Clinical Trial
Results of the Randomized Aldosterone Antagonism in Heart Failure With Preserved Ejection Fraction Trial (RAAM-PEF)

https://doi.org/10.1016/j.cardfail.2011.04.007Get rights and content

Abstract

Background

Cardiac fibrosis is a major determinant of myocardial stiffness, diastolic dysfunction, and heart failure (HF). By reducing cardiac fibrosis, aldosterone antagonists have the potential to be beneficial in heart failure with preserved ejection fraction (HFpEF).

Methods and Results

In a randomized, double-blind, placebo-controlled trial of 44 patients with HFpEF, we examined the effects of eplerenone, an aldosterone antagonist, on changes in 6-minute walk distance (primary end point), diastolic function, and biomarkers of collagen turnover (secondary end points). All patients had a history of hypertension, 61% were diabetic, and 52% had prior HF hospitalization. After 6 months of treatment, similar improvements in 6 minute walk distance were noted in the eplerenone and placebo groups (P = .91). However, compared with placebo, eplerenone was associated with a significant reduction in serum markers of collagen turnover (procollagen type I aminoterminal peptide, P = .009 and carboxy-terminal telopeptide of collagen type I, P = .026) and improvement in echocardiographic measures of diastolic function (E/E’, P = .01).

Conclusions

Although eplerenone was not associated with an improvement in exercise capacity compared to placebo, it was associated with significant reduction in markers of collagen turnover and improvement in diastolic function. Whether these favorable effects will translate into morbidity and mortality benefit in HFpEF remains to be determined.

Section snippets

Study Design and Subjects

We performed a single-center, randomized, double blind, placebo-controlled trial to evaluate the benefit of eplerenone in patients with HFpEF (ClinicalTrials.gov number NCT00108251). The study was conducted at the Michael E. DeBakey VA Medical Center, Houston, TX. After a 2-week open label period of eplerenone 25 mg daily to establish tolerability, eligible patients were randomized in a 1:1 ratio to either eplerenone or matching placebo (detailed study design in Fig. 1). Tolerability was

Study Population

The trial profile is shown in Figure 2. Of the 198 patients screened, 150 were excluded, of which 28 patients refused to participate or appeared unable to adhere to the study procedures and 122 met at least 1 exclusion criterion including significant comorbidities (n = 27) such as severe lung disease, nonrevascularizable coronary artery disease or malignancy, serum creatinine > 2.5 mg/dL (n = 30), serum potassium > 5 mEq/L (n = 5), BNP < 100 pg/mL (n = 15), significant valvular heart disease

Discussion

This study is the first double-blind, randomized, placebo controlled trial that examines the effect of eplerenone, an aldosterone antagonist, on exercise capacity in relation to changes in circulating biomarkers of collagen turnover and diastolic function, in patients with established and symptomatic HFpEF. In a population of predominantly elderly male patients with HFpEF treated for 6 months, as compared with placebo, eplerenone did not result in benefit in exercise capacity as measured by the

Conclusions

This study represents the first double-blind, randomized, placebo-controlled trial to examine the benefit of the aldosterone antagonist, eplerenone, on exercise capacity in patients with established and symptomatic HFpEF. As compared to placebo, treatment with eplerenone over 6 months did not confer any benefit on exercise capacity, although it did result in favorable changes in some of the collagen markers and in diastolic function. Whether the changes in collagen turnover and diastolic

Acknowledgments

The authors thank Dr. Mark Dunlap and Dr. Nancy Petersen for their invaluable efforts as members of the DSMB, Ms. Adrienne Chee for her relentless work as study coordinator, and the patients that participated in this research study.

The views expressed in this article are those of the authors and do not necessarily represent those of the Department of Veteran Affairs.

Disclosure

None.

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    Supported by a VA Clinical Research Service grant # CLIN-010-03S (to Dr. Deswal).

    Clinical Trial Registration information at www.clinicaltrials.gov:NCT00108251.

    Conflict of Interest: None.

    See page 641 for disclosure information.

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