Heart failure (HF) is a major and growing public health

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1 Increased 90-Day Mortality in Patients With Acute Heart Failure With Elevated Copeptin Secondary Results From the Biomarkers in Acute Heart Failure (BACH) Study Alan Maisel, MD; Yang Xue, MD; Kevin Shah, BS; Christian Mueller, MD; Richard Nowak, MD; W. Frank Peacock, MD, FACEP; Piotr Ponikowski, MD, PhD, FESC; Martin Mockel, MD, FESC, FAHA; Christopher Hogan, MD; Alan H.B. Wu, PhD; Mark Richards, MD, PhD, FRACP; Paul Clopton, MS; Gerasimos S. Filippatos, MD, FACC, FCCP, FESC; Salvatore Di Somma, MD; Inder S. Anand, MD, FRCP, DPhil (Oxon); Leong Ng, MD; Lori B. Daniels, MD, MAS, FACC; Sean-Xavier Neath, MD, PhD; Robert Christenson, PhD, DABCC, FACB; Mihael Potocki, MD; James McCord, MD; Garret Terracciano, BS; Dimitrios Kremastinos, MD; Oliver Hartmann, MSc; Stephan von Haehling, MD; Andreas Bergmann, PhD; Nils G. Morgenthaler, MD, PhD; Stefan D. Anker, MD, PhD 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: NCT (Circ Heart Fail. 2011;4: ) Key Words: heart failure sodium death copeptin vasopressin Heart failure (HF) is a major and growing public health issue in the United States. 1 Accurate prognostic evaluation can help to identify highrisk individuals who would benefit from closer follow-up and more intensive intervention. The Biomarkers in Acute Heart Failure (BACH) trial was a multinational study of 1641 patients who presented to the emergency department (ED) with acute dyspnea. In the primary analysis of BACH, midregion prohormone adrenomedullin was shown to be highly prognostic in patients with acute HF. 2 The secondary goal of the study was to Received November 14, 2010; accepted June 14, From the VA San Diego Healthcare System, San Diego, CA (A.M., Y.X., K.S., P.C.); University Hospital Basel, Basel, Switzerland (C.M., M.P.); Henry Ford Health System, Detroit, MI (R.N., J.M.); The Cleveland Clinic, Cleveland, OH (W.F.P.); Medical University, Faculty of Public Health, Wroclaw, Poland (P.P.); Charite, Campus Virchow-Klinikum, Berlin, Germany (M.M., S.H., S.D.A.); Virginia Commonwealth University, Richmond, VA (C.H.); University of California San Francisco, San Francisco, CA (A.H.B.W.); University of Otago, Christchurch, New Zealand (M.R.); Athens University Hospital Attikon, Athens, Greece (D.K.); Sant Andrea Hospital, University La Sapienza, Rome, Italy (S.D.S.); VA Minneapolis, Minneapolis, MN (I.S.A.); University of Leicester and NIHR Cardiovascular BRU, Leicester, United Kingdom (L.N.); University of California San Diego, San Diego, CA (A.M., Y.X., K.S., L.B.D., S.-X.N.); University of Maryland, Baltimore, MD (R.C.); University of California San Diego, School of Medicine, San Diego, CA (G.T.); BRAHMS GmbH Biotechnology Centre Hennigsdorf, Berlin, Germany (O.H., A.B., N.G.M.); and Centre for Clinical and Basic Research IRCCS San Raffaele, Rome, Italy (S.D.A.). Correspondence to Yang Xue, MD, University of California San Diego, 200 W Arbor Dr, MC 8411, San Diego, CA yxue100@yahoo.com 2011 American Heart Association, Inc. Circ Heart Fail is available at DOI: /CIRCHEARTFAILURE

2 614 Circ Heart Fail September 2011 evaluate the prognostic potential of other novel biomarkers. Copeptin, the C-terminal fragment of the arginine vasopressin (AVP) precursor, preprovasopression, was one of the biomarkers evaluated in the BACH study. Clinical Perspective on p 620 It is well known that patients with severe HF commonly present with hyponatremia, which is an indicator of poor prognosis. 3,4 Hyponatremia in Patients with HF is mediated in part by AVP, which is a posterior pituitary peptide hormone with both antidiuretic and vasoconstrictive properties. AVP concentrations are commonly elevated in patients with HF. 5 Despite its critical role in free water regulation, AVP is a suboptimal biomarker due its in vitro instability and rapid clearance. 