Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy

https://doi.org/10.1016/j.cardfail.2022.12.013Get rights and content

PERSPECTIVES

  • COMPETENCY IN MEDICAL KNOWLEDGE: This prospectively planned secondary analysis of the VICTORIA study preselected 5 biomarkers measured at baseline and 16 weeks thought to reflect the potentially beneficial nonvasodilatory mechanisms of action of vericiguat, a sGC stimulator, in patients with heart failure with a reduced ejection fraction.

  • COMPETENCY IN PATIENT CARE: In this population with a high event rate, baseline hs-cTnT, GDF-15, and IL-6 were prognostic in a comprehensive adjustment model inclusive of NT-proBNP levels.

  • TRANSLATIONAL OUTLOOK: This study is one of the first to identify that progressively lower baseline levels of hs-cTnT could distinguish participants deriving increasing benefit from a specific heart failure treatment to decrease cardiovascular death.

Abstract

Background

Circulating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect.

Methods and Results

High-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14–1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed.

Conclusions

hs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

Section snippets

Lay Summary

We evaluated 5 blood tests that evaluate heart injury (cardiac troponin T [cTnT]), inflammation, and renal function for associations with outcomes and efficacy of treatment with the drug vericiguat in the VICTORIA study of patients with HFrEF. Higher baseline levels of a measure of cTnT and two measures of inflammation were associated with the primary outcome of cardiovascular death or HF hospitalization. Lower levels of cTnT identified patients when treated with vericiguat had a lower risk of

Study Design and Procedures

The design, baseline characteristics, and primary results of VICTORIA have been published.11,13 The trial included 5050 participants with HFrEF and a left ventricular EF of less than 45%, New York Heart Association functional class of II o higher, HF hospitalization within 6 months or receipt of intravenous diuretics within 3 months, and an elevated BNP (≥300 pg/mL) or NT-proBNP of 1000 pg/mL or higher (≥500 pg/mL and 1600 pg/mL, respectively, for those with atrial fibrillation) within 30 days

Results

Of the 5050 VICTORIA participants, 4652 (92%) had at least 1 biomarker measured. The baseline characteristics of the study patients, coupled with their associated baseline (before randomization) biomarker levels are shown according to their treatment assignment and were well-balanced between placebo and vericiguat (Table 1). The number of participants with each biomarker measured at baseline and with a paired measurement at 16 weeks is shown in Supplemental Fig. 1. The median serum levels of

Discussion

Several findings emerged from this prospectively planned analysis of circulating biomarkers of cardiac injury, systemic inflammation, and renal function in patients with HFrEF treated with vericiguat or placebo. First, the baseline levels of all biomarkers were elevated, as expected in a HF population; however, the levels were higher than those seen in other recent randomized clinical trials in HFrEF.2,3,5,21 This latter observation is consistent with the clinical characteristics and higher

Conclusions

Higher values of baseline hs-cTnT, GDF-15, and IL-6 levels were associated with an increased risk of the primary outcome in the VICTORIA study. These biomarkers, indicative of myocardial injury, inflammation, and renal dysfunction, are elevated in patients with HFrEF and a recent worsening HF event, but were not modified with vericiguat therapy. Uniquely, lower baseline hs-cTnT levels were associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with

Disclosures

deFilippi: Research funding to Inova from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics; consulting for FujiRebio, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics. Alemayehu: Nothing to report. Voors: Research grants from Boehringer Ingelheim and Roche Diagnostics; consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Kaye: Nothing to report. Blaustein:

Proposed Social Media Text

In the VICTORIA biomarker sub-study of vericiguat in HFrEF, cTnT, IL-6 and GDF-15 are prognostic, but cTnT levels also identify patients when treated with vericiguat that had a lower risk of cardiovascular death.

Sources of Funding

Supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, and Bayer AG, Wuppertal, Germany. Reagents were donated by Roche Diagnostics (hs-cTnT and GDF-15) and Siemens Healthineers (Cystatin C, hs-CRP and IL-6).

Acknowledgments

The authors acknowledge Elizabeth E.S. Cook of the Duke Clinical Research Institute for editorial assistance and preparation of the manuscript submission.

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    Clinical Trial Registration: Clinicaltrials.gov (NCT02861534).

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