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Background: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. Design: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (e.g., severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The two independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the two co-primary outcomes. Summary: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery. Population Health Research Institute

Implantable cardioverter defibrillators (ICDs) improve survival in patients at risk for cardiac arrest, but are associated with intravascular lead-related complications. The subcutaneous ICD (S-ICD), with no intravascular components, was developed to minimize lead-related complications.To assess key ICD performance measures related to delivery of ICD therapy, including inappropriate ICD shocks (delivered in absence of life-threatening arrhythmia) and failed ICD shocks (which did not terminate ventricular arrhythmia).Randomized, multicenter trial. (ClinicalTrials.gov: NCT02881255).The ATLAS trial.544 eligible patients (141 female) with a primary or secondary prevention indication for an ICD who were younger than age 60 years, had a cardiogenetic phenotype, or had prespecified risk factors for lead complications were electrocardiographically screened and 503 randomly assigned to S-ICD (251 patients) or transvenous ICD (TV-ICD) (252 patients). Mean follow-up was 2.5 years (SD, 1.1). Mean age was 49.0 years (SD, 11.5).The primary outcome was perioperative major lead-related complications.There was a statistically significant reduction in perioperative, lead-related complications, which occurred in 1 patient (0.4%) with an S-ICD and in 12 patients (4.8%) with TV-ICD (-4.4%; 95% CI, -6.9 to -1.9;At present, the ATLAS trial is underpowered to detect differences in clinical shock outcomes; however, extended follow-up is ongoing.The S-ICD reduces perioperative, lead-related complications without significantly compromising the effectiveness of ICD shocks, but with more early postoperative pain and a trend for more inappropriate shocks.Boston Scientific.

Hypervolemia and vitamin D deficiency occur frequently in patients receiving peritoneal dialysis and may contribute to left ventricular (LV) hypertrophy. The effect of bioelectrical impedance analysis (BIA)-guided volume management or vitamin D supplementation on LV mass among those receiving peritoneal dialysis is uncertain.Two-by-two factorial randomized controlled trial.Sixty-five patients receiving maintenance peritoneal dialysis.BIA-guided volume management versus usual care and oral cholecalciferol 50,000 U weekly for 8 weeks followed by 10,000 U weekly for 44 weeks or matching placebo.Change in LV mass at 1 year measured by cardiac magnetic resonance imaging.Total body water decreased by 0.9 + 2.4 (SD) L in the BIA group compared with a 1.5 ± 3.4 L increase in the usual care group (adjusted between-group difference: -2.4 [95% CI, -4.1 to -0.68] L, P = 0.01). LV mass increased by 1.3 ± 14.3 g in the BIA group and decreased by 2.4 ± 37.7 g in the usual care group (between-group difference: +2.2 [95% CI, -13.9 to 18.3] g, P = 0.8). Serum 25-hydroxyvitamin D concentration increased by a mean of 17.2 ± 30.8 nmol/L in the cholecalciferol group and declined by 8.2 ± 24.3 nmol/L in the placebo group (between-group difference: 28.3 [95% CI, 17.2-39.4] nmol/L, P 0.001). LV mass decreased by 3.0 ± 28.1 g in the cholecalciferol group and increased by 2.0 ± 31.2 g in the placebo group (between-group difference: -4.5 [95% CI, -20.4 to 11.5] g, P = 0.6).Relatively small sample size with larger than expected variation in change in LV mass.BIA-guided volume management had a modest impact on volume status with no effect on the change in LV mass. Vitamin D supplementation increased serum vitamin D concentration but had no effect on LV mass.Unrestricted Baxter International extramural grant and the Kidney Foundation of Canada.Registered at ClinicalTrials.gov with study number NCT01045980.

Background: Diabetes and cardiovascular disease increase the risk of incident cognitive dysfunction. Identification of novel biochemical markers for cognitive dysfunction may identify people at the highest risk while yielding insights regarding the pathophysiology of cognitive dysfunction. Objective: To identify cardiovascular biomarkers in serum that are independent predictors of cognitive dysfunction in individuals with dysglycemia. Methods: This analysis was conducted in 8,365 participants in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial whose stored serum was analyzed for 238 cardio-metabolic biomarkers and completed a baseline Mini-Mental State Examination (MMSE). Fine and Gray sub distribution hazard models accounting for the competing risk of death accounting for clinical risk factors and the baseline MMSE were used to identify biomarkers that predicted incident cognitive dysfunction (MMSE

OBJECTIVE The glucagon-like peptide-1 receptor agonist dulaglutide reduced MACE in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. This article expores the relationship of selected biomarkers to both dulaglutide and major adverse cardiovascular events (MACE). RESEARCH DESIGN AND METHODS In this post hoc analysis, stored fasting baseline and 2-year plasma samples from 824 REWIND participants with MACE during follow-up and 845 matched non-MACE participants were analyzed for 2-year changes in 19 protein biomarkers. Two-year changes in 135 metabolites were also analyzed in 600 participants with MACE during follow-up and in 601 matched non-MACE participants. Linear and logistic regression models were used to identify proteins that were associated with both dulaglutide treatment and MACE. Similar models were used to identify metabolites that were associated with both dulaglutide treatment and MACE. RESULTS Compared with placebo, dulaglutide was associated with a greater reduction or lesser 2-year rise from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein, and a greater 2-year rise in C-peptide. Compared with placebo, dulaglutide was also associated with a greater fall from baseline in 2-hydroxybutyric acid and a greater rise in threonine (P < 0.001). Increases from baseline in two of the proteins (but neither metabolite) were associated with MACE, including NT-proBNP (OR 1.267; 95% CI 1.119, 1.435; P < 0.001) and GDF-15 (OR 1.937; 95% CI 1.424, 2.634; P < 0.001). CONCLUSIONS Dulaglutide was associated with a reduced 2-year rise from baseline of NT-proBNP and GDF-15. Higher rises of these biomarkers were also associated with MACE.

