Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease

Abstract

Objectives: This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy.

Background: FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse.

Methods: FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years.

Results: After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function.

Conclusions: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558).

Keywords: angiotensin-converting enzyme inhibitors; biomarkers; coronary artery disease; fibroblast growth factor-23; kidney.

Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Cumulative Incidence Curves for the Composite of Cardiovascular Death or Heart Failure Among Patients in the Placebo Arm (n = 1,815)

Patients are categorized by quartiles of fibroblast growth factor (FGF)-23. The p value is for log-rank test for trend across quartiles.

Figure 2. 6-Year Incidence Rates for the Composite of Cardiovascular Mortality or Heart Failure in Placebo Patients Stratified by FGF-23, and Either eGFR, Cystatin C, or Microalbuminuria

Patients are categorized dichotomously according to whether their level of FGF-23 was in the top quartile (high) or not (low) and their eGFR was 2 or not (A) and their cystatin C level was in the top quartile (≥0.91 mg/l: high) or not (<0.91 mg/l: low) (B), and by the presence or absence of microalbuminuria (urinary albumin to creatinine ratio of ≥25 µg/mg in women and ≥17 µg/mg in men) (C). P values in figure represent global p value for differences in rates. Furthermore, for all pairwise comparisons p < 0.05. eGFR = estimated glomerular filtration rate; FGF = fibroblast growth factor.

Figure 3. Cumulative Incidence Curves for the Composite of Cardiovascular Death or Heart Failure in Patients Categorized by FGF-23 Level and Treatment With Trandolapril

Red lines indicate patients with high FGF-23 levels (>70.20 RU/ml): the solid line indicates patients treated with placebo (n = 455); and the dashed line indicates patients treated with trandolapril (n = 451). Blue lines indicate patients with low FGF-23 levels (≤70.20 RU/ml): the solid line indicates patients treated with placebo (n = 1,360); and the dashed line indicates patients treated with trandolapril (n = 1,361). CI = confidence interval; FGF = fibroblast growth factor; HR = hazard ratio.