What is the clinical evidence from this study?

Study design: RCT. Population: Heart failure with preserved ejection fraction (HFpEF) (n=381). Intervention: Spironolactone vs. Placebo. Primary outcome: E:e' ratio (p=<0.05).

April 30, 2018Open Access

Biomarker-Based Phenotyping of Myocardial Fibrosis Identifies Patients with Heart Failure with Preserved Ejection Fraction Resistant to the Beneficial Effects of Spironolactone: Results From the Aldo-DHF Trial

Q: What are the key findings of this study?

Spironolactone reduced the E:e' ratio in HFpEF patients, but those with high collagen cross-linking (lower CITP:MMP-1 levels) were resistant to this beneficial effect (P<0.05 for interaction).

Key Result

Spironolactone reduced the E:e' ratio in HFpEF patients, but those with high collagen cross-linking (lower CITP:MMP-1 levels) were resistant to this beneficial effect (P<0.05 for interaction).

Study Design

Type

RCT (n=381)

Randomization

Randomized

Multicenter

Yes

Structured PICO

Does spironolactone improve left ventricular diastolic dysfunction (E:e' ratio) in HFpEF patients, and is this effect modified by baseline collagen cross-linking biomarkers?

Population

381 patients with heart failure with preserved ejection fraction (HFpEF) from the multicentre Aldo-DHF trial

Intervention

Spironolactone 25 mg once daily for 1 year

Comparator

Placebo for 1 year

Outcome

Change in E:e' ratio after 1-year treatmentsurrogate

High baseline collagen cross-linking (indicated by low CITP:MMP-1 levels) identifies a biochemical phenotype of HFpEF patients who are resistant to the beneficial effects of spironolactone on diastolic function.

Main Result

p-value: p=<0.05

Abstract

BACKGROUND: Myocardial fibrosis is characterized by excessive cross-linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross-linking and/or deposition. METHODS AND RESULTS: We investigated 381 HFpEF patients from the multicentre, randomized, placebo-controlled Aldo-DHF trial with measures of the E:e' ratio. The ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1, an inverse index of myocardial collagen cross-linking) and serum carboxy-terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1-year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP-1 and PICP tertiles at baseline. While CITP:MMP-1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP-1 levels, this ratio was significantly reduced in the remaining spironolactone-treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP-1 levels but was reduced in the remaining spironolactone-treated patients. CONCLUSIONS: A biochemical phenotype of high collagen cross-linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross-linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients.