External Validation of the MEESSI Acute Heart Failure Risk Score: A Cohort Study.

Background: The MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF) score was developed to predict 30-day mortality in patients presenting with acute heart failure (AHF) to emergency departments (EDs) in Spain. Whether it performs well in other countries is unknown. Objective: To externally validate the MEESSI-AHF score in another country. Design: Prospective cohort study. (ClinicalTrials.gov: NCT01831115). Setting: Multicenter recruitment of dyspneic patients presenting to the ED. Participants: The external validation cohort included 1572 patients with AHF. Measurements: Calculation of the MEESSI-AHF score using an established model containing 12 independent risk factors. Results: Among 1572 patients with adjudicated AHF, 1247 had complete data that allowed calculation of the MEESSI-AHF score. Of these, 102 (8.2%) died within 30 days. The score predicted 30-day mortality with excellent discrimination (c-statistic, 0.80). Assessment of cumulative mortality showed a steep gradient in 30-day mortality over 6 predefined risk groups (0 patients in the lowest-risk group vs. 35 [28.5%] in the highest-risk group). Risk was overestimated in the high-risk groups, resulting in a Hosmer-Lemeshow P value of 0.022. However, after adjustment of the intercept, the model showed good concordance between predicted risks and observed outcomes (P = 0.23). Findings were confirmed in sensitivity analyses that used multiple imputation for missing values in the overall cohort of 1572 patients. Limitations: External validation was done using a reduced model. Findings are specific to patients with AHF who present to the ED and are clinically stable enough to provide informed consent. Performance in patients with terminal kidney failure who are receiving long-term dialysis cannot be commented on. Conclusion: External validation of the MEESSI-AHF risk score showed excellent discrimination. Recalibration may be needed when the score is introduced to new populations. Primary Funding Source: The European Union, the Swiss National Science Foundation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel, the University of Basel, and University Hospital Basel.

Automatically computed ECG algorithm for the quantification of myocardial scar and the prediction of mortality.

BACKGROUND: Myocardial scar is associated with adverse cardiac outcomes. The Selvester QRS-score was developed to estimate myocardial scar from the 12-lead ECG, but its manual calculation is difficult. An automatically computed QRS-score would allow identification of patients with myocardial scar and an increased risk of mortality. OBJECTIVES: To assess the diagnostic and prognostic value of the automatically computed QRS-score. METHODS: The diagnostic value of the QRS-score computed automatically from a standard digital 12-lead was prospectively assessed in 2742 patients with suspected myocardial ischemia referred for myocardial perfusion imaging (MPI). The prognostic value of the QRS-score was then prospectively tested in 1151 consecutive patients presenting to the emergency department (ED) with suspected acute heart failure (AHF). RESULTS: Overall, the QRS-score was significantly higher in patients with more extensive myocardial scar: the median QRS-score was 3 (IQR 2-5), 4 (IQR 2-6), and 7 (IQR 4-10) for patients with 0, 5-20 and > 20% myocardial scar as quantified by MPI (p < 0.001 for all pairwise comparisons). A QRS-score ≥ 9 (n = 284, 10%) predicted a large scar defined as > 20% of the LV with a specificity of 91% (95% CI 90-92%). Regarding clinical outcomes in patients presenting to the ED with symptoms suggestive of AHF, mortality after 1 year was 28% in patients with a QRS-score ≥ 3 as opposed to 20% in patients with a QRS-score < 3 (p = 0.001). CONCLUSIONS: The QRS-score can be computed automatically from the 12-lead ECG for simple, non-invasive and inexpensive detection and quantification of myocardial scar and for the prediction of mortality. TRIAL-REGISTRATION: http://www.clinicaltrials.gov . Identifier, NCT01838148 and NCT01831115.

Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study.

BACKGROUND: Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis. OBJECTIVES: This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome. METHODS: This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 µmol/l or 50% higher than the admission value within 5 days of presentation. RESULTS: During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval [CI]: 1.24 to 2.00; p < 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p < 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels <133.3 pmol/l and >211.3 pmol/l detected low-risk and high-risk patients, respectively. CONCLUSIONS: PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up.