BackgroundBetter understanding of global variation in simple tests of cognition and function would aid the delivery and interpretation of multi-national studies of the prevention of dementia and functional decline.MethodsWe aim to describe the variation in simple measures of cognition and function by world region, study, recruitment centre or individual level factors. In six RCTs that measured cognition with the mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), and instrumental activities of daily living (IADL) with the Standardised Assessment of Everyday Global Activities (SAGEA), we estimated average scores by global region with multilevel mixed-effects models. We estimated the proportion of participants with cognitive or functional impairment with previously defined thresholds (MMSE≤24 or MoCA≤25, SAGEA≥7), and with a country-standardised z-score threshold of cognitive or functional score of ≤-1.ResultsIn 91,396 participants (mean age 66.6±7.8 years, 31% females) from seven world regions, all global regions differed significantly in estimated cognitive function (z-score differences 0.11–0.45, pConclusionsAccounting for country-level factors reduced large differences between world regions in estimates of cognitive impairment. Measures of IADL were less variable across world regions, and could be used to better estimate dementia incidence in large studies.Impact statementWe certify that this work is novel. After analysing data from a large cohort of participants with a history of cardiovascular disease or cardiovascular risk factors, who were recruited in six international randomised controlled trials (RCTs) we found that accounting for country-level factors reduced large differences between world regions in estimates of cognitive impairment, while measures of functional impairment were less variable across world regions.Key PointsCognitive and functional test scores in randomized controlled clinical trial cohorts vary widely across world regions.The difference in cognitive test performance was large in comparison to difference in measures of activities of daily living (ADLs). Accounting for country-level factors reduced the differences between world regions in estimates of cognitive impairment.Cognitive test measures were less variable and could be used to better estimate dementia incidence in international studies.Why this study matters?We found that cognitive and functional test scores in RCT cohorts varied widely across world regions. The difference in cognitive test performance was large in comparison to difference in measures of activities of daily living. The impact of differences on the performance of cognitive tests, which were developed in high-income countries, creates challenges for harmonized studies of cognitive decline prevention in different world regions. Future studies using the same test around the world could standardise cognitive score by country, and consider using in addition measures of instrumental and basic activities of daily living, where there is less variation across world regions.

In patients with ST-segment elevation myocardial infarction (STEMI), early initiation of high-intensity statin therapy, regardless of low-density lipoprotein (LDL) cholesterol levels, is the standard of practice worldwide. Aims: We sought to determine the effect of a similar early initiation strategy, using a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor added to the high-intensity statin, on LDL cholesterol in acute STEMI.In a randomised, double-blind trial we assigned 68 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) to early treatment with alirocumab 150 mg subcutaneously or to a matching sham control. The first injection was given before primary PCI regardless of the baseline LDL level, then at 2 and 4 weeks. The primary outcome was the percent reduction in direct LDL cholesterol up to 6 weeks, analysed using a linear mixed model. Results: High-intensity statin use was 97% and 100% in the alirocumab and sham-control groups, respectively. At a median of 45 days, the primary outcome of LDL cholesterol decreased by 72.9% with alirocumab (2.97 mmol/L to 0.75 mmol/L) versus 48.1% with the sham control (2.87 mmol/L to 1.30 mmol/L), for a mean between-group difference of -22.3% (p0.001). More patients achieved the European Society of Cardiology/European Atherosclerosis Society dyslipidaemia guideline target of LDL ≤1.4 mmol/L in the alirocumab group (92.1% vs 56.7%; p0.001). Within the first 24 hours, LDL declined slightly more rapidly in the alirocumab group than in the sham-control group (-0.01 mmol/L/hour; p=0.03) with similar between-group mean values. Conclusions: In this randomised trial of routine early initiation of PCSK9 inhibitors in patients undergoing primary PCI for STEMI, alirocumab reduced LDL cholesterol by 22% compared with sham control on a background of high-intensity statin therapy. A large trial is needed to determine if this simplified approach followed by long-term therapy improves cardiovascular outcomes in patients with acute STEMI. (ClinicalTrials.gov: NCT03718286).

Background Different instruments have been used to assess ability to perform everyday functional activities, such as activities of daily living (ADL) and instrumental activities of daily living (IADL). No measures of functional activity have been validated in cardiac surgery. We assessed the reliability and validity of the Standardized Assessment of Global activities in the Elderly (SAGE) scale. Methods We undertook an observational sub-study of VISION Cardiac Surgery. Patients were assessed post-discharge after cardiac surgery using SAGE and comparator measures to determine convergent validity. A blinded independent assessor administered SAGE by phone within 7 days to determine test–retest reliability. We sought to demonstrate a correlation of ≥0.5 between SAGE and each corresponding measure. We also sought to define the SAGE score corresponding to severe functional disability, defined using the World Health Organisation Disability Assessment Schedule (WHODAS). Results There were 152 patients included. Inter-rater reliability was excellent (intra-class correlation coefficient=0.99; 95% confidence interval [CI], 0.98–0.99). Convergent validity was evident, ranging from adequate for the overall SAGE score (0.54; 95% CI, 0.42–0.65) to very good for the SAGE mobility sub-score (0.80; 95% CI, 0.73–0.85). SAGE was initially poorly correlated with the IADL index (–0.24) but increased to –0.60 after post-hoc adjustment of SAGE scoring. A SAGE score ≥7 was associated with severe functional disability and occurred in 42/152 (27.6%) of patients. Conclusion These results demonstrate the reliability and validity of the SAGE scale as a measure of global function in patients discharged home after cardiac surgery. Clinical trial registration NCT01842568.

Objective To evaluate the power of responder analyses in a randomized controlled trial. Study design and setting Simulations were based on the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST), which compared sertraline to placebo for the treatment of depression in kidney disease. Baseline disease severity, placebo response, effect size, and the proportion of responders were varied across 72 scenarios. Power was assessed using a t-test for change scores, and the chi-square test for dichotomized outcomes of the minimal important difference (MID), improvement and remission in 10,000 datasets with a fixed sample size of 193. Results The t-test had >80% power except for scenarios with the lowest sertraline effect size. The chi-square test using the MID had 80% power only at higher effect sizes and/or when the proportion of responders was highest at 0.5. The chi-square test for improvement had marginal power increases compared to the t-test (4/72 scenarios = 5.6%) and that for remission did not outperform the t-test in any scenario. Conclusions The t-test outperforms the chi-square test for dichotomized outcomes regardless of baseline disease severity, placebo response, effect size and the proportion of responders to the intervention.

