Signs or symptoms of suspected preeclampsia - A retrospective national database study of prevalence, costs, and outcomes.

BACKGROUND: Most patients with signs or symptoms (s/s) of suspected preeclampsia are not diagnosed with preeclampsia. We sought to determine and compare the prevalence of s/s, pregnancy outcomes, and costs between patients with and without diagnosed preeclampsia. METHODS: This retrospective cohort study analyzed a large insurance research database. Pregnancies with s/s of preeclampsia versus a confirmed preeclampsia diagnosis were identified using International Classification of Diseases codes. S/s include hypertension, proteinuria, headache, visual symptoms, edema, abdominal pain, and nausea/vomiting. Pregnancies were classed as 1) s/s of preeclampsia without a confirmed preeclampsia diagnosis (suspicion only), 2) s/s with a confirmed diagnosis (preeclampsia with suspicion), 3) diagnosed preeclampsia without s/s recorded (preeclampsia only), and 4) no s/s, nor preeclampsia diagnosis (control). RESULTS: Of 1,324,424 pregnancies, 29.2 % had ≥1 documented s/s of suspected preeclampsia, and 14.2 % received a preeclampsia diagnosis. Hypertension and headache were the most common s/s, leading 20.2 % and 9.2 % pregnancies developed to preeclampsia diagnosis, respectively. Preeclampsia, with or without suspicion, had the highest rates of hypertension-related severe maternal morbidity (HR [95 % CI]: 3.0 [2.7, 3.2] and 3.6 [3.3, 4.0], respectively) versus controls. A similar trend was seen in neonatal outcomes such as preterm delivery and low birth weight. Cases in which preeclampsia was suspected but not confirmed had the highest average total maternal care costs ($6096 [95 % CI: 602, 6170] over control). CONCLUSION: There is a high prevalence but poor selectivity of traditional s/s of preeclampsia, highlighting a clinical need for improved screening method and cost-effectiveness disease management.

Prognosis is worse with elevated cardiac troponin in nonacute coronary syndrome compared with acute coronary syndrome.

BACKGROUND: Cardiac troponin (cTn) can be elevated in many patients presenting to the emergency department (ED) with chest pain but without a diagnosis of acute coronary syndrome (ACS). We compared the prognostic significance of cTn in these different populations. METHODS: We retrospectively analyzed the CHOPIN study, which enrolled patients who presented to the ED with chest pain. Patients were grouped as ACS, non-ACS cardiovascular disease, noncardiac chest pain and chest pain not otherwise specified (NOS). We examined the prognostic ability of cTnI for the clinical endpoints of mortality and major adverse cardiovascular event (MACE; a composite of acute myocardial infarction, unstable angina, revascularization, reinfarction, and congestive heart failure and stroke) at 180-day follow-up. RESULTS: Among 1982 patients analyzed, 14% had ACS, 21% had non-ACS cardiovascular disease, 31% had a noncardiac diagnosis and 34% had chest pain NOS. cTnI elevation above the 99th percentile was observed in 52, 18, 6 and 7% in these groups, respectively. cTnI elevation was associated with mortality and MACE, and their relationships were more prominent in noncardiac diagnosis and chest pain NOS than in ACS and non-ACS cardiovascular diagnoses for mortality, and in non-ACS patients than in ACS patients for MACE (hazard ratio for doubling of cTnI 1.85, 2.05, 8.26 and 4.14, respectively; P for interaction 0.011 for mortality; 1.04, 1.23, 1.54 and 1.42, respectively; P for interaction <0.001 for MACE). CONCLUSION: In patients presenting to the ED with chest pain, cTnI elevation was associated with a worse prognosis in non-ACS patients than in ACS patients.

Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction.

BACKGROUND: The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cTn assays. However, it remains to be determined how to diagnose, risk-stratify, and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. METHODS: Patients presenting to the emergency department with chest pain, enrolled in the CHOPIN study (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction), were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic curve analysis. The biomarkers analyzed were cTnI, copeptin, MR-proANP (midregional proatrial natriuretic peptide), CT-proET1 (C-terminal proendothelin-1), MR-proADM (midregional proadrenomedullin), and procalcitonin. The prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (a composite of acute myocardial infarction, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. RESULTS: Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, whereas those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the receiver operating characteristic curve for the diagnosis of T2MI was higher for CT-proET1, MR-proADM, and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, P=0.294). Addition of biomarkers to the clinical model yielded the highest area under the receiver operating characteristic curve (0.917). Other biomarkers, but not cTnI, were associated with mortality and major adverse cardiovascular event at 180 days among all patients, with no interaction between the diagnosis of T1MI or T2MI. CONCLUSIONS: Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. All biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of the type of myocardial infarction.

Copeptin to rule out myocardial infarction in Blacks versus Caucasians.

