Association of Fibroblast Growth Factor 23 With Recurrent Cardiovascular Events in Patients After an Acute Coronary Syndrome: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with myocardial fibrosis and renin-angiotensin system upregulation, potentially providing prognostic information distinct from standard cardiovascular (CV) biomarkers.

Objective: To evaluate the association of FGF-23 with recurrent CV events in patients after an acute coronary syndrome (ACS).

Design, setting, and participants: C-terminal FGF-23 was measured in plasma samples using an established enzyme-linked immunosorbent assay system for 4947 patients within 30 days of ACS (median, 14 days) and with 1 additional CV risk factor in the Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) trial of the lipoprotein-associated phospholipase A2 inhibitor darapladib vs placebo performed from December 1, 2009, to April 24, 2014 (median follow-up, 2.5 years). Analyses were adjusted for clinical risk factors, renal function, and established cardiorenal biomarkers. This secondary analysis was performed from September 25, 2014, to October 1, 2017.

Exposure: The FGF-23 concentration at baseline.

Main outcomes and measures: The primary end point for this post hoc analysis was the composite of CV death or hospitalization for heart failure.

Results: In this study, baseline FGF-23 concentrations were available for 4947 patients (median age, 64.0 years; interquartile range, 59.0-71.0 years; 1276 [25.8%] female). Patients with higher FGF-23 concentrations were older and more likely female, with a greater proportion of hypertension, diabetes, and previous myocardial infarction. After multivariable adjustment for baseline clinical characteristics and established biomarkers (high-sensitivity troponin I, brain-type natriuretic peptide, and high-sensitivity C-reactive protein), FGF-23 concentration in the top quartile was independently associated with an increased risk of CV death or heart failure hospitalization (adjusted hazard ratio [HR], 2.35; 95% CI, 1.82-3.02; P < .001) and its individual components. Elevated FGF-23 concentration was also associated with an increased risk of all-cause mortality (adjusted HR, 2.27; 95% CI, 1.73-2.97; P < .001) and CV death, myocardial infarction, or stroke (adjusted HR, 1.42; 95% CI, 1.17-1.71; P < .001). When analyses were stratified by patient sex, the association between FGF-23 and CV risk, including CV death or heart failure, appeared to be attenuated in women (adjusted HR, 1.11; 95% CI, 0.70-1.76; P = .67) compared with men (HR, 3.11; 95% CI, 2.29-4.22; P < .001; P < .001 for interaction).

Conclusions and relevance: In patients stabilized after ACS, elevated FGF-23 concentrations may be associated with recurrent major CV events and all-cause mortality, providing information independent of established clinical risk factors and cardiorenal biomarkers. A potential sex difference in these findings deserves further study.

Figure 1.. Observed 3-Year Incidence of the Composite of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization for Quartile 4 vs Quartiles 1 Through 3 Fibroblast Growth Factor 23 Concentration

HR indicates hazard ratio.

Figure 2.. Adjusted Risk for Quartile 4 vs Quartiles 1 Through 3 Fibroblast Growth Factor 23 (FGF-23) Concentration

Covariates in the adjustment model were age, sex, current smoker, diabetes, body mass index, race/ethnicity, hypertension, hyperlipidemia, region, prior myocardial infarction (MI), index diagnosis (non–ST-elevation MI vs ST-elevation MI, unstable angina vs ST-elevation MI), low-density lipoprotein cholesterol level, days from qualifying event, randomized treatment arm, estimated glomerular filtration rate (Modification of Diet in Renal Dysfunction), high-sensitivity troponin I concentration, brain-type natriuretic peptide concentration, and high-sensitivity C-reactive protein concentration. CV indicates cardiovascular; HR, hazard ratio.

Figure 3.. Observed 3-Year Incidence of Cardiovascular (CV) Death or Hospitalization for Heart Failure (HF)

Biomarker stratifications are as follows: for fibroblast growth factor 23 (FGF-23) and brain-type natriuretic peptide (BNP), quartile 4 was high and quartiles 1 through 3 were low; for estimated glomerular filtration rate (eGFR), greater than 60 mL/min/1.73 m² was high and 60 mL/min/1.73 m² or less was low; and for high-sensitivity troponin I (hsTnI), quartiles 2 through 4 were high and quartile 1 was low.