Apolipoprotein A-I Infusions and Cardiovascular Outcomes in Acute Myocardial Infarction According to Baseline LDL-Cholesterol Levels: The AEGIS-II Trial.

BACKGROUND AND AIMS: In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days versus placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C. METHODS: Overall, 18,219 patients with acute MI, multivessel coronary artery disease, and additional risk factors were randomized to either four weekly infusions of 6 g CSL112 or placebo. This exploratory post-hoc analysis evaluated cardiovascular outcomes by baseline LDL-C in patients prescribed guideline-directed statin therapy at the time of randomization (n=15,731). RESULTS: As baseline LDL-C increased, risk of the primary endpoint at 90 days lowered in those treated with CSL112 compared with placebo. In patients with LDL-C ≥100 mg/dL at randomization, there was a significant risk reduction of cardiovascular death, MI, or stroke in the CSL112 vs. placebo group at 90, 180, and 365 days (hazard ratio 0.69 [0.53-0.90], 0.71 [0.57-0.88], and 0.78 [0.65-0.93]). In contrast, there was no difference between treatment groups among those with LDL-C <100 mg/dL at baseline. CONCLUSIONS: In this population, treatment with CSL112 compared to placebo was associated with a significantly lower risk of recurrent cardiovascular events among patients with a baseline LDL-C ≥100 mg/dL. Further studies need to confirm that CSL112 efficacy is influenced by baseline LDL-C.

Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome.

BACKGROUND: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations. OBJECTIVES: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial. METHODS: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations. RESULTS: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82). CONCLUSIONS: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

ApoA-I Infusions and Burden of Ischemic Events After Acute Myocardial Infarction: Insights From the AEGIS-II Trial.

BACKGROUND: Following an acute myocardial infarction (AMI), patients remain at risk for subsequent cardiovascular (CV) events. In the AEGIS-II trial, CSL112, a human apolipoprotein A-I derived from plasma that enhances cholesterol efflux, did not significantly reduce the first occurrence of CV death, myocardial infarction (MI), or stroke through 90 days compared with placebo. However, an analysis involving only the first event may not capture the totality of the clinical impact of an intervention because patients may experience multiple events. OBJECTIVES: This prespecified exploratory analysis examines the effect of CSL112 on total burden of nonfatal ischemic events (ie, recurrent MI and stroke) and CV death. METHODS: A total of 18,219 patients with AMI, multivessel coronary artery disease, and additional CV risk factors were randomized to either 4 weekly infusions of 6 g CSL112 (n = 9,112) or matching placebo (n = 9,107). A negative binomial regression model was applied to estimate the effect of CSL112 compared with placebo on the rate ratio (RR) of ischemic events. RESULTS: For CV death, MI, and stroke, there were numerically fewer total events at 90 days (503 vs 545 events; rate ratio [RR]: 0.88; 95% CI: 0.76-1.03, P = 0.11), and nominally significantly fewer total events at 180 days (745 vs 821 events, RR: 0.87; 95% CI: 0.77-0.99; P = 0.04) and 365 days (1,120 vs 1,211 events; RR 0.89; 95% CI: 0.80-0.99; P = 0.04). Subsequent events constituted 13% of events at 90 days, 17% at 180 days, and 22% at 1 year. Similar findings were seen with the total occurrence of nonfatal MI and CV death. When type II MIs, unlikely to be modified by enhancing cholesterol efflux, were excluded, there were nominally significant reductions in the total occurrence of nonfatal MI (excluding type 2) and CV death at all timepoints (90 days: RR: 0.81; 95% CI: 0.68-0.97; P = 0.02; 180 days: RR: 0.82; 95% CI: 0.71-0.95; P < 0.01; 365 days: RR: 0.86; 95% CI: 0.76-0.98; P = 0.02). CONCLUSIONS: In this prespecified exploratory analysis of the AEGIS-II trial, 4 weekly infusions of CSL112 among high-risk patients after AMI significantly reduced the total burden of nonfatal ischemic events and CV death at 180 and 365 days compared with placebo. (AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome]; NCT03473223).

