Safety Of The Pcsk9 Inhibitor Alirocumab: insights From 47,296 Patient-Years Of Observation.

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared to that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection-site reactions. Further, the safety of alirocumab compared to placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

Long-term cardiovascular risks and the impact of statin treatment on socioeconomic inequalities: a microsimulation model.

BACKGROUND: UK cardiovascular disease (CVD) incidence and mortality have declined in recent decades but socioeconomic inequalities persist. AIM: To present a new CVD model, and project health outcomes and the impact of guideline-recommended statin treatment across quintiles of socioeconomic deprivation in the UK. DESIGN AND SETTING: A lifetime microsimulation model was developed using 117 896 participants in 16 statin trials, 501 854 UK Biobank (UKB) participants, and quality-of-life data from national health surveys. METHOD: A CVD microsimulation model was developed using risk equations for myocardial infarction, stroke, coronary revascularisation, cancer, and vascular and non-vascular death, estimated using trial data. The authors calibrated and further developed this model in the UKB cohort, including further characteristics and a diabetes risk equation, and validated the model in UKB and Whitehall II cohorts. The model was used to predict CVD incidence, life expectancy, quality-adjusted life years (QALYs), and the impact of UK guideline-recommended statin treatment across socioeconomic deprivation quintiles. RESULTS: Age, sex, socioeconomic deprivation, smoking, hypertension, diabetes, and cardiovascular events were key CVD risk determinants. Model-predicted event rates corresponded well to observed rates across participant categories. The model projected strong gradients in remaining life expectancy, with 4-5-year (5-8 QALYs) gaps between the least and most socioeconomically deprived quintiles. Guideline-recommended statin treatment was projected to increase QALYs, with larger gains in quintiles of higher deprivation. CONCLUSION: The study demonstrated the potential of guideline-recommended statin treatment to reduce socioeconomic inequalities. This CVD model is a novel resource for individualised long-term projections of health outcomes of CVD treatments.

Sex differences in outcomes after acute coronary syndrome vary with age: a New Zealand national study.

AIMS: This study investigated age-specific sex differences in short- and long-term clinical outcomes following hospitalization for a first-time acute coronary syndrome (ACS) in New Zealand (NZ). METHODS AND RESULTS: Using linked national health datasets, people admitted to hospital for a first-time ACS between January 2010 and December 2016 were included. Analyses were stratified by sex and 10-year age groups. Logistic and Cox regression were used to assess in-hospital death and from discharge the primary outcome of time to first cardiovascular (CV) readmission or death and other secondary outcomes at 30 days and 2 years. Among 63 245 people (mean age 69 years, 40% women), women were older than men at the time of the ACS admission (mean age 73 vs. 66 years), with a higher comorbidity burden. Overall compared with men, women experienced higher rates of unadjusted in-hospital death (10% vs. 7%), 30-day (16% vs. 12%) and 2-year (44% vs. 34%) death, or CV readmission (all P < 0.001). Age group-specific analyses showed sex differences in outcomes varied with age, with younger women (<65 years) at higher risk than men and older women (≥85 years) at lower risk than men: unadjusted hazard ratio of 2-year death or CV readmission for women aged 18-44 years = 1.51 [95% confidence interval (CI) 1.21-1.84] and aged ≥85 years = 0.88 (95% CI 0.83-0.93). The increased risk for younger women was no longer significant after multivariable adjustment whereas the increased risk for older men remained. CONCLUSION: Men and women admitted with first-time ACS have differing age and comorbidity profiles, resulting in contrasting age-specific sex differences in the risk of adverse outcomes between the youngest and oldest age groups.

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Development and validation of a quantitative Proximity Extension Assay instrument with 21 proteins associated with cardiovascular risk (CVD-21).

BACKGROUND: Treatment of cardiovascular diseases (CVD) is a substantial burden to healthcare systems worldwide. New tools are needed to improve precision of treatment by optimizing the balance between efficacy, safety, and cost. We developed a high-throughput multi-marker decision support instrument which simultaneously quantifies proteins associated with CVD. METHODS AND FINDINGS: Candidate proteins independently associated with different clinical outcomes were selected from clinical studies by the screening of 368 circulating biomarkers. We then custom-designed a quantitative PEA-panel with 21 proteins (CVD-21) by including recombinant antigens as calibrator samples for normalization and absolute quantification of the proteins. The utility of the CVD-21 tool was evaluated in plasma samples from a case-control cohort of 4224 patients with chronic coronary syndrome (CCS) using multivariable Cox regression analyses and machine learning techniques. The assays in the CVD-21 tool gave good precision and high sensitivity with lower level of determination (LOD) between 0.03-0.7 pg/ml for five of the biomarkers. The dynamic range for the assays was sufficient to accurately quantify the biomarkers in the validation study except for troponin I, which in the modeling was replaced by high-sensitive cardiac troponin T (hs-TnT). We created seven different multimarker models, including a reference model with NT-proBNP, hs-TnT, GDF-15, IL-6, and cystatin C and one model with only clinical variables, for the comparison of the discriminative value of the CVD-21 tool. All models with biomarkers including hs-TnT provided similar discrimination for all outcomes, e.g. c-index between 0.68-0.86 and outperformed models using only clinical variables. Most important prognostic biomarkers were MMP-12, U-PAR, REN, VEGF-D, FGF-23, TFF3, ADM, and SCF. CONCLUSIONS: The CVD-21 tool is the very first instrument which with PEA simultaneously quantifies 21 proteins with associations to different CVD. Novel pathophysiologic and prognostic information beyond that of established biomarkers were identified by a number of proteins.