BACKGROUND: Copeptin in combination with troponin has been shown to have incremental value for the early rule-out of myocardial infarction, but its performance in Black patients specifically has never been examined. In light of a potential for wider use, data on copeptin in different relevant cohorts are needed. This is the first study to determine whether copeptin is equally effective at ruling out myocardial infarction in Black and Caucasian races. METHODS: This analysis of the CHOPIN trial included 792 Black and 1075 Caucasian patients who presented to the emergency department with chest pain and had troponin-I and copeptin levels drawn. RESULTS: One hundred and forty-nine patients were diagnosed with myocardial infarction (54 Black and 95 Caucasian). The negative predictive value of copeptin at a cut-off of 14 pmol/l (as in the CHOPIN study) for myocardial infarction was higher in Blacks (98.0%, 95% confidence interval (CI) 96.2-99.1%) than Caucasians (94.1%, 95% CI 92.1-95.7%). The sensitivity at 14 pmol/l was higher in Blacks (83.3%, 95% CI 70.7-92.1%) than Caucasians (53.7%, 95% CI 43.2-64.0%). After controlling for age, hypertension, heart failure, chronic kidney disease and body mass index in a logistic regression model, the interaction term had a P value of 0.03. A cut-off of 6 pmol/l showed similar sensitivity in Caucasians as 14 pmol/l in Blacks. CONCLUSIONS: This is the first study to identify a difference in the performance of copeptin to rule out myocardial infarction between Blacks and Caucasians, with increased negative predictive value and sensitivity in the Black population at a cut-off of 14 pmol/l. This also holds true for non-ST-segment elevation myocardial infarction and, although numbers were small, similar trends exist in the normal troponin population. This may have significant implications for early rule-out strategies using copeptin.

Proenkephalin (PENK) as a Novel Biomarker for Kidney Function.

BACKGROUND: The assessment of kidney function and detection of acute kidney injury (AKI) remain cumbersome. On the one hand, because of limited accuracy of established tests: The most widely used methods are creatinine based, which lack in sensitivity, as creatinine is not purely filtrated by the kidney and rises relatively late after onset of AKI. On the other hand, because of labor-intensiveness: Gold standard inulin clearance and comparable methods involve intravenous compound infusion, blood sampling at several time points, and have error-sensitive determination methods. In recent years, several biomarkers have been put forward (e.g., NGAL, KIM-1, TIMP-2*IGFBP-7), but clinical implementation is limited up to now. CONTENT: Proenkephalin (PENK) represents a new candidate to determine kidney function. This peptide is cleaved from the precursor peptide preproenkephalin A alongside enkephalins (endogenous opioids) and is filtrated in the glomerulus. PENK plasma concentration appears to accurately represent glomerular filtration rate in patients diagnosed with sepsis or cardiac diseases. Moreover, increased PENK concentration is found to be associated with longer-term outcome concerning AKI and cardiac diseases. Lastly, the predominant receptor of enkephalins, the δ-opioid receptor, is expressed with the highest density in the kidney, suggesting that enkephalins could also exert a direct effect on kidney function. SUMMARY: In this review, we present an overview of enkephalins and the assessment of kidney function using this possible new functional biomarker PENK and compare it with established and novel biomarkers.

Necessity of hospitalization and stress testing in low risk chest pain patients.

BACKGROUND: Copeptin is a marker of endogenous stress including early myocardial infarction(MI) and has value in early rule out of MI when used with cardiac troponin I(cTnI). OBJECTIVES: The goal of this study was to demonstrate that patients with a normal electrocardiogram and cTnI<0.040µg/l and copeptin<14pmol/l at presentation and after 2 h may be candidates for early discharge with outpatient follow-up potentially including stress testing. METHODS: This study uses data from the CHOPIN trial which enrolled 2071 patients with acute chest pain. Of those, 475 patients with normal electrocardiogram and normal cTnI(<0.040µg/l) and copeptin<14pmol/l at presentation and after 2 h were considered "low risk" and selected for further analysis. RESULTS: None of the 475 "low risk" patients were diagnosed with MI during the 180day follow-up period (including presentation). The negative predictive value of this strategy was 100% (95% confidence interval(CI):99.2%-100.0%). Furthermore no one died during follow up. 287 (60.4%) patients in the low risk group were hospitalized. In the "low risk" group, the only difference in outcomes (MI, death, revascularization, cardiac rehospitalization) was those hospitalized underwent revascularization more often (6.3%[95%CI:3.8%-9.7%] versus 0.5%[95%CI:0.0%-2.9%], p=.002). The hospitalized patients were tested significantly more via stress testing or angiogram (68.6%[95%CI:62.9%-74.0%] vs 22.9%[95%CI:17.1%-29.6%], p<.001). Those tested had less cardiac rehospitalizations during follow-up (1.7% vs 5.1%, p=.040). CONCLUSIONS: In conclusion, patients with a normal electrocardiogram, troponin and copeptin at presentation and after 2 h are at low risk for MI and death over 180days. These low risk patients may be candidates for early outpatient testing and cardiology follow-up thereby reducing hospitalization.

