Christopher Hogan

Mid-Region Pro-Hormone Markers for Diagnosis and Prognosis in Acute Dyspnea: Results From the BACH (Biomarkers in Acute Heart Failure) Trial

OBJECTIVES Our purpose was to assess the diagnostic utility of mid-regional pro-atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with AHF. BACKGROUND There are some caveats and limitations to natriuretic peptide testing in the acute dyspneic patient. METHODS The BACH (Biomarkers in Acute Heart Failure) trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. A noninferiority test of MR-proANP versus B-type natriuretic peptide (BNP) for diagnosis of AHF and a superiority test of MR-proADM versus BNP for 90-day survival were conducted. Other end points were exploratory. RESULTS MR-proANP (> or =120 pmol/l) proved noninferior to BNP (> or =100 pg/ml) for the diagnosis of AHF (accuracy difference 0.9%). In tests of secondary diagnostic objectives, MR-proANP levels added to the utility of BNP levels in patients with intermediate BNP values and with obesity but not in renal insufficiency, the elderly, or patients with edema. Using cut-off values from receiver-operating characteristic analysis, the accuracy to predict 90-day survival of heart failure patients was 73% (95% confidence interval: 70% to 77%) for MR-proADM and 62% (95% confidence interval: 58% to 66%) for BNP (difference p < 0.001). In adjusted multivariable Cox regression, MR-proADM, but not BNP, carried independent prognostic value (p < 0.001). Results were consistent using NT-proBNP instead of BNP (p < 0.001). None of the biomarkers was able to predict rehospitalization or visits to the emergency department with clinical relevance. CONCLUSIONS MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret. MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628).

Copeptin Helps in the Early Detection of Patients With Acute Myocardial Infarction Primary Results of the CHOPIN Trial (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction)

OBJECTIVES The goal of this study was to demonstrate that copeptin levels <14 pmol/L allow ruling out acute myocardial infarction (AMI) when used in combination with cardiac troponin I (cTnI) <99 th percentile and a nondiagnostic electrocardiogram at the time of presentation to the emergency department (ED). BACKGROUND Copeptin is secreted from the pituitary early in the course of AMI. METHODS This was a 16-site study in 1,967 patients with chest pain presenting to an ED within 6 hours of pain onset. Baseline demographic characteristics and clinical data were collected prospectively. Copeptin levels and a contemporary sensitive cTnI (99 th percentile 40 ng/l; 10% coefficient of variation 0.03 μg/l) were measured in a core laboratory. Patients were followed up for 180 days. The primary outcome was diagnosis of AMI. Final diagnoses were adjudicated by 2 independent cardiologists blinded to copeptin results. RESULTS AMI was the final diagnosis in 156 patients (7.9%). A negative copeptin and cTnI at baseline ruled out AMI for 58% of patients, with a negative predictive value of 99.2% (95% confidence interval: 98.5 to 99.6). AMIs not detected by the initial cTnI alone were picked up with copeptin >14 pmol/l in 23 (72%) of 32 patients. Non-ST-segment elevation myocardial infarctions undetected by cTnI at 0 h were detected with copeptin >14 pmol/l in 10 (53%) of 19 patients. Projected average time-to-decision could be reduced by 43% (from 3.0 h to 1.8 h) by the early rule out of 58% of patients. Both abnormal copeptin and cTnI were predictors of death at 180 days (p < 0.0001 for both; c index 0.784 and 0.800, respectively). Both were independent of age and each other and provided additional predictive value (all p < 0.0001). CONCLUSIONS Adding copeptin to cTnI allowed safe rule out of AMI with a negative predictive value >99% in patients presenting with suspected acute coronary syndromes. This combination has the potential to rule out AMI in 58% of patients without serial blood draws.