Background\ud The LACE index—length of stay (L), acuity (A), Charlson co-morbidities (C), and emergent visits (E)—predicts 30-day outcomes following heart failure (HF) hospitalization but is complex to score. A simpler LE index (length of stay and emergent visits) could offer a practical advantage in point-of-care risk prediction.\ud \ud Methods and results\ud This was a sub-study of the patient-centred care transitions in HF (PACT-HF) multicentre trial. The derivation cohort comprised patients hospitalized for HF, enrolled in the trial, and followed prospectively. External validation was performed retrospectively in a cohort of patients hospitalized for HF. We used log-binomial regression models with LACE or LE as the predictor and either 30-day composite all-cause readmission or death or 30-day all-cause readmission as the outcomes, adjusting only for post-discharge services. There were 1985 patients (mean [SD] age 78.1 [12.1] years) in the derivation cohort and 378 (mean [SD] age 73.1 [13.2] years) in the validation cohort. Increments in the LACE and LE indices were associated with 17% (RR 1.17; 95% CI 1.12, 1.21; C-statistic 0.64) and 21% (RR 1.21; 95% CI 1.15, 1.26; C-statistic 0.63) increases, respectively, in 30-day composite all-cause readmission or death; and 16% (RR 1.16; 95% CI 1.11, 1.20; C-statistic 0.64) and 18% (RR 1.18; 95% CI 1.13, 1.24; C-statistic 0.62) increases, respectively, in 30-day all-cause readmission. The LE index provided better risk discrimination for the 30-day outcomes than did the LACE index in the external validation cohort.\ud \ud Conclusions\ud The LE index predicts 30-day outcomes following HF hospitalization with similar or better performance than the more complex LACE index.

Aims The LE index (Length of hospitalization plus number of Emergent visits ≤6 months) predicts 30 day all‐cause readmission or death following hospitalization for heart failure (HF). We combined N‐terminal pro‐B type natriuretic peptide (NT‐proBNP) levels with the LE index to derive and validate the LENT index for risk prediction at the point of care on the day of hospital discharge. Methods and results In this prospective cohort sub‐study of the Patient‐centred Care Transitions in HF clinical trial, we used log‐binomial regression models with LE index and either admission or discharge NT‐proBNP as the predictors and 30 day composite all‐cause readmission or death as the primary outcome. No other variables were added to the model. We used regression coefficients to derive the LENT index and bootstrapping analysis for internal validation. There were 772 patients (mean [SD] age 77.0 [12.4] years, 49.9% female). Each increment in the LE index was associated with a 25% increased risk of the primary outcome (RR 1.25, 95% CI 1.16–1.35; C‐statistic 0.63). Adjusted for the LE index, every 10‐fold increase in admission and discharge NT‐proBNP was associated with a 48% (RR 1.48; 95% CI 1.10, 1.99; C‐statistic 0.64; net reclassification index [NRI] 0.19) and 56% (RR 1.56; 95% CI 1.08, 2.25; C‐statistic 0.64; NRI 0.21) increased risk of the primary outcome, respectively. The predicted probability of the primary outcome increased to a similar extent with incremental LENT, regardless of whether admission or discharge NT‐proBNP level was used. Conclusions The point‐of‐care LENT index predicts 30 day composite all‐cause readmission or death among patients hospitalized with HF, with improved risk reclassification compared with the LE index. The performance of this simple, 3‐variable index ‐ without adjustment for comorbidities ‐ is comparable to complex risk prediction models in HF. Trial Registration: ClinicalTrials.gov Identifier: NCT02112227

Dulaglutide (DU) reduced the risk of CV outcomes compared with placebo (PL) in the REWIND trial (NCT01394952) , with a MACE-3 (major adverse CV events) hazard ratio of 0.88 over 5.4 years. Participants were ≥50 years of age with T2D, A1C ≤9.5%, BMI ≥23 kg/m2, and CV risk and received either DU (1.5 mg weekly) or PL. This post-hoc analysis explored the hypothesized relationship between metabolite biomarkers and MACE-3 in a nested case-control substudy comprising 600 MACE cases and 6non-MACE REWIND participants. A total of 135 plasma metabolites were measured by targeted metabolomics using mass spectrometry. Biomarkers significantly associated with DU were first identified in analyses that adjusted for 135 multiple comparisons (discovery approach) . Predefined clusters of the remainder based on non-REWIND data were then assessed using principal component analyses (hypothesis testing) . DU was associated with 2-year changes in 2-hydroxybutyric acid, threonine, acylcarnitines and homocitrulline; of these, only the acylcarnitines were linked with MACE (Table) . In the literature, higher levels of acylcarnitines are associated with CV events. These analyses suggest that DU-associated reductions in acylcarnitines are associated with its MACE benefit. Disclosure V.Pirro: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. G.Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. S.Lee: None. H.M.Colhoun: Advisory Panel; Bayer AG, Eli Lilly and Company, Novo Nordisk, Consultant; AstraZeneca, Research Support; AstraZeneca, Stock/Shareholder; Bayer AG, Roche Pharmaceuticals. Y.Lin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.M.Wilson: Employee; Eli Lilly and Company. H.Qian: Employee; Eli Lilly and Company, Stock/Shareholder; Apple, Eli Lilly and Company. A.Hoover: Employee; Eli Lilly and Company. K.L.Duffin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. Funding Eli Lilly and Company

In the REWIND trial, dulaglutide (DU) reduced the risk of CV outcomes compared with placebo (PL) (Major Adverse Cardiovascular Event [MACE]-3 hazard ratio 0.88) . This post hoc analysis studied circulating protein biomarkers associated with CV events to better understand how DU reduces CV risk. Patients ≥50 years of age with T2D, A1C ≤9.5%, BMI ≥23 kg/m2, and CV risk were treated DU (1.5 mg weekly) or PL. This case/control study matched 9 cases with MACE with 9 non-MACE controls. A total of protein biomarkers were measured by immunoassay in plasma and serum. Biomarkers associated with DU were first identified by fitting the natural log (ln) of biomarker changes from baseline to 2 years of treatment to an ANCOVA model; the p value cutoff was 0.0026 after Bonferroni correction. Then, the identified biomarkers were fit to a logistic regression model for MACE case/control to test possible impact on CV outcome. Four biomarkers were associated with DU: C-reactive protein (hsCRP) , N-terminal prohormone of brain natriuretic peptide (NT-proBNP) , and Growth/Differentiation Factor-15 (GDF-15) had attenuated increases over 2 years for DU vs. PL, and C-peptide had a greater increase over 2 years for DU vs. PL. Logistic regression analyses showed that patients with smaller increases in hsCRP, NT-proBNP, and GDF-15 were less likely to have MACE. C-peptide levels did not significantly impact MACE occurrence. Disclosure J.M.Wilson: Employee; Eli Lilly and Company. K.L.Duffin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. G.Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. S.Lee: None. H.M.Colhoun: Advisory Panel; Bayer AG, Eli Lilly and Company, Novo Nordisk, Consultant; AstraZeneca, Research Support; AstraZeneca, Stock/Shareholder; Bayer AG, Roche Pharmaceuticals. H.Qian: Employee; Eli Lilly and Company, Stock/Shareholder; Apple, Eli Lilly and Company. V.Pirro: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Hoover: Employee; Eli Lilly and Company. M.Lakshmanan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. G.Ruotolo: None. Funding Eli Lilly and Company

