Improving the prediction of long-term readmission and mortality using a novel biomarker panel.

OBJECTIVE: Several short-term readmission and mortality prediction models have been developed using clinical risk factors or biomarkers among patients undergoing coronary artery bypass graft (CABG) surgery. The use of biomarkers for long-term prediction of readmission and mortality is less well understood. Given the established association of cardiac biomarkers with short-term adverse outcomes, we hypothesized that 5-year prediction of readmission or mortality may be significantly improved using cardiac biomarkers. MATERIALS AND METHODS: Plasma biomarkers from 1149 patients discharged alive after isolated CABG surgery from eight medical centers were measured in a cohort from the Northern New England Cardiovascular Disease Study Group between 2004 and 2007. We assessed the added predictive value of a biomarker panel with a clinical model against the clinical model alone and compared the model discrimination using the area under the receiver operating characteristic (AUROC) curves. RESULTS: In our cohort, 461 (40%) patients were readmitted or died within 5 years. Long-term outcomes were predicted by applying the STS ASCERT clinical model with an AUROC of 0.69. The biomarker panel with the clinical model resulted in a significantly improved AUROC of 0.74 (p value <.0001). Across 5 years, the hazard ratio for patients in the second to fifth quintile predicted probabilities from the biomarker augmented STS ASCERT model ranged from 2.2 to 7.9 (p values <.001). CONCLUSIONS: We report that a panel of biomarkers significantly improved prediction of long-term readmission or mortality risk following CABG surgery. Our findings suggest biomarkers help clinical care teams better assess the long-term risk of readmission or mortality.

Post-operative acute kidney injury is associated with a biomarker of acute brain injury after paediatric cardiac surgery.

INTRODUCTION: Children with CHD who undergo cardiopulmonary bypass are at an increased risk of acute kidney injury. This study evaluated the association of end-organ specific injury plasma biomarkers for brain: glial fibrillary acidic protein and heart: Galectin 3, soluble suppression of tumorgenicity 2, and N-terminal pro b-type natriuretic peptide with acute kidney injury in children undergoing cardiopulmonary bypass. MATERIALS AND METHODS: We enrolled consecutive children undergoing cardiac surgery with cardiopulmonary bypass. Blood samples were collected pre-bypass in the operating room and in the immediate post-operative period. Acute kidney injury was defined as a rise of serum creatinine ≥50% from pre-operative baseline within 7 days after surgery. RESULTS: Overall, 162 children (mean age 4.05 years, sd 5.28 years) were enrolled. Post-operative acute kidney injury developed in 55 (34%) children. Post-operative plasma glial fibrillary acidic protein levels were significantly higher in patients with acute kidney injury (median 0.154 (inter-quartile range 0.059-0.31) ng/ml) compared to those without acute kidney injury (median 0.056 (inter-quartile range 0.001-0.125) ng/ml) (p = 0.043). After adjustment for age, weight, and The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category, each natural log increase in post-operative glial fibrillary acidic protein was significantly associated with a higher risk for subsequent acute kidney injury (adjusted odds ratio glial fibrillary acidic protein 1.25; 95% confidence interval 1.01-1.59). Pre/post-operative levels of galectin 3, soluble suppression of tumorgenicity 2, and N-terminal pro b-type natriuretic peptide did not significantly differ between patients with and without acute kidney injury. CONCLUSIONS: Higher plasma glial fibrillary acidic protein levels measured in the immediate post-operative period were independently associated with subsequent acute kidney injury in children after cardiopulmonary bypass. Elevated glial fibrillary acidic protein likely reflects intraoperative brain injury which may occur in the context of acute kidney injury-associated end-organ dysfunction.

sST2 as a novel biomarker for the prediction of in-hospital mortality after coronary artery bypass grafting.

