Biniyam G Demissei1,2, Gad Cotter3, Margaret F Prescott4, G Michael Felker5, Gerasimos Filippatos6, Barry H Greenberg7, Peter S Pang8, Piotr Ponikowski9, Thomas M Severin10, Yi Wang4, Min Qian11, John R Teerlink12, Marco Metra13, Beth A Davison3, Adriaan A Voors1. 1. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3. Momentum Research, Durham, NC, USA. 4. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 5. Duke Clinical Research Institute, Durham, NC, USA. 6. Athens University Hospital, Attikon, Athens, Greece. 7. University of California at San Diego, San Diego, CA, USA. 8. Indiana University School of Medicine, Indianapolis, IN, USA. 9. Medical University, Clinical Military Hospital, Wroclaw, Poland. 10. Novartis Pharma AG, Basel, Switzerland. 11. Department of Biostatistics, Columbia University, New York, NY, USA. 12. University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA. 13. University of Brescia, Brescia, Italy.
Abstract
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.
RCT Entities:
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.