Increased 90-Day Mortality in Patients With Acute Heart Failure With Elevated Copeptin Secondary Results From the Biomarkers in Acute Heart Failure (BACH) Study

Background— In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations. Methods and Results— The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality ( P <0.001; hazard ratio, 3.85). Mortality was significantly increased in patients with elevated copeptin and hyponatremia ( P <0.001; hazard ratio, 7.36). Combined end points of mortality, readmissions, and emergency department visits were significantly increased in patients with elevated copeptin. There was no correlation between copeptin and sodium ( r =0.047). Conclusions— This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides. Clinical Trial Registration— URL: . Unique identifier: [NCT00537628][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00537628&atom=%2Fcirchf%2F4%2F5%2F613.atomBackground— In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations. Methods and Results— The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality (P<0.001; hazard ratio, 3.85). Mortality was significantly increased in patients with elevated copeptin and hyponatremia (P<0.001; hazard ratio, 7.36). Combined end points of mortality, readmissions, and emergency department visits were significantly increased in patients with elevated copeptin. There was no correlation between copeptin and sodium (r=0.047). Conclusions— This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00537628.

Midregion Prohormone Adrenomedullin and Prognosis in Patients Presenting With Acute Dyspnea : Results From the BACH (Biomarkers in Acute Heart Failure) Trial

OBJECTIVES The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath. BACKGROUND The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p < 0.001) in acute heart failure. METHODS The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission. RESULTS Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 90-day all-cause mortality in patients presenting with acute dyspnea (c index = 0.755, p < 0.0001). Furthermore, MR-proADM added significantly to all clinical variables (all adjusted hazard ratios: >3.28), and it was also superior to all other biomarkers. MR-proADM added significantly to the best clinical model (bootstrap-corrected c index increase: 0.775 to 0.807; adjusted standardized hazard ratio: 2.59; 95% confidence interval: 1.91 to 3.50; p < 0.0001). Within the model, MR-proADM was the biggest contributor to the predictive performance, with a net reclassification improvement of 8.9%. Serial evaluation of MR-proADM performed in patients admitted provided a significant added value compared with a model with admission values only (p = 0.0005). More than one-third of patients originally at high risk could be identified by the biomarker evaluation at discharge as low-risk patients. CONCLUSIONS MR-proADM identifies patients with high 90-day mortality and adds prognostic value to natriuretic peptides in patients presenting with acute shortness of breath. Serial measurement of this biomarker may also prove useful for monitoring, although further studies will be required. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628).

Use of procalcitonin for the diagnosis of pneumonia in patients presenting with a chief complaint of dyspnoea: results from the BACH (Biomarkers in Acute Heart Failure) trial.

Biomarkers have proven their ability in the evaluation of cardiopulmonary diseases. We investigated the utility of concentrations of the biomarker procalcitonin (PCT) alone and with clinical variables for the diagnosis of pneumonia in patients presenting to emergency departments (EDs) with a chief complaint of shortness of breath.

Increased 90-Day Mortality in Patients With Acute Heart Failure With Elevated CopeptinClinical Perspective

Background— In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations. Methods and Results— The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality ( P <0.001; hazard ratio, 3.85). Mortality was significantly increased in patients with elevated copeptin and hyponatremia ( P <0.001; hazard ratio, 7.36). Combined end points of mortality, readmissions, and emergency department visits were significantly increased in patients with elevated copeptin. There was no correlation between copeptin and sodium ( r =0.047). Conclusions— This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides. Clinical Trial Registration— URL: . Unique identifier: [NCT00537628][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00537628&atom=%2Fcirchf%2F4%2F5%2F613.atomBackground— In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations. Methods and Results— The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality (P<0.001; hazard ratio, 3.85). Mortality was significantly increased in patients with elevated copeptin and hyponatremia (P<0.001; hazard ratio, 7.36). Combined end points of mortality, readmissions, and emergency department visits were significantly increased in patients with elevated copeptin. There was no correlation between copeptin and sodium (r=0.047). Conclusions— This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00537628.