Objectives: Soluble suppression of tumorigenicity 2 (sST2) biomarker is an emerging predictor of adverse clinical outcomes, but its prognostic value for in-hospital mortality after coronary artery bypass grafting (CABG) is not well understood. This study measured the association between operative sST2 levels and in-hospital mortality after CABG. Methods: A prospective cohort of 1560 CABG patients were analyzed from the Northern New England Cardiovascular Disease Study Group Biomarker Study. The primary outcome was in-hospital mortality after CABG surgery (n = 32). Results: After risk adjustment, patients in the third tercile of pre-, post- and pre-to-postoperative sST2 values experienced significantly greater odds of in-hospital death compared to patients in the first tercile of sST2 values. The addition of both postoperative and pre-to-postoperative sST2 biomarker significantly improved ability to predict in-hospital mortality status following CABG surgery, compared to using the EuroSCORE II mortality model alone, (c-statistic: 0.83 [95% CI: 0.75, 0.92], p value 0.0213) and (c-statistic: 0.83 [95% CI: 0.75, 0.92], p value 0.0215), respectively. Conclusion: sST2 values are associated with in-hospital mortality after CABG surgery and postoperative and pre-to-post operative sST2 values improve prediction. Our findings suggest that sST2 can be used as a biomarker to identify adult patients at greatest risk of in-hospital death after CABG surgery.

Biomarkers associated with 30-day readmission and mortality after pediatric congenital heart surgery.

OBJECTIVES: Novel cardiac biomarkers serum (suppression of tumorigenicity [ST2]) and Galectin-3 may be associated with an increased likelihood of important events after cardiac surgery. Our objective was to explore the association between pre- and postoperative serum biomarker levels and 30-day readmission or mortality for pediatric patients. METHODS: We prospectively enrolled pediatric patients <18 years of age who underwent at least one cardiac surgical operation at Johns Hopkins Children's Center from 2010 to 2014 (N = 162). Blood samples were collected immediately before surgery and at the end of bypass. We evaluated the association between pre- and postoperative Galectin-3 and ST2 with 30-day readmission or mortality, using backward stepwise logistic regression, adjusting for covariates based on the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Mortality Risk Model. RESULTS: In our cohort, 21 (12.9%) patients experienced readmission or mortality 30-days from discharge. Before adjustment, preoperative ST2 terciles demonstrated a strong association with readmission and/or mortality after surgery (OR: 2.58; 95% CI: 1.17-3.66 and OR: 4.37; 95% CI: 1.31-14.57). After adjustment for covariates based on the STS congenital risk model, Galectin-3 postoperative mid-tercile was significantly associated with 30-day readmission or mortality (OR: 6.17; 95% CI: 1.50-0.43) as was the highest tercile of postoperative ST2 (OR: 4.98; 95% CI: 1.06-23.32). CONCLUSIONS: Elevated pre-and postoperative levels of ST2 and Galectin-3 are associated with increased risk of readmission or mortality after pediatric heart surgery. These clinically available biomarkers can be used for improved risk stratification and may guide improved patient care management.

Biomarkers improve prediction of 30-day unplanned readmission or mortality after paediatric congenital heart surgery.

OBJECTIVE: To evaluate the association between novel pre- and post-operative biomarker levels and 30-day unplanned readmission or mortality after paediatric congenital heart surgery. METHODS: Children aged 18 years or younger undergoing congenital heart surgery (n = 162) at Johns Hopkins Hospital from 2010 to 2014 were enrolled in the prospective cohort. Collected novel pre- and post-operative biomarkers include soluble suppression of tumorgenicity 2, galectin-3, N-terminal prohormone of brain natriuretic peptide, and glial fibrillary acidic protein. A model based on clinical variables from the Society of Thoracic Surgery database was developed and evaluated against two augmented models. RESULTS: Unplanned readmission or mortality within 30 days of cardiac surgery occurred among 21 (13%) children. The clinical model augmented with pre-operative biomarkers demonstrated a statistically significant improvement over the clinical model alone with a receiver-operating characteristics curve of 0.754 (95% confidence interval: 0.65-0.86) compared to 0.617 (95% confidence interval: 0.47-0.76; p-value: 0.012). The clinical model augmented with pre- and post-operative biomarkers demonstrated a significant improvement over the clinical model alone, with a receiver-operating characteristics curve of 0.802 (95% confidence interval: 0.72-0.89; p-value: 0.003). CONCLUSIONS: Novel biomarkers add significant predictive value when assessing the likelihood of unplanned readmission or mortality after paediatric congenital heart surgery. Further exploration of the utility of these novel biomarkers during the pre- or post-operative period to identify early risk of mortality or readmission will aid in determining the clinical utility and application of these biomarkers into routine risk assessment.

The Association between Cytokines and 365-Day Readmission or Mortality in Adult Cardiac Surgery.

