Alan H.B. Wu

B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study.

Background—We sought to determine the degree to which B-type natriuretic peptide (BNP) adds to clinical judgment in the diagnosis of congestive heart failure (CHF). Methods and Results—The Breathing Not Properly Multinational Study was a prospective diagnostic test evaluation study conducted in 7 centers. Of 1586 participants who presented with acute dyspnea, 1538 (97%) had clinical certainty of CHF determined by the attending physician in the emergency department. Participants underwent routine care and had BNP measured in a blinded fashion. The reference standard for CHF was adjudicated by 2 independent cardiologists, also blinded to BNP results. The final diagnosis was CHF in 722 (47%) participants. At an 80% cutoff level of certainty of CHF, clinical judgment had a sensitivity of 49% and specificity of 96%. At 100 pg/mL, BNP had a sensitivity of 90% and specificity of 73%. In determining the correct diagnosis (CHF versus no CHF), adding BNP to clinical judgment would have enhanced diagnostic accuracy from 74% to 81%. In those participants with an intermediate (21% to 79%) probability of CHF, BNP at a cutoff of 100 pg/mL correctly classified 74% of the cases. The areas under the receiver operating characteristic curve were 0.86 (95% CI 0.84 to 0.88), 0.90 (95% CI 0.88 to 0.91), and 0.93 (95% CI 0.92 to 0.94) for clinical judgment, for BNP at a cutoff of 100 pg/mL, and for the 2 in combination, respectively (P <0.0001 for all pairwise comparisons). Conclusions—The evaluation of acute dyspnea would be improved with the addition of BNP testing to clinical judgment in the emergency department.

Cardiac Troponin and Outcome in Acute Heart Failure

BACKGROUND Cardiac troponin provides diagnostic and prognostic information in acute coronary syndromes, but its role in acute decompensated heart failure is unclear. The purpose of our study was to describe the association between elevated cardiac troponin levels and adverse events in hospitalized patients with acute decompensated heart failure. METHODS We analyzed hospitalizations for acute decompensated heart failure between October 2001 and January 2004 that were recorded in the Acute Decompensated Heart Failure National Registry (ADHERE). Entry criteria included a troponin level that was obtained at the time of hospitalization in patients with a serum creatinine level of less than 2.0 mg per deciliter (177 micromol per liter). A positive troponin test was defined as a cardiac troponin I level of 1.0 microg per liter or higher or a cardiac troponin T level of 0.1 microg per liter or higher. RESULTS Troponin was measured at the time of admission in 84,872 of 105,388 patients (80.5%) who were hospitalized for acute decompensated heart failure. Of these patients, 67,924 had a creatinine level of less than 2.0 mg per deciliter. Cardiac troponin I was measured in 61,379 patients, and cardiac troponin T in 7880 patients (both proteins were measured in 1335 patients). Overall, 4240 patients (6.2%) were positive for troponin. Patients who were positive for troponin had lower systolic blood pressure on admission, a lower ejection fraction, and higher in-hospital mortality (8.0% vs. 2.7%, P<0.001) than those who were negative for troponin. The adjusted odds ratio for death in the group of patients with a positive troponin test was 2.55 (95% confidence interval, 2.24 to 2.89; P<0.001 by the Wald test). CONCLUSIONS In patients with acute decompensated heart failure, a positive cardiac troponin test is associated with higher in-hospital mortality, independently of other predictive variables. (ClinicalTrials.gov number, NCT00366639 [ClinicalTrials.gov].).

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes

I. OVERVIEW OF THE ACUTE CORONARYSYNDROME e357A. Definition of Terms e357B. Pathogenesis and Management of ACS e357II. USE OF BIOCHEMICAL MARKERS IN THEINITIAL EVALUATION OF ACS e358A. Diagnosis of Myocardial Infarction e3581. Biochemical Markers of MyocardialNecrosis e3582. Optimal Timing of Sample Acquisition.......e3593. Criteria for Diagnosis of MI e3604. Additional Considerations in the Use ofBiomarkers for Diagnosis of MI e360B. Early Risk Stratification e3611. Biochemical Markers of Cardiac Injury.......e361a. Pathophysiology e361b. Relationship to Clinical Outcomes.........e361c. Decision-Limits e362d. Therapeutic Decision-Making e3622. Natriuretic Peptides e362a. Pathophysiology e362b. Relationship to Clinical Outcomes.........e363c. Decision-Limits e364d. Therapeutic Decision-Making e3653. Biochemical Markers of Inflammation........e365a. Pathophysiology e365b. Relationship to Clinical Outcomes.........e365c. Decision-Limits e365d. Therapeutic Decision-Making e3674. Biochemical Markers of Ischemia e3675. Multimarker Approach e3676. Other Novel Markers e368III. USE OF BIOCHEMICAL MARKERS IN THEMANAGEMENT OF NSTEACS e368A. Clinical Decision-Making e3681. Biochemical Markers of Cardiac Injury.......e3682. Other Biochemical Markers e369

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).

