Accepted Manuscript Effects of Spironolactone Treatment in Elderly Women with Heart Failure and Preserved Left Ventricular Ejection Fraction Karla M. Kurrelmeyer , MD Yelena Ashton , Jiaqiong Xu , PhD Sherif F. Nagueh , MD Guillermo Torre-Amione , MD, PhD Anita Deswal , MD, MPH PII:

S1071-9164(14)00215-2

DOI:

10.1016/j.cardfail.2014.05.010

Reference:

YJCAF 3306

To appear in:

Journal of Cardiac Failure

Received Date: 2 December 2013 Revised Date:

19 May 2014

Accepted Date: 23 May 2014

Please cite this article as: Kurrelmeyer KM, Ashton Y, Xu J, Nagueh SF, Torre-Amione G, Deswal A, Effects of Spironolactone Treatment in Elderly Women with Heart Failure and Preserved Left Ventricular Ejection Fraction, Journal of Cardiac Failure (2014), doi: 10.1016/j.cardfail.2014.05.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Effects of Spironolactone Treatment in Elderly Women

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Short title: Spironolactone and Women with HFpEF

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Ejection Fraction

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with Heart Failure and Preserved Left Ventricular

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Karla M. Kurrelmeyer, MD1, Yelena Ashton2, Jiaqiong Xu2, PhD, Sherif F. Nagueh, MD1,

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Guillermo Torre-Amione, MD, PhD1, Anita Deswal, MD, MPH3

1: Methodist DeBakey Heart and Vascular Center, Houston, TX 2: Methodist Hospital Research Institute, Houston, TX 3: Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX

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Correspondence author:

Karla M. Kurrelmeyer, MD

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Methodist DeBakey Cardiology Associates 6550 Fannin Street Suite 1901

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Houston, TX 77030 (713) 441-1100 Phone

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(713) 790-2643 Fax

Email: [email protected]

Sources of Funding

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This study was supported by a grant from the Women’s Fund; Houston, Texas.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier:

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NCT00206232, Houston, Texas, USA

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Abstract: Background: Although spironolactone has been shown to decrease morbidity and

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mortality in patients with heart failure and reduced left ventricular ejection fraction , its role in patients with heart failure and preserved left ventricular ejection fraction (HFpEF)

women with HFpEF are treated with spironolactone.

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is not well defined. In this study we investigate the mechanisms involved when elderly

Methods and Results: Forty-eight women with HFpEF were enrolled in a randomized,

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placebo controlled trial and were assigned to spironolactone 25 mg daily (n=24) or placebo (n=24) for 6 months. Six-minute walk distance, clinical composite score, Doppler echocardiography, and biomarkers were determined at baseline, and after 3 and 6 months of therapy. Six months of spironolactone treatment stabilized clinical

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symptoms as demonstrated by significant worsening of the clinical composite score in the placebo group (p=0.02). In addition, spironolactone treatment improved diastolic function by significantly increasing early diastolic tissue Doppler velocity of the lateral

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mitral annulus (lateral e’) (p=0.003) and significantly reducing the mitral peak E velocity to lateral e’ ratio (lateral E/e’) (p=0.0001). Finally, spironolactone favorably affected

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remodeling through a reduction in myocardial fibrosis measured by a reduction in type III procollagen (PIIINP) levels (p=0.035). Six minute walk distance did not significantly improve with spironolactone treatment compared to placebo. Conclusions: Spironolactone stabilizes functional capacity and symptoms and improves diastolic function possibly through its ability to suppress type III pro-collagen synthesis.

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Key Words: Heart failure; Diastolic function; Biomarkers; Spironolactone; Clinical trials

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Introduction Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in women.1 In the OPTIMIZE-HF Registry, 62% of the more than 20,000

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enrolled patients with HFpEF were women. Patients with HFpEF were significantly older than those enrolled with heart failure with reduced ejection fraction (HFrEF),

indicating that HFpEF is predominantly a disease of elderly women.1 Women with

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HFpEF suffer from impaired exercise tolerance, recurrent HF hospitalizations and

death. Several studies have demonstrated similar rehospitalization rates and post

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discharge mortality rates in patients with HFpEF as in patients with HFrEF.1 Unlike HFrEF, no therapy has been proven definitely to be beneficial in patients with HFpEF.2-4 Heart Failure and hypertension (HTN) are associated with renin angiotensin aldosterone system (RAAS) activation. Chronic RAAS activation leads to an increase in

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myocardial extracellular matrix (ECM) fibrillar collagen, subsequent LV hypertrophy and increased myocardial stiffness, reduced ventricular/ vascular compliance, diastolic and systolic dysfunction and HF.5 Disease processes which alter diastolic function also alter

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the ECM fibrillar collagen. Treatments that improve diastolic function, are associated with normalization of fibrillar collagen.6

Previous clinical trials in HFpEF have focused

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on suppression of RAAS through angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy with disappointing results.2-4 Perhaps in patients with HFpEF, complete inhibition of the RAAS is required to see a beneficial effect. In patients with HTN and HFrEF, after several months of ACEI or ARB therapy, aldosterone levels increased7-8 as a result of angiotensin-independent stimuli for aldosterone production. However, when low dose spironolactone, an aldosterone

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receptor blocker, was given in addition to ACEI, a reduction in serum procollagen peptides consistent with a decrease in myocardial collagen content, a reduction in serum brain natriuretic peptide (BNP), a reduction in LV volumes and LV mass9-11 and a

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reduction in morbidity and mortality9 were seen. By decreasing myocardial fibrosis, spironolactone may be beneficial in patients with HFpEF already receiving ACEI or ARB therapy. Therefore, we conducted an exploratory clinical trial to evaluate the effects of

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spironolactone in elderly women with HFpEF on chronic ACEI or ARB therapy. We specifically examined short-term functional outcomes, diastolic function measured using

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Doppler echocardiography, and biomarkers.

Methods

Patients and study procedures. We enrolled 48 women from The Methodist Hospital,

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Houston, TX into this randomized, double blind, placebo-controlled trial between the years 2004-2008. Subjects were randomly allocated, using pharmacy controlled concealed randomization methods. All patients provided written informed consent and

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were at least 18 years old with a previous diagnosis of HFpEF. HFpEF was defined as current NYHA functional class II or III HF symptoms or signs (NYHA class), LVEF

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≥50% by echocardiography, diastolic dysfunction with elevated LV filling pressure by Doppler echocardiography defined according to ASE guidelines as a lateral e’1512 and a BNP ≥62 pg/ml, based on the ROC analysis performed by Lubien et al.13 They had to have a blood pressure ≤150/95 mm Hg for four weeks prior to enrollment and the ability to walk ≥50 meters at the time of enrollment. Treatment with an ACEI, or ARB if ACEI intolerant, was required for at least 4 weeks prior to

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enrollment. Exclusion criteria included current treatment with spironolactone or epleronone, previous intolerance to spironolactone, a creatinine level >2.5 mg/dl, serum potassium >5.0 mEq/L, significant valvular heart disease, pericardial disease, severe

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chronic lung disease with cor pulmonale, unstable angina or myocardial infarction within 4 weeks prior to enrollment, severe peripheral vascular disease with claudication that limits walking distance, presence of other severe co-morbid conditions with a life

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expectancy less than six months, and pregnant or lactating women. Patients were treated with open label spironolactone 25 mg for 1week prior to randomization to ensure

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drug tolerability defined as a serum potassium level