Cardiac surgery results in a multifactorial systemic inflammatory response with inflammatory cytokines, such as interleukin-10 and 6 (IL-10 and IL-6), shown to have potential in the prediction of adverse outcomes including readmission or mortality. This study sought to measure the association between IL-6 and IL-10 levels and 1-year hospital readmission or mortality following cardiac surgery. Plasma biomarkers IL-6 and IL-10 were measured in 1,047 patients discharged alive after isolated coronary artery bypass graft surgery from eight medical centers participating in the Northern New England Cardiovascular Disease Study Group between 2004 and 2007. Readmission status and mortality were ascertained using Medicare, state all-payer claims, and the National Death Index. We evaluated the association between preoperative and postoperative cytokines and 1-year readmission or mortality using Kaplan-Meier estimates and Cox's proportional hazards modeling, adjusting for covariates used in the Society of Thoracic Surgeons 30-day readmission model. The median follow-up time was 1 year. After adjustment, patients in the highest tertile of postoperative IL-6 values had a significantly increased risk of readmission or death within 1 year (HR: 1.38; 95% CI: 1.03-1.85), and an increased risk of death within 1 year of discharge (HR: 4.88; 95% CI: 1.26-18.85) compared with patients in the lowest tertile. However, postoperative IL-10 levels, although increasing through tertiles, were not found to be significantly associated independently with 1-year readmission or mortality (HR: 1.25; 95% CI: .93-1.69). Pro-inflammatory cytokine IL-6 and anti-inflammatory cytokine IL-10 may be postoperative markers of cardiac injury, and IL-6, specifically, shows promise in predicting readmission and mortality following cardiac surgery.

Elevated preoperative Galectin-3 is associated with acute kidney injury after cardiac surgery.

BACKGROUND: Previous research suggests that novel biomarkers may be used to identify patients at increased risk of acute kidney injury following cardiac surgery. The purpose of this study was to evaluate the relationship between preoperative levels of circulating Galectin-3 (Gal-3) and acute kidney injury after cardiac surgery. METHODS: Preoperative serum Gal-3 was measured in 1498 patients who underwent coronary artery bypass graft (CABG) surgery and/or valve surgery as part of the Northern New England Biomarker Study between 2004 and 2007. Preoperative Gal-3 levels were measured using multiplex assays and grouped into terciles. Univariate and multinomial logistic regression was used to assess the predictive ability of Gal-3 terciles and AKI occurrence and severity. RESULTS: Before adjustment, patients in the highest tercile of Gal-3 had a 2.86-greater odds of developing postoperative KDIGO Stage 2 or 3 (p < 0.001) and 1.70-greater odds of developing KDIGO Stage 1 (p = < 0.001), compared to the first tercile. After adjustment, patients in the highest tercile had 2.95-greater odds of developing KDIGO Stage 2 or 3 (p < 0.001) and 1.71-increased odds of developing KDIGO Stage 1 (p = 0.001), compared to the first tercile. Compared to the base model, the addition of Gal-3 terciles improved discriminatory power compared to without Gal-3 terciles (test of equality = 0.042). CONCLUSION: Elevated preoperative Gal-3 levels significantly improves predictive ability over existing clinical models for postoperative AKI and may be used to augment risk information for patients at the highest risk of developing AKI and AKI severity after cardiac surgery.

Variation in Utilization and Need for Tympanostomy Tubes across England and New England.

OBJECTIVES: To compare rates of typmanostomy tube insertions for otitis media with effusion with estimates of need in 2 countries. STUDY DESIGN: This cross-sectional analysis used all-payer claims to calculate rates of tympanostomy tube insertions for insured children ages 2-8 years (2007-2010) across pediatric surgical areas (PSA) for Northern New England (NNE; Maine, Vermont, and New Hampshire) and the English National Health Service Primary Care Trusts (PCT). Rates were compared with expected rates estimated using a Monte Carlo simulation model that integrates clinical guidelines and published probabilities of the incidence and course of otitis media with effusion. RESULTS: Observed rates of tympanostomy tube placement varied >30-fold across English PCT (N = 150) and >3-fold across NNE PSA (N = 30). At a 25 dB hearing threshold, the overall difference in observed to expected tympanostomy tubes provided was -3.41 per 1000 child-years in England and -0.01 per 1000 child-years in NNE. Observed incidence of insertion was less than expected in 143 of 151 PCT, and was higher than expected in one-half of the PSA. Using a 20 dB hearing threshold, there were fewer tube insertions than expected in all but 2 England and 7 NNE areas. There was an inverse relationship between estimated need and observed tube insertion rates. CONCLUSIONS: Regional variations in observed tympanostomy tube insertion rates are unlikely to be due to differences in need and suggest overall underuse in England and both overuse and underuse in NNE.