Short-term Mortality Risk in Emergency Department Acute Heart Failure

OBJECTIVES Few tools exist that provide objective accurate prediction of short-term mortality risk in patients presenting with acute heart failure (AHF). The purpose was to describe the accuracy of several biomarkers for predicting short-term death rates in patients diagnosed with AHF in the emergency department (ED). METHODS The Biomarkers in ACute Heart failure (BACH) trial was a prospective, 15-center, international study of patients presenting to the ED with nontraumatic dyspnea. Clinicians were blinded to all investigational markers, except troponin and natriuretic peptides, which used the local hospital reference range. For this secondary analysis, a core lab was used for all markers except troponin. This study evaluated patients diagnosed with AHF by the on-site emergency physician (EP). RESULTS In the 1,641 BACH patients, 466 (28.4%) had an ED diagnosis of AHF, of whom 411 (88.2%) had a final diagnosis of AHF. In the ED-diagnosed HF patients, 59% were male, 69% had a HF history, and 19 (4.1%) died within 14 days of their ED visit. The area under the curve (AUC) for the 14-day mortality receiver operating characteristic (ROC) curve was 0.484 for brain natriuretic peptide (BNP), 0.586 for N-terminal pro-B-type natriuretic peptide (NT-proBNP), 0.755 for troponin (I or T), 0.742 for adrenomedullin (MR-proADM), and 0.803 for copeptin. In combination, MR-proADM and copeptin had the best 14-day mortality prediction (AUC = 0.818), versus all other markers. CONCLUSIONS MR-proADM and copeptin, alone or in combination, may provide superior short-term mortality prediction compared to natriuretic peptides and troponin. Presented results are explorative due to the limited number of events, but validation in larger trials seems promising.

S3 Detection as a Diagnostic and Prognostic Aid in Emergency Department Patients With Acute Dyspnea

STUDY OBJECTIVE Dyspneic emergency department (ED) patients present a diagnostic dilemma. Recent technologic advances have made it possible to capture information about pathologic heart sounds at ECG recording. This study evaluates the effect of an S3 captured by acoustic cardiography on emergency physician diagnostic accuracy and confidence in their diagnosis of acute decompensated heart failure, as well as the patients prognosis. METHODS Dyspneic ED patients older than 40 years who were not dialysis dependent were prospectively enrolled in this multinational study. Treating emergency physicians, initially blinded to all laboratory and acoustic cardiography results, estimated acute decompensated heart failure probability from 0% to 100% on a visual analog scale. The emergency physician repeated the visual analog scale after acoustic cardiography results were provided. Physician diagnostic accuracy for and confidence in acute decompensated heart failure were evaluated against a reference standard diagnosis, as determined by 2 independent cardiologists blinded to acoustic cardiography. Patients were followed through 90 days to determine the relationship of the S3 to adverse events. RESULTS Nine hundred ninety-five patients with acoustic cardiography results were enrolled from March to October 2006 at 7 US and 2 international sites. Median age was 63 years, 55% were men, and 44% were white. The reference diagnosis was acute decompensated heart failure in 41.5%. After initial history and physical examination, the treating physicians initial sensitivity, specificity, and accuracy for acute decompensated heart failure as a possible diagnosis were 89.0% (95% confidence interval [CI] 85.5% to 91.8%), 58.2% (95% CI 54.0% to 62.2%), and 71.0% (95% CI 68.4% to 73.8%), respectively. Acoustic cardiography had an accuracy of 68% (95% CI 65.4% to 71.3%), sensitivity of 40.2% (95% CI 35.5% to 45.1%), and specificity of 88.5% (95% CI 85.5% to 90.9%). Emergency physician confidence and diagnostic accuracy were influenced by adding information about the presence or absence of S3. In a multivariable model, the S3 added no independent prognostic information for 30-day (odds ratio 1.20; 95% CI 0.67 to 2.14) or 90-day events (odds ratio 1.22; 95% CI 0.78 to 1.90). CONCLUSION In patients presenting with acute dyspnea, the acoustic cardiography S3 was specific for acute decompensated heart failure and affected physician confidence but did not improve diagnostic accuracy for acute decompensated heart failure, largely because of its low sensitivity. Further, the acoustic cardiography S3 provided no significant independent prognostic information.

