of death or brain injury by 36 weeks' corrected gestational age. These results lay a foundation for future trials evaluating the effectiveness and safety of using higher initial Fio2 levels for preterm infant resuscitation. Trial Registration:ANZCTR Identifier: ACTRN12618000879268.

Background While the use of pre-hospital extracorporeal cardiopulmonary resuscitation for refractory out of hospital cardiac arrest is increasing, there is little data on whether it is cost-effective. This study investigated its cost-effectiveness of based on our current study data. Methods Using data from the PRECARE trial, the New South Wales Ambulance Cardiac Arrest Registry (CAR) and in-hospital costings, we performed a cost effectiveness analysis of pre-hospital extracorporeal cardiopulmonary resuscitation (ECPR). A Markov model was used to integrate PRECARE service costs and patient outcomes, team time allocation to ECPR, patient volume, organ donation and alternate pre-hospital delivery strategies. Bridging formulae were used with ECPR survivor Cerebral Performance Category scores to estimate Quality Adjusted Life Years and Incremental Cost Effectiveness Ratios. Probabilistic sensitivity analysis was undertaken to assess the joint uncertainty in model parameters. Results Sixteen patients were analysed (mean age 52 ± 10 years). Five patients (31%) survived to hospital discharge; all with a cerebral performance category score of 1 or 2. Three (60%) of survivors returned to work during the study period. There was one organ donor. The total cost per patient was $94,460 (±$103,455), with a base-case incremental cost-effectiveness ratio of AUD 34,000 per quality adjusted life year (assuming 100 patients per year, and ECPR cases occupying 15% of the PH-ECPR team’s time). If the PRECARE team were exclusively dedicated to ECPR cases, the cost per quality adjusted life year would increase to $95,000. Conclusion PH-ECPR in Sydney is likely to be cost-effective, assuming a 15% allocation of prehospital team time to ECPR. Survival rate, organ donation and the team’s ability to perform other clinical tasks when not performing ECPR are key factors influencing cost effectiveness. A PH team exclusively dedicated to ECPR is much less cost-effective.

BACKGROUND:Survival from refractory out of hospital cardiac arrest (OHCA) treated with conventional cardiopulmonary resuscitation (CCPR) remains low. Extracorporeal cardiac resuscitation (ECPR) is increasingly be utilised in refractory OHCA, with outcomes influenced by the duration of cardiac arrest prior establishing ECMO flow (low flow time). Pre-hospital ECPR aims to reduce the low flow time. Pre-hospital physicians may represent a workforce who could deliver ECPR, increasing access and sustainability. METHODS:A single-arm open-label feasibility trial of pre-hospital ECPR delivered by pre-hospital physicians. Patients under the age of 70 years with a witnessed collapse, an initial shockable rhythm and within a 45-minute radius of the mobile team were eligible for pre-hospital ECPR. Once extracorporeal support flow was established, patients were transported to one of three ECMO capable centers. The primary aim was to assess the feasibility of pre-hospital ECPR in this setting. RESULTS:From August 2023 to June 2024, over 103 recruitment days, the pre-hospital ECPR team attended 123 confirmed cardiac arrests, 12 (10%) patients received pre-hospital ECPR equating to one case per 8 shifts. All patients were successfully cannulated on scene while the patient was in cardiac arrest. The mean time from dispatch to team arrival was 18.5 min (range 9-29); mean time from decision to ECMO flow was 17 min (range 10-34) and the mean total low flow time (arrest to ECMO flow) was 39 min (range 24-56). Four (33%) patients were successfully liberated from VA ECMO support, 3 (25%) patients survived to hospital discharge neurologically intact (CPC 1-2). CONCLUSIONS:Pre-hospital ECPR delivery by trained pre-hospital medical teams is possible and reduces OHCA low flow times. Larger studies are required to assess efficacy and cost effectiveness.