Population-Based Estimates of the Prevalence of Children With Congenital Heart Disease and Associated Comorbidities in the United States.

BACKGROUND: Congenital heart defects (CHD) are the most common birth defects and previous estimates report the disease affects 1% of births annually in the United States. To date, CHD prevalence estimates are inconsistent due to varied definitions, data reliant on birth registries, and are geographically limited. These data sources may not be representative of the total prevalence of the CHD population. It is therefore important to derive high-quality, population-based estimates of the prevalence of CHD to help care for this vulnerable population. METHODS: We performed a descriptive, retrospective 8-year analysis using all-payer claims data from Colorado from 2012 to 2019. Children with CHD were identified by applying International Classification of Diseases-Ninth Revision (ICD-9) and International Classification of Diseases-Tenth Revision (ICD-10) diagnosis codes from the American Heart Association-American College of Cardiology harmonized cardiac codes. We included children with CHD <18 years of age who resided in Colorado, had a documented zip code, and had at least 1 health care claim. CHD type was categorized as simple, moderate, and severe disease. Association with comorbid conditions and genetic diagnoses were analyzed using χ2 test. We used direct standardization to calculate adjusted prevalence rates, controlling for age, sex, primary insurance provider, and urban-rural residence. RESULTS: We identified 1 566 328 children receiving care in Colorado from 2012 to 2019. Of those, 30 512 children had at least 1 CHD diagnosis, comprising 1.95% (95% CI, 1.93-1.97) of the pediatric population. Over half of the children with CHD also had at least 1 complex chronic condition. After direct standardization, the adjusted prevalence rates show a small increase in simple severity diagnoses across the study period (adjusted rate of 11.5 [2012]-14.4 [2019]; P<0.001). CONCLUSIONS: The current study is the first population-level analysis of pediatric CHD in the United States. Using administrative claims data, our study found a higher CHD prevalence and comorbidity burden compared with previous estimates.

Cardiac Biomarkers Associated With Hospital Length of Stay After Pediatric Congenital Heart Surgery.

BACKGROUND: Prolonged hospital length of stay after congenital heart surgery is a significant cost burden and is associated with postoperative morbidity. Our goal was to evaluate the association between pre- and postoperative biomarker levels and in-hospital length of stay for children after congenital heart surgery. METHODS: We enrolled patients <18 years of age who underwent at least 1 congenital heart operation at Johns Hopkins Hospital from 2010 to 2014. Blood samples were collected before the index operation and at the end of the bypass. ST2 and N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements were evaluated as log-transformed, median, and tercile cut-points. We evaluated the association between pre- and postoperative NT-proBNP and ST2 measurements with in-hospital postoperative length of stay using multivariate logistic regression. We adjusted for covariates used in The Society of Thoracic Surgeons Congenital Heart Surgery Mortality Risk Model. RESULTS: In our cohort 45% of our patients had an in-hospital postoperative length of stay longer than the median. Before adjustment preoperative NT-proBNP above the population median and the highest tercile exhibited a significantly longer in-hospital length of stay. After adjustment for covariates in the risk model, pre- and postoperative ST2 and NT-proBNP demonstrated a significantly longer length of stay. CONCLUSIONS: Perioperative ST2 and NT-proBNP had a significant association with increased postoperative in-hospital length of stay before and after adjustment. ST2 in particular could be used to guide an earlier assessment of patient risk for complications that may lead to adverse outcomes.