Background Delirium is common after cardiac surgery and is associated with adverse outcomes. Perioperative benzodiazepine use is associated with delirium and is common during cardiac surgery, which may increase the risk of postoperative delirium. We undertook a pilot study to inform the feasibility of a large randomised cluster crossover trial examining whether an institutional policy of restricted benzodiazepine administration during cardiac surgery (compared with liberal administration) would reduce delirium. Methods We conducted a two-centre, pilot, randomised cluster crossover trial with four 4 week crossover periods. Each centre was randomised to a policy of restricted or liberal use, and then alternated between the two policies during the remaining three periods. Our feasibility outcomes were adherence to each policy (goal ≥80%) and outcome assessment (one delirium assessment per day in the ICU in ≥90% of participants). We also evaluated the incidence of intraoperative awareness in one site using serial Brice questionnaires. Results Of 800 patients undergoing cardiac surgery during the trial period, 127/800 (15.9%) had delirium. Of these, 355/389 (91.3%) received benzodiazepines during the liberal benzodiazepine periods and 363/411 (88.3%) did not receive benzodiazepines during the restricted benzodiazepine periods. Amongst the 800 patients, 740 (92.5%) had ≥1 postoperative delirium assessment per day in the ICU. Of 521 patients screened for intraoperative awareness, one patient (0.2%), managed during the restricted benzodiazepine period (but who received benzodiazepine), experienced intraoperative awareness. Conclusions This pilot study demonstrates the feasibility of a large, multicentre, randomised, cluster crossover trial examining whether an institutional policy of restricted vs liberal benzodiazepine use during cardiac surgery will reduce postoperative delirium. Clinical trial registration NCT03053869.

Aims Data on patient characteristics, prevalence, and outcomes of atrial fibrillation (AF) patients without traditional risk factors, often labelled ‘lone AF’, are sparse. Methods and results The RE-LY AF registry included 15 400 individuals who presented to emergency departments with AF in 47 countries. This analysis focused on patients without traditional risk factors, including age ≥60 years, hypertension, coronary artery disease, heart failure, left ventricular hypertrophy, congenital heart disease, pulmonary disease, valve heart disease, hyperthyroidism, and prior cardiac surgery. Patients without traditional risk factors were compared with age- and region-matched controls with traditional risk factors (1:3 fashion). In 796 (5%) patients, no traditional risk factors were present. However, 98% (779/796) had less-established or borderline risk factors, including borderline hypertension (130–140/80–90 mmHg; 47%), chronic kidney disease (eGFR 30; 19%), diabetes (5%), excessive alcohol intake (>14 units/week; 4%), and smoking (25%). Compared with patients with traditional risk factors (n = 2388), patients without traditional risk factors were more often men (74% vs. 59%, P Conclusion Almost all patients without traditionally defined AF risk factors have less-established or borderline risk factors. These patients have a favourable 1-year prognosis, but risk of AF-related re-hospitalization remains high. Greater emphasis should be placed on recognition and management of less-established or borderline risk factors.

Aims To examine the rates of venous thromboembolism (VTE) in high-income, upper middle-income, and lower middle/low-income countries (World Bank Classification). Methods and results We examined the rates of VTE in high-income, upper middle-income, and lower middle/low-income countries (World Bank Classification) in a cohort derived from four prospective international studies (PURE, HOPE-3, ORIGIN, and COMPASS). The primary outcome was a composite of pulmonary embolism, deep vein thrombosis, and thrombophlebitis. We calculated age- and sex-standardized incidence rates (per 1000 person-years) and used a Cox frailty model adjusted for covariates to examine associations between the incidence of VTE and country income level. A total of 215 307 individuals (1.5 million person-years of follow-up) from high-income (n = 60 403), upper middle-income (n = 42 066), and lower middle/low-income (n = 112 838) countries were included. The age- and sex-standardized incidence rates of VTE per 1000 person-years in high-, upper middle-, and lower middle/low-income countries were 0.87, 0.25, and 0.06, respectively. After adjusting for age, body mass index (BMI), smoking, antiplatelet therapy, anticoagulant therapy, education level, ethnicity, and incident cancer diagnosis or hospitalization, individuals from high-income and upper middle-income countries had a significantly higher risk of VTE than those from lower middle/low-income countries [hazard ratio (HR) 3.57, 95% confidence interval (CI) 2.40–5.30 and HR 2.27, 95% CI 1.59–3.23, respectively]. The effect of country income level on VTE risk was markedly stronger in people with a lower BMI, hypertension, diabetes, non-White ethnicity, and higher education. Conclusion The rates of VTE are substantially higher in high-income than in low-income countries. The factors underlying the increased VTE risk in higher-income countries remain unknown.

The stepped-wedge (SW) cluster randomized controlled trial, in which clusters cross over in a randomized sequence from control to intervention, is ideal for the implementation and testing of complex health service interventions. In certain cases however, implementation of the intervention may pose logistical challenges, and variations in SW design may be required. We examine the logistical and statistical implications of variations in SW design using the optimization of the Patient-Centered Care Transitions in Heart Failure trial for illustration. We review the following complete SW design variations: a typical SW design; an SW design with multiple clusters crossing over per period to achieve balanced cluster sizes at each step; hierarchical randomization to account for higher-level clustering effects; nested substudies to measure outcomes requiring a smaller sample size than the primary outcomes; and hybrid SW design, which combines parallel cluster with SW design to improve efficiency. We also reviewed 3 incomplete SW design variations in which data are collected in some but not all steps to ease measurement burden. These include designs with a learning period that improve fidelity to the intervention, designs with reduced measurements to minimize collection burden, and designs with early and late blocks to accommodate cluster readiness. Variations in SW design offer pragmatic solutions to logistical challenges but have implications to statistical power. Advantages and disadvantages of each variation should be considered before finalizing the design of an SW randomized controlled trial.

BACKGROUND Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to >= 70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.)

OBJECTIVE Diabetes is a major risk factor for renal function decline and failure. The availability of multiplex panels of biochemical markers provides the opportunity to identify novel biomarkers that can better predict changes in renal function than routinely available clinical markers. RESEARCH DESIGN AND METHODS The concentration of 239 biochemical markers was measured in stored serum from participants in the biomarker substudy of Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Repeated-measures mixed-effects models were used to compute the annual change in eGFR (measured as mL/min/1.73 m2/year) for the 7,482 participants with a recorded baseline and follow-up eGFR. Linear regression models using forward selection were used to identify the independent biomarker determinants of the annual change in eGFR after accounting for baseline HbA1c, baseline eGFR, and routinely measured clinical risk factors. The incidence of the composite renal outcome (i.e., renal replacement therapy, renal death, renal failure, albuminuria progression, doubling of serum creatinine) and death within each fourth of change in eGFR predicted from these models was also estimated. RESULTS During 6.2 years of median follow-up, the median annual change in eGFR was −0.18 mL/min/1.73 m2/year. Fifteen biomarkers independently predicted eGFR decline after accounting for cardiovascular risk factors, as did 12 of these plus 1 additional biomarker after accounting for renal risk factors. Every 0.1 mL/min/1.73 m2 predicted annual fall in eGFR predicted a 13% (95% CI 12, 14%) higher mortality. CONCLUSIONS Adding up to 16 biomarkers to routinely measured clinical risk factors improves the prediction of annual change in eGFR in people with dysglycemia.