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Paired risk scores to predict ischaemic and bleeding risk twenty-eight days to one year after an acute coronary syndrome.

OBJECTIVE: The recommended duration of dual anti-platelet therapy (DAPT) following acute coronary syndrome (ACS) varies from 1 month to 1 year depending on the balance of risks of ischaemia and major bleeding. We designed paired ischaemic and major bleeding risk scores to inform this decision. METHODS: New Zealand (NZ) patients with ACS investigated with coronary angiography are recorded in the All NZ ACS Quality Improvement registry and linked to national health datasets. Patients were aged 18-84 years (2012-2020), event free at 28 days postdischarge and without atrial fibrillation. Two 28-day to 1-year postdischarge multivariable risk prediction scores were developed: (1) cardiovascular mortality/rehospitalisation with myocardial infarction or ischaemic stroke (ischaemic score) and (2) bleeding mortality/rehospitalisation with bleeding (bleeding score). FINDINGS: In 27 755 patients, there were 1200 (4.3%) ischaemic and 548 (2.0%) major bleeding events. Both scores were well calibrated with moderate discrimination performance (Harrell's c-statistic 0.75 (95% CI, 0.74 to 0.77) and 0.69 (95% CI, 0.67 to 0 .71), respectively). Applying these scores to the 2020 European Society of Cardiology ACS antithrombotic treatment algorithm, the 31% of the cohort at elevated (>2%) bleeding and ischaemic risk would be considered for an abbreviated DAPT duration. For those at low bleeding risk, but elevated ischaemic risk (37% of the cohort), prolonged DAPT may be appropriate, and for those with low bleeding and ischaemic risk (29% of the cohort) short duration DAPT may be justified. CONCLUSION: We present a pair of ischaemic and bleeding risk scores specifically to assist clinicians and their patients in deciding on DAPT duration beyond the first month post-ACS.

Impact of Complete Revascularization in the ISCHEMIA Trial.

BACKGROUND: Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported. OBJECTIVES: Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management. METHODS: ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management. RESULTS: ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference -3.5; 95% CI: -7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was -2.4%. Results were similar but less pronounced with FCR. CONCLUSIONS: The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Impact of complete revascularization in the IschemiaTrial

BACKGROUND: Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported. OBJECTIVES: Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management. METHODS: ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management. RESULTS: ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference -3.5; 95% CI: -7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was -2.4%. Results were similar but less pronounced with FCR. CONCLUSIONS: The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Health status and clinical outcomes in older adults with chronic coronary disease: the ISCHEMIA trial

BACKGROUND: Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. OBJECTIVES: The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. METHODS: One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure. RESULTS: Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (Pinteraction = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (Pinteraction = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (Pinteraction = 0.29). CONCLUSIONS: Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Health Status and Clinical Outcomes in Older Adults With Chronic Coronary Disease: The ISCHEMIA Trial.

BACKGROUND: Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. OBJECTIVES: The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. METHODS: One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure. RESULTS: Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (Pinteraction = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (Pinteraction = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (Pinteraction = 0.29). CONCLUSIONS: Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Lipoprotein(a) and the Effect of Alirocumab on Revascularization After Acute Coronary Syndrome.

BACKGROUND: Many patients require revascularization after index acute coronary syndrome (ACS). Lipoprotein(a) is thought to play a pathogenic role in atherothrombosis. In ODYSSEY OUTCOMES, alirocumab reduced major adverse cardiovascular events after ACS, with greater reduction among those with higher lipoprotein(a) levels. We explored whether risk of revascularization after ACS was modified by the level of lipoprotein(a) and treatment with alirocumab or placebo. METHODS: In ODYSSEY OUTCOMES alirocumab was compared with placebo in 18,924 patients with ACS and elevated atherogenic lipoprotein levels despite optimized statin treatment. In this post hoc analysis, treatment effects are summarized using competing risks proportional hazard models. RESULTS: A total of 1559 (8.2%) patients had coronary, 204 (1.1%) had limb, and 40 (0.2%) had carotid revascularization. Alirocumab reduced coronary revascularization (2.8 vs 3.2 events per 100 patient-years; hazard ratio [HR], 0.88 [95% confidence interval (CI), 0.80-0.97]; P = 0.01) and any revascularization (3.2 vs 3.7 events per 100 patient-years; HR, 0.85 [95% CI, 0.78-0.94]; P = 0.001). Baseline lipoprotein(a) quartile was directly associated with risk of coronary or any revascularization in the placebo arm and inversely related to treatment HRs (all P for trend < 0.01). Alirocumab produced the greatest reduction of coronary revascularization in patients with baseline lipoprotein(a) in the top quartile (≥ 59.6 mg/dL; HR, 0.69 [95% CI, 0.57-0.84]), but no apparent reduction in the bottom quartile (HR, 1.00 [95% CI, 0.82-1.22]). Findings were similar for the effect of alirocumab on any revascularization. CONCLUSIONS: Alirocumab reduced revascularization rates after ACS. The risk of revascularization and reduction in that risk with alirocumab were greatest in patients with elevated lipoprotein(a) at baseline.