Introduction and Objective: Mitochondrial dysfunction contributes to cardiovascular and microvascular disease risks in type 2 diabetes (T2D). This study investigates whether mitochondrial DNA copy number (mtDNA-CN) in whole blood can serve as a biomarker for these complications. Methods: mtDNA-CN was measured in the DNA extracted from whole blood samples of 497 T2D adults from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. The relationship of mtDNA-CN with cardiovascular and microvascular complications over 5 years was assessed. Results: The cohort (29.8 % women, mean(SD) age 62(7) years, HbA1c 7.1(1.4)%) showed no variation in mtDNA-CN by sex. There were no significant associations of mtDNA-CN with traditional risk factors of age, BMI, HbA1c, diabetic duration (P>0.05), but mtDNA-CN correlated with eGFR (Pearson r = 0.117, P = 0.009) and plasma uric acid (Pearson r = -0.114, P = 0.012). mtDNA-CN was not related to new on-trial total CVD events, but inversely associated with new on-trial total microvascular events (Table 1). Conclusion: Mitochondrial DNA copy number could serve as a biomarker for assessing microvascular disease risk in T2D patients. A. Mangani: None. A.S. Januszewski: None. K. Ong: None. H. Francis: None. R.L. O'Connell: None. L. Li: None. D. Sullivan: Other Relationship; Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Other Relationship; Novartis Pharmaceuticals Corporation, Merck Sharp & Dohme Corp. Research Support; Ionis Pharmaceuticals. R.S. Scott: None. P.G. Colman: None. A. Jenkins: Advisory Panel; Abbott. Speaker's Bureau; GlaxoSmithKline plc. Research Support; Abbott, Metronics, Ypsomed AG, Insulet Corporation, Jaeb Center for Health Research, Endogenex, Hemsley Charitable Trust. Speaker's Bureau; CSL Seqirus. Research Support; AbbVie Inc, National Institutes of Health, Juvenile Diabetes Research Foundation (JDRF). A.C. Keech: Research Support; Abbott, Amgen Inc, ASPEN Australia, Mylan. Speaker's Bureau; Novartis AG, Pfizer Inc. Research Support; Kowa Company, Ltd. Speaker's Bureau; Sanofi. Research Support; AbbVie Inc, Viatris Inc. Laboratoires Fournier, Dijon, France and the National Health and MedicalResearch Council of Australia (457103, 1024105, 1037786, 1105467, 1121272, 1137071 and 2018537)

Introduction The safest oxygen levels needed for preterm infant respiratory support at birth are uncertain. We aimed to compare the outcomes of infants up to 286 weeks gestation who had respiratory care initiated at birth with fractional inspired oxygen (FiO2) 0.3 or 0.6, which was adjusted to meet specific oxygen saturations (SpO2).Methods This randomised controlled phase III trial was stratified by (1) site, (2) gestation and (3) multiplicity. Infants between 23+0 to 28+6 weeks gestation were randomised to initial respiratory support with FiO2 0.3 or 0.6, adjusted to meet common SpO2 targets for the first 10 min.Primary outcome Survival to 36 weeks gestation without documented brain injury.Assessments FiO2, SpO2 and heart rate were recorded each minute from delivery for 10 min. Assessments were obtained at baseline, 36 weeks, discharge and at 2 years corrected gestation, along with a parent questionnaire.Statistical analysis plan Assuming 32% of infants would die or survive with brain injury by 36 weeks, 735 infants per arm (1470 total) were needed to detect a risk difference of 8% (25% relative risk reduction), with 10% non-adherence to protocol, 85% β and 5% α.Ethics Approved by the John Hunter Human Research Ethics Committee (2019/ETH/3837) for waiver of consent for all Australian sites for randomised allocation and primary outcome.Conclusion Recruitment started in 2018 and was achieved on 30 September 2024. The Data and Safety Committee review found no major safety concerns at 50% recruitment.Trial registration number ACTRN 12618000879268.