ObjectiveTo assess whether long-term treatment with candesartan/hydrochlorothiazide, rosuvastatin, or their combination can slow cognitive decline in older people at intermediate cardiovascular risk.MethodsThe Heart Outcomes Prevention Evaluation-3 (HOPE-3) study was a double-blind, randomized, placebo-controlled clinical trial using a 2 × 2 factorial design. Participants without known cardiovascular disease or need for treatment were randomized to candesartan (16 mg) plus hydrochlorothiazide (12.5 mg) or placebo and to rosuvastatin (10 mg) or placebo. Participants who were ≥70 years of age completed the Digit Symbol Substitution Test (DSST), the modified Montreal Cognitive Assessment, and the Trail Making Test Part B at baseline and study end.ResultsCognitive assessments were completed by 2,361 participants from 228 centers in 21 countries. Compared with placebo, candesartan/hydrochlorothiazide reduced systolic blood pressure by 6.0 mm Hg, and rosuvastatin reduced low-density lipoprotein cholesterol by 24.8 mg/dL. Participants were followed up for 5.7 years (median), and 1,626 completed both baseline and study-end assessments. Mean participant age was 74 years (SD ±3.5 years); 59% were women; 45% had hypertension; and 24% had ≥12 years of education. The mean difference in change in DSST scores was −0.91 (95% confidence interval [CI] −2.25 to 0.42) for candesartan/hydrochlorothiazide compared with placebo, −0.54 (95% CI −1.88 to 0.80) for rosuvastatin compared with placebo, and −1.43 (95% CI −3.37 to 0.50) for combination therapy vs double placebo. No significant differences were found for other measures.ConclusionsLong-term blood pressure lowering with candesartan plus hydrochlorothiazide, rosuvastatin, or their combination did not significantly affect cognitive decline in older people.ClinicalTrials.gov identifierNCT00468923.Classification of evidenceThis study provides Class II evidence that for older people, candesartan plus hydrochlorothiazide, rosuvastatin, or their combination does not significantly affect cognitive decline.

Importance The relative safety and patency of skeletonized vs pedicled internal mammary artery grafts in patients undergoing coronary artery bypass graft (CABG) surgery are unknown. Objective To investigate the association of skeletonized vs pedicled harvesting with internal mammary artery graft patency and clinical outcomes 1 year after CABG surgery. Design, setting, and participants This study was a post hoc analysis of the multicenter, randomized, double-blind, placebo-controlled Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) clinical trial, which enrolled 27 395 patients from 602 centers in 33 countries from March 2013 through May 2016. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 grafts implanted and an estimated glomerular filtration rate of at least 30 mL/min. A total of 1002 of 1448 patients were randomized to the CABG arm of the COMPASS trial and underwent skeletonized (282 [28.1%]) or pedicled (720 [71.9%]) internal mammary artery harvesting. The patients had evaluable angiography results 1 year after surgery. Data were analyzed from October 11, 2019, to May 14, 2020. Interventions Patients underwent graft harvesting with either the pedicled technique or skeletonized technique. Main outcomes and measures The primary outcome was graft occlusion 1 year after CABG surgery, as assessed by computed tomography angiography. Results A total of 1002 patients underwent skeletonized (282 [28.1%]; mean [SD] age, 65.9 [8.1] years; 229 men [81.2%]; 194 White patients [68.8%]) or pedicled (720 [71.9%]; mean [SD] age, 64.8 [7.6] years; 603 men [83.8%]; 455 White patients [63.2%]) internal mammary artery harvesting. Rates of internal mammary artery graft occlusion 1 year after CABG surgery were higher in the skeletonized group than in the pedicled group (33 of 344 [9.6%] vs 30 of 764 [3.9%]; graft-level adjusted odds ratio, 2.41; 95% CI, 1.39-4.20; P = .002), including the left internal mammary artery to left anterior descending artery (21 of 289 [7.3%] vs 25 of 725 [3.4%]; graft-level adjusted odds ratio, 2.10; 95% CI, 1.14-3.88, P = .02). After a mean follow-up of 23 months, skeletonized graft harvesting was also associated with a higher rate of major adverse cardiovascular events (20 [7.1%] vs 15 [2.1%]; adjusted hazard ratio, 3.19; 95% CI, 1.53-6.67; P = .002) and repeated revascularization (14 [5.0%] vs 10 [1.4%]; adjusted hazard ratio, 2.75; 95% CI, 1.10-6.88; P = .03). Conclusions and relevance This post hoc analysis of the COMPASS randomized clinical trial found that harvesting of the internal mammary artery during CABG surgery using a skeletonized technique was associated with a higher rate of graft occlusion and worse clinical outcomes than the traditional pedicled technique. Future randomized clinical trials are needed to establish the safety and patency of the skeletonized technique. Trial registration ClinicalTrials.gov Identifier: NCT01776424.

Background Patients with recent coronary artery bypass graft (CABG) surgery are at risk for early graft failure, which is associated with a risk of myocardial infarction and death. In the COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) trial, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced the primary major adverse cardiovascular events (MACE) outcome of cardiovascular death, stroke, or myocardial infarction. Rivaroxaban 5 mg twice daily alone did not significantly reduce MACE. Objectives This pre-planned substudy sought to determine whether the COMPASS treatments are more effective than aspirin alone for preventing graft failure and MACE after CABG surgery. Methods The substudy randomized 1,448 COMPASS trial patients 4 to 14 days after CABG surgery to receive the combination of rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone. The primary outcome was graft failure, diagnosed by computed tomography angiogram 1 year after surgery. Results The combination of rivaroxaban and aspirin and the regimen of rivaroxaban alone did not reduce the graft failure rates compared with aspirin alone (combination vs. aspirin: 113 [9.1%] vs. 91 [8.0%] failed grafts; odds ratio [OR]: 1.13; 95% confidence interval [CI]: 0.82 to 1.57; p = 0.45; rivaroxaban alone vs. aspirin: 92 [7.8%] vs. 92 [8.0%] failed grafts; OR: 0.95; 95% CI: 0.67 to 1.33; p = 0.75). Compared with aspirin, the combination was associated with fewer MACE (12 [2.4%] vs. 16 [3.5%]; hazard ratio [HR]: 0.69; 95% CI: 0.33 to 1.47; p = 0.34), whereas rivaroxaban alone was not (16 [3.3%] vs. 16 [3.5%]; HR: 0.99, CI: 0.50 to 1.99; p = 0.98). There was no fatal bleeding or tamponade within 30 days of randomization. Conclusions The combination of rivaroxaban 2.5 mg twice daily plus aspirin or rivaroxaban 5 mg twice daily alone compared with aspirin alone did not reduce graft failure in patients with recent CABG surgery, but the combination of rivaroxaban 2.5 mg twice daily plus aspirin was associated with similar reductions in MACE, as observed in the larger COMPASS trial. (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS [COMPASS]; NCT01776424)