Transiently achieved very low LDL-cholesterol levels by statin and alirocumab after acute coronary syndrome are associated with cardiovascular risk reduction: the ODYSSEY OUTCOMES trial.

AIMS: Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus PCSK9 inhibitor. METHODS AND RESULTS: In 18,924 patients post-acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score-matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median 8.3 months from randomization, after a median 6.0 months with LDL-C < 0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C versus 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047). CONCLUSIONS: A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01663402.

Vascular endothelial growth factor-D plasma levels and VEGFD genetic variants are independently associated with outcomes in patients with cardiovascular disease.

AIMS: The vascular endothelial growth factor (VEGF) family is involved in pathophysiological mechanisms underlying cardiovascular (CV) diseases. The aim of this study was to investigate the associations between circulating VEGF ligands and/or soluble receptors and CV outcome in patients with acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). METHODS AND RESULTS: Levels of VEGF biomarkers, including bFGF, Flt-1, KDR (VEGFR2), PlGF, Tie-2, VEGF-A, VEGF-C, and VEGF-D, were measured in the PLATO ACS cohort (n = 2091, discovery cohort). Subsequently, VEGF-D was also measured in the STABILITY CCS cohort (n = 4015, confirmation cohort) to verify associations with CV outcomes. Associations between plasma VEGF-D and outcomes were analysed by multiple Cox regression models with hazard ratios (HR [95% CI]) comparing the upper vs. the lower quartile of VEGF-D. Genome-wide association study (GWAS) of VEGF-D in PLATO identified SNPs that were used as genetic instruments in Mendelian randomization (MR) meta-analyses vs. clinical endpoints. GWAS and MR were performed in patients with ACS from PLATO (n = 10 013) and FRISC-II (n = 2952), and with CCS from the STABILITY trial (n = 10 786). VEGF-D, KDR, Flt-1, and PlGF showed significant association with CV outcomes. VEGF-D was most strongly associated with CV death (P = 3.73e-05, HR 1.892 [1.419, 2.522]). Genome-wide significant associations with VEGF-D levels were identified at the VEGFD locus on chromosome Xp22. MR analyses of the combined top ranked SNPs (GWAS P-values; rs192812042, P = 5.82e-20; rs234500, P = 1.97e-14) demonstrated a significant effect on CV mortality [P = 0.0257, HR 1.81 (1.07, 3.04) per increase of one unit in log VEGF-D]. CONCLUSION: This is the first large-scale cohort study to demonstrate that both VEGF-D plasma levels and VEGFD genetic variants are independently associated with CV outcomes in patients with ACS and CCS. Measurements of VEGF-D levels and/or VEGFD genetic variants may provide incremental prognostic information in patients with ACS and CCS.

Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations.

This position statement provides guidance to cardiologists and related specialists on the management of adult patients with elevated lipoprotein(a) [Lp(a)]. Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). While circulating Lp(a) levels are largely determined by ancestry, they are also influenced by ethnicity, hormones, renal function, and acute inflammatory events, such that measurement should be done after accounting for these factors. Further, circulating Lp(a) concentrations should be estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L). Selective screening strategies of high-risk patients are recommended, but universal screening of the population is currently not advised. Testing for elevated Lp(a) is recommended in all patients with premature ASCVD and those considered to be at intermediate-to-high risk of ASCVD. Elevated Lp(a) should be employed to assess and stratify risk and to enable a decision on initiation or intensification of preventative treatments, such as cholesterol lowering therapy. In adult patients with elevated Lp(a) at intermediate-to-high risk of ASCVD, absolute risk should be reduced by addressing all modifiable behavioural, lifestyle, psychosocial and clinical risk factors, including maximising cholesterol-lowering with statin and ezetimibe and, where appropriate, PCSK9 inhibitors. Apheresis should be considered in patients with progressive ASCVD. New ribonucleic acid (RNA)-based therapies which directly lower Lp(a) are undergoing clinical trials.