Introduction and Objective: Haptoglobin (HP) is a circulating glycoprotein with antioxidant and anti-inflammatory properties. It scavenges toxic free hemoglobin. Cardiovascular disease (CVD) risk in Type 2 diabetes (T2D) patients may differ by HP phenotype. It is unknown if CVD risk and fenofibrate benefits differ by HP levels. Methods: HP phenotype and levels were measured in baseline plasma from 8047 T2D adults in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial by ELISA and immunoturbidimetric assay, respectively. Results: Frequencies of HP 1-1, 2-1 and 2-2 phenotypes were 15.6%, 47.6% and 36.9% respectively. Higher HP level tertiles, but not HP phenotype, were associated with a higher risk of total CVD events, especially coronary heart disease events (P=0.019) and CVD mortality (P=0.003) in placebo group, after adjustment for CVD risk factors (overall P for trend =0.032, Fig. 1A). The HP level association was independently significant only in the HP 1-1 phenotype (P for level/phenotype interaction =0.039, Fig. 1B). Participants with both HP 1-1 phenotype and the lowest HP tertile levels tended to have the lowest CVD risk (Fig. 1C). Fenofibrate benefits on total CVD events did not differ by HP phenotype or levels. Conclusion: HP levels and phenotype help to identify T2D patients at high CVD risk for treatment, especially those with HP 1-1 phenotype. K. Ong: None. A.S. Januszewski: None. H. Francis: None. R.L. O'Connell: None. A. Mangani: None. L. Li: None. P.G. Colman: None. D. Sullivan: Other Relationship; Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Other Relationship; Novartis Pharmaceuticals Corporation, Merck Sharp & Dohme Corp. Research Support; Ionis Pharmaceuticals. J.D. Best: None. R.S. Scott: None. A. Jenkins: Advisory Panel; Abbott. Speaker's Bureau; GlaxoSmithKline plc. Research Support; Abbott, Metronics, Ypsomed AG, Insulet Corporation, Jaeb Center for Health Research, Endogenex, Hemsley Charitable Trust. Speaker's Bureau; CSL Seqirus. Research Support; AbbVie Inc, National Institutes of Health, Juvenile Diabetes Research Foundation (JDRF). A.C. Keech: Research Support; Abbott, Amgen Inc, ASPEN Australia, Mylan. Speaker's Bureau; Novartis AG, Pfizer Inc. Research Support; Kowa Company, Ltd. Speaker's Bureau; Sanofi. Research Support; AbbVie Inc, Viatris Inc. Laboratoires Fournier, Dijon, France and the National Health and Medical Research Council of Australia (457103, 1024105, 1037786, 1105467, 1121272, 1137071 and 2018537)

BACKGROUND:The benefit of expedited intra-arrest transport with ongoing resuscitation versus more extended on-scene resuscitation for refractory out of hospital cardiac arrest (OHCA) is uncertain. We aimed to determine whether expedited intra-arrest transfer to hospital in adults with refractory OHCA improves favourable neurological outcomes. METHODS:We conducted a prospective, parallel, multi-centre, open-label randomised, superiority trial across greater Sydney, NSW, Australia. Patients aged 18-70 years with a witnessed OHCA of presumed medical cause, bystander cardiopulmonary resuscitation (CPR), and an initial shockable rhythm or pulseless electrical activity without return of spontaneous circulation after 15 mins of advanced life support or three rounds of professional resuscitation were randomly assigned (1:1) at the scene by New South Wales Ambulance paramedics using a secure online randomisation system. Masking of allocation from ambulance staff and hospital staff receiving the patients was not possible. The intervention consisted of a predefined expedited bundle of pre-hospital care followed by intra-arrest transport with mechanical compression to a cardiac catheterisation centre (15 receiving hospitals) for immediate assessment for coronary angiography, extracorporeal cardiopulmonary resuscitation (ECPR), or both. The control arm consisted of a standard transport strategy of more extended on-scene advanced life support before considering transport and the same therapies. The primary outcome was survival with a good neurological outcome (defined as Cerebral Performance Category [CPC] score of 1-2) at hospital discharge, stratified by initial rhythm. Patients were followed-up until death or for 6 months (last patient followed-up Aug 29, 2024). All analyses were done on an intention-to-treat basis. The trial was prospectively registered with the Australian Clinical Trials Registry, ACTRN12621000668808 and is now complete. Data on safety and adverse events were collected throughout the study period and reported to a data safety monitoring board on a 6 monthly basis. FINDINGS:Between July 15, 2021 and March 3, 2024, we enrolled 206 patients. Eight patients were later deemed to be ineligible and one patient was excluded due to a randomisation application failure. 197 patients were therefore enrolled; 102 to the expedited strategy (intervention) and 95 to the standard strategy (control). The median age was 57·0 years (range 47-64); 161 (82%) were men and 78 (40%) were White. At hospital discharge, 15 (15%) of 102 patients in the expedited transportation group were alive with a favourable neurological outcome, compared with 15 (16%) of 95 patients in the standard care group (risk difference -1·1% [95% CI -12·2% to 10·0%]; adjusted relative risk 0·95 [95% CI 0·50 to 1·8], p=0·87). 38 patients had a serious adverse event (19%)-35 (92%) were diagnosed with a hypoxic brain injury (17 [49%] in the expedited arm, 18 [51%] in the standard arm), one (3%) had a cerebral stroke, one (3%) had a pulmonary haemorrhage, and one (3%) had a gastrointestinal haemorrhage (all in the standard arm). Adverse events were evenly distributed between treatment arms. No unanticipated (ie, expected sequelae seen in a cardiac arrest trial or in intensive care) adverse events were identified. INTERPRETATION:Among patients with refractory out-of-hospital cardiac arrest, expedited intra-arrest transport did not significantly improve survival with neurologically favourable outcome. However, the study might have been underpowered to detect a smaller than expected treatment effect. FUNDING:New South Wales Health Translational Research Grant Scheme (H20/93572).