Introduction Heart Failure (HF) is a common cause of hospitalization in older adults. The transition from hospital to home is high-risk, and gaps in transitional care can increase the risk of re-hospitalization and death. Combining health care services supported by meta-analyses, we designed the PACT-HF transitional care model. Methods Adopting an integrated Knowledge Translation (iKT) approach in which decision-makers and clinicians are partners in research, we implement and test the effectiveness of PACT-HF among patients hospitalized for HF. We use a pragmatic stepped wedge cluster randomized trial design to introduce the complex health service intervention to 10 large hospitals in a randomized sequence until all hospitals initiate the intervention. The goal is for all patients hospitalized with HF to receive self-care education, multidisciplinary care, and early follow-up with their health care providers; and in addition, for high-risk patients to receive post-discharge nurse-led home visits and outpatient care in Heart Function clinics. This requires integration of care across hospitals, home care agencies, and outpatient clinics in our publicly funded health care system. While hospitals are the unit of recruitment and analysis, patients (estimated sample size of 3200) are the unit of analysis. Primary outcomes are hierarchically ordered as time to composite all-cause readmissions / emergency department (ED) visits / death at 3 months and time to composite all-cause readmissions / ED visits at 30 days. In a nested study of 8 hospitals, we measure the patient-centered outcomes of Discharge Preparedness, Care Transitions Quality, and Quality Adjusted Life Years (QALY); and the 6-month health care resource use and costs. We obtain all clinical and cost outcomes via linkages to provincial administrative databases. Conclusions This protocol describes the implementation and testing of a transitional care model comprising health care services informed by high-level evidence. The study adopts an iKT and pragmatic approach, uses a robust study design, links clinical trial data with outcomes held in administrative databases, and includes patient-reported outcomes. Findings will have implications on clinical practice, health care policy, and Knowledge Translation (KT) research methodology.

Increasingly, clinicians and researchers recognize that studies of interventions need to evaluate not only their therapeutic efficacy (i.e., the effect on an outcome in ideal, controlled settings) but also their real-world effectiveness in broad, unselected patient groups. Effectiveness trials inform clinical practice by comparing variations in therapeutic approaches that fall within the standard of care. In this article, we discuss the need for studies of comparative effectiveness in anesthesia and the limitations of individual patient randomized-controlled trials in determining comparative effectiveness. We introduce the concept of randomized cluster crossover trials as a means of answering questions of comparative effectiveness in anesthesia, using the design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial (Clinicaltrials.gov identifier NCT03053869).

Introduction: Fibrinolytic factors, plasminogen activator inhibitor-1, tissue plasminogen activator, tissue plasminogen activator/plasminogen activator-complex and the haemostatic factor von Willebrand factor are known markers of cardiovascular disease. Their plasma levels are adversely affected in patients with dysglycaemia, and glucose normalization with insulin glargine might improve the levels of these factors. Methods: Prespecified Swedish substudy of the Outcome Reduction with an Initial Glargine Intervention trial (ClinicalTrials.gov number, NCT00069784). Tissue plasminogen activator activity, tissue plasminogen activator antigen, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor were analysed at study start, after 2 years and at the end of the study (median follow-up of 6.2 years). Results: Of 129 patients (mean age of 64 ± 7 years, females: 19%), 68 (53%) and 61 (47%) were randomized to the insulin glargine and standard care group, respectively. Allocation to insulin glargine did not significantly affect the studied fibrinolytic markers or von Willebrand factor compared to standard care. Likewise, there were no significant differences in plasminogen activator inhibitor-1, tissue plasminogen activator antigen and von Willebrand factor. During the whole study period, the within-group analysis revealed a curvilinear pattern and significant changes for tissue plasminogen activator/plasminogen activator inhibitor-1 complex, tissue plasminogen activator antigen and von Willebrand factor in the insulin glargine but not in the standard care group. Conclusion: In people with dysglycaemia and other cardiovascular risk factors, basal insulin does not improve the levels of markers of fibrinolysis or von Willebrand factor compared to standard glucose-lowering treatments.

In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable. Yet the benefits of relying on real-world data sources must be weighed against difficulties with ensuring data integrity and completeness. Additionally, appropriately monitoring patient safety in randomized trials of new drugs using healthcare system data that might not be available in real time can be quite difficult. Recognizing that these and other concerns are critical to the development and acceptability of PCTs, a group of stakeholders from academia, industry, professional organizations, regulatory bodies, government agencies, and patient advocates discussed a path forward for PCT growth and sustainability at a think tank meeting entitled "Monitoring and Analyzing Data from Pragmatic Streamlined Randomized Clinical Trials," which took place in January 2019 (Washington, DC). The goals of this meeting were to: (1) evaluate study design and methodological options specific to PCTs that have the potential to yield high-quality evidence; (2) discuss best practices to ensure data quality in PCTs; and (3) identify appropriate methods for study monitoring. Proceedings from the think tank meeting are summarized in this manuscript.

