Journal of Thrombosis and Thrombolysis

, Volume 44, Issue 4, pp 457–465 | Cite as

N-terminal pro-B-type natriuretic peptide and the risk of stroke among patients hospitalized with acute heart failure: an APEX trial substudy

  • Gerald Chi
  • James L. Januzzi
  • Serge Korjian
  • Yazan Daaboul
  • Samuel Z. Goldhaber
  • Adrian F. Hernandez
  • Russell D. Hull
  • Alex Gold
  • Alexander T. Cohen
  • Robert A. Harrington
  • C. Michael GibsonEmail author



Among patients hospitalized with acute heart failure (HF), the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in short-term stroke prediction remains unclear.


In the APEX trial, 7513 patients hospitalized for an acute medical illness were randomized to receive either extended-duration betrixaban (80 mg once daily for 35–42 days) or standard-of-care enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Baseline NT-proBNP concentrations were obtained in 3261 patients admitted for HF. Stroke events were adjudicated by an independent clinical events committee blinded to thromboprophylaxis allocation. The association of NT-proBNP level and other risk factors and biomarkers with stroke was assessed at 77 days after randomization.


In univariate analysis, the risk of stroke at 77 days was associated with baseline NT-proBNP (HR 3.63 [95% CI 1.47–8.99]; P = 0.005), D-dimer (HR 2.73 [95% CI 1.03–7.20]; P = 0.043), and hsCRP (HR 3.03 [95% CI 1.36–6.75]; P = 0.007). In multivariable analysis adjusting for hsCRP and thromboprophylaxis, NT-proBNP was associated with the risk of stroke (adjusted HR 3.64 [95% CI 1.35–9.83]; P = 0.011). The interaction of NT-proBNP with the treatment effect was not significant (Pint = 0.30).


Baseline NT-proBNP concentration was associated with short-term stroke among patients hospitalized with acute HF. Stroke risk assessment models should consider incorporation of NT-proBNP measurement.


Natriuretic peptide NT-proBNP Stroke Heart failure Thromboprophylaxis 



Atrial fibrillation


Acute Medically Ill VTE Prevention with Extended Duration Betrixaban trial


Brain natriuretic peptide


Heart failure


High-sensitivity C-reactive protein


N-terminal pro-B-type natriuretic peptide


Transient ischemic attack


Upper limit of normal



The study was funded by the Portola Pharmaceuticals Inc.

Compliance with ethical standards

Conflict of interest

Dr. Chi has received research grant support paid to the Beth Israel Deaconess Medical Center from Portola, Bayer, and Janssen Research. Dr. Januzzi is supported by the Hutter Family Professorship; has received grant support from Siemens, Singulex, and Prevencio; has received consulting income from Roche Diagnostics, Critical Diagnostics, Sphingotec, Phillips, Novartis, Janssen and Boehringer Ingelheim; and participates in clinical endpoint committees/data safety monitoring boards for Pfizer, Novartis, Amgen, Janssen, and Boehringer Ingelheim. Dr. Korjian has received research grant support paid to the Beth Israel Deaconess Medical Center from Portola, Bayer, and Janssen Research. Dr. Daaboul has received research grant support paid to the Beth Israel Deaconess Medical Center from Portola, Bayer, and Janssen Research. Dr. Goldhaber has provided consulting for Boehringer Ingelheim, Bayer, Portola, Daiichi-Sankyo, Janssen, BiO2 Medical, EKOS/BTG, BMS, and Zafgen. Dr. Hernandez reports receipt of grant support from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Luitpold, Merck, and Novartis; and personal fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boston Scientific, Luitpold, and Novartis outside the submitted work. Dr. Hull reports grant support from Portola Pharmaceuticals during the conduct of the study, and grant support and personal fees from Leo Pharma outside the submitted work. Dr. Gold reports personal fees (salary support) from Portola Pharmaceuticals outside the submitted work. Dr. Cohen reports grant support, personal fees, and non-financial support from Portola Pharmaceuticals during the conduct of the study; grant support, personal fees, and non-financial support from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Janssen, and Bayer Pharmaceuticals, personal fees from Boehringer Ingelheim and Sanofi, and personal fees and non-financial support from Johnson & Johnson and Aspen Pharmaceuticals outside the submitted work. Dr. Harrington reports grant support from Portola Pharma during the conduct of the study; grant support from CSL Behring, AstraZeneca, GlaxoSmithKline, Regado, and Sanofi Aventis, grant support and personal fees from Merck and The Medicines Company, personal fees from Amgen, Gilead Sciences, MyoKardia, and WebMD, and other support from Scanadu, SignalPath, Element Science, Vida Health, and Adverse Events outside the submitted work. Dr. Gibson reports research grant support from Portola Pharmaceuticals during the conduct of the study, and grant support from Johnson & Johnson and Bayer outside the submitted work all of which was paid to the Beth Israel Deaconess Medical Center. He has also received modest consulting fees from these same entities in compliance with hospital and Harvard Medical School policies.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11239_2017_1552_MOESM1_ESM.pdf (148 kb)
Supplementary material 1 (PDF 148 KB)


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Gerald Chi
    • 1
  • James L. Januzzi
    • 2
  • Serge Korjian
    • 1
  • Yazan Daaboul
    • 1
  • Samuel Z. Goldhaber
    • 3
  • Adrian F. Hernandez
    • 4
  • Russell D. Hull
    • 5
  • Alex Gold
    • 6
  • Alexander T. Cohen
    • 7
  • Robert A. Harrington
    • 8
  • C. Michael Gibson
    • 1
    Email author
  1. 1.PERFUSE Study Group, Cardiovascular Division, Departments of Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Cardiology Division, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  3. 3.Cardiovascular Division, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  4. 4.Duke University and Duke Clinical Research InstituteDurhamUSA
  5. 5.Division of Cardiology, R.A.H Faculty of MedicineUniversity of CalgaryAlbertaCanada
  6. 6.Portola Pharmaceuticals Inc.South San FranciscoUSA
  7. 7.Department of Haematological Medicine, Guy’s and St Thomas’ HospitalsKing’s CollegeLondonUK
  8. 8.Division of Cardiovascular Medicine, Department of MedicineStanford UniversityStanfordUSA

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