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.

Keywords: Collagen markers; Fibrosis; Heart failure prevention; Spironolactone.

Figure 1

Consort diagram showing patient disposition, including screening, randomization, and follow-up.

Figure 2

Changes from baseline to 1 month and final visits for serum concentrations of (A) procollagen type-III N-terminal pro-peptide (PIIINP); (B) procollagen type-III N-terminal pro-peptide for those with a baseline serum galectin above or below median; (C) procollagen type-I C-terminal pro-peptide (PICP); (D) collagen type-1 C-terminal telopeptide (CITP); (E) the ratio of procollagen type-I C-terminal pro-peptide to collagen type-1 C-terminal telopeptide; (F) Galectin-3. Data shown are mean change and standard deviation. P-values are for the comparison between intervention and control except for (B) where the P-values refer to the interaction between baseline serum galectin-3 and changes in plasma concentrations of procollagen type-III N-terminal pro-peptide. The interaction between baseline galectin-3 and change from baseline to final visit in procollagen type-III N-terminal pro-peptide was the primary endpoint of the trial (P = 0.947 for the interaction).

Figure 3

Changes from baseline to 1 month and to the final visit in (A) systolic blood pressure; (B) plasma concentrations of NT-proBNP; (C) left atrial volume index; (D) E/A ratio; (E) serum potassium; (F) estimated glomerular filtration rate. Data shown are mean change and standard deviation. P-values are for the comparison between intervention and control.

Take home figure:

Diagram showing the evolution from risk factors, through structural heart disease to heart failure and the randomized controlled trials of mineralo-corticoid receptor antagonists (MRA) that have addressed each stage. The PATHWAY-2 trial demonstrated the effects of spironolactone on blood pressure, a key risk factor for heart failure. HOMAGE is the only trial, to date, that has focused on patients with structural heart disease with few or no symptoms of heart failure. The ALDO-DHF trial showed favourable effects on ventricular filling in patients with a preserved left ventricular ejection fraction (LVEF) and heart failure (HFpEF). Many patients in ALDO-DHF had less severe cardiac dysfunction than in HOMAGE; there is substantial overlap in the patient characteristics of these two trials. TOPCAT investigated the effects of spironolactone in HFpEF with equivocal results. EMPHASIS, AREA IN-CHF, and RALES investigated the effects of mineralo-corticoid receptor antagonists in HFrEF (heart failure with a reduced left ventricular ejection fraction). In HOMAGE, spironolactone caused an early reduction in weight, blood pressure, and natriuretic peptides, suggesting a natriuretic and diuretic effect. Changes in serum markers of type-1, although not type-III, collagen metabolism were also observed within 1 month. This combination of effects was followed by favourable cardiac remodelling. Type-1 collagen is the more important contributor to myocardial stiffness. The magnitude of changes in collagen metabolites observed suggests a systemic effect of spironolactone rather than only on the myocardium.