Impact of haemoconcentration during acute heart failure therapy on mortality and its relationship with worsening renal function.

AIMS: Treatment goals in acute heart failure (AHF) are poorly defined. We aimed to characterize further the impact of in-hospital haemoconcentration and worsening renal function (WRF) on short- and long-term mortality. METHODS AND RESULTS: Haematocrit, haemoglobin, total protein, serum creatinine, and albumin levels were measured serially in 1019 prospectively enrolled AHF patients. Haemoconcentration was defined as an increase in at least three of four of the haemoconcentration-defining parameters above admission values at any time during the hospitalization. Patients were divided into early (Day 1-4) and late haemoconcentration (>Day 4). Ninety-day mortality was the primary endpoint. Haemoconcentration occurred in 392 (38.5%) patients, with a similar incidence of the early (44.6%) and late (55.4%) phenotype. Signs of decongestion (reduction in BNP blood concentrations, P = 0.003; weight loss, P = 0.002) were significantly more pronounced in haemoconcentration patients. WRF was more common in haemoconcentration patients (P = 0.04). After adjustment for established risk factors for AHF mortality, including WRF and HF therapy at discharge, haemoconcentration was significantly associated with a reduction in 90-day mortality [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.95, P = 0.01]. The beneficial effect of haemoconcentration seemed to be exclusive for late haemoconcentration (late vs. early: adjusted HR 0.41, 95% CI 0.19-0.90, P = 0.03) and persisted in patients with or without WRF. CONCLUSIONS: Haemoconcentration represents an inexpensive and easily assessable pathophysiological signal of adequate decongestion in AHF and is associated with lower mortality. WRF in the setting of haemoconcentration does not appear to offset the benefits of haemoconcentration.

One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I.

UNLABELLED: We aimed to prospectively derive and validate a novel 0-/1-hour algorithm using high-sensitivity cardiac troponin I (hs-cTnI) for the early "rule-out" and "rule-in" of acute myocardial infarction (AMI). METHODS: In a prospective multicenter diagnostic study, we enrolled 1,500 patients presenting with suspected AMI to the emergency department. The final diagnosis was centrally adjudicated by 2 independent cardiologists blinded to hs-cTnI concentrations. The hs-cTnI (Siemens Vista) 0-/1-hour algorithm incorporated measurements performed at baseline and absolute changes within 1 hour, was derived in the first 750 patients (derivation cohort), and then validated in the second 750 (validation cohort). RESULTS: Overall, AMI was the final diagnosis in 16% of patients. Applying the hs-cTnI 0-/1-hour algorithm developed in the derivation cohort to the validation cohort, 57% of patients could be classified as "rule-out"; 10%, as "rule-in"; and 33%, as "observe." In the validation cohort, the sensitivity and the negative predictive value for AMI in the "rule-out" zone were 100% (95% CI 96%-100%) and 100% (95% CI 99%-100%), respectively. The specificity and the positive predictive value (PPV) for AMI in the "rule-in" zone were 96% (95% CI 94%-97%) and 70% (95% CI 60%-79%), respectively. Negative predictive value and positive predictive value of the 0-/1-hour algorithm were higher compared to the standard of care combining hs-cTnI with the electrocardiogram (both P < .001). CONCLUSION: The hs-cTnI 0-/1-hour algorithm performs very well for early rule-out as well as rule-in of AMI. The clinical implications are that used in conjunction with all other clinical information, the 0-/1-hour algorithm will be a safe and effective approach to substantially reduce time to diagnosis.

Delayed release of brain natriuretic peptide to identify myocardial ischaemia.

