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.

A Risk Model to Predict Statin Non-Adherence Following an Acute Coronary Syndrome.

BACKGROUND: Patients at risk of statin non-adherence are often not identified during hospital admission with an acute coronary syndrome (ACS). METHODS: In 19,942 patients hospitalised for ACS, statin dispensing was determined from the national pharmaceutical dispensing database. A risk score for non-adherence was developed from a multivariable Poisson regression model of associations between risk factors and the statin Medication Possession Ratio (MPR) <0.8 6-18 months after hospital discharge. RESULTS: Statin MPR was <0.8 in 4,736 (24%) patients. MPR <0.8 was more likely in patients with a history of cardiovascular disease (CVD) (RR 3.79, CI 95% 3.42-4.20) and those without known CVD (RR 2.25, 95% CI 2.04-2.48) who were not taking a statin on ACS admission, compared to patients with low density lipoprotein (LDL) cholesterol <2 mmol/L who were on a statin. For patients taking a statin on admission, higher LDL was associated with MPR <0.8 (≥3 versus <2 mmol/L, RR 1.96, 95%CI 1.72-2.24). Other independent risk factors for MPR <0.8 were age <45 years, female, disadvantaged ethnic groups, and no coronary revascularisation during the ACS admission. The risk score, which included nine variables, had a C-statistic of 0.67. MPR was <0.8 in 12% of 5,348 patients with a score ≤5 (lowest quartile) and 45% of 5,858 patients with a score ≥11 (highest quartile). CONCLUSION: A risk score generated from routinely collected data predicts statin non-adherence in patients hospitalised with ACS. This may be used to target inpatient and outpatient interventions to improve medication adherence.

B-Type Natriuretic Peptide and Long-Term Cardiovascular Mortality in Patients With Coronary Heart Disease.

Background The plasma concentration of B-type natriuretic peptide (BNP) is a strong predictor of adverse cardiovascular events. The aim of this study was to determine whether the association between plasma BNP concentration and cardiovascular mortality is sustained or diminishes with increasing time after BNP is measured. Methods and Results Six thousand seven hundred forty patients with a history of myocardial infarction or unstable angina who participated in the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trial had plasma BNP concentration measured at baseline and after 1 year. Associations with cardiovascular mortality were evaluated in landmark analyses 1 to <5, 5 to <10, and 10 to 16 years after randomization. There were 1640 cardiovascular deaths. The cardiovascular mortality rate increased progressively from 10.2 to 19.1 to 26.3/1000 patient-years from 1 to <5, 5 to <10, and 10 to 16 years after baseline, respectively. The average of baseline and 1-year BNP concentration was more strongly associated with cardiovascular mortality compared with baseline or 1-year BNP only. The hazard ratio (HR) for cardiovascular death associated with each doubling of average BNP concentration was similar during years 1 to <5 (HR, 1.53 [95% CI, 1.44-1.63]), years 5 to <10 (HR, 1.52 [95% CI, 1.44-1.60]), and years 10-16 (HR, 1.43 [95% CI, 1.36-1.50]), P<0.0001 for all. Conclusions BNP concentration remains an independent predictor of cardiovascular mortality more than a decade after it is measured. Because of random variation in plasma concentrations, the average of >1 BNP measurement improves long-term risk prediction.

Circulating Cystatin C Is an Independent Risk Marker for Cardiovascular Outcomes, Development of Renal Impairment, and Long-Term Mortality in Patients With Stable Coronary Heart Disease: The LIPID Study.

