The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart ‘OMics’ in AGEing (HOMAGE) randomized clinical trial

Abstract

Aims To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure. Methods and results Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): −0.15; 95% confidence interval (CI) −0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: −8.1; 95% CI −11.9 to −4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: −2.9; 95% CI −4.3 to −1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: −10; 95% CI −13 to −7 mmHg; P < 0.0001), left atrial volume (mdiff: −1; 95% CI −2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: −57; 95% CI −81 to −33 ng/L; P < 0.0001) were reduced in those assigned spironolactone. Conclusions Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

The combination of carboxy‐terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy – A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy

“…One smaller study using EMB and circulating PICP in 25 DCM patients demonstrated that both levels of PICP and histological fibrosis decreased after treatment with spironolactone 31 . In the HOMAGE (‘Heart Omics in AGEing’) trial, 527 persons who are at risk of developing HF demonstrated similar decreasing levels of PICP after spironolactone treatment, with corresponding reductions in ventricular pre‐ and afterload 32 . Also, a prospective study of 60 CRT patients showed that lower circulating PICP levels are associated with a positive response to CRT, defined by a combination of event‐free survival, no HF hospitalization and occurrence of left ventricular reverse remodelling 33 .…”

Proteomic mechanistic profile of patients with diabetes at risk of developing heart failure: insights from the HOMAGE trial

“…People at increased risk of developing HF were randomly assigned to receive either spironolactone or standard care (ClinicalTrials.gov Identifier: NCT02556450). The rationale, trial design and main results have been published [ 5 , 6 ]. The study was approved by all relevant ethics committees and regulatory bodies.…”

“…The HOMAGE (Heart OMics in AGEing) trial showed that treatment with spironolactone (vs. usual care) in patients at risk of developing HF led to a decrease in collagen synthesis markers, N-terminal pro brain natriuretic peptide (NT-proBNP), reduced blood pressure and improved cardiac remodelling [ 5 , 6 ]. Small studies have suggested that spironolactone could impair endothelial function and increase glycated hemoglobin (HbA1c) in patients with DM [ 7 , 8 ].…”

Effect On Cardiac Function Among Patients With Type 2 Diabetes Following High-Dose Mineralocorticoid Receptor Antagonist Using Echocardiography; Data From The MIRAD Randomized Clinical Trial

“…Indeed, summarizing the effects of the addition of MRAs, two metaanalyses on improvements in cardiac function in patients with HFpEF and HFrEF restricted to echocardiography have highlighted improvements in diastolic function, especially, with improvements in E/e', E/A and atrial volume as the most consistent results following MRA treatment [14,15]. Further substantiating these results, a recent publication from the HOMAGE trial, investigating high-dose spironolactone in patients without HF, of whom 42% had diabetes, reported improvements in diastolic function [23]. A plausible explanation to the absence of change is given by the proportion of patients with baseline diastolic dysfunction in the current trial differs markedly from previous reports, with only an abnormal E/e' and LAi of 31% and 11%, respectively.…”