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
John G F Cleland, João Pedro Ferreira, Beatrice Mariottoni, Pierpaolo Pellicori, Joe Cuthbert, Job A J Verdonschot, Johannes Petutschnigg, Fozia Z Ahmed, Franco Cosmi, Hans-Peter Brunner La Rocca, Mamas A Mamas, Andrew L Clark, Frank Edelmann, Burkert Pieske, Javed Khan, Ken McDonald, Philippe Rouet, Jan A Staessen, Blerim Mujaj, Arantxa González, Javier Diez, Mark Hazebroek, Stephane Heymans, Roberto Latini, Stéphanie Grojean, Anne Pizard, Nicolas Girerd, Patrick Rossignol, Tim J Collier, Faiez Zannad, HOMAGE Trial Committees and Investigators
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.