Background Elevated plasma cystatin C levels reflect reduced renal function and increased cardiovascular risk. Less is known about whether the increased risk persists long-term or is independent of renal function and other important biomarkers. Methods and Results Cystatin C and other biomarkers were measured at baseline (in 7863 patients) and 1 year later (in 6106 patients) in participants in the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) study, who had a previous acute coronary syndrome. Outcomes were ascertained during the study (median follow-up, 6 years) and long-term (median follow-up, 16 years). Glomerular filtration rate (GFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration equations (first GFR-creatinine, then GFR-creatinine-cystatin C). Over 6 years, in fully adjusted multivariable time-to-event models, with respect to the primary end point of coronary heart disease mortality or nonfatal myocardial infarction, for comparison of Quartile 4 versus 1 of baseline cystatin C, the hazard ratio was 1.37 (95% CI, 1.07-1.74; P=0.01), and for major cardiovascular events was 1.47 (95% CI, 1.19-1.82; P<0.001). Over 16 years, the association of baseline cystatin C with coronary heart disease, cardiovascular, and all-cause mortality persisted (each P<0.001) and remained significant after adjustment for estimated GFR-creatinine-cystatin C. Cystatin C also predicted the development of chronic kidney disease for 6 years (odds ratio, 6.61; 95% CI, 4.28-10.20) independently of estimated GFR-creatinine and other risk factors. However, this association was no longer significant after adjustment for estimated GFR-creatinine-cystatin C. Conclusions Cystatin C independently predicted major cardiovascular events, development of chronic kidney disease, and cardiovascular and all-cause mortality. Prediction of long-term mortality was independent of improved estimation of GFR. Registration URL: https://anzctr.org.au; Unique identifier: ACTRN12616000535471.

First Identified Case of Fatal Fulminant Necrotizing Eosinophilic Myocarditis Following the Initial Dose of the Pfizer-BioNTech mRNA COVID-19 Vaccine (BNT162b2, Comirnaty): an Extremely Rare Idiosyncratic Hypersensitivity Reaction.

RATIONALE: Transient myopericarditis has been recognised as an uncommon and usually mild adverse event predominantly linked to mRNA-based COVID-19 vaccines. These have mostly occurred in young males after the second dose of mRNA COVID-19 vaccines. OBJECTIVES: Fulminant necrotising eosinophilic myocarditis triggered by a variety of drugs or vaccines is an extremely rare hypersensitivity reaction carrying a substantial mortality risk. Early recognition of this medical emergency may facilitate urgent hospital admission for investigation and treatment. Timely intervention can lead to complete cardiac recovery, but the non-specific clinical features and rarity make early diagnosis challenging. FINDINGS: The clinical and pathological observations from a case of fatal fulminant necrotising myocarditis in a 57-year-old woman, following the first dose of the Pfizer-BioNTech vaccine, are described. Other causes have been discounted with reasonable certainty. CONCLUSION: These extremely rare vaccine-related adverse events are much less common than the risk of myocarditis and other lethal complications from COVID-19 infection. The benefits of vaccination far exceed the risks of COVID-19 infection.

Body Mass Index and Association With Cardiovascular Outcomes in Patients With Stable Coronary Heart Disease - A STABILITY Substudy.

BACKGROUND The obesity paradox states that patients with higher body mass index (BMI) and cardiovascular disease may experience better prognosis. However, this is less clear in patients with coronary heart disease. METHODS AND RESULTS The prospective STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial included 15 828 patients with stable coronary heart disease with 3 to 5 years' follow-up on optimal secondary preventive treatment. BMI was measured at baseline (n=15 785). Associations between BMI and cardiovascular outcomes were evaluated by Cox regression analyses with multivariable adjustments. Mean age was 64±9 years and 19% women. Most risk markers (diabetes, hypertension, inflammatory biomarkers, triglycerides) showed a graded association with higher BMI. The frequency of smoking, levels of high-density lipoprotein, growth differentiation factor 15, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) were higher at lower BMI. Low BMI (<20 kg/m2; n=244 [1.5%]) was associated with doubled risk of total death (hazard ratio [HR], 2.27; 95% CI, 1.60-3.22), cardiovascular death (HR, 2.26; 95% CI, 1.46-3.49), and heart failure (HR, 2.51; 95% CI, 1.35-4.68) compared with BMI of 25 to <30 kg/m2 (n=6752 [42.8%]) as reference. Similarly, high BMI of ≥35 kg/m2 (n=1768 [11.2%]) was associated with increased risk of the same outcomes. A BMI between 20 and <25 kg/m2 was associated with increased risk of cardiovascular death (HR, 1.26; 95% CI, 1.03-1.54) and total death (HR, 1.21; 95% CI, 1.03-1.42). CONCLUSIONS Patients with stable coronary heart disease showed a graded increase in cardiometabolic and inflammatory risk factors with increasing BMI category >25 kg/m2. All-cause and cardiovascular mortality were lowest at BMI of 25 to 35 kg/m2. Underweight with BMI of <20 kg/m2 and very high BMI of ≥35 kg/m2 were strong risk markers for poor prognosis. REGISTRATION URL: https://clinicaltrials.gov/; Unique identifier NCT00799903.