Associations between psychosocial burden and prognostic biomarkers in patients with chronic coronary syndrome: a STABILITY substudy.

AIM: To investigate associations between psychosocial burden and biomarkers reflecting pathophysiological pathways in patients with chronic coronary syndrome. METHODS: Psychosocial (PS) factors were collected from self-assessed questionnaires and biomarkers representing inflammation (high-sensitivity [hs]-C-reactive protein [CRP], interleukin-6 [IL-6], lipoprotein-associated phospholipase A2 [Lp-PLA2]) and cardiac injury/stress (hs-troponin T [hs-TnT], N-terminal pro-B type natriuretic peptide [NT-proBNP]) were measured in 12,492 patients with chronic coronary syndrome in the STABILITY trial. Associations between level of each psychosocial factor (never-rarely (reference), sometimes, often-always) and biomarkers were evaluated using linear models with adjusted geometric mean ratios (GMR). A score comprising four factors ('feeling down', 'loss of interest', financial stress', 'living alone') that previously demonstrated association with cardiovascular (CV) outcome was created, and categorized into three levels: low, moderate and high PS burden. Associations between PS score and biomarkers were evaluated similarly. RESULTS: Greater PS burden was significantly associated with a gradual increase in inflammatory biomarkers (GMR [95% CI] for moderate vs low PS burden; and high vs low PS burden): hs-CRP (1.09 [1.04-1.14]; 1.12 [1.06-1.17]), IL-6 (1.05 [1.02-1.07]; 1.08 [1.05-1.11]), LpPLA2 (1.01 [1.00 - 1.02]; 1.02 [1.01-1.04]) and cardiac biomarkers hs-TnT (1.03 [1.01-1.06]; 1.06 [1.03-1.09]) and NT-proBNP (1.09 [1.04-1.13]; 1.21 [1.15-1.27]). CONCLUSIONS: In patients with chronic coronary syndrome, greater psychosocial burden was associated with increased levels of inflammatory and cardiac biomarkers. While this observational study does not establish causal nature of these associations, the findings suggest inflammation and cardiac injury/stress as plausible pathways linking psychosocial burden to an elevated CV risk, that needs to be further explored.

We studied the association between psychosocial factors and various circulating protein biomarkers, reflecting different underlying mechanisms of disease, with the hope of shedding light on the link between psychological factors like depression and stress and the risk of cardiovascular events in patients with chronic coronary syndrome. We analysed data from the global large-scale STABILITY trial, which included more than 12,000 patients with chronic coronary syndrome. Participants filled out a questionnaire assessing their level of psychosocial burden, including experiences of depressive symptoms, stress at home, at work and financial stress. Additionally, blood samples were collected in which biomarkers (NTproBNP, high-sensitive Troponin-T, Interleukin-6, CRP and LpPLA2) were analysed. Our findings revealed a significant association between higher psychosocial burden and increased concentrations of biomarkers in patients with chronic coronary syndrome. These biomarkers reflect both inflammatory processes and cardiac damage or dysfunction which could be potential disease mechanisms explaining the increased risk of adverse events in patients with chronic coronary syndrome and high psychosocial burden. Although causal relationships cannot be determined from this study, the findings suggest that inflammation and cardiac stress may play crucial roles in linking psychosocial factors to heightened cardiovascular risk in this patient population. These insights could pave the way for better understanding and managing cardiovascular health in individuals with chronic coronary syndrome, offering hope for more targeted interventions in the future.

Restrictive Versus Liberal Transfusion in Patients with Type 1 or Type 2 Myocardial Infarction: A Prespecified Analysis of the Myocardial Ischemia and Transfusion (MINT) Trial.