6 Copeptin is synthesized and secreted in equimolar amounts to AVP. Both AVP and copeptin have short halflives in vivo. Therefore, plasma copeptin concentrations mirror plasma AVP concentrations. Unlike AVP, copeptin is very stable in vitro, making it an ideal surrogate biomarker for AVP. 7 Previous studies have shown that increased copeptin concentration is a strong predictor of mortality in patients with chronic HF and HF caused by acute myocardial infarction. 8,9,10 This secondary analysis of the BACH trial aims to evaluate the effectiveness of copeptin as a prognostic biomarker in patients with acute HF. Methods The methods of the BACH study were previously reported in detail. 2 Briefly, 1641 patients presenting to the ED with acute dyspnea were prospectively enrolled in the study. To determine the gold standard diagnosis of acute HF, 2 cardiologists independently reviewed all medical records pertaining to the patients and classified the diagnosis as dyspnea caused by acute HF or other causes. For the current analysis, BACH patients were included if they had a primary diagnosis of acute HF by the reviewing cardiologists and had both copeptin and sodium concentrations measured during the initial evaluation. Biomarker Measurement All blood samples were collected in ethylenediaminetetraacetic acid (EDTA)-containing plastic tubes through venipuncture. Plasma was separated from the blood sample immediately and stored at 70 C. The plasma samples were then sent to a central laboratory at the University of Maryland School of Medicine for biomarker analysis. Copeptin was measured with a standard sandwich immunoluminometric assay (B.R.A.H.M.S. LUMItest CT-proAVP, B.R.A.H.M.S AG, Hennigsdorf/Berlin, Germany), which was described in detail in previous studies This assay used a murine monoclonal antibody directed to amino acids 137 to 144 (GPAGAL) of preprovasopressin as a capture antibody. Performance of the copeptin assay included a limit of quantification of 0.4 pmol/l and within-run imprecision of 10%. Total imprecision was 10% for levels 9 pmol/l and 20% for levels 2.25 pmol/l. B-type natriuretic peptide (BNP) was measured with a Triage 2-site immunoassay (Biosite, San Diego, CA) formatted for Beckman-Coulter instrumentation (Brea, California). Performance of the BNP assay in the laboratory included a limit of quantification of 5.0 ng/l, within-run imprecision of 1.5%, and total imprecision of 3.0%. N-terminal pro B-type natriuretic peptide (NT-proBNP) was measured by electrochemiluminescence on the Elec- Sys 2010 analyzer (Roche Diag-nostics, Indianapolis, IN). Performance in the laboratory included a limit of quantification of 10.0 ng/l, within-run imprecision of 1.5%, and total imprecision of 3.0%. Statistical Analysis Values are expressed as means and standard deviations or counts and percentages as appropriate. Diagnostic groups were compared with the use of independent-samples t tests, 2 tests, ANOVA, Kruskal- Wallis tests, and Mann Whitney tests as appropriate. Correlation between sodium and copeptin was tested by Spearman test. All analyses were exploratory and used a probability value of 0.05 for significance. For the prognostic evaluation of copeptin, we first constructed Kaplan Meier survival curves and performed log rank tests for mortality by copeptin quartiles and by subgroups divided by a predetermined sodium cut-point of 135 meq/l and copeptin median. We then performed Cox regressions for copeptin quartiles for the mortality end point and the 4 subgroups, based on sodium and copeptin cut-points for the mortality end point, the combined end point of mortality and HF-related readmission, and the combined end point of mortality, HF related readmission, and HF-related ED visits. Copeptin quartile 1 and the elevated sodium and low copeptin subgroup were used as the comparison groups. Correlation and interaction between sodium and copeptin was also analyzed. Receiver operating characteristic (ROC) curves were generated for