Galectin-3 as a Predictor of Long-term Survival After Isolated Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Galectin-3 (Gal-3) is a well-established biomarker of adverse clinical outcomes, but its prognostic value for long-term survival after cardiac surgery is not well understood. Elevated levels of Gal-3 have been found to be remarkably associated with higher risk of death in both acute decompensated and chronic heart failure populations. Its prognostic value for long-term survival after cardiac surgery is not known. METHODS: A sample of patients contributing to the Northern New England Cardiovascular Disease Study Group Cardiac Surgery Registry from 2004 to 2007 were enrolled in a prospective biomarker cohort (N = 1690). Preoperative Gal-3 levels were measured and categorized by quartile. We used Kaplan-Meier survival analysis and Cox regression models, adjusting for variables in The Society of Thoracic Surgeons Collaboration on the Comparative Effectiveness of Revascularization Strategy probability calculator to evaluate the association between elevated Gal-3 levels and survival to 6 years. RESULTS: Preoperative Gal-3 levels ranged from 1.72 to 28.89 ng/mL (mean, 8.96 ng/mL; median, 8.06 ng/mL; interquartile range, 5.42-11.08 ng/mL). Crude survival decreased by increasing quartile. After adjustment, serum levels of Gal-3 in the highest quartile of the cohort were associated with significantly decreased survival compared with the lowest quartile (hazard ratio [HR] 2.22; 95% confidence interval [CI], 1.40-3.54; P = .001). No decrease in survival was found for the middle quartiles (HR 1.36; 95% CI, 0.87-2.12; P = .177). CONCLUSIONS: A substantial association was found between elevated preoperative Gal-3 levels and risk of mortality after isolated coronary artery bypass grafting surgery. An assessment of the relationship between preoperative serum biomarkers and long-term survival can be used for risk stratification or estimating postsurgical prognosis.

Novel Biomarkers Improve Prediction of 365-Day Readmission After Pediatric Congenital Heart Surgery.

BACKGROUND: The purpose of this study was to evaluate the association between preoperative biomarker levels and 365-day readmission or mortality after pediatric congenital heart surgery. METHODS: Children aged 18 years or younger undergoing congenital heart surgery (n = 145) at Johns Hopkins Hospital from 2010 to 2014 were enrolled in the prospective cohort. Novel biomarkers suppression of tumorgenicity 2, galectin-3, N-terminal prohormone brain natriuretic peptide, and glial fibrillary acidic protein were measured. The composite study endpoint was unplanned readmission within 365 days after discharge or mortality either in hospital during the surgical admission or within 365 days after discharge. A clinical model based on covariates used in The Society of Thoracic Surgeons Congenital Heart Surgery Database mortality risk model and an augmented model using the clinical model in conjunction with a novel biomarker panel were evaluated. RESULTS: Readmission or mortality within 365 days of surgery occurred among 39 pediatric patients (27%). The clinical model alone resulted in a c-statistic of 0.719 (95% confidence interval, 0.63 to 0.81). The clinical model in conjunction with the log-transformed biomarkers improved the c-statistic to 0.805 (95% confidence interval, 0.73 to 0.88). The addition of biomarkers resulted in a significant improvement to the clinical model alone (P value = 0.035). CONCLUSIONS: Novel biomarkers may add predictive value when assessing the likelihood of 365-day readmission or mortality after pediatric congenital heart surgery. After adjusting for clinical and novel biomarkers, preoperative and postoperative suppression of tumorgenicity 2 remained associated with 365-day readmission or mortality. Currently, The Society of Thoracic Surgeons clinical congenital mortality risk model can be applied to identify children with increased risk of repeat hospitalizations and postdischarge mortality and may inform preventative care interventions that aim to reduce these adverse events.

ST2 Predicts Risk of Unplanned Readmission Within 1 Year After Pediatric Congenital Heart Surgery.

BACKGROUND: Approximately 10% to 20% of children are readmitted after congenital heart surgery. Very little is known about biomarkers as predictors of risk of unplanned readmission after pediatric congenital heart surgery. Novel cardiac biomarker ST2 may be associated with risk of unplanned readmission. ST2 concentrations are believed to reflect cardiovascular stress and fibrosis. Our objective was to explore the relationship between pre- and postoperative ST2 biomarker levels and risk of readmission within 1 year after congenital heart surgery. METHODS: We prospectively enrolled pediatric patients aged < 18 years who underwent at least 1 congenital heart operation at Johns Hopkins Hospital from 2010 to 2014. Plasma samples were collected immediately before surgery and at the end of bypass. We used Kaplan-Meier survival analysis and multivariable Cox regression models to adjust for variables used in The Society of Thoracic Surgeons Congenital Heart Surgery Database mortality risk model. RESULTS: Of our cohort of 145 patients, we found 39 children with readmissions within 365 days. The median time to unplanned readmission was 54 days (interquartile range, 10-153). Kaplan-Meier analysis demonstrated a significant difference across terciles of pre- and postoperative ST2 biomarker levels. After adjustment, elevated serum levels of ST2 measured preoperatively and postoperatively were associated with increased risk of readmission (hazard ratio, 2.5-3.7; all P < .05). CONCLUSIONS: Elevated levels of ST2 are significantly associated with increased risk of unplanned readmission within 1 year after pediatric congenital heart surgery. Novel serum biomarker ST2 can be used for risk stratification or estimating postsurgical prognosis.