BACKGROUND: The MINT trial raised concern for harm from a restrictive versus liberal transfusion strategy in patients with acute myocardial infarction (MI) and anemia. Type 1 and type 2 MI are distinct pathophysiological entities that may respond differently to blood transfusion. This analysis sought to determine if the effects of transfusion varied among patients with a type 1 or a type 2 MI and anemia. We hypothesized that the liberal transfusion strategy would be of greater benefit in type 2 than in type 1 MI. METHODS: We compared rates of death or MI at 30 days in patients with type 1 (n=1460) and type 2 (n=1955) MI and anemia who were randomly allocated to a restrictive (threshold of 7 to 8 g/dL) or a liberal (threshold of 10 g/dL) transfusion strategy. RESULTS: The primary outcome of death or MI was observed in 16% of type 1 MI and 15.4% of type 2 MI patients. The rate of death or MI was higher in patients with type 1 MI randomized to a restrictive (18.2%) versus liberal (13.2%) transfusion strategy (RR 1.32, 95% CI 1.04 - 1.67) with no difference observed between the restrictive (15.8% ) and liberal (15.1% ) transfusion strategies in patients with type 2 MI (RR 1.05 95% CI 0.85-1.29). The test for a differential effect of transfusion strategy by MI type was not statistically significant (P-interaction = 0.16). CONCLUSIONS: The concern for harm with a restrictive transfusion strategy in patients with acute MI and anemia raised in the MINT primary outcome manuscript may be more apparent in patients with type 1 than type 2 MI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02981407.

Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study.

BACKGROUND: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). OBJECTIVE: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. METHODS: This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. RESULTS: Women were older, had higher baseline low-density lipoprotein cholesterol (LDL-C) levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes. CONCLUSIONS: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).

Intracoronary thrombolysis in ST-elevation myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: Despite restoration of epicardial blood flow in acute ST-elevation myocardial infarction (STEMI), inadequate microcirculatory perfusion is common and portends a poor prognosis. Intracoronary (IC) thrombolytic therapy can reduce microvascular thrombotic burden; however, contemporary studies have produced conflicting outcomes. OBJECTIVES: This meta-analysis aims to evaluate the efficacy and safety of adjunctive IC thrombolytic therapy at the time of primary percutaneous coronary intervention (PCI) among patients with STEMI. METHODS: Comprehensive literature search of six electronic databases identified relevant randomised controlled trials. The primary outcome was major adverse cardiac events (MACE). The pooled risk ratio (RR) and weighted mean difference (WMD) with a 95% CI were calculated. RESULTS: 12 studies with 1915 patients were included. IC thrombolysis was associated with a significantly lower incidence of MACE (RR=0.65, 95% CI 0.51 to 0.82, I2=0%, p<0.0004) and improved left ventricular ejection fraction (WMD=1.87; 95% CI 1.07 to 2.67; I2=25%; p<0.0001). Subgroup analysis demonstrated a significant reduction in MACE for trials using non-fibrin (RR=0.39, 95% CI 0.20 to 0.78, I2=0%, p=0.007) and moderately fibrin-specific thrombolytic agents (RR=0.62, 95% CI 0.47 to 0.83, I2=0%, p=0.001). No significant reduction was observed in studies using highly fibrin-specific thrombolytic agents (RR=1.10, 95% CI 0.62 to 1.96, I2=0%, p=0.75). Furthermore, there were no significant differences in mortality (RR=0.91; 95% CI 0.48 to 1.71; I2=0%; p=0.77) or bleeding events (major bleeding, RR=1.24; 95% CI 0.47 to 3.28; I2=0%; p=0.67; minor bleeding, RR=1.47; 95% CI 0.90 to 2.40; I2=0%; p=0.12). CONCLUSION: Adjunctive IC thrombolysis at the time of primary PCI in patients with STEMI improves clinical and myocardial perfusion parameters without an increased rate of bleeding. Further research is needed to optimise the selection of thrombolytic agents and treatment protocols.

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 with 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 with 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.

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.

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.

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.).

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.

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).