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure

### A. Context of Biochemical Marker Testing in Heart Failure Biochemical marker testing has revolutionized the approach to diagnosis and management of heart failure over the past decade. There is an unsurpassed excitement in the heart failure community that significant advances in our understanding of currently available and future cardiac biomarkers will facilitate improved characterization of heart failure disease states and promote individualized therapy in heart failure and beyond. However, like most novel diagnostic tests, the promising findings from pivotal trials have met with ongoing challenges when applied in the clinical setting. The material discussed in this guidelines document addresses clinical use of BNP/NT-proBNP and cardiac troponin testing in the context of heart failure diagnosis, risk stratification and management, including therapeutic guidance in adult (>18 year-old) patients. Together with the associated document titled “ National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure ”, …

Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 -1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 -1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 -1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the -1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

Biological variation for N-Terminal Pro- and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure

Given the limitations of low enrollments, this study suggests that a change of 130% for B-type natiuretic peptide (BNP) and 90% for N-terminal (NT)-proBNP are necessary before results of serially collected data can be considered statistically different. This study also shows that there are important differences in the performance of BNP versus NT-proBNP in monitoring patients with congestive heart failure that need to be further explored.

Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis

Abstract Objectives To evaluate the haematological findings of patients with severe acute respiratory syndrome (SARS). Design Analysis of the demographic, clinical, and laboratory characteristics of patients with SARS. Setting Prince of Wales Hospital, Hong Kong. Subjects All patients with a diagnosis of SARS between 11 March and 29 March 2003 who had no pre-existing haematological disorders. Main outcome measures Clinical end points included the need for intensive care and death. Univariate and multivariate analyses were performed to examine factors associated with adverse outcome. Results 64 male and 93 female patients were included in this study. The most common findings included lymphopenia in 153 (98%) of the 157 patients, neutrophilia in 129 (82%), thrombocytopenia in 87 patients (55%), followed by thrombocytosis in 77 (49%), and isolated prolonged activated partial thromboplastin time in 96 patients (63%). The haemoglobin count dropped by more than 20 g/l from baseline in 95 (61%) patients. Four patients (2.5%) developed disseminated intravascular coagulation. Lymphopenia was shown in haemato-lymphoid organs at postmortem examination. Multivariate analysis showed that advanced age and a high concentration of lactate dehydrogenase at presentation were independent predictors of an adverse outcome. Subsets of peripheral blood lymphocytes were analysed in 31 patients. The counts of CD4 positive and CD8 positive T cells fell early in the course of illness. Low counts of CD4 and CD8 cells at presentation were associated with adverse outcomes. Conclusions Abnormal haematological variables were common among patients with SARS. Lymphopenia and the depletion of T lymphocyte subsets may be associated with disease activity.

Short- and Long-Term Biological Variation in Cardiac Troponin I Measured with a High-Sensitivity Assay: Implications for Clinical Practice

BACKGROUND The improved detection limit and precision in new-generation commercial assays for cardiac troponin I (cTnI) have lowered the 99th-percentile cutoff value, yielding higher frequencies of positive test results. Because serial testing is important in interpreting low concentrations, we evaluated the biological variation of cTnI in both the short (hours) and long (weeks) terms and determined reference change values (RCVs) and the index of individuality (II) for cTnI. METHODS To assess short- and long-term variation, we collected blood from 12 healthy volunteers hourly for 4 h and from 17 healthy individuals once every other week for 8 weeks, measured cTnI with a high-sensitivity assay (detection limit, 0.2 ng/L), and computed analytical, intraindividual, interindividual, and total CVs (CV(A), CV(I), CV(G), and CV(T), respectively; CV(T) = CV(A) + CV(I) + CV(G)) as well as the II. Because of the slight right-skewness of the data, RCVs were calculated with a lognormal approach. RESULTS Within-day CV(A), CV(I), and CV(G) values were 8.3%, 9.7%, and 57%, respectively; the corresponding between-day values were 15%, 14%, and 63%. Within- and between-day IIs were 0.21 and 0.39, respectively. Lognormal within-day RCVs were 46% and -32%, respectively; the corresponding between-day values were 81% and -45%. CONCLUSIONS The low II indicates that population-based reference intervals are less useful for interpreting cTnI values than following serial changes in values in individual patients. This criterion is particularly important for interpreting results from patients who show cTnI increases at low concentrations measured with very high-sensitivity assays, from patients presenting with chest pain (short term), and for evaluating drugs for cardiotoxicity (long term).

High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure

Background—Soluble ST2 reflects activity of an interleukin-33–dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches. Methods and Results—We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ⩽22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P<0.0001) that remained significant after multivariable adjustment (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.9; P=0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B–type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P=0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P=0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories (P=0.017). Conclusions—ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.