Atrial fibrillation detection in primary care during blood pressure measurements and using a smartphone cardiac monitor.

Improved atrial fibrillation (AF) screening methods are required. We detected AF with pulse rate variability (PRV) parameters using a blood pressure device (BP+; Uscom, Sydney, Australia) and with a Kardia Mobile Cardiac Monitor (KMCM; AliveCor, Mountain View, CA). In 421 primary care patients (mean (range) age: 72 (31-99) years), we diagnosed AF (n = 133) from 12-lead electrocardiogram recordings, and performed PRV and KMCM measurements. PRV parameters detected AF with area under curve (AUC) values of up to 0.92. Using the mean of two sequential readings increased AUC to up to 0.94 and improved positive predictive value at a given sensitivity (by up to 18%). The KMCM detected AF with 83% sensitivity and 68% specificity. 89 KMCM recordings were "unclassified" or blank, and PRV detected AF in these with AUC values of up to 0.88. When non-AF arrhythmias (n = 56) were excluded, the KMCM device had increased specificity (73%) and PRV had higher discrimination performance (maximum AUC = 0.96). In decision curve analysis, all PRV parameters consistently achieved a positive net benefit across the range of clinical thresholds. In primary care, AF can be detected by PRV accurately and by KMCM, especially in the absence of non-AF arrhythmias or when combinations of measurements are used.

Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome.

Importance: Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease. Objective: To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function. Design, Setting, and Participants: This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020. Exposures: Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2]). Main Outcomes and Measures: Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. Results: This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]). Conclusions and Relevance: In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.

High flow oxygen and risk of mortality in patients with a suspected acute coronary syndrome: pragmatic, cluster randomised, crossover trial.

OBJECTIVE: To determine the association between high flow supplementary oxygen and 30 day mortality in patients presenting with a suspected acute coronary syndrome (ACS). DESIGN: Pragmatic, cluster randomised, crossover trial. SETTING: Four geographical regions in New Zealand. PARTICIPANTS: 40 872 patients with suspected or confirmed ACS included in the All New Zealand Acute Coronary Syndrome Quality Improvement registry or ambulance ACS pathway during the study periods. 20 304 patients were managed using the high oxygen protocol and 20 568 were managed using the low oxygen protocol. Final diagnosis of ST elevation myocardial infarction (STEMI) and non-STEMI were determined from the registry and ICD-10 discharge codes. INTERVENTIONS: The four geographical regions were randomly allocated to each of two oxygen protocols in six month blocks over two years. The high oxygen protocol recommended oxygen at 6-8 L/min by face mask for ischaemic symptoms or electrocardiographic changes, irrespective of the transcapillary oxygen saturation (SpO2). The low oxygen protocol recommended oxygen only if SpO2 was less than 90%, with a target SpO2 of less than 95%. MAIN OUTCOME MEASURE: 30 day all cause mortality determined from linkage to administrative data. RESULTS: Personal and clinical characteristics of patients managed under both oxygen protocols were well matched. For patients with suspected ACS, 30 day mortality for the high and low oxygen groups was 613 (3.0%) and 642 (3.1%), respectively (odds ratio 0.97, 95% confidence interval 0.86 to 1.08). For 4159 (10%) patients with STEMI, 30 day mortality for the high and low oxygen groups was 8.8% (n=178) and 10.6% (n=225), respectively (0.81, 0.66 to 1.00) and for 10 218 (25%) patients with non-STEMI was 3.6% (n=187) and 3.5% (n=176), respectively (1.05, 0.85 to 1.29). CONCLUSION: In a large patient cohort presenting with suspected ACS, high flow oxygen was not associated with an increase or decrease in 30 day mortality. TRIAL REGISTRATION: ANZ Clinical Trials ACTRN12616000461493.

Risk markers of incident atrial fibrillation in patients with coronary heart disease.

BACKGROUND: In patients with coronary heart disease (CHD), atrial fibrillation (AF) is associated with increased morbidity and mortality. We investigated the associations between clinical risk factors and biomarkers with incident AF in patients with CHD. METHODS AND RESULTS: Around 13,153 patients with optimally treated CHD included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial with plasma samples obtained at randomization. Mean follow-up time was 3.5 years. The association between clinical risk factors and biomarkers with incident AF was estimated with Cox-regression models. Validation was performed in 1,894 patients with non-ST-elevation acute coronary syndrome included in the FRISC-II trial. The median (min-max) age was 64 years (range 26-92) and 2,514 (19.1%) were women. A total of 541 patients, annual incidence rate of 1.2%, developed AF during follow-up. In multivariable models, older age, higher levels of NT-proBNP, higher body mass index (BMI), male sex, geographic regions, low physical activity, and heart failure were independently associated with increased risk of incident AF with hazard ratios ranging from 1.04 to 1.79 (P ≤ .05). NT-proBNP improved the C-index from 0.70 to 0.71. In the validation cohort, age, BMI, and NT-proBNP were associated with increased risk of incident AF with similar hazard ratios. CONCLUSIONS: In patients with optimally treated CHD, the incidence of new AF was 1.2% per year. Age, NT-proBNP as a marker of impaired cardiac function, and BMI were the strongest factors, independently and consistently associated with incident AF. Male sex and low physical activity may also contribute to the risk of AF in patients with CHD.

Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.

BACKGROUND: Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. METHODS AND FINDINGS: The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events. CONCLUSIONS: Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00799903.

Left ventricular thrombus after ST segment elevation myocardial infarction: a single-centre observational study.

AIMS: The incidence of left ventricular (LV) thrombus following ST segment elevation myocardial infarction (STEMI) has reduced with modern reperfusion therapies. There is scant local data on the incidence and outcomes of LV thrombus in the contemporary era of rapid reperfusion. METHODS: Patients with STEMI admitted to Auckland City Hospital between January 2014 and December 2015 were identified using the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry and their clinical notes were retrospectively reviewed. RESULTS: Among the 997 patients admitted with STEMI, 53 patients (5%) had LV thrombus. Most patients with LV thrombus had an anterior STEMI (87%). The median time from admission to echocardiography was 48 hours (range 6-552 hours); the median LV ejection fraction was 38% (range 15-53%). Oral anticoagulation was initiated in 44 (83%) patients. LV thrombus resolved in 81% by six months in 42 patients given warfarin. Total mortality at 12 months was 13%. Bleeding occurred in 11% and was the most common treatment-related morbidity. CONCLUSIONS: The incidence of LV thrombus following STEMI was low and it was associated with a low rate of stroke and systemic embolism but high mortality. Randomised studies are needed to evaluate the efficacy of NOAC's in this context.

In patients with stable coronary heart disease, low-density lipoprotein-cholesterol levels < 70 mg/dL and glycosylated hemoglobin A1c < 7% are associated with lower major cardiovascular events.