Introduction and Objective: We have previously identified 50 proteins associated with T2D vascular complications (CX). We now measured their mRNA expression in T2D patients with and without CX. Methods: RNA was extracted from citrate plasma samples of 542 people with T2D from the Fenofibrate Intervention and Event Lowering in Diabetes trial (Age: 62±7 yrs; T2D duration: 6±6 yrs; HbA1c: 6.8±1.3%). There were n=179 participants with CX at baseline, n=142 developing first CX during follow-up (FUP) and n=221 who had no CX. OpenArray was used to measure mRNA with normalisation using housekeeping gene (MT-ATP6). For differences between groups ΔΔCT values were used. Results: Seven genes had circulating mRNA levels below the detection limit in all samples, 32 were detected in < 20% of samples. The remaining 11 genes were detected in 23-90% of samples. Genes differentially expressed between T2D patients with and without CX were involved in vascular repair and extracellular matrix remodeling. E.g. FERMT3 mRNA was 1.8-fold higher in those developing macroCX during FUP vs. no CX group. Clusterin mRNA was 1.1-1.5-fold higher with CX during FUP and 1.3-1.7-fold higher with baseline CX vs. no CX. Comparisons of proteomic and mRNA levels across the study groups revealed that in 32% of cases differences in mRNA levels were paralleled in protein level differences. E.g. TLN1 exhibited reduced mRNA and protein expression in subjects who developed both micro- and/or macroCX during FUP. In contrast, in 45% of instances, differences in mRNA were not paralleled by the same differences in protein expression, suggesting potential post-transcriptional regulation in those pathways. Conclusion: These findings underscore the importance of integrating transcriptomic and proteomic analyses to better understand the molecular mechanisms driving vascular complications in T2D and to identify potential therapeutic targets. H. Francis: None. A.S. Januszewski: None. M. O'Rourke: None. M.L. Huang: None. F. Ema: None. A.A. Hardikar: None. M.V. Joglekar: None. D. Sullivan: Other Relationship; Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Other Relationship; Novartis Pharmaceuticals Corporation, Merck Sharp & Dohme Corp. Research Support; Ionis Pharmaceuticals. R.S. Scott: None. A. Jenkins: Advisory Panel; Abbott. Speaker's Bureau; GlaxoSmithKline plc. Research Support; Abbott, Metronics, Ypsomed AG, Insulet Corporation, Jaeb Center for Health Research, Endogenex, Hemsley Charitable Trust. Speaker's Bureau; CSL Seqirus. Research Support; AbbVie Inc, National Institutes of Health, Juvenile Diabetes Research Foundation (JDRF). M.P. Molloy: None. A.C. Keech: Research Support; Abbott, Amgen Inc, ASPEN Australia, Mylan. Speaker's Bureau; Novartis AG, Pfizer Inc. Research Support; Kowa Company, Ltd. Speaker's Bureau; Sanofi. Research Support; AbbVie Inc, Viatris Inc. National Health and Medical Research Council of Australia (GNT1147879)