Cardiac Biomarkers Predict Long-term Survival After Cardiac Surgery.

BACKGROUND: Cardiac biomarkers soluble ST-2 (sST-2) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) may be associated with long-term survival after cardiac surgery. This study explored the relationship between long-term survival after cardiac surgery and serum biomarker levels. METHODS: Patients undergoing cardiac surgery from 2004 to 2007 were enrolled in a prospective biomarker cohort in the Northern New England Cardiovascular Disease Study Group Registry. Preoperative serum biomarker levels, postoperative serum biomarker levels, and the change in serum biomarker levels were categorized by quartile. The study used Kaplan-Meier survival analysis and Cox regression models adjusted for variables in the American College of Cardiology Foundation-Society of Thoracic Surgeons Collaboration on the Comparative Effectiveness of Revascularization Strategy (ASCERT) long-term survival calculator to study the association of biomarker levels with long-term survival. After Kaplan-Meier analysis, quartiles 2 and 3 were found to have similar survival and were therefore combined into 1 category. RESULTS: In the study cohort (n = 1648), median follow-up time was 8.5 years (interquartile range, 7.6-9.7 years), during which there were 227 deaths. The 10-year survival rate was 86%. Kaplan-Meier survival analysis demonstrated a significant (P < .001) difference across quartiles of each biomarker level measurement. After adjustment, preoperative levels, postoperative levels, and the change in biomarker levels in quartile 4 (highest serum levels or change) were significantly predictive of worse survival (hazard ratio range, 1.77-2.89; all P < .05) compared with quartile 1; however, levels of sST-2 and NT-proBNP in quartiles 2 and 3 demonstrated a nonstatistically significant trend with long-term survival. CONCLUSIONS: Elevated preoperative and postoperative levels of sST-2 or NT-proBNP and large changes in these biomarkers' levels are associated with an increased risk of worse survival after cardiac surgery. These biomarkers can be used for risk stratification or assessing postsurgical prognosis.

The Association Between Cardiac Biomarker NT-proBNP and 30-Day Readmission or Mortality After Pediatric Congenital Heart Surgery.

BACKGROUND: Very little is known about clinical and biomarker predictors of readmissions following pediatric congenital heart surgery. The cardiac biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) can help predict readmission in adult populations, but the estimated utility in predicting risk of readmission or mortality after pediatric congenital heart surgery has not previously been studied. Our objective was to evaluate the association between pre- and postoperative serum biomarker levels and 30-day readmission or mortality for pediatric patients undergoing congenital heart surgery. METHODS: We measured pre- and postoperative NT-proBNP levels in two prospective cohorts of 522 pediatric patients <18 years of age who underwent at least one congenital heart operation from 2010 to 2014. Blood samples were collected before and after surgery. We evaluated the association between pre- and postoperative NT-proBNP with readmission or mortality within 30 days of discharge, using multivariate logistic regression, adjusting for covariates based on the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Mortality Risk Model. RESULTS: The Johns Hopkins Children's Center cohort and the Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury (TRIBE-AKI) cohort demonstrate event rates of 12.9% and 9.4%, respectively, for the composite end point. After adjustment for covariates in the STS congenital risk model, we did not find an association between elevated levels of NT-proBNP and increased risk of readmission or mortality following congenital heart surgery for either cohort. CONCLUSIONS: In our two cohorts, preoperative and postoperative values of NT-proBNP were not significantly associated with readmission or mortality following pediatric congenital heart surgery. These findings will inform future studies evaluating multimarker risk assessment models in the pediatric population.

Predictive Ability of Novel Cardiac Biomarkers ST2, Galectin-3, and NT-ProBNP Before Cardiac Surgery.