BACKGROUND: In patients with stable coronary heart disease, it is not known whether achievement of standard of care (SOC) targets in addition to evidence-based medicine (EBM) is associated with lower major adverse cardiovascular events (MACE): cardiovascular death, myocardial infarction, and stroke. METHODS: EBM use was recommended in the STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY trial. SOC targets were blood pressure (BP) <140/90 mm Hg and low-density lipoprotein-cholesterol (LDL-C) <100 mg/dL and <70 mg/dL. In patients with diabetes, glycosylated hemoglobin A1c (HbA1c) < 7% and BP of <130/80 mm Hg were recommended. Feedback to investigators about rates of EBM and SOC was provided regularly. RESULTS: In 13,623 patients, 1-year landmark analysis assessed the association between EBM, SOC targets, and MACE during follow-up of 2.7 years (median) after adjustment in a Cox proportional hazards model. At 1 year, aspirin was prescribed in 92.5% of patients, statins in 97.2%, ß-blockers in 79.0%, and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers in 76.9%. MACE was lower with LDL-C < 100 mg/dL (70-99 mg/dL) compared with LDL-C ≥ 100 mg/dL (hazard ratio [HR] 0.694, 95% CI 0.594-0.811) and lower with LDL-C < 70 mg/dL compared with LDL-C < 100 mg/dL (70-99 mg/dL) (HR 0.834, 95% CI 0.708-0.983). MACE was lower with HbA1c < 7% compared with HbA1c ≥ 7% (HR 0.705, 95% CI 0.573-0.866). There was no effect of BP targets on MACE. CONCLUSIONS: MACE was lower with LDL-C < 100 mg/dL (70-99 mg/dL) and even lower with LDL-C < 70 mg/dL. MACE in patients with diabetes was lower with HbA1c < 7%. Achievement of targets is associated with improved patient outcomes.

Prediction of Residual Risk by Ceramide-Phospholipid Score in Patients With Stable Coronary Heart Disease on Optimal Medical Therapy.

Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide- and phospholipid-based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography-mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein-associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow-up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25-1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35-1.59) for cardiovascular death, 1.32 (95% CI, 1.16-1.49) for stroke, 1.23 (95% CI, 1.14-1.33) for myocardial infarction, and 1.56 (95% CI, 1.39-1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation (P<0.001, r>0.2) with inflammatory markers high-sensitivity C-reactive protein, interleukin 6, the heart failure marker N-terminal pro-B-type natriuretic peptide, and low-density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT00799903.

Cardiovascular and Lifestyle Risk Factors and Cognitive Function in Patients With Stable Coronary Heart Disease.

Background Vascular risk factors have been associated with differences in cognitive performance in epidemiological studies, but evidence in patients with coronary heart disease is more limited. Methods and Results The Montreal Cognitive Assessment score obtained 3.2±0.37 years after randomization to darapladib, a reversible inhibitor of lipoprotein phospholipase A2 or placebo was evaluated for 10 634 patients with coronary heart disease from 38 countries in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial. The Montreal Cognitive Assessment scores for darapladib and placebo groups were similar (mean± SD , 25.3±3.84 versus 25.4±3.73, respectively; P=0.27) and the adjusted odds ratio ( OR ) for mild cognitive impairment (Montreal Cognitive Assessment score <26) was 1.00 (95% CI , 0.93-1.09). Mild cognitive impairment was more likely with increasing age ( OR , 1.33 [1.27-1.41], +5 years after 65). For other baseline clinical characteristics, the strongest independent predictors of cognitive impairment were education (≤8 years versus college/university, OR , 2.95 [2.60-3.35]; >8 years/trade school versus college/university, OR , 1.38 [1.25-1.52] and geographic grouping). Cardiovascular risk factors independently associated with cognitive impairment were history of stroke ( OR , 1.43 [1.20-1.71]); <2.5 hours of moderate or vigorous intensity exercise/week ( OR , 1.19 [1.04-1.37]); high-density lipoprotein cholesterol <1.16 mmol/L ( OR , 1.19 [1.04-1.37]); diabetes mellitus requiring treatment ( OR , yes versus no: 1.15 [1.05-1.26]); and history of hypertension ( OR , 1.12 [1.02-1.23]). Conclusions In patients with stable coronary heart disease, cognitive performance was associated with modifiable cardiovascular risk factors, educational level, and global region, but was not influenced by darapladib. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00799903.

Effects and costs of real-time cardiac telerehabilitation: randomised controlled non-inferiority trial.