Introduction and Objective: Socio-economic status (SES) is linked to health outcomes but remains challenging to measure. The conventional approach, relying on SES indices for large geographical units (e.g., postcodes), may overlook SES effects detectable at smaller scales. Methods: We analyzed Australian participants from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. SES was assessed using percentile rankings of SES indices for areas (SEIFA) derived from small geographical units (~400 people). Higher values indicate better SES. This percentile-based approach preserves relative SES positioning over time, reducing inconsistencies in SEIFA calculations across census periods. Results: Among 5,147 FIELD participants, higher SES (measured by the index of relative socio-economic disadvantage [IRSD] and index of economic resources [IER]) was associated with a lower prevalence of cardiovascular disease (CVD) at baseline and during 5 years of follow-up (FUP). The median rank (95% CI) IRSD for participants with no prior CVD at baseline was 50.9%ile (25.4-76.7) vs 42.7%ile (19.9-68.4) for those with CVD; p<0.0001. IER was 55.9%ile (30.5-79.5) vs 46.9%ile (23.6-73.2) respectively; p<0.0001. Higher SES was also linked to lower incidence of new CVD events during follow-up: the IRSD was 49.4%ile (24.7-75.5) vs 46.4%ile (21.6-69.1); p=0.017, and IER: 54.8%ile (29.4-78.4) vs 49.7%ile (25.5-74.9); p=0.039 for those without vs those with new CVD events during FUP. When SES was assessed using larger geographical units (postcode, ~10,000 people), the association with on-trial CVD was lost (IRSD: 56.4%ile (25.8-80.4) vs 58.1%ile (26.9-77.3); p=0.75, IER: 49.7%ile (25.2-76.0) vs 47.7%ile (22.9-72.9); p=0.28). Conclusion: Assessing SES at smaller geographical scales offers a more nuanced understanding of socio-economic disparities and their health impacts. Our approach highlights the need for greater granularity in SES analysis to reveal trends in health outcomes. A.S. Januszewski: None. L. Li: None. R.L. O'Connell: None. J.D. Best: None. R.J. Simes: Research Support; Bayer Pharmaceuticals, Inc, Roche Pharmaceuticals, Bristol-Myers Squibb Company, Merck Sharp & Dohme Corp. Advisory Panel; Detsamma FivepHusion. Research Support; AstraZeneca. D. Sullivan: Other Relationship; Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Other Relationship; Novartis Pharmaceuticals Corporation, Merck Sharp & Dohme Corp. Research Support; Ionis Pharmaceuticals. T. Davis: Speaker's Bureau; Novo Nordisk A/S. Research Support; Eli Lilly and Company. A.C. Keech: Research Support; Abbott, Amgen Inc, ASPEN Australia, Mylan. Speaker's Bureau; Novartis AG, Pfizer Inc. Research Support; Kowa Company, Ltd. Speaker's Bureau; Sanofi. Research Support; AbbVie Inc, Viatris Inc.

BACKGROUND:Patients with an autoimmune or inflammatory disease (AIID) are at increased cardiovascular risk and may benefit more from statin therapy. In the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab lowered low-density lipoprotein cholesterol levels, but not hsCRP (high-sensitivity C-reactive protein) levels, and reduced the risk of cardiovascular events. METHODS:FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with stable atherosclerosis who were taking statins. This analysis focused on the effect of evolocumab in patients with or without an AIID, defined as any autoimmune or chronic inflammatory condition. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization. RESULTS:At baseline, 889 patients (3.2%) had an AIID, most commonly rheumatoid arthritis (33.7%) or psoriasis (15.6%). Median (interquartile range) low-density lipoprotein cholesterol levels were 90.0 mg/dL (79.5-105.5) and 91.5 mg/dL (79.5-108.5) in patients with or without an AIID, respectively (P=0.025), and the placebo-adjusted percent reduction with evolocumab was consistent (60.2% versus 59.0%; P=0.57). Baseline hsCRP was higher in patients with an AIID (median 2.1 versus 1.7 mg/L; P<0.001) and did not significantly change with evolocumab in either group. Compared with placebo, evolocumab reduced the rate of the primary end point by 14% in patients without an AIID (hazard ratio, 0.86 [95% CI, 0.80-0.93]) and by 42% in patients with an AIID (hazard ratio, 0.58 [95% CI, 0.38-0.89]; Pinteraction=0.066). Likewise, evolocumab reduced the key secondary end point of cardiovascular death, myocardial infarction, or stroke by 19% in patients without an AIID (hazard ratio, 0.81 [95% CI, 0.74-0.89]) and 58% in those with an AIID (hazard ratio, 0.42 [95% CI, 0.24-0.74]; Pinteraction=0.022). CONCLUSIONS:Intensive lowering of low-density lipoprotein cholesterol levels with evolocumab may lead to greater relative reduction in cardiovascular events in patients with an AIID. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633.