BACKGROUND: Current preoperative models use clinical risk factors alone in estimating risk of in-hospital mortality following cardiac surgery. However, novel biomarkers now exist to potentially improve preoperative prediction models. An assessment of Galectin-3, N-terminal pro b-type natriuretic peptide (NT-ProBNP), and soluble ST2 to improve the predictive ability of an existing prediction model of in-hospital mortality may improve our capacity to risk-stratify patients before surgery. METHODS AND RESULTS: We measured preoperative biomarkers in the NNECDSG (Northern New England Cardiovascular Disease Study Group), a prospective cohort of 1554 patients undergoing coronary artery bypass graft surgery. Exposures of interest were preoperative levels of galectin-3, NT-ProBNP, and ST2. In-hospital mortality and adverse events occurring after coronary artery bypass graft were the outcomes. After adjustment, NT-ProBNP and ST2 showed a statistically significant association with both their median and third tercile categories with NT-ProBNP odds ratios of 2.89 (95% confidence interval [CI]: 1.04-8.05) and 5.43 (95% CI: 1.21-24.44) and ST2 odds ratios of 3.96 (95% CI: 1.60-9.82) and 3.21 (95% CI: 1.17-8.80), respectively. The model receiver operating characteristic score of the base prediction model (0.80 [95% CI: 0.72-0.89]) varied significantly from the new multi-marker model (0.85 [95% CI: 0.79-0.91]). Compared with the Northern New England (NNE) model alone, the full prediction model with biomarkers NT-proBNP and ST2 shows significant improvement in model classification of in-hospital mortality. CONCLUSIONS: This study demonstrates a significant improvement of preoperative prediction of in-hospital mortality in patients undergoing coronary artery bypass graft and suggests that biomarkers can be used to identify patients at higher risk.

Preoperative serum ST2 level predicts acute kidney injury after adult cardiac surgery.

OBJECTIVE: The purpose of this study was to evaluate the relationship between preoperative levels of serum soluble ST2 (ST2) and acute kidney injury (AKI) after cardiac surgery. Previous research has shown that biomarkers facilitate the prediction of AKI and other complications after cardiac surgery. METHODS: Preoperative ST2 proteins were measured in 1498 patients undergoing isolated coronary artery bypass graft surgery at 8 hospitals participating in the Northern New England Biomarker Study from 2004 to 2007. AKI severity was defined using the Acute Kidney Injury Network (AKIN) definition. Preoperative ST2 levels were measured using multiplex assays. Ordered logistic regression was used to examine the relationship between ST2 levels and levels of AKI severity. RESULTS: Participants in this study showed a significant association between elevated preoperative ST2 levels and acute kidney risk. Before adjustment, the odds of patients developing AKIN stage 2 or 3, compared with AKIN stage 1, are 2.43 times higher (95% confidence interval, 1.86-3.16; P < .001) for patients in the highest tercile of preoperative ST2. After adjustment, patients in the highest tercile of preoperative ST2 had significantly greater odds of developing AKIN stage 2 or 3 AKI (odds ratio, 1.99; 95% confidence interval, 1.50-2.65; P < .001) compared with patients with AKIN stage 1. CONCLUSIONS: Preoperative ST2 levels are associated with postoperative AKI risk and can be used to identify patients at higher risk of developing AKI after cardiac surgery.

Utility of Biomarkers to Improve Prediction of Readmission or Mortality After Cardiac Surgery.

BACKGROUND: Hospital readmission within 30 days is associated with higher risks of complications, death, and increased costs. Accurate statistical models to stratify the risk of 30-day readmission or death after cardiac surgery could help clinical teams focus care on those patients at highest risk. We hypothesized biomarkers could improve prediction for readmission or mortality. METHODS: Levels of ST2, galectin-3, N-terminal pro-brain natriuretic peptide, cystatin C, interleukin-6, and interleukin-10 were measured in samples from 1,046 patients discharged after isolated coronary artery bypass graft surgery from eight medical centers, with external validation in 1,194 patients from five medical centers. Thirty-day readmission or mortality were ascertained using Medicare, state all-payer claims, and the National Death Index. We tested and externally validated the clinical models and the biomarker panels using area under the receiver-operating characteristics (AUROC) statistics. RESULTS: There were 112 patients (10.7%) who were readmitted or died within 30 days after coronary artery bypass graft surgery. The Society of Thoracic Surgeons augmented clinical model resulted in an AUROC of 0.66 (95% confidence interval: 0.61 to 0.71). The biomarker panel with The Society of Thoracic Surgeons augmented clinical model resulted in an AUROC of 0.74 (bootstrapped 95% confidence interval: 0.69 to 0.79, p < 0.0001). External validation of the model showed limited improvement with the addition of a biomarker panel, with an AUROC of 0.51 (95% confidence interval: 0.45 to 0.56). CONCLUSIONS: Although biomarkers significantly improved prediction of 30-day readmission or mortality in our derivation cohort, the external validation of the biomarker panel was poor. Biomarkers perform poorly, much like other efforts to improve prediction of readmission, suggesting there are many other factors yet to be explored to improve prediction of readmission.