OBJECTIVE: Compare the effects and costs of remotely monitored exercise-based cardiac telerehabilitation (REMOTE-CR) with centre-based programmes (CBexCR) in adults with coronary heart disease (CHD). METHODS: Participants were randomised to receive 12 weeks of telerehabilitation or centre-based rehabilitation. REMOTE-CR provided individualised exercise prescription, real-time exercise monitoring/coaching and theory-based behavioural strategies via a bespoke telerehabilitation platform; CBexCR provided individualised exercise prescription and coaching via established rehabilitation clinics. Outcomes assessed at baseline, 12 and/or 24 weeks included maximal oxygen uptake (V̇O2max, primary) modifiable cardiovascular risk factors, exercise adherence, motivation, health-related quality of life and programme delivery, hospital service utilisation and medication costs. The primary hypothesis was a non-inferior between-group difference in V̇O2max at 12 weeks (inferiority margin=-1.25 mL/kg/min); inferiority margins were not set for secondary outcomes. RESULTS: 162 participants (mean 61±12.7 years, 86% men) were randomised. V̇O2 max was comparable in both groups at 12 weeks and REMOTE-CR was non-inferior to CBexCR (REMOTE-CR-CBexCR adjusted mean difference (AMD)=0.51 (95% CI -0.97 to 1.98) mL/kg/min, p=0.48). REMOTE-CR participants were less sedentary at 24 weeks (AMD=-61.5 (95% CI -117.8 to -5.3) min/day, p=0.03), while CBexCR participants had smaller waist (AMD=1.71 (95% CI 0.09 to 3.34) cm, p=0.04) and hip circumferences (AMD=1.16 (95% CI 0.06 to 2.27) cm, p=0.04) at 12 weeks. No other between-group differences were detected. Per capita programme delivery (NZD1130/GBP573 vs NZD3466/GBP1758) and medication costs (NZD331/GBP168 vs NZD605/GBP307, p=0.02) were lower for REMOTE-CR. Hospital service utilisation costs were not statistically significantly different (NZD3459/GBP1754 vs NZD5464/GBP2771, p=0.20). CONCLUSION: REMOTE-CR is an effective, cost-efficient alternative delivery model that could-as a complement to existing services-improve overall utilisation rates by increasing reach and satisfying unique participant preferences.

Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial.

BACKGROUND: Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease. METHODS: Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results. RESULTS: In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]). CONCLUSIONS: The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.

Cardiometabolic risk factors in vegans; A meta-analysis of observational studies.

BACKGROUND: There is increasing evidence that plant based diets are associated with lower cardiovascular risk. OBJECTIVE: To evaluate effects of a vegan compared to an omnivorous diet on cardio-metabolic risk factors. METHODS: Meta-analysis of observational studies published between 1960 and June 2018 that reported one or more cardio-metabolic risk factors in vegans and controls eating an omnivorous diet were undertaken. Macro-nutrient intake and cardio-metabolic risk factors were compared by dietary pattern. The Newcastle Ottawa Scale (NOS) was used to assess the quality of each study. The inverse-variance method was used to pool mean differences. Statistical analyses were performed using RevMan software version 5•2 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen. RESULTS: 40 studies with 12 619 vegans and 179 630 omnivores were included. From food frequency questionnaires in 28 studies, vegans compared to omnivores consumed less energy (-11%, 95% confidence interval -14 to -8) and less saturated fat (- 51%, CI -57 to -45). Compared to controls vegans had a lower body mass index (-1.72 kg/m2, CI -2.30 to -1.16), waist circumference (-2.35 cm, CI -3.93 to -0.76), low density lipoprotein cholesterol (-0.49 mmol/L CI -0.62 to -0.36), triglycerides (-0.14 mmol/L, CI -0.24 to -0.05), fasting blood glucose (-0.23 mmol/, CI -0.35 to -0.10), and systolic (-2.56 mmHg, CI -4.66 to -0.45) and diastolic blood pressure (-1.33 mmHg, CI -2.67 to -0.02), p<0.0001 for all. Results were consistent for studies with < and ≥ 50 vegans, and published before and after 2010. However in several large studies from Taiwan a vegan diet was not associated with favourable cardio-metabolic risk factors compared to the control diets. CONCLUSION: In most countries a vegan diet is associated with a more favourable cardio- metabolic profile compared to an omnivorous diet.