BACKGROUND:Interstitial lung disease (ILD) has a profound impact upon health-related quality of life (HRQoL) and mortality. Patients with ILD have identified their desire for tools to improve self-management. This study compares the clinical efficacy and cost-effectiveness of delivering an ILD-specific self-management package through a mobile health smartphone application (the REBUILD app), with standard care. It also evaluates the barriers and facilitators to adoption of the intervention in clinical practice. METHODS:This is a prospective, multicentre, randomised control trial (RCT) with embedded economic and implementation evaluations, with recruitment via ILD clinics at four Australian tertiary hospitals. Participants are allocated 1:1 to intervention and control groups, with randomisation stratified by disease severity, diagnosis, and site. The intervention group receives the self-management package and four phone health coaching sessions over 12 weeks. The control group receives standard care and four phone calls to control for attention. Outcomes will be measured at 12, 26 and 52 weeks. The primary outcome is change in HRQoL at 12 weeks, measured by the King's Brief Interstitial Lung Disease questionnaire. DISCUSSION:Enhanced self-management has been associated with better HRQoL in several chronic respiratory conditions, however its effect in people with ILD is not known. This is the first multicentre RCT to evaluate the effect of a digital self-management intervention delivered through a smartphone app in people with ILD. If successful, this intervention has the potential to enhance access to self-management support for people with ILD. TRIAL REGISTRATION:This project was prospectively registered with the Clinical Trial Registry (NCT06122233|| https://www. CLINICALTRIALS:gov/ /{08/11/2023}}.

BACKGROUND:Socio-economic status (SES) is strongly associated with health outcomes, yet it remains relatively difficult to measure, particularly for longitudinal comparisons. AIM:We have developed an interactive online tool (available at bit.ly/SEIFA-POA) that facilitates SES assessment based on postcodes (POA). METHODS:By utilising percentiles of socio-economic indices for areas (SEIFA) derived from postcode-based rankings across Australia, this tool enables comparisons of SEIFA indices provided by the Australian Bureau of Statistics (ABS) censuses from 1986 through to 2021. A percentile-based methodology preserves the relative socio-economic position of areas over time, thereby circumventing the methodological inconsistencies inherent in SEIFA calculations across different census periods. The tool simplifies SES assessment, offering researchers and policymakers a practical solution for both cross-sectional and longitudinal studies. RESULTS:In 6051 participants of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial from Australia, we demonstrated that favourable SES is associated with a lower frequency of vascular complications in the participants' medical history. The absence of an observed association between SES and on-trial complications may be attributed to the relatively short 5-year average time horizon of the analysis. CONCLUSION:Our SES assessment tool provides a more nuanced understanding of SES disparities and their implications for health and well-being.

