Biomarkers Associated With Risk of CV Mortality and Hospitalization in HFrEF

In patients with HFrEF, biomarkers related to inflammation, renal function, and risk for HF hospitalization and CV mortality have been identified.

Higher baseline levels of high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor 15 (GDF-15), and interleukin-6 (IL-6) are associated with an increased risk of cardiovascular (CV) death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF), according to a study in the Journal of Cardiac Failure.

The prospective VICTORIA ( Identifier: NCT02861534) substudy assessed biomarkers of cardiac injury, inflammation, and renal function with outcomes and vericiguat treatment effect in patients with HFrEF.

VICTORIA enrolled 5050 participants with HFrEF and a left ventricular ejection fraction of less than 45%, HF hospitalization within 6 months or intravenous diuretic treatment within 3 months, New York Heart Association functional class II or higher, and an increased level of B-type natriuretic peptide (BNP) of 300 pg/mL or higher or N-terminal pro-BNP (NT-proBNP) level increase of 1000 pg/mL or higher (≥500 pg/mL and 1600 pg/mL, respectively, for patients with atrial fibrillation) within 30 days of randomization.

Serum samples were obtained at baseline and at 16 weeks. Cystatin C, IL-6, and high-sensitivity C-reactive protein (hs-CRP) were measured followed by a second freeze-thaw cycle with measurement of hs-cTnT and GDF-15.

This is one of the first studies to identify that progressively lower baseline levels of hs-cTnT could distinguish participants deriving increasing benefit from a specific heart failure treatment to reduce cardiovascular death.

A composite of CV death or time to first HF hospitalization with events that were centrally adjudicated was the primary outcome. Individual components of the primary outcome also were assessed.

Among the 5050 participants, 4652 (92%) had 1 or more biomarkers measured, and 2320 received vericiguat (mean [SD] age, 67.9 [12.0] years; 75.9% men), and 2332 received placebo (mean age, 67.6 [12.0] years; 75.6% men).

Baseline levels of the 5 biomarkers were associated with the primary outcome and individual endpoints in unadjusted analysis. After multivariable adjustment with baseline NT-proBNP level, hs-cTnT level (hazard ratio [HR], 1.21; 95% CI, 1.14-1.27), GDF-15 level (HR, 1.19; 95% CI, 1.12-1.27), and IL-6 level (HR, 1.07; 95% CI, 1.01-1.13) were associated with the primary outcome. Comparable results were found for the individual components of the primary endpoint for hs-cTnT and GDF-15, and modest differences were found for IL-6, hs-CRP, and cystatin C.

The 5 biomarkers were then assessed for an interaction with treatment by vericiguat vs placebo for the primary outcome, and only hs-cTnT had a potential treatment interaction (P =.12) after multivariable adjustment. HS-cTnT significantly modified the effect of vericiguat for preventing CV death (P =.036) but not HF hospitalization (P =.38). The other biomarkers did not have a significant interaction with vericiguat for the primary endpoint or components.

The researchers also evaluated whether baseline NT-proBNP and hs-cTnT levels together could further distinguish the treatment benefit with vericiguat. NT-proBNP and hs-cTnT levels had a moderate correlation (R =0.41; P <.001), which indicates that the 2 cardiac-specific circulating biomarker levels were accounted for in part by different mechanisms.

At 16 weeks, 1 or more biomarkers were measured in 4063 participants (87.3%). All biomarkers significantly decreased from randomization by 2.2% to 16.1%, except for cystatin C. No difference was found in vericiguat treatment effect regarding the primary outcome according to the extent of change in baseline level to 16 weeks for any of the 5 biomarkers.

Some limitations of the study include the selection of the circulating biomarkers that were analyzed is based on animal model data for the mechanisms of action of vericiguat and findings from a phase 2b study. Also, inadequate statistical power may have influenced the tests for interaction regarding vericiguat’s treatment effect, and the interaction terms need to be interpreted with caution as multiple endpoints were analyzed for each biomarker.

“This is one of the first studies to identify that progressively lower baseline levels of hs-cTnT could distinguish participants deriving increasing benefit from a specific heart failure treatment to reduce cardiovascular death,” the investigators wrote.

Disclosure: This work was supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, and Bayer AG. Reagents were donated by Roche Diagnostics (hs-cTnT and GDF-15) and Siemens Healthineers (cystatin C, hs-CRP and IL-6). Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


deFilippi CR, Alemayehu WG, Voors AA, et al.; on behalf of the VICTORIA Study Group. Assessment of biomarkers of myocardial injury, inflammation, and renal function in heart failure with reduced ejection fraction: the VICTORIA biomarker substudy. J Card Fail. Published online January 9, 2023. doi: 10.1016/j.cardfail.2022.12.013