BACKGROUND: A recent pilot study suggested that exercise-induced myocardial ischaemia may lead to a delayed release of cardiac biomarkers, so that later sampling, for example, at 4 h after exercise could be used for diagnostic purpose. MATERIALS AND METHODS: In an observational study, we enrolled 129 consecutive patients referred for evaluation of a suspected coronary artery disease by rest/stress myocardial perfusion single-photon emission computed tomography. The treating cardiologist used all available clinical information to quantify clinical judgment regarding the presence of myocardial ischaemia using a visual analogue scale twice: prior and after stress testing. BNP levels were determined in a blinded fashion at rest, at peak stress and 4 h after peak stress. The presence of myocardial ischaemia was adjudicated based on perfusion single-photon emission computed tomography and coronary angiography findings by an independent cardiologist. RESULTS: Myocardial ischaemia was detected in 58 patients (45%). Patients with myocardial ischaemia had significantly higher BNP levels at all times, compared to patients without ischaemia: BNP rest (99 vs. 61 pg/mL P = 0·007), BNP stress (125 vs. 77 pg/mL P = 0·02) and BNP 4 h (114 vs. 71 pg/mL P = 0·018). Diagnostic accuracy as quantified by the area under the receiver operating characteristics curve (AUC) was moderate for all time points (AUC 0·64-0·66). The change in BNP between rest and 4 h did not provide added value, neither to the baseline BNP level nor to clinical judgment. CONCLUSION: In contrast to our hypothesis, myocardial ischaemia did not lead to a differential delayed release of BNP. Late sampling did not seem clinically useful.

Prediction of mortality using quantification of renal function in acute heart failure.

BACKGROUND: Renal function, as quantified by the estimated glomerular filtration rate (eGFR), is a predictor of death in acute heart failure (AHF). It is unknown whether one of the clinically-available serum creatinine-based formulas to calculate eGFR is superior to the others for predicting mortality. METHODS AND RESULTS: We quantified renal function using five different formulas (Cockroft-Gault, MDRD-4, MDRD-6, CKD-EPI in patients<70 years, and BIS-1 in patients≥70 years) in 1104 unselected AHF patients presenting to the emergency department and enrolled in a multicenter study. Two independent cardiologists adjudicated the diagnosis of AHF. The primary endpoint was the accuracy of the five eGFR equations to predict death as quantified by the time-dependent area under the receiver-operating characteristics curve (AUC). The secondary endpoint was the accuracy to predict all-cause readmissions and readmissions due to AHF. In a median follow-up of 374 days (IQR: 221 to 687 days), 445 patients (40.3%) died. eGFR as calculated by all equations was an independent predictor of mortality. The Cockcroft-Gault formula showed the highest prognostic accuracy (AUC 0.70 versus 0.65 for MDRD-4, 0.55 for MDRD-6, and 0.67 for the combined formula CKD-EPI/BIS-1, p<0.05). These findings were confirmed in patients with varying degrees of renal function and in three vulnerable subgroups: women, patients with severe left ventricular dysfunction, and the elderly. The prognostic accuracy for readmission was poor for all equations, with an AUC around 0.5. CONCLUSIONS: Calculating eGFR using the Cockcroft-Gault formula assesses the risk of mortality in patients with AHF more accurately than other commonly used formulas.

Early rule-out and rule-in of myocardial infarction using sensitive cardiac Troponin I.

BACKGROUND: It is currently unknown, whether and to what extent sensitive cardiac troponin (s-cTn) allows shortening of the time required for safe rule-out and rule-in of acute myocardial infarction (AMI). METHODS: We aimed to develop and validate early rule-out and rule-in algorithms for AMI using a thoroughly-examined and commonly used s-cTnI assay in a prospective multicenter study including 2173 patients presenting to the emergency department with suspected AMI. S-cTnI was measured in a blinded fashion at 0 h, 1 h, and 2 h. The final diagnosis was centrally adjudicated by two independent cardiologists. In the derivation cohort (n = 1496), we developed 1h- and 2h-algorithms assigning patients to "rule-out", "rule-in", or "observe". The algorithms were then prospectively validated in the validation cohort (n = 677). RESULTS: AMI was the adjudicated diagnosis in 17% of patients. After applying the s-cTnI 1h-algorithm developed in the derivation cohort to the validation cohort, 65% of patients were classified as "rule-out", 12% as "rule-in", and 23% to "observe". The negative predictive value for AMI in the "rule-out" group was 98.6% (95% CI, 96.9-99.5), the positive predictive value for AMI in the "rule-in" group 76.3% (95% CI, 65.4-85.1). Overall, 30-day mortality was 0.2% in the "rule-out" group, 1.0% in the "observe" group, and 3.0% in the "rule-in" group. Similar results were obtained for the 2h-algorithm. CONCLUSION: When used in conjunction with other clinical information including the ECG, a simple algorithm incorporating s-cTnI values at presentation and after 1h (or 2h) will allow safe rule-out and accurate rule-in of AMI in the majority of patients.

Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction.

BACKGROUND: It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined. METHODS AND RESULTS: In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease-estimated glomerular filtration rate <60 mL·min(-1)·1.73 m(-2)). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction was the most common diagnosis for all assays (range, 45%-80%). In patients with renal dysfunction, diagnostic accuracy at presentation, quantified by the area under the receiver-operator characteristic curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve-derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9-3.4). CONCLUSIONS: More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I.

OBJECTIVE: We aimed to prospectively derive and validate a novel 1h-algorithm using high-sensitivity cardiac troponin I (hs-cTnI) for early rule-out and rule-in of acute myocardial infarction. METHODS: We performed a prospective multicenter diagnostic study enrolling 1811 patients with suspected acute myocardial infarction. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography, echocardiography, follow-up data, and serial measurements of hs-cTnT (but not hs-cTnI). The hs-cTnI 1h-algorithm, incorporating measurements performed at baseline and absolute changes within 1 hour, was derived in a randomly selected sample of 906 patients (derivation cohort), and then validated in the remaining 905 patients (validation cohort). RESULTS: Acute myocardial infarction was the final diagnosis in 18% of patients. After applying the hs-cTnI 1h-algorithm developed in the derivation cohort to the validation cohort, 50.5% of patients could be classified as "rule-out," 19% as "rule-in," 30.5% as "observe." In the validation cohort, the negative predictive value for acute myocardial infarction in the "rule-out" zone was 99.6% (95% confidence interval, 98.4%-100%), and the positive predictive value for acute myocardial infarction in the "rule-in" zone was 73.9% (95% confidence interval, 66.7%-80.2%). Negative predictive value of the 1h-algorithm was higher compared with the classical dichotomous interpretation of hs-cTnI and to the standard of care combining hs-cTnI with the electrocardiogram (both P < .001). Positive predictive value also was higher compared with the standard of care (P < .001). CONCLUSION: Using a simple algorithm incorporating baseline hs-cTnI values and the absolute change within the first hour allows safe rule-out as well as accurate rule-in of acute myocardial infarction in 70% of patients presenting with suspected acute myocardial infarction.

Prevalence, characteristics and outcome of non-cardiac chest pain and elevated copeptin levels.

OBJECTIVE: Copeptin, a quantitative marker of endogenous stress, seems to provide incremental value in addition to cardiac troponin in the early rule-out of acute myocardial infarction (AMI). Prevalence, characteristics and outcome of acute chest pain patients with causes other than AMI and elevated copeptin are poorly understood. METHODS: A total of 984 consecutive patients with non-cardiac chest pain were selected from a prospective multicentre study of acute chest pain patients presenting to the emergency department. Levels of copeptin were determined in a blinded fashion and considered elevated if above 13 pmol/L (the 97,5th centile of healthy individuals). The final diagnosis was adjudicated by two independent cardiologists. Median duration of follow-up was 756 days. RESULTS: Elevated copeptin levels were seen in 215 patients (22%). In comparison to patients with normal copeptin levels, patients with elevated levels were older, had more pre-existing cardiac and non-cardiac disorders, more silent cardiomyocyte injury and increased haemodynamic stress as quantified by levels of high-sensitivity cardiac troponin T (9.6 ng/L (3.6-18.3) vs 5.8 ng/L (2.9-9.4)) and B-type natriuretic peptide (75 ng/L (37-187) vs 35 ng/L (15-77)) (both p<0.001), more electrocardiographic abnormalities, more often an adjudicated diagnosis of gastroesophageal reflux or bronchitis/pneumonia and higher 2- year mortality (HR 2.9, 95% CI 1.5  to 5.7). The increased mortality rate seemed to be largely explained by age and comorbidities. CONCLUSIONS: Elevated levels of copeptin are present in about one in five patients with non-cardiac chest pain and are associated with aging, cardiac and non-cardiac comorbidities as well as mortality.