Serial sampling of copeptin levels improves diagnosis and risk stratification in patients presenting with chest pain: results from the CHOPIN trial.

BACKGROUND: Copeptin has demonstrated a role in early rule out for acute myocardial infarction (AMI) in combination with a negative troponin. However, management of patients with chest pain with a positive copeptin in the setting of a negative troponin is unclear. METHODS: The multicentre CHOPIN trial enrolled 2071 patients with acute chest pain. Of these, 476 subjects with an initial negative troponin but an elevated copeptin (>14 pmol/L) were included in this study. Copeptin and troponin levels were rechecked at 2 h and the final diagnosis of AMI was made by two independent, blinded cardiologists. Follow-up at 30 days was obtained for major adverse cardiac events (MACEs), including death, AMI and urgent revascularisation. RESULTS: Of the 476 patients analysed, 365 (76.7%) had a persistently elevated copeptin at 2 h and 111 patients (23.3%) had a copeptin that fell below the cut-off of 14 pmol/L. When the second copeptin was elevated there were 18 AMIs (4.9%) compared with 0 (0%) when the second copeptin was negative (p=0.017), yielding a negative predictive value of 100% (95% CI 96.7% to 100%). On 30-day follow-up there were 36 MACEs (9.9%) in the positive second copeptin group and 2 (1.8%) MACEs in the negative second copeptin group (p=0.006). CONCLUSIONS: Patients with chest pain with an initial negative troponin but positive copeptin are common and carry an intermediate risk of AMI. A second copeptin drawn 2 h after presentation may help risk stratify and potentially rule out AMI in this cohort.

Midregional proadrenomedullin predicts mortality and major adverse cardiac events in patients presenting with chest pain: results from the CHOPIN trial.

OBJECTIVES: Chest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR-proADM) in prediction of mortality and major adverse cardiac events (MACE). METHODS: This was a subanalysis of the CHOPIN study, a 16-center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6-month all-cause mortality and the secondary endpoint was 30-day and 6-month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure. RESULTS: MR-proADM performed similarly to troponin (cTnI; c-statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR-proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6-month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR-proADM, history of coronary artery disease (CAD), and hypertension were predictors of short-term MACE, while history of CAD, hypertension, cTnI, and MR-proADM were predictors of long-term MACE. CONCLUSIONS: In patients with chest pain, MR-proADM predicts mortality and MACE in all-comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses-generating and future prospective studies to identify its utility in risk stratification should be considered.

The current and future landscape of urinary thromboxane testing to evaluate atherothrombotic risk.

Biomarker testing for efficacy of therapy is an accepted way for clinicians to individualize dosing to genetic and/or environmental factors that may be influencing a treatment regimen. Aspirin is used by nearly 43 million Americans on a regular basis to reduce risks associated with various atherothrombotic diseases. Despite its widespread use, many clinicians are unaware of the link between suboptimal response to aspirin therapy and increased risk for inferior clinical outcomes in several disease states, and biomarker testing for efficacy of aspirin therapy is not performed as routinely as efficacy testing in other therapeutic areas. This article reviews the clinical and laboratory aspects of determining whole-body thromboxane production, particularly as it pertains to efficacy assessment of aspirin responsiveness.

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.

Mid-regional pro-adrenomedullin improves disposition strategies for patients with acute dyspnoea: results from the BACH trial.

OBJECTIVES: To assess the value of mid-regional pro-adrenomedullin (MR-proADM) in guiding patient disposition from the emergency department (ED), as one of the key factors of hospital resource utilisation, in undifferentiated patients with acute dyspnoea. METHODS: We used clinical and outcome data from a large international biomarker study (BACH trial) and analysed data of all 1557 patients of the European and US sites presenting with acute dyspnoea. Patients were discharged or transferred from the ED to different levels of care (general ward, monitoring unit, intensive care unit). This original patient disposition was compared with the hypothetical disposition based on an adapted method of net reclassification improvement (NRI), which upgraded or downgraded patients from one level of care to the other based on the MR-proADM test result. RESULTS: MR-pro-ADM was significantly higher in patients who died during the follow-up than in survivors (p<0.0001). When applying the adapted NRI model, 30 additional patients from the European Union (EU) and 55 additional patients from USA were theoretically discharged (increase of 16.5%) if MR-proADM had been used for patient management. The overall NRI, adding up the rates of upgrades and downgrades, in the EU was 16.0% (95% CI 8.2% to 23.9%). A total of n=72 (9.9%) patients changed disposition when adding MR-pro ADM. In the USA, the overall NRI was 12.0% (5.7%-18.4%) and a total of n=81 (11.2%) patients changed disposition. CONCLUSIONS: MR-proADM has the potential to guide initial disposition of undifferentiated ED patients with acute dyspnoea and might therefore be helpful to improve resource utilisation and patient care.

