Mihael Potocki

Early Diagnosis of Myocardial Infarction with Sensitive Cardiac Troponin Assays

BACKGROUND The rapid and reliable diagnosis of acute myocardial infarction is a major unmet clinical need. METHODS We conducted a multicenter study to examine the diagnostic accuracy of new, sensitive cardiac troponin assays performed on blood samples obtained in the emergency department from 718 consecutive patients who presented with symptoms suggestive of acute myocardial infarction. Cardiac troponin levels were determined in a blinded fashion with the use of four sensitive assays (Abbott-Architect Troponin I, Roche High-Sensitive Troponin T, Roche Troponin I, and Siemens Troponin I Ultra) and a standard assay (Roche Troponin T). The final diagnosis was adjudicated by two independent cardiologists. RESULTS Acute myocardial infarction was the adjudicated final diagnosis in 123 patients (17%). The diagnostic accuracy of measurements obtained at presentation, as quantified by the area under the receiver-operating-characteristic curve (AUC), was significantly higher with the four sensitive cardiac troponin assays than with the standard assay (AUC for Abbott-Architect Troponin I, 0.96; 95% confidence interval [CI], 0.94 to 0.98; for Roche High-Sensitive Troponin T, 0.96; 95% CI, 0.94 to 0.98; for Roche Troponin I, 0.95; 95% CI, 0.92 to 0.97; and for Siemens Troponin I Ultra, 0.96; 95% CI, 0.94 to 0.98; vs. AUC for the standard assay, 0.90; 95% CI, 0.86 to 0.94). Among patients who presented within 3 hours after the onset of chest pain, the AUCs were 0.93 (95% CI, 0.88 to 0.99), 0.92 (95% CI, 0.87 to 0.97), 0.92 (95% CI, 0.86 to 0.99), and 0.94 (95% CI, 0.90 to 0.98) for the sensitive assays, respectively, and 0.76 (95% CI, 0.64 to 0.88) for the standard assay. We did not assess the effect of the sensitive troponin assays on clinical management. CONCLUSIONS The diagnostic performance of sensitive cardiac troponin assays is excellent, and these assays can substantially improve the early diagnosis of acute myocardial infarction, particularly in patients with a recent onset of chest pain. (ClinicalTrials.gov number, NCT00470587.)

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 Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of Acute Myocardial Infarction

Background— Current guidelines for the diagnosis of acute myocardial infarction (AMI), among other criteria, also require a rise and/or fall in cardiac troponin (cTn) levels. It is unknown whether absolute or relative changes in cTn have higher diagnostic accuracy and should therefore be preferred. Methods and Results— In a prospective, observational, multicenter study, we analyzed the diagnostic accuracy of absolute (&Dgr;) and relative (&Dgr;%) changes in cTn in 836 patients presenting to the emergency department with symptoms suggestive of AMI. Blood samples for the determination of high-sensitive cTn T and cTn I ultra were collected at presentation and after 1 and 2 hours in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists. The area under the receiver operating characteristic curve for diagnosing AMI was significantly higher for 2-hour absolute (&Dgr;) versus 2-hour relative (&Dgr;%) cTn changes (area under the receiver operating characteristic curve [95% confidence interval], high-sensitivity cTn T: 0.95 [0.92 to 0.98] versus 0.76 [0.70 to 0.83], P<0.001; cTn I ultra: 0.95 [0.91 to 0.99] versus 0.72 [0.66 to 0.79], P<0.001). The receiver operating characteristic curve–derived cutoff value for 2-hour absolute (&Dgr;) change was 0.007 &mgr;g/L for high-sensitivity cTn T and 0.020 &mgr;g/L for cTn I ultra (both cutoff levels are half of the 99th percentile of the respective cTn assay). Absolute changes were superior to relative changes in patients with both low and elevated baseline cTn levels. Conclusions— Absolute changes of cTn levels have a significantly higher diagnostic accuracy for AMI than relative changes, and seem therefore to be the preferred criteria to distinguish AMI from other causes of cTn elevations. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Incremental value of copeptin for rapid rule out of acute myocardial infarction.

