Multimarker Analysis of Serially Measured GDF-15, NT-proBNP, ST2, GAL-3, cTnI, Creatinine, and Prognosis in Acute Heart Failure

Abstract

BACKGROUND: Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk. METHODS: TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling. RESULTS: Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78–2.57) unadjusted, 1.96 (1.49–2.53) after adjustment for clinical confounders and 1.44 (1.05–1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78–3.33) and 1.52 (1.15–2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785). CONCLUSIONS: Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice. REGISTRATION: URL: https://www.trialregister.nl/trial/1783 ; Unique Identifier: NTR1893. (The trial can be found temporarily at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893 .)

A Peek Into the Future: Will Serial Multimarker Testing Help Bring a New Era of Precision Medicine in Heart Failure Patients?

“…This allowed higher event rates within the follow-up time to adequately assess the multimarker's ability to predict clinical outcomes, as evidenced by 40% of the study cohort reaching the primary end point of all-cause mortality or HF hospitalization. 4 Not surprisingly, baseline NT-proBNP was the best single-marker predictor for clinical outcomes. But in this head-to-head comparison, baseline GDF-15 levels showed strong predictive power along with ST2 and troponin I, depending on the exact model evaluated.…”

“…In this issue of Circulation: Heart Failure , Gürgöze and colleagues 4 bring a comprehensive approach to evaluating a prognostic multimarker HF panel by utilizing blood samples from the TRIUMPH study (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure), a multi-center, prospective, observational study. The investigators chose 6 of the best-established biomarkers for HF prognosis (NT-proBNP, troponin I, soluble ST2, galectin-3, creatinine, and GDF-15) in a head-to-head comparison.…”

“…They extended existing literature on multimarker panels by measuring up to 7 biomarker measurements from acute as well as chronic ambulatory HF settings up to 12 months and followed the cohort up to 400 days. 4 This HF cohort was at high risk; all were hospitalized for an acute HF episode at the time of enrollment and the majority had advanced HF with a New York Heart Association class III or greater functional classification. This allowed higher event rates within the follow-up time to adequately assess the multimarker’s ability to predict clinical outcomes, as evidenced by 40% of the study cohort reaching the primary end point of all-cause mortality or HF hospitalization.…”

“…This allowed higher event rates within the follow-up time to adequately assess the multimarker’s ability to predict clinical outcomes, as evidenced by 40% of the study cohort reaching the primary end point of all-cause mortality or HF hospitalization. 4…”

The Therapeutic Role of SGLT-2 Inhibitors in Acute Heart Failure: From Pathophysiologic Mechanisms to Clinical Evidence with Pooled Analysis of Relevant Studies across Safety and Efficacy Endpoints of Interest

“…Another research area of specific interest is the assessment of the effect of SGLT-2 inhibitors on circulating levels of protein biomarkers in the field of proteomics. There is increasing evidence that markers such as growth differentiation factor 15 (GDF-15) and ST2 can provide useful prognostic implications for subjects with established cardiovascular disease, including both acute and chronic HF [80][81][82]. SGLT-2 inhibitors, such as empagliflozin and dapagliflozin, were shown to significantly affect plasma levels of those protein biomarkers [83][84][85], despite the fact that in the Canagliflozin Cardiovascular Assessment Study (CANVAS) it was documented that GDF-15 reduction did not mediate the cardio-protective effects of canagliflozin [84].…”