copeptin, BNP, sodium, and NT-proBNP. Optimal cut-points for NT-proBNP and Copeptin were selected on the basis of the points closest to the left upper corner of their respective ROC curves. We then performed univariate Cox regressions for the prediction of mortality for NT-proBNP and copeptin. A multivariate analysis including copeptin, sodium, and NT-proBNP by their respective cut-points was also performed. To construct a multivariate model for the prediction of mortality, we performed univariate analysis for clinical and laboratory predictors of mortality (Table 1). For the statistically significant parameters with the exception of the biomarkers, we ran a stepwise multivariate analysis by Cox model both forward and backward. Significant parameters from this multivariate analysis were included in a new multivariate analysis, which also included sodium, copeptin, and NT-proBNP. To determine the incremental value of sodium and copeptin, we first constructed a multivariate model with body mass index (BMI), systolic blood pressure (BP), and NT-proBNP. We then added sodium and copeptin individually to this model to determine their incremental 2 value. We also calculated the incremental C-statistic when both sodium and copeptin were added to this model. 12 Net reclassification improvement for the mortality end point was calculated for adding copeptin to NT-proBNP, adding copeptin to sodium, and adding both sodium and copeptin added to NT-proBNP. Results Baseline Characteristics In the BACH trial, 1641 subjects were originally enrolled, of which 568 were diagnosed with acute HF. From the acute HF cohort, 557 patients with valid measurements of sodium and copeptin were included in the current analysis. Of this group, there were 64 deaths, 149 death- or HF-related readmission events, and 172 death- or HF-related readmission or HF related ED visit events. Patient demographic information by mortality within 90 days versus alive after 90 days is summarized in Table 1. Demographic information of the 4 subgroups by sodium and copeptin medians is summarized in Table 2. Sodium and Copeptin in HF There was no correlation between copeptin and sodium concentrations by Spearman test (r 0.047). Copeptin concentrations by quartiles of sodium were very similar without significant differences between the 4 groups (P 0.438) (Figure 1). The prognostic effects of sodium and copeptin were additive (P 0.001) but not synergistic (P 0.376).

3 Maisel et al Copeptin and Heart Failure Mortality 615 Table 1. Demographic Information by Alive Versus Mortality Parameter Alive After 90 Days Mortality Within 90 Days P Value Age Heart rate Temperature Systolic blood pressure Diastolic blood pressure Respiratory rate Body mass index Black race 22.6% 9.5% Male 62.9% 57.8% Smoking 78.0% 71.2% Supplemental oxygen 41.7% 46.9% Wheezing 20.6% 24.6% 0.49 Weight gain 27.5% 32.0% Paroxysmal nocturnal dyspnea 47.8% 41.0% Orthopnea 63.8% 62.9% Dyspnea at rest 49.5% 58.7% S 3 6.6% 8.1% Heart murmur 26.6% 41.3% Edema 60.7% 68.7% Rales 53.6% 64.1% Jugular venous distension 36.4% 50.0% Arrhythmia 42.5% 50.8% Asthma 6.1% 1.6% Chronic renal insufficiency 30.1% 41.0% Congestive heart failure 65.2% 64.5% 0.92 Coronary artery disease 49.3% 52.5% Chronic obstructive pulmonary 23.5% 27.4% disease Diabetes 38.3% 38.1% Hyperlipidemia 46.5% 37.9% Hypertension 79.1% 74.2% 0.38 Myocardial infarction 31.4% 32.8% Pneumonia 15.8% 13.8% Pulmonary embolism 6.5% 6.4% Coronary artery bypass graft 16.5% 14.3% 0.65 Angioplasty/stent 19.9% 18.0% Stroke 12.1% 25.0% Pacemaker/defibrillator 19.6% 12.5% Prosthetic valve 5.0% 6.4% Blood urea nitrogen, mg/dl 23.0 ( ) 31.0 ( ) Creatinine, mg/dl 1.2 ( ) 1.4 ( ) B-type natriuretic peptide, ng/l ( ) ( ) N-terminal pro B-type natriuretic ( ) ( ) peptide, ng/l Sodium, meq/l 139 ( ) 137 ( ) Copeptin, pmol/l 24.2 ( ) 55.2 ( ) Values are mean SD unless otherwise shown. Median values are shown with 25th to 75th percentile ranges in parentheses.

