A multimarker multi-time point-based risk stratification strategy in acute heart failure: results from the RELAX-AHF trial

Biniyam G. Demissei, Gad Cotter, Margaret F. Prescott, G. Michael Felker, Gerasimos Filippatos, Barry H. Greenberg, Peter S. Pang, Piotr Ponikowski, Thomas M. Severin, Yi Wang, Min Qian, John R. Teerlink, Marco Metra, Beth A. Davison, Adriaan A. Voors

Research output: Contribution to journalArticle

34 Scopus citations


Aims: We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF). Methods and results: Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83–0.91]. Conclusion: In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy.

Original languageEnglish (US)
Pages (from-to)1001-1010
Number of pages10
JournalEuropean Journal of Heart Failure
Issue number8
StatePublished - Aug 2017



  • Acute heart failure
  • Biomarkers
  • Multimarker strategy
  • Prognosis
  • Risk stratification
  • Serial measurement

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Demissei, B. G., Cotter, G., Prescott, M. F., Felker, G. M., Filippatos, G., Greenberg, B. H., Pang, P. S., Ponikowski, P., Severin, T. M., Wang, Y., Qian, M., Teerlink, J. R., Metra, M., Davison, B. A., & Voors, A. A. (2017). A multimarker multi-time point-based risk stratification strategy in acute heart failure: results from the RELAX-AHF trial. European Journal of Heart Failure, 19(8), 1001-1010. https://doi.org/10.1002/ejhf.749