The Association Between Novel Biomarkers and 1-Year Readmission or Mortality After Cardiac Surgery.

BACKGROUND: Novel cardiac biomarkers including soluble suppression of tumorigenicity 2, galectin-3, and the N-terminal prohormone of brain natriuretic peptide may be associated with long-term adverse outcomes after cardiac surgery. We sought to measure the association between cardiac biomarker levels and 1-year hospital readmission or mortality. METHODS: Plasma biomarkers from 1,047 patients discharged alive after isolated coronary artery bypass graft surgery from 8 medical centers were measured in a cohort from the Northern New England Cardiovascular Disease Study Group between 2004 and 2007. We evaluated the association between preoperative and postoperative biomarkers and 1-year readmission or mortality using Kaplan-Meier estimates and Cox proportional hazards modeling, adjusting for covariates used in The Society of Thoracic Surgeons 30-day readmission model. RESULTS: The median follow-up time was 365 days. After adjustment for established risk factors, above-median levels of postoperative galectin-3 (median 10.35 ng/mL; hazard ratio, 1.40; 95% confidence interval, 1.08 to 1.80; p = 0.010) and N-terminal prohormone of brain natriuretic peptide (median = 15.21 ng/mL, hazard ratio, 1.42; 95% confidence interval, 1.07 to 1.87; p = 0.014) were each significantly associated with 1-year readmission or mortality. CONCLUSIONS: In patients undergoing cardiac surgery, novel cardiac biomarkers were associated with readmission or mortality independent of established risk factors. Measurement of these biomarkers may improve our ability to identify patients at highest risk for readmission or mortality before discharge. This will also allow resource allocation accordingly, while implementing strategies for personalized medicine based on the biomarker profile of the patient.

Excess Readmission vs Excess Penalties: Maximum Readmission Penalties as a Function of Socioeconomics and Geography.

BACKGROUND: The Hospital Readmission Reduction Program (HRRP) penalizes hospitals with "excess" readmissions up to 3% of Medicare reimbursement. Approximately 75% of eligible hospitals received penalties, worth an estimated $428 million, in fiscal year 2015. OBJECTIVE: To identify demographic and socioeconomic disparities between matched and localized maximum-penalty and no-penalty hospitals. DESIGN: A case-control study in which cases included were hospitals to receive the maximum 3% penalty under the HRRP during the 2015 fiscal year. Controls were drawn from no-penalty hospitals and matched to cases by hospital characteristics (primary analysis) or geographic proximity (secondary analysis). SETTING: A selectiion of 3383 US hospitals eligible for HRRP. PARTICIPANTS: Thirty-nine case and 39 control hospitals from the HRRP cohort. MEASUREMENTS: Socioeconomic status variables were collected by the American Community Survey. Hospital and health system characteristics were drawn from Centers for Medicare and Medicaid Services, American Hospital Association, and Dartmouth Atlas of Health Care. The statistical analysis was conducted using Student t tests. RESULTS: Thirty-nine hospitals received a maximum penalty. Relative to controls, maximum-penalty hospitals in counties with lower SES profiles are defined by increased poverty rates (19.1% vs 15.5%, 𝑃 = 0.015) and lower rates of high school graduation (82.2% vs 87.5%, 𝑃 = 0.001). County level age, sex, and ethnicity distributions were similar between cohorts. CONCLUSIONS: Cases were more likely than controls to be in counties with low socioeconomic status; highlighting potential unintended consequences of national benchmarks for phenomena underpinned by environmental factors; specifically, whether maximum penalties under the HRRP are a consequence of underperforming hospitals or a manifestation of underserved communities.