Background Risk prediction models in heart failure (HF) are typically complex, derived retrospectively from administrative databases, and modest in their ability to discriminate between high, medium, and low risk categories. The complexity of these models makes them difficult to use at the point of care. Purpose To determine if a simple risk index using Length of hospital stay (L), number of Emergency department visits in the preceding 6 months (E), and either admission or discharge N-Terminal (NT) prohormone of Brain Natriuretic Peptide (pro-BNP) at the point of care can predict 30-day readmissions in patients hospitalized for HF. Methods This is a sub-study of the Patient-Centered Care Transitions in HF (PACT-HF) stepped-wedge cluster randomized trial. We included 772 patients hospitalized for HF at 10 Canadian hospitals. We used log-binomial regression models with Length of stay, Emergency department visits in the preceding 6 months, and either admission or discharge N-Terminal prohormone of Brain Natriuretic Peptide (NT-pro-BNP) as the predictor variables and 30-day all-cause readmission as the outcome. We derived the LENT risk score from the β-coefficients of the regression model (Fig. 1). All the models were adjusted for post-discharge services. We assessed model discrimination with C-statistics and model calibration with the net reclassification index (NRI). We used the bootstrapping approach with 100 runs for internal validation. Results The LENT index had a possible score ranging from 1 to 13 (Fig 1). Increments in the LENT risk score were associated with an increased risk of 30-day readmission; a 1-point increase in the LENT index using the admission and discharge NT-pro-BNP predicted a 23% and 19% increase in 30-day readmission risk, respectively. The internal validation produced similar results. Compared to a null model, the LE index had an NRI of 0.35 [95% CI 0.18, 0.53], and admission and discharge NT-pro-BNP further improved calibration of the LE index (NRI 0.15 [95% CI 0, 0.32] and 0.20 [95% CI 0.03, 0.37], respectively). The LENT index offered modest discrimination for 30-day readmission (C-statistic 0.64 [95% CI 0.59, 0.69]), similar to more complex risk models. Figure 1. The LENT index scoring system Conclusion A simple risk index based on Length of stay, Emergent visits, and NT-pro-BNP at the point of care can reliably predict 30-day readmissions. The LENT index offers ease of use over traditional risk prediction models. Acknowledgement/Funding Canadian Institutes of Health Research, Ontario MOHLTC, Roche Diagnostics

Summary Background In non-surgical settings, covert stroke is more common than overt stroke and is associated with cognitive decline. Although overt stroke occurs in less than 1% of adults after non-cardiac surgery and is associated with substantial morbidity, we know little about perioperative covert stroke. Therefore, our primary aim was to investigate the relationship between perioperative covert stroke (ie, an acute brain infarct detected on an MRI after non-cardiac surgery in a patient with no clinical stroke symptoms) and cognitive decline 1 year after surgery. Methods NeuroVISION was a prospective cohort study done in 12 academic centres in nine countries, in which we assessed patients aged 65 years or older who underwent inpatient, elective, non-cardiac surgery and had brain MRI after surgery. Two independent neuroradiology experts, masked to clinical data, assessed each MRI for acute brain infarction. Using multivariable regression, we explored the association between covert stroke and the primary outcome of cognitive decline, defined as a decrease of 2 points or more on the Montreal Cognitive Assessment from preoperative baseline to 1-year follow-up. Patients, health-care providers, and outcome adjudicators were masked to MRI results. Findings Between March 24, 2014, and July 21, 2017, of 1114 participants recruited to the study, 78 (7%; 95% CI 6–9) had a perioperative covert stroke. Among the patients who completed the 1-year follow-up, cognitive decline 1 year after surgery occurred in 29 (42%) of 69 participants who had a perioperative covert stroke and in 274 (29%) of 932 participants who did not have a perioperative covert stroke (adjusted odds ratio 1·98, 95% CI 1·22–3·20, absolute risk increase 13%; p=0·0055). Covert stroke was also associated with an increased risk of perioperative delirium (hazard ratio [HR] 2·24, 95% CI 1·06–4·73, absolute risk increase 6%; p=0·030) and overt stroke or transient ischaemic attack at 1-year follow-up (HR 4·13, 1·14–14·99, absolute risk increase 3%; p=0·019). Interpretation Perioperative covert stroke is associated with an increased risk of cognitive decline 1 year after non-cardiac surgery, and perioperative covert stroke occurred in one in 14 patients aged 65 years and older undergoing non-cardiac surgery. Research is needed to establish prevention and management strategies for perioperative covert stroke. Funding Canadian Institutes of Health Research; The Ontario Strategy for Patient Oriented Research support unit; The Ontario Ministry of Health and Long-Term Care; Health and Medical Research Fund, Government of the Hong Kong Special Administrative Region, China; and The Neurological Foundation of New Zealand.

Diabetes is the most common cause of renal failure accounting for more than 50% of cases. Whereas HbA1c, age and albuminuria are independent risk factors for renal decline, adding novel serum biomarkers to routine clinical risk factors may help identify patients at high risk for renal decline. One ml of stored serum from 7,482 ORIGIN participants with a recorded eGFR at baseline and either the 2 year and/or final visit was assayed for 237 biomarkers using Myriad RBM’s customized human discovery multi-analyte profile 250+ panel, and hs troponin and anti-GAD biomarkers were measured locally. During a median follow-up of 6.2 years, 1,646 (22%) developed the renal outcome comprising renal failure, albuminuria regression or doubling of some creatinine. A linear mixed model using a forward selection approach was used to identify the subset of biomarkers that independently predicted a decline in eGFR after accounting for 9 clinical risk factors for renal decline including age, sex, smoking, body mass index, mean arterial pressure, log (albumin:creatinine), cholesterol, baseline eGFR and HbA1c. A Bonferroni-corrected P value for inclusion in the model of less than 0.00021 (i.e., 0.05/239) identified 13 significant and independent biomarkers that included: alpha 1 microglobulin (beta = -0.157); NT-pro BNP (beta = -0.081); IGF binding protein 4 (beta = -0.110); growth differentiation factor 15 (beta = -0.091); RAGE (beta = -0.052); myoglobin (beta = -0.073); growth regulated alpha protein (beta = 0.058); fibulin-1C (beta = -0.048); apolipoprotein A-4 (beta = -0.057); apolipoprotein A-2 (beta = 0.065); fas ligand (beta = -0.099); eotaxin E (beta = -0.052); and beta amyloid 1-40 (beta = -0.057). The addition of these selected biomarkers to the clinical variables improved the variance of the eGFR from 0.053 to 0.155 (difference in log likelihood = 849, P < 0.001). These novel biomarkers are potential therapeutic targets. They can also help identify dysglycemic people at risk for renal decline. (NCT00069784) Disclosure H. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Sanofi. G. Pare: Consultant; Self; Amgen Inc., Bristol-Myers Squibb Company, Lexicomp, Sanofi. Research Support; Self; Canada Research Chair in Genetic and Molecular Epidemiology, CISCO Professorship in Integrated Health Biosystems, Sanofi. M.J. McQueen: None. S. Lee: None. A. Kannt: Employee; Self; Sanofi. S. Hess: None. Funding Sanofi; Innovative Medicines Initiative (115974); European Union; European Federation of Pharmaceutical Industries; JDRF