BACKGROUND:Concerns about the efficacy and safety of intensive low-density lipoprotein cholesterol lowering in older patients have led to weaker recommendations in the U.S. guidelines for patients ≥75 years of age compared to younger patients. Data are sparse on long-term benefits of proprotein convertase subtilisin/kexin type 9 inhibition in older patients. OBJECTIVES:This study aims to assess the long-term benefit of evolocumab among patients aged ≥75 years. METHODS:The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial randomized 27,564 patients who were 18 to 85 years of age with atherosclerotic cardiovascular disease to evolocumab vs placebo with 2.2 years of median follow-up. In the open-label extension (FOURIER-OLE), 6,635 participants were transitioned to open-label evolocumab for an additional 5-year median follow-up. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) was compared based on the original allocation to evolocumab vs placebo stratified by age (<75 vs ≥75 years). Analyses were underpowered for individual components of the composite endpoint. The annualized incidence rates for adverse events of interest were calculated for the OLE population across age groups during the parent FOURIER trial by randomized treatment arm and during the combined parent and FOURIER-OLE studies for patients originally allocated to evolocumab. RESULTS:Of 27,564 patients, 2,526 (9%) were ≥75 years of age at entry into FOURIER (median age: 77 years [Q1-Q3: 76-79 years]). The median follow-up in FOURIER and FOURIER-OLE was 7.1 years (Q1-Q3: 6.7-7.6 years), with a maximum of 8.7 years. Earlier initiation of evolocumab reduced the rate of the primary endpoint at least as well in older (HR: 0.79; 95% CI: 0.64-0.97) as in younger patients (HR: 0.86; 95% CI: 0.80-0.92; P interaction = 0.43). The absolute risk reductions were 5.4% (95% CI: -2.0% to 12.8%) in older and 2.3% (95% CI: 0.1%-4.5%) in younger patients, leading to numbers needed to treat of 19 and 44, respectively. The annualized incidence rates of safety events generally appeared similar across treatment arms in both age groups. CONCLUSIONS:Early initiation of long-term evolocumab provides older patients with atherosclerotic cardiovascular disease cardiovascular benefits at least as good as those observed in younger patients, with a more favorable number needed to treat in older patients for reducing a composite endpoint and no significant safety concerns. These findings may be helpful in guiding future recommendations.

Objective We have shown that men aged 50 years+ at high risk of type 2 diabetes treated with testosterone together with a lifestyle program reduced the risk of type 2 diabetes at 2 years by 40% compared to a lifestyle program alone. To develop a personalized approach to treatment, we aimed to explore a prognostic model for incident type 2 diabetes at 2 years and investigate biomarkers predictive of the testosterone effect.Design Model development in 783 men with impaired glucose tolerance but not type 2 diabetes from Testosterone for Prevention of Type 2 Diabetes; a multicenter, 2-year trial of Testosterone vs placebo. External validation performed in 236 men from the Examining Outcomes in Chronic Disease in the 45 and Up Study (EXTEND-45, n = 267 357).Methods Type 2 diabetes at 2 years defined as 2-h fasting glucose by oral glucose tolerance test (OGTT) >= 11.1 mmol/L. Risk factors, including predictive biomarkers of testosterone treatment, were assessed using penalized logistic regression.Results Baseline HbA1c and 2-h OGTT glucose were dominant predictors, together with testosterone, age, and an interaction between testosterone and HbA1c (P = .035, greater benefit with HbA1c >= 5.6%, 38 mmol/mol). The final model identified men who developed type 2 diabetes, with C-statistics 0.827 in development and 0.798 in validation. After recalibration, the model accurately predicted a participant's absolute risk of type 2 diabetes.Conclusions Baseline HbA1c and 2-h OGTT glucose predict incident type 2 diabetes at 2 years in high-risk men, with risk modified independently by testosterone treatment. Men with HbA1c >= 5.6% (38 mmol/mol) benefit most from testosterone treatment, beyond a lifestyle program.

AIMS:Haptoglobin (HP) phenotype has been reported to modulate fenofibrate benefit on coronary artery disease in type 2 diabetes. It is unknown whether HP phenotype and levels modulate fenofibrate benefit on sight-threatening diabetic retinopathy (STDR). METHODS:In plasma from 8,047 Australasian adults with type 2 diabetes in the FIELD trial, HP phenotype was determined, and HP levels were measured at baseline and after six-week fenofibrate run-in. RESULTS:There were 307 new first on-trial STDR events over five years. Baseline HP levels and phenotype were not related to STDR risk. Fenofibrate benefit on STDR vs. placebo (-32 % overall), was greatest in participants with the lowest baseline HP level tertile (hazard ratio [95 % CI] 0.41 [0.26-0.65], vs. 0.82 [0.56-1.21] and 0.84 [0.56-1.27] for tertiles 2 and 3 respectively, P for heterogeneity = 0.019). During run-in, fenofibrate reduced HP levels by 20.7 %. However, fenofibrate benefit on STDR did not differ significantly by HP phenotype or change in HP levels during run-in after adjustment for confounding factors. CONCLUSIONS:Regarding STDR, fenofibrate benefit is greatest in type 2 diabetes patients with the lowest baseline HP levels, which may reflect patients more susceptible to oxidative retinal injury. All HP phenotypes benefit from fenofibrate.