Biomarker-based assessment of collagen cross-linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the HOMAGE clinical trial

Aims: The HOMAGE randomised trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (PICP) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 (CITP:MMP-1) ratio, associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial. Methods and Results: Patients at risk of HF were randomized to spironolactone (n=260) or not (n=255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 ratio (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (P=0.003) and nine (P=0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) (mean-differencesspiro/control: -1.77 [95%CI:-2.94 to -0.59] and -2.52 [95%CI:-4.46 to -0.58] mL/m2; interaction-Pacross-tertiles=0.005; interaction-P3rd tertile=0.008) with a similar trend for NT-proBNP which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile (mean-differencesspiro/control:-0.47[95%CI:-0.66 to -0.28] and -0.31[95% CI:-0.59 to -0.04] ng/L; interaction-Pacross-tertiles=0.09; interaction-P3rd tertile<0.0001). Conclusions: These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1)