4 616 Circ Heart Fail September 2011 Table 2. Demographic Information by Sodium and Copeptin Median Parameter Elevated Sodium, Low Copeptin (n 118) Low Sodium, Low Copeptin (n 160) Elevated Sodium, Elevated Copeptin (n 135) Low Sodium, Elevated Copeptin (n 144) P Value Age Heart rate Temperature Systolic blood pressure Diastolic blood pressure Respiratory rate Body mass index Black 20.3% 17.6% 25.4% 21.7% 0.44 Male 55.9% 60.6% 68.9% 63.2% Smoking 25.6% 21.8% 24.8% 19.7% Supplemental oxygen 6.0% 9.6% 10.0% 9.1% Wheezing 15.2% 17.6% 29.3% 22.3% Weight gain 29.2% 26.4% 31.4% 25.2% Paroxysmal nocturnal dyspnea 53.1% 45.1% 52.5% 45.8% Orthopnea 57.9% 57.0% 72.7% 67.6% Dyspnea at rest 45.3% 46.5% 56.8% 53.6% S 3 7.4% 4.3% 10.9% 6.5% Murmur 25.7% 27.0% 23.0% 39.3% Edema 53.9% 61.1% 66.3% 70.1% Rales 53.2% 49.0% 58.5% 64.2% Jugular venous distension 34.7% 33.0% 34.9% 54.5% Arrhythmia 41.4% 41.6% 46.1% 44.6% Asthma 5.2% 6.3% 6.3% 4.2% Chronic renal insufficiency 14.8% 18.7% 42.3% 48.2% Congestive heart failure 63.2% 56.3% 70.5% 71.3% 0.02 Coronary artery disease 55.0% 44.9% 45.7% 54.2% Chronic obstructive pulmonary 16.5% 21.4% 22.5% 34.0% disease Diabetes 36.4% 35.8% 46.6% 34.7% Hyperlipid 44.2% 49.0% 47.1% 41.7% Hypertension 77.1% 74.2% 84.1% 79.2% Myocardial infarction 38.3% 27.8% 30.2% 31.4% Pneumonia 16.8% 15.8% 12.1% 17.4% Pulmonary embolus 6.1% 7.6% 5.6% 6.3% Coronary artery bypass graft 15.5% 17.6% 10.9% 20.3% Angioplasty 19.8% 21.0% 18.4% 19.1% Stroke 13.9% 14.6% 11.7% 13.9% Pacemaker/defibrillator 14.5% 17.7% 21.5% 20.8% Prosthetic valve 1.7% 5.7% 3.9% 8.4% Blood urea nitrogen, mg/dl 18 ( ) 19 ( ) 29.9 ( ) 33.3 ( ) Creatinine, mg/dl 1.0 ( ) 1.04 ( ) 1.40 ( ) 1.50 ( ) B-type natriuretic peptide, ng/l 523 ( ) 564 ( ) 1033 ( ) 1105 ( ) N-terminal pro B-type natriuretic peptide, ng/l 2863 ( ) 3879 ( ) 7703 ( ) 8243 ( ) Values are mean SD unless otherwise shown. Median values are shown with 25th to 75th percentile ranges in parentheses. Prognostic Value of Copeptin in HF When copeptin was divided into deciles, most of the mortalities occurred in deciles 8 to 10 (Figure 2). When analyzed as quartiles, patients in the highest copeptin quartile had significantly increased 90-day mortality when compared with patients in the lowest copeptin quartile (P 0.001, hazard ratio [HR], 3.85), whereas patients in the second and third quartiles did not have significantly increased mortality (Figure 3 and Table 3).