OBJECTIVES The purpose of this study was to examine the incremental value of copeptin for rapid rule out of acute myocardial infarction (AMI). BACKGROUND The rapid and reliable exclusion of AMI is a major unmet clinical need. Copeptin, the C-terminal part of the vasopressin prohormone, as a marker of acute endogenous stress may be useful in this setting. METHODS In 487 consecutive patients presenting to the emergency department with symptoms suggestive of AMI, we measured levels of copeptin at presentation, using a novel sandwich immunoluminometric assay in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists using all available data. RESULTS The adjudicated final diagnosis was AMI in 81 patients (17%). Copeptin levels were significantly higher in AMI patients compared with those in patients having other diagnoses (median 20.8 pmol/l vs. 6.0 pmol/l, p < 0.001). The combination of troponin T and copeptin at initial presentation resulted in an area under the receiver-operating characteristic curve of 0.97 (95% confidence interval: 0.95 to 0.98), which was significantly higher than the 0.86 (95% confidence interval: 0.80 to 0.92) for troponin T alone (p < 0.001). A copeptin level <14 pmol/l in combination with a troponin T < or =0.01 microg/l correctly ruled out AMI with a sensitivity of 98.8% and a negative predictive value of 99.7%. CONCLUSIONS The additional use of copeptin seems to allow a rapid and reliable rule out of AMI already at presentation and may thereby obviate the need for prolonged monitoring and serial blood sampling in the majority of patients. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE]; NCT00470587).

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.

Use of Myeloperoxidase for Risk Stratification in Acute Heart Failure

BACKGROUND Myeloperoxidase (MPO) is a biomarker of inflammation and oxidative stress produced by neutrophils, monocytes, and endothelial cells. Concentrations of MPO predict mortality in patients with chronic heart failure. This study sought to investigate the diagnostic accuracy and prognostic value of MPO in patients with acute heart failure (AHF). METHODS We prospectively enrolled 667 patients presenting to the emergency department with dyspnea and observed them for 1 year. MPO and B-type natriuretic peptide (BNP) were measured at presentation. Two independent cardiologists adjudicated final discharge diagnoses. RESULTS MPO concentrations were similar in patients with AHF (n = 377, median 139 pmol/L) and patients with noncardiac causes of dyspnea (n = 290, median 150 pmol/L, P = 0.26). The diagnostic accuracy of MPO for AHF was limited [area under the ROC curve (AUC) 0.53] and inferior to that of BNP (AUC 0.95, P < 0.001). In patients with AHF, MPO concentrations above the lowest tertile (MPO >99 pmol/L) were associated with significantly increased 1-year mortality (hazard ratio 1.58, P = 0.02). The combination of MPO (< or = 99 vs >99 pmol/L) and BNP (median of < or = 847 vs >847 ng/L) improved the prediction of 1-year mortality (hazard ratio 2.80 for both variables increased vs both low, P < 0.001). After adjustment for cardiovascular risk factors in multivariable Cox proportional hazard analysis, increases in MPO contributed significantly toward the prediction of 1-year mortality (hazard ratio 1.51, P = 0.045). CONCLUSIONS MPO is an independent predictor of 1-year mortality in AHF, is additive to BNP, and could be helpful in identifying patients with a favorable prognosis despite increased BNP concentrations.

Midregional pro-Adrenomedullin in addition to b-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study

IntroductionThe identification of patients at highest risk for adverse outcome who are presenting with acute dyspnea to the emergency department remains a challenge. This study investigates the prognostic value of the newly described midregional fragment of the pro-Adrenomedullin molecule (MR-proADM) alone and combined to B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) in patients with acute dyspnea.MethodsWe conducted a prospective, observational cohort study in the emergency department of a University Hospital and enrolled 287 unselected, consecutive patients (48% women, median age 77 (range 68 to 83) years) with acute dyspnea.ResultsMR-proADM levels were elevated in non-survivors (n = 77) compared to survivors (median 1.9 (1.2 to 3.2) nmol/L vs. 1.1 (0.8 to 1.6) nmol/L; P < 0.001). The areas under the receiver operating characteristic curve (AUC) to predict 30-day mortality were 0.81 (95% CI 0.73 to 0.90), 0.76 (95% CI 0.67 to 0.84) and 0.63 (95% CI 0.53 to 0.74) for MR-proADM, NT-proBNP and BNP, respectively (MRproADM vs. NTproBNP P = 0.38; MRproADM vs. BNP P = 0.009). For one-year mortality the AUC were 0.75 (95% CI 0.69 to 0.81), 0.75 (95% CI 0.68 to 0.81), 0.69 (95% CI 0.62 to 0.76) for MR-proADM, NT-proBNP and BNP, respectively without any significant difference. Using multivariate linear regression analysis, MR-proADM strongly predicted one-year all-cause mortality independently of NT-proBNP and BNP levels (OR = 10.46 (1.36 to 80.50), P = 0.02 and OR = 24.86 (3.87 to 159.80) P = 0.001, respectively). Using quartile approaches, Kaplan-Meier curve analyses demonstrated a stepwise increase in one-year all-cause mortality with increasing plasma levels (P < 0.0001). Combined levels of MR-proADM and NT-proBNP did risk stratify acute dyspneic patients into a low (90% one-year survival rate), intermediate (72 to 82% one-year survival rate) or high risk group (52% one-year survival rate).ConclusionsMR-proADM alone or combined to NT-proBNP has a potential to assist clinicians in risk stratifying patients presenting with acute dyspnea regardless of the underlying disease.