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FOCUS ISSUE: BIOMARKERS IN CARDIOVASCULAR DISEASE: CLINICAL RESEARCH: BIOMARKERS AND ACUTE DYSPNEA

Mid-Region Pro-Hormone Markers for Diagnosis and Prognosis in Acute Dyspnea

Results From the BACH (Biomarkers in Acute Heart Failure) Trial

Alan Maisel, MD^_*,_***,_*, Christian Mueller, MD, Richard Nowak, MD, W. Frank Peacock, MD, Judd W. Landsberg, MD^||, Piotr Ponikowski, MD, PhD^¶, Martin Mockel, MD^#, Christopher Hogan, MD^_**, Alan H.B. Wu, PhD, Mark Richards, MD, PhD, Paul Clopton, MS^_*, Gerasimos S. Filippatos, MD, Salvatore Di Somma, MD^||||, Inder Anand, MD, DPhil (Oxon)^¶¶, Leong Ng, MD^##, Lori B. Daniels, MD, MAS^_***, Sean-Xavier Neath, MD, PhD^_***, Robert Christenson, PhD, 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 and Stefan D. Anker, MD, PhD^#,||||||

^_* VA San Diego Healthcare System, San Diego, California
University Hospital Basel, Basel, Switzerland
Henry Ford Health System, Detroit, Michigan
The Cleveland Clinic, Cleveland, Ohio
^|| Pulmonary Care Fellowship, University of California, and San Diego School of Medicine Medical Intensive Care Unit, Veterans Administration Medical Center, La Jolla, California
^¶ Medical University, Faculty of Public Health, Wroclaw, Poland
^# Charite, Campus Virchow-Klinikum, Berlin, Germany
^_** Virginia Commonwealth University, Richmond, Virginia
University of California, San Francisco, California
University of Otago, Christchurch, New Zealand
Athens University Hospital Attikon, Athens, Greece
^|||| Sant'Andrea Hospital, University La Sapienza, Rome, Italy
^¶¶ VA Minneapolis, Minnesota
^## University of Leicester, Leicester, United Kingdom
^_*** University of California, San Diego, California
University of Maryland, Baltimore, Maryland
University of California, San Diego School of Medicine, San Diego, California
BRAHMS Aktiengesellschaft Biotechnology Centre Hennigsdorf, Berlin, Germany
^|||||| Centre for Clinical and Basic Research IRCCS San Raffaele, Rome, Italy

Manuscript received August 18, 2009; revised manuscript received February 4, 2010, accepted February 4, 2010.

^_* Reprint requests and correspondence: Dr. Alan Maisel, VA San Diego Healthcare System Cardiology 9111-A, 3350 La Jolla Village Drive, San Diego, California 92161 (Email: amaisel{at}ucsd.edu).

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 (120 pmol/l) proved noninferior to BNP (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)

Key Words: pro-hormone • markers • acute dyspnea • BACH

Abbreviations and Acronyms   AHF = acute heart failure   AUC = area under the curve   BNP = B-type natriuretic peptide   CI = confidence interval   CV = coefficient of variation   ED = emergency department   HR = hazard ratio   IQR = interquartile range   MR-proADM = mid-regional pro-adrenomedullin   MR-proANP = mid-regional pro-atrial natriuretic peptide   NP = natriuretic peptide   NT-proBNP = N-terminal pro–B-type natriuretic peptide   ROC = receiver-operating characteristic

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