5 Maisel et al Copeptin and Heart Failure Mortality 617 Figure 1. Copeptin concentration by sodium quartiles. The ROC curve for morality according to BNP had an area under the curve (AUC) of and standard error (SE) of The ROC curve for morality according to NT-proBNP had an AUC of and SE of The ROC curve for morality according to copeptin had an AUC of and SE of The ROC curve for morality according to sodium had an AUC of and SE of Because NT-proBNP had higher AUC than BNP, NT-proBNP was used in our multivariate model. ROC for the mortality end point for NT-proBNP, BNP, copeptin, and sodium are shown in Figure 4. Optimal cut-points by ROC for copeptin and NT-proBNP were 38.5 pmol/l and 6305 ng/l, respectively. A predetermined sodium cut-point of 135mEq/L was used in our analyses. Both NT-proBNP and copeptin were statistically significant predictors of mortality by univariate analysis (NT-proBNP: P 0.001, hazard ratio [HR], 3.466; Copeptin: P 0.001, HR, 2.872). Copeptin, sodium, and NT-proBNP by their cut-points were statistically significant predictors of mortality in a multivariate model (copeptin: P 0.007, HR, 2.115; sodium: P 0.001, HR, 2.739; NT-proBNP: P 0.003, HR, 2.383). Statistically significant clinical and laboratory predictors of mortality in our patient population were age (P 0.01), Figure 2. Mortality by deciles of copeptin. Figure 3. Survival by copeptin quartiles. systolic BP (P 0.001), diastolic BP (P 0.04), BMI (P 0.001), black race (P 0.022), cardiac murmur on examination (P 0.019), jugular venous distention (P 0.038), wheezing on examination (P 0.013), history of stroke (P 0.005), log creatinine (P 0.020), log blood urea nitrogen (P 0.018), NT-proBNP (P 0.001), copeptin (P 0.001), and sodium (P 0.001). When these parameters with the exception of sodium, copeptin, and NT-proBNP were entered into a stepwise multivariate analysis by Cox model, log creatinine (P 0.006), systolic BP (P 0.010), and BMI (P 0.001) were statistically significant. In a subsequent multivariate analysis with log creatinine, systolic BP, BMI, NT-proBNP, copeptin, and sodium, statistically significant parameters were systolic BP, BMI, copeptin, and sodium. Log creatinine and NT-proBNP did not reach statistical significance in this model (Table 4). When patients were divided into subgroups on the basis of copeptin median (26.99 pmol/l) and the predetermined sodium cut-point of 135mEq/L, mortality was significantly increased in the elevated sodium and elevated copeptin subgroup and the low sodium and elevated copeptin subgroup when compared with patients in the elevated sodium and low copeptin subgroup (P , HR, and P 0.001, HR, 7.364, respectively) (Figure 5). For the composite end point Table 3. Cox Regression for All-Cause Mortality by Copeptin Quartiles Copeptin Quartiles Intergroup variability Copeptin quartile 2, cutoff: 11 pmol/l Copeptin quartile 3, cutoff: 27 pmol/l Copeptin quartile 4, cutoff: 57 pmol/l Hazard Ratio Lower CI indicates confidence interval. All curves are compared with copeptin quartile 1. Upper P Value

6 618 Circ Heart Fail September 2011 Figure 4. Receiver operating characteristic for N-terminal pro-btype natriuretic peptide (NT-proBNP), copeptin, sodium, and B-type natriuretic peptide (BNP). of 90-day mortality and HF-related readmission (149 events), compared with the elevated sodium and low copeptin subgroup, the elevated sodium and elevated copeptin subgroup and the low sodium and elevated copeptin subgroup both had increased event rates (P 0.027, HR, and P 0.001, HR, 4.264, respectively). For the composite end point of mortality, HF-related readmission and HF-related ED visit (172 events), significantly increased event rates were again seen in the elevated sodium and elevated copeptin subgroup and the low sodium and elevated copeptin subgroup (P , HR, and P 0.001, HR, 3.871, respectively) (Table 5). When sodium was added to a model including BMI, systolic BP, and NT-proBNP, the incremental 2 was (P 0.012). When copeptin was added to the same model, the incremental 2 was 4.13 (P 0.042). The C-statistic for the model including BMI, systolic BP, and NT-proBNP was (95% confidence interval [CI], to 0.789). Adding both sodium and copeptin to the model raised the C-statistic to (, to 0.817). Furthermore, when copeptin was added to NT-proBNP for the mortality end point, the net reclassification improvement (NRI) was 11.2% (P 0.096). When copeptin was added to sodium for the mortality end point, the NRI was 27.4% (P 0.001). When both sodium and copeptin was added to NT-proBNP for the mortality end point, the NRI was 32.7% (P 0.001). Figure 5. Survival by copeptin median and sodium cut-point of 135 meq/l. Discussion This current study was the first large-scale