The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure

This study has been completed.
Sponsor:
Information provided by:
St Vincent's University Hospital, Ireland
ClinicalTrials.gov Identifier:
NCT00505336
First received: July 19, 2007
Last updated: February 10, 2009
Last verified: February 2009
  Purpose

To investigate whether the medicines eplerenone or atorvastatin have a favourable effect on diastolic heart failure.

Eplerenone is a drug that has been shown to be beneficial in Chronic Heart Failure due to pump failure. It can increase life expectancy and improve symptoms in these patients. It is not known whether or not eplerenone might be beneficial in heart failure with normal pump function (diastolic heart failure).

Atorvastatin is one of a group of cholesterol lowering medicines called statins, which have been shown to reduce cardiovascular disease in patients irrespective of whether cholesterol levels are high or normal. It is not known whether atorvastatin also reduces fibrosis of the heart which is one of the causes of diastolic heart failure.

Study hypothesis

  1. To investigate the impact of aldosterone antagonism or statin therapy on markers of collagen turnover in patients with diastolic heart failure.
  2. To assess the impact of aldosterone antagonism or statin therapy on markers of diastolic dysfunction and indices of clinical well being in patients with diastolic heart failure.

Condition Intervention
Diastolic Heart Failure
Drug: Eplerenone
Other: No additional treatment
Drug: Atorvastatin

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure

Resource links provided by NLM:


Further study details as provided by St Vincent's University Hospital, Ireland:

Primary Outcome Measures:
  • To investigate the impact of aldosterone antagonism or statin therapy on markers of collagen turnover in patients with diastolic heart failure. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To assess the impact of aldosterone antagonism or statin therapy on markers of diastolic dysfunction by echocardiography [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • To assess the impact of aldosterone antagonism or statin therapy on indices of clinical well being [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • The assess the impact of aldosterone antagonism or statin therapy on diastolic indices by cardiac MRI [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Enrollment: 43
Study Start Date: April 2006
Study Completion Date: December 2008
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Eplerenone
Drug: Eplerenone
oral Eplerenone titrated to 50mg for duration of 12 months
Other Name: Inspra
Active Comparator: 3
no additional treatment
Other: No additional treatment
normal disease modifying therapy for heart failure i.e. ACE-I, beta blockers
Experimental: 2
Atorvastatin
Drug: Atorvastatin
oral Atorvastatin 40mg
Other Name: Lipitor

Detailed Description:

Diastolic heart failure is a significant contributor to the heart failure syndrome. However, little work has been done on the causes of diastolic heart failure, and in contradistinction to those with systolic heart failure, little is know about the aetiology and therefore, there are few effective therapies.

It is generally believed that diastolic heart failure represents a problem with compliance and relaxation of the ventricle. One possible explanation for this is thought to be an abnormality of collagen structure in the myocardium. There are data from hypertensive populations as well as from hypertensive experimental models indicating an abnormal fibrotic process in patients with hypertensive heart disease. However, there are a few data on this potential aetiological explanation for diastolic heart failure.

It is now possible to measure serum markers of fibrosis in circulating blood. Work in this area has established the reproducibility and reliability of measurements of pro-collagen I and pro-collagen III amino-terminal, secreted as the collagen molecules are released from the fibroblast. These markers have been analysed in several settings, including normal individuals, hypertensive populations and in those with established heart failure due to systolic dysfunction. Recently we have completed a study on analysis of these factors in patients with proven diastolic heart failure. These data have demonstrated an increased activity of the amino terminal pro-collagen III (PIIINP) with a trend towards an increase in the amino-terminal pro-collagen I (PINP). Other relevant markers of the fibrotic process were not altered, including metalloproteinase enzymes (MMP) and tissue inhibitors of metalloproteinase enzymes (TIMP)

These observational data support the hypothesis that diastolic heart failure may be the result of an aggressive uncontrolled myocardial fibrotic process. The purpose of this project is to assess whether aldosterone inhibition or statin therapy may have an impact on increased levels of collagen markers, and thereby have a positive influence on parameters of diastolic function. Aldosterone is known to be a potent stimulus of the fibrotic process and therefore is a likely contributor. Support for this hypothesis comes from the observation in the systolic heart failure population where the administration of an aldosterone antagonist was found to be of benefit especially in those individuals who had serum evidence of heightened fibrotic activity. Statin therapy has been shown to reduce myocardial fibrosis in a rat model. Furthermore, preliminary data presented from the EPHESUS study has shown that greater benefits of eplerenone in those receiving concomitant statin therapy. We therefore propose to analyse the impact of atorvastatin therapy or aldosterone inhibition on markers of collagen turnover and also indices of diastolic function and markers of clinical well being.

We therefore propose to analyse the impact of aldosterone inhibition or statin therapy on markers of collagen turnover and also indices of diastolic function and markers of clinical well being.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with diastolic heart failure.
  • Diastolic heart failure is defined as symptoms of heart failure with an ejection fraction >45%, BNP >100pg/ml and Doppler evidence of diastolic dysfunction.

Exclusion Criteria:

  • Clinically unstable as defined by any change in diuretic dose in the month prior to enrolment.
  • Evidence of significant inflammatory disease or hepatic disease or metabolic bone disease which may alter parameters of collagen metabolism.
  • Patients already receiving statin, aldosterone or eplerenone therapy
  • Pregnant women and women of child bearing age
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00505336

Locations
Ireland
St Vincent's University Hospital
Ballsbridge, Dublin, Ireland, 4
Sponsors and Collaborators
St Vincent's University Hospital, Ireland
Investigators
Study Director: Ken McDonald, MD FRCP Heart Failure Unit, St Vincent's University Hospital
Principal Investigator: George Mak, MB MRCPI St Vincent's University Hospital
Principal Investigator: Niamh Murphy, MD MRCPI St Vincent's University Hospital
  More Information

No publications provided by St Vincent's University Hospital, Ireland

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Professor Kenneth McDonald MD, St Vincent's University Hospital, Ireland
ClinicalTrials.gov Identifier: NCT00505336     History of Changes
Other Study ID Numbers: SVUH 042
Study First Received: July 19, 2007
Last Updated: February 10, 2009
Health Authority: Ireland: Irish Medicines Board

Keywords provided by St Vincent's University Hospital, Ireland:
Diastolic heart failure
Markers of collagen turnover
Statins
Aldosterone receptor blockers

Additional relevant MeSH terms:
Heart Failure
Heart Failure, Diastolic
Heart Diseases
Cardiovascular Diseases
Atorvastatin
Eplerenone
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses
Aldosterone Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 17, 2014