Aims: Total and free testosterone and sex hormone-binding globulin may affect cardiovascular prognosis in women. The objective was to study the association between sex hormones and prognosis in women with dysglycemia and high cardiovascular risk. Methods: This epidemiological report included dysglycemic women from the Outcome Reduction with an Initial Glargine Intervention trial ( n = 2848) with baseline total testosterone and sex hormone-binding globulin. Free testosterone was calculated with the Vermeulen formula. Cox regression analyses adjusted for variables including age, previous diseases and pharmacological treatments were used to estimate the association between these levels and the composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke) and all-cause mortality per one standard deviation. Results: Patients (73% post-menopausal) were followed for a median of 6.1 years during which 377 cardiovascular events and 389 deaths occurred. In Cox analyses, total and free testosterone were not associated with any outcomes, but sex hormone-binding globulin was related to all-cause mortality in age adjusted (HR 1.15; 95% CI 1.06–1.24; p Conclusions: Increasing levels of baseline sex hormone-binding globulin were associated with an increased risk of all-cause mortality in dysglycemic women at high cardiovascular risk. Trial registration ClinicalTrials.gov no. NCT00069784.

Background The Length of stay, Acuity, Comorbidities, Emergency department visits in prior 6 months (LACE) index threshold of 10 predicts readmission or death in general medical patients in administrative databases. We assessed whether the unadjusted LACE index, computed at the bedside, can predict 30-day outcomes in patients hospitalized for heart failure. Methods We used logistic regression with LACE as the continuous predictor and 30-day readmissions and 30-day readmission or death as outcomes. We determined a suitable LACE threshold using logistic regression and the closest-to-(0,1) criterion for dichotomized LACE scores. We assessed model discrimination with C statistics and 95% CI. Results Of 378 patients, a majority (91%) had LACE scores ≥10. Incremental LACE scores increased the odds of 30-day readmissions (odds ratio [OR] 1.13, 95% CI 1.02-1.24) and 30-day readmissions or death (OR 1.11, 95% CI 1.01-1.22). C statistics for 30-day readmissions (0.59, 95% CI 0.52-0.65) and 30-day readmission or death (0.57, 95% CI 0.51-0.64) were nonsignificantly lower than the Centers for Medicare/Medicaid Services–endorsed readmission risk score (0.61, 95% CI 0.55-0.67 and 0.62, 95% CI 0.55-0.68, respectively). LACE ≥13 predicted 30-day readmissions (OR 1.91, 95% CI 1.17-3.09) and 30-day readmission or death (OR 1.59, 95% CI 1.00-2.54), and met the closest-to-(0,1) criterion for optimal threshold. Conclusions LACE calculated at the bedside predicts 30-day clinical outcomes in hospitalized heart failure patients. While there is a continuum of risk, a threshold of ≥13 is more suitable than ≥10 to identify high-risk patients. Given its modest discrimination, however, we do not recommend its preferential use over validated risk prediction tools such as readmission risk score.

Well-designed randomized controlled trials (RCTs) are the gold standard for informing clinical practice. However, RCTs often do not enroll participants representative of the patient population for whom the tested interventions will be applied. The aim of this study was to estimate the enrolment of

Aims: Testosterone and its binding protein sex hormone-binding globulin have been associated with cardiovascular disease and dysglycaemia. However, information on the prognostic implication in patients at high cardiovascular risk with dysglycaemia is inconsistent. The study objective was to determine whether testosterone and/or sex hormone-binding globulin predict cardiovascular events or death in dysglycaemic patients. Methods: Dysglycaemic males at high cardiovascular risk ( n = 5553) who participated in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial and provided baseline blood samples were studied. Testosterone and sex hormone-binding globulin were measured at baseline and used to estimate free testosterone. Low levels of total and free testosterone were defined as ≤300 ng/dl and ≤7 ng/dl, respectively. Patients were followed for six years for cardiovascular events (defined as the composite of cardiovascular death, non-fatal myocardial infarction or stroke) and all-cause mortality. Results: The mean total and free testosterone levels were 416.6 ng/dl and 8.4 ng/dl, and low levels were present in 13% and 37% of the patients. The median sex hormone-binding globulin level was 35 nmol/l. In Cox regression models adjusted for age, previous diseases and pharmacological treatment, neither total nor free testosterone predicted cardiovascular events. However, a one-standard-deviation increase in sex hormone-binding globulin predicted both cardiovascular events (hazard ratio 1.07; 95% confidence interval 1.00–1.14; p = 0.03) and all-cause mortality (hazard ratio 1.13; 95% confidence interval 1.06–1.21; p Conclusion: Sex hormone-binding globulin, but not total testosterone, predicts cardiovascular disease and all-cause mortality in dysglycaemic males at high cardiovascular risk.

Background A wide range of prophylactic antibiotic regimens are used for patients undergoing open-heart cardiac surgery. This reflects clinical equipoise in choice and duration of antibiotic agents. Although individual-level randomized control trials (RCT) are considered the gold standard when evaluating the efficacy of an intervention, this approach is highly resource intensive and a cluster RCT can be more appropriate for testing clinical effectiveness in a real-world setting. Methods/design We are conducting a factorial cluster-randomized crossover pilot trial in cardiac surgery patients to evaluate the feasibility of this design for a definite trial to evaluate the optimal duration and choice of perioperative antibiotic prophylaxis. Specifically, we will evaluate: (a) the non-inferiority of a single preoperative dose compared to prolonged prophylaxis and (b) the potential superiority of adding vancomycin to routine cefazolin in terms of preventing deep and organ/space sternal surgical site infections (s-SSIs). There are four strategies: (i) short-term cefazolin, (ii) long-term cefazolin, (iii) short-term cefazolin + vancomycin, and (iv) long-term cefazolin + vancomycin. These strategies are delivered in a different order in each health-care center participating in the trial. The centers are randomized to an order, and the current strategy becomes the standard operating procedure in that center during the study. The three feasibility outcomes include: (1) the proportion of patients receiving preoperative, intra-operative, and postoperative antibiotics according to the study protocol, (2) the proportion of completed follow-up assessments, and (3) a full and final assessment of the incidence of s-SSIs by the outcome adjudication committee. Discussion We believe that a cluster-randomized factorial crossover trial is an effective and feasible design for these research questions, allowing an evaluation of the clinical effectiveness in a real-world setting. A waiver of individual informed consent was considered appropriate by the research ethics boards in each participating site in Canada as long as an information letter with an opt-out option was provided. However, a waiver of consent was not approved at two sites in Germany and Switzerland, respectively. Trial registration Clinicaltrials.gov, NCT02285140. Registered on 15 October 2015. Electronic supplementary material The online version of this article (10.1186/s13063-018-3080-y) contains supplementary material, which is available to authorized users.