investigation to evaluate the prognostic potential of copeptin in patients with acute HF. This study demonstrated that elevated copeptin concentrations were associated with increased 90-day mortality, HF-related readmissions, and HF-related ED visits in patients with acute HF, highlighting the prognostic utility of copeptin. For the prediction of 90-day mortality in patients with acute HF, copeptin was comparable to NT-proBNP and added incremental predictive value to clinical predictors of mortality. Although there were large variations in the copeptin and sodium concentrations in this study, we found that sodium and copeptin were independent predictors of mortality with additive prognostic value. Patients with elevated copeptin concentrations had significantly increased risk for 90-day mortality and adverse outcomes, especially in those with concurrent hyponatremia. Prior studies have shown that AVP was a major contributor to hyponatremia and that hyponatremia was associated with poor prognosis in Patients with HF. 5,6 Although AVP was a major contributor to hyponatremia, there was no correlation between sodium and copeptin concentrations in our acute HF population. This observation was noted in previous studies as well. 5 The lack of correlation between sodium and copeptin concentrations in our study might be due to the complex interactions of various pathophysiological processes and Table 4. Multivariate Analysis by Cox Model for the End Point of Mortality With Parameters Including Significant Clinical and Laboratory Predictors of Mortality, With Sodium, Copeptin, and NT pro-bnp by Cut-Point Parameter Hazard Ratio Lower Lower P Value Systolic blood pressure, mm Hg Body mass index, kg/m Sodium by cut-point, 135 meq/l Copeptin by cut-point, 38.5 pmol/l NT-pro-BNP cut-point, 6305 ng/l Log creatinine, mg/dl CI indicates confidence interval.

7 Maisel et al Copeptin and Heart Failure Mortality 619 Table 5. Cox Regression for Mortality, the Composite End Point of Mortality and Heart Failure Related Readmission, and the Composite End Point of Mortality, Heart Failure Related Readmission, and Heart Failure Related Emergency Department Visit Hazard Ratio Lower Upper P Value End point: Mortality Intergroup variability High sodium, high copeptin Low sodium, low copeptin Low sodium, high copeptin End point: Mortality and readmission Intergroup variability High sodium, high copeptin Low sodium, low copeptin Low sodium, high copeptin End point: Mortality, readmission, and emergency department visit Intergroup variability High sodium, high copeptin Low sodium, low copeptin Low sodium, high copeptin CI indicates confidence interval. Patients were divided into 4 subgroups by copeptin median (26.99 pmol/l) and sodium cut-point 135 meq/l. All subgroups were compared with the subgroup with elevated sodium and low copeptin. medications involved in sodium and free water regulation in patients with acute HF. Because copeptin concentrations were directly related to AVP concentrations, it could be postulated that elevated AVP concentrations is a potent predictor for mortality, rehospitalization, and ED visits in acute Patients with HF, especially in those with hyponatremia. We must also point out that the correlation between elevated copeptin concentrations and mortality did not necessarily establish a causal relationship. Lately, the association between hyponatremia and increased mortality prompted great interest in using AVP antagonists to treat Patients with HF with hyponatremia. Although AVP antagonists have been used to treat hyponatremia in the general population with encouraging results, efforts to use them in Patients with HF were not as successful. 13 The findings from our study might suggest why AVP antagonists were not effective in all Patients with HF. Future studies using AVP antagonists should be considered in patients with elevated copeptin concentrations and low sodium concentrations because these patients are most likely to have mortality benefit from AVP antagonist therapy. Our study was limited by the modest size of the acute HF cohort and short follow-up period, resulting in a relatively small number of mortality end points, which limited the number of covariates that could be analyzed in the multivariate models. Future studies focusing primarily on a larger acute HF cohort with longer follow-up are needed to confirm the findings of our study and to further examine the incremental prognostic value copeptin adds to traditional clinical predictors and current biomarkers. In conclusion, elevated copeptin concentrations were associated with increased 90-day mortality, HF-related readmissions, and HF-related ED visits in patients with acute HF. In addition, mortality was significantly