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.

The effect of diabetes on the diagnostic and prognostic performance of mid-region pro-atrial natriuretic peptide and mid-region pro-adrenomedullin in patients with acute dyspnea.

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.

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.

AIMS: 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. METHODS AND RESULTS: The BACH trial was a prospective, international, study of 1641 patients presenting to EDs with dyspnoea. Blood samples were analysed for PCT and other biomarkers. Relevant clinical data were also captured. Patient outcomes were assessed at 90 days. The diagnosis of pneumonia was made using strictly validated guidelines. A model using PCT was more accurate [area under the curve (AUC) 72.3%] than any other individual clinical variable for the diagnosis of pneumonia in all patients, in those with obstructive lung disease, and in those with acute heart failure (AHF). Combining physician estimates of the probability of pneumonia with PCT values increased the accuracy to >86% for the diagnosis of pneumonia in all patients. Patients with a diagnosis of AHF and an elevated PCT concentration (>0.21 ng/mL) had a worse outcome if not treated with antibiotics (P = 0.046), while patients with low PCT values (<0.05 ng/mL) had a better outcome if they did not receive antibiotic therapy (P = 0.049). CONCLUSION: Procalcitonin may aid in the diagnosis of pneumonia, particularly in cases with high diagnostic uncertainty. Importantly, PCT may aid in the decision to administer antibiotic therapy to patients presenting with AHF in which clinical uncertainty exists regarding a superimposed bacterial infection.

Influence of age, race, sex, and body mass index on interpretation of midregional pro atrial natriuretic peptide for the diagnosis of acute heart failure: results from the BACH multinational study.

AIMS: Midregional pro atrial natriuretic peptide (MR-proANP) is useful for diagnosing acute heart failure (HF) in patients presenting to the Emergency Department with dyspnoea. Optimal interpretation of MR-proANP requires understanding of how various demographic variables influence its levels and performance as a diagnostic marker. We sought to determine how age, race, sex, and body mass index (BMI) affect the levels and interpretation of MR-proANP for the diagnosis of acute HF. METHODS AND RESULTS: The Biomarkers in Acute Heart Failure (BACH) study was an international 15-centre study of 1641 patients presenting to the Emergency Department with acute dyspnoea. Of these, 1352 had complete information on age, race, sex, and BMI. MR-proANP levels increased with age and were higher in men and in patients with lower BMI. MR-proANP performed better as a diagnostic marker in younger individuals and in blacks compared with whites. Despite this, MR-proANP at the recommended cut-off point of 120 pmol/L was >90 % sensitive in ruling out the diagnosis of acute HF in all subgroups of patients except white subjects <50 years old. CONCLUSION: Age, race, sex, and BMI affect MR-proANP levels to various degrees. However, the diagnostic performance of the recommended cut-off point of 120 pmol/L to rule out acute HF was robust across most subgroups. Although both sex and BMI affected MR-proANP levels, they did not alter its overall diagnostic performance. Lower cut-off points for MR-proANP could be considered in younger patients and in patients with a higher BMI, to optimize diagnostic sensitivity.

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.

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).

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: http://www.clinicaltrials.gov. Unique identifier: NCT00537628.

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).

Utility of impedance cardiography to improve physician estimation of hemodynamic parameters in the emergency department.

Emergency physicians must often make assessments of complex hemodynamic parameters. To assess the utility of impedance cardiography (ICG) in the emergency department, the authors examined treating physicians' abilities to assess stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) by comparing the clinicians' estimates of these values to ICG measurements. Treating physicians were asked to estimate the SV, CO, and SVR of acutely ill patients as being low, normal, or high. ICG measurements of SV, CO, and SVR were also categorized as low, normal, or high. Physician estimates were compared with ICG measures for concordance. Changes of therapy initiated as a result of discordance between physician's estimates and ICG measurements were recorded. The treating physician assessments and ICG hemodynamic measurements were concordant in 62 of 101 (62%) cases for SV (kappa=0.068), in 53 of 101 (53%) cases for CO (p=0.125), and in 50 of 101 (50%) measurements for SVR (p=0.148). The low concordance suggests that treating physicians did not consistently estimate SV, CO, and SVR accurately. ICG provides noninvasive hemodynamic measurements of SV, CO, and SVR that offer clinical utility and potential value in the emergency department.