Atrial Fibrillation Impairs the Diagnostic Performance of Cardiac Natriuretic Peptides in Dyspneic Patients: Results From the BACH Study (Biomarkers in ACute Heart Failure)

OBJECTIVES The purpose of this study was to assess the impact of atrial fibrillation (AF) on the performance of mid-region amino terminal pro-atrial natriuretic peptide (MR-proANP) in comparison with the B-type peptides (BNP and NT-proBNP) for diagnosis of acute heart failure (HF) in dyspneic patients. BACKGROUND The effects of AF on the diagnostic and prognostic performance of MR-proANP in comparison with the B type natriuretic peptides have not been previously reported. METHODS A total of 1,445 patients attending the emergency department with acute dyspnea had measurements taken of MR-proANP, BNP, and NT-proBNP values on enrollment to the BACH trial and were grouped according to presence or absence of AF and HF. RESULTS AF was present in 242 patients. Plasma concentrations of all three peptides were lowest in those with neither AF nor HF and AF without HF was associated with markedly increased levels (p < 0.00001). HF with or without AF was associated with a significant further increment (p < 0.00001 for all three markers). Areas under receiver operator characteristic curves (AUCs) for discrimination of acute HF were similar and powerful for all peptides without AF (0.893 to 0.912; all p < 0.001) with substantial and similar reductions (0.701 to 0.757) in the presence of AF. All 3 peptides were independently prognostic but there was no interaction between any peptide and AF for prediction of all-cause mortality. CONCLUSIONS AF is associated with increased plasma natriuretic peptide (MR-proANP, BNP and NT-proBNP) levels in the absence of HF. The diagnostic performance of all three peptides is impaired by AF. This warrants consideration of adjusted peptide thresholds for diagnostic use in AF and mandates the continued search for markers free of confounding by AF.

Development and Reproducibility of a Brief Food Frequency Questionnaire for Assessing the Fat, Fiber, and Fruit and Vegetable Intakes of Rural Adolescents

OBJECTIVE To describe the systematic development and reproducibility of a food frequency questionnaire (FFQ) designed to meet the specific research requirements of the Goals for Health cancer prevention intervention program for rural middle school children. DESIGN A 4-step process was used to develop a brief FFQ for scoring intakes of total fat, fiber, and fruits and vegetables. The resulting questionnaire consisted of 25 food frequency items and 10 supplemental questions. Reproducibility of the questionnaire was determined by comparing responses at the beginning and end of a 4-month interval. SUBJECTS Study subjects were sixth- and seventh-grade students attending middle schools in rural areas of Virginia and upstate New York. Seventh-grade students participated in the pilot study, and sixth-grade students participated in the reproducibility study. The final version of the FFQ was completed twice by 539 sixth graders. After exclusions for missing and unreliable data, the usable sample size was 415. Boys were somewhat more likely than girls to be excluded for missing data. African-American students comprised 32% of the population. STATISTICAL ANALYSES PERFORMED Each food frequency item was associated with 3 scores--a fat score, a fiber score, and a combined score for the number of servings of fruits and vegetables. Means and standard deviations were determined for nutrient variables, differences between repeat administrations were tested for significance by paired t test, and Pearson correlation coefficients were calculated for nutrients and for individual food items. RESULTS Correlation coefficients for nutrient scores were 0.58 for fat, 0.49 for fiber, and 0.51 for fruits and vegetables. For individual food items, correlations ranged from 0.24 to 0.59 (mean=0.41). APPLICATIONS/CONCLUSIONS Using a systematic approach to developing a study-specific FFQ for rural adolescents is feasible. Further, the reproducibility of the Goals for Health questionnaire was demonstrated for the 3 nutrient scores it was designed to measure. This developmental approach may be readily adapted to other populations, study designs, and nutrients of interest. The validity of the questionnaire remains to be tested.