increased in the subgroup of patients with elevated copeptin and hyponatremia. Copeptin was an excellent predictor of 90-day mortality in multivariate models and provided additional prognostic information over sodium and clinical predictors. When combined, sodium and copeptin provided significant incremental prognostic value to clinical predictors of mortality and NT-proBNP. These findings from the BACH trial demonstrated the utility of using the novel biomarker copeptin to risk stratify patients with acute HF. Sources of Funding This study was supported by BRAHMS GmbH Biotechnology Centre, Hennigsdorf, Berlin, Germany. Disclosures Dr Mueller received research grants from BRAHMS, Roche, and Abbott; was on the speaker s bureau from BRAHMS, Roche, Abbott, and Alere; and was a consultant from BRAHMS and Roche. Dr Peacock was on the scientific advisory board for Abbott, Alere, Beckman-Coulter, Electrocore, Nanosphere, and The Medicines Co; received research grants from Abbott, Alere, BAS, BRAHMS, EKR, Nanosphere, and The Medicines Co; was on the speaker s bureau for Abbott and Alere; and had Ownership Interest in Comprehensive Research Associates and Vital Sensors. Dr Ponikowski was part of a speaker s bureau for Merck-Serono, Pfizer, and Sanofi-Aventis and was a consultant for Vifor and Athera. Dr Richards received research support from Roche and Inverness Medical. Dr Filippatos received research support from Biosite, BRAHMS, and Roche. Dr Ng was a consultant for Inverness and BRAHMS. Dr Daniels received research support from Biosite and Roche and was a consultant for

8 620 Circ Heart Fail September 2011 Roche. Dr Neath received honoraria from BRAHMS and was a consultant for TMO USA. Dr Christenson received research support from Siemens, BG-Medicine, BRAHMS, Roche, Inverness, and Nanosphere and was a consultant for Siemens, BG-Medicine, Critical Care Diagnostics, Inverness, and Abbott. Dr McCord received research support from BRAHMS and honoraria from Emory University. Dr von Haehling received honoraria from BRAHMS. Dr Morgenthaler was employed by BRAHMS. Dr Anker received a research grant from BRAHMS; received honoraria from Abbott and Biosite; and was a consultant for BRAHMS. References 1. 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J Physiol. 1969;204: Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem. 2006;52: Voors AA, von Haehling S, Anker SD, Hillege HL, Struck J, Hartmann O, Bergmann A, Squire I, van Veldhuisen DJ, Dickstein K; OPTIMAAL Investigators. C-terminal provasopressin (copeptin) is a strong prognostic marker in patients with heart failure after an acute myocardial infarction: results from the OPTIMAAL study. Eur Heart J. 2009;30: Khan SQ, Dhillon OS, O Brien RJ, Struck J, Quinn PA, Morgenthaler NG, Squire IB, Davies JE, Bergmann A, Ng LL. C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study. Circulation. 2007;115: Neuhold S, Huelsmann M, Strunk G, Stoiser B, Struck J, Morgenthaler NG, Bergmann A, Moertl D, Berger R, Pacher R. Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-b-type natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the disease J Am Coll Cardiol. 2008;52: Struck J, Morgenthaler NG, Bergmann A. Copeptin, a stable peptide derived from the vasopressin precursor, is elevated in serum of sepsis patients. Peptides. 2005;26: Kremers WK. Concordance for survival time data: fixed and timedependent covariates and possible ties in predictor and time. Technical Report Series No. 80, Rochester, MN: Mayo Clinic; April Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297: CLINICAL PERSPECTIVE This study demonstrated the potential use of the novel biomarker copeptin for the risk stratification of acute heart failure patients. Copeptin is a stable and easily measurable surrogate biomarker for arginine vasopressin. Because copeptin concentrations mirror that of arginine vasopressin, the ability to reliably measure copeptin concentrations will give clinicians insight into an important pathophysiological process in acute heart failure patients. When used by itself, copeptin is a strong independent prognostic biomarker in acute heart failure patients. Copeptin concentrations do not correlate with serum sodium. The prognostic utility of copeptin is additive to the prognostic utility of serum sodium. When used in combination with other biomarkers such as natriuretic peptides, midregion proadrenomedullin, and troponin, copeptin can help to provide the clinician with better insight into the pathophysiology and a more complete risk profile of patients with acute heart failure. In addition, copeptin concentrations can help clinicians identify high-risk patients who may benefit the most from arginine vasopressin antagonist therapy.