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) Randomised Clinical Trial.

Abstract

Importance: Cardiovascular accumulation of collagen (fibrosis) may contribute to the progression from ventricular dysfunction to heart failure. Galectin-3, a potential marker of pro-fibrotic activity, might identify those at greater risk.
Objective: To investigate the effects of spironolactone, according to serum galectin-3 concentration, on serum markers of fibrosis and on cardiac structure and function, in people at increased risk of developing heart failure.
Design: Prospective, randomized, open-label, blinded endpoint (PROBE) trial.
Setting: Clinical research facilities in ten European hospitals.
Participants: People with, or at high-risk of, coronary disease with increased plasma concentrations of B-type natriuretic peptides (BNP or NT-proBNP).
Interventions: spironolactone (up to 50 mg/day) or control for up to nine months.
Main Outcomes and Measures: The primary outcome was the interaction between baseline serum galectin-3 and change in serum procollagen type-III N-terminal pro-peptide (PIIINP), a by-product of type-III collagen synthesis. Serum procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), respectively reflecting synthesis and degradation of type-I collagen, were also measured.
Results: Of 527 participants, the median age was 73 years and 26% were women. Median follow-up was 267 days. Changes in PIIINP were similar for those assigned to spironolactone and control (mean difference -0.15; 95% confidence interval [CI] -0.44 to 0.15 µg/L; p=0.32) and did not differ when serum galectin-3 was above or below median. Those assigned to spironolactone had greater declines in PICP (mean difference -8.1; -95% CI -11.9 to -4.3 µg/L; p<0.0001) and PICP/CITP ratio (mean difference -2.9; 95% CI -4.3 to -1.5; <0.0001). Systolic blood pressure (mean difference -10; 95% CI -13 to -7 mmHg; p<0.0001), left atrial volume (mean difference -1; 95% CI -2 to 0 mL/m2; p=0.010) and NT-proBNP (mean difference -57; 95% CI -81 to -33 ng/L; p<0.0001) were lower on spironolactone at the final assessment.
Conclusions and Relevance: Spironolactone reduced PICP/CITP ratio, consistent with reduced synthesis and increased degradation of type-I collagen, and reduced NT-proBNP and left atrial volume, suggesting favourable effects on cardiac function. Further research is required to determine whether spironolactone can delay or prevent progression to symptomatic heart failure.