Statin Therapy in Heart Failure: Potential Mechanisms of Benefit - Full Text View

Sponsors and Collaborators:	University of California, Los Angeles Pfizer
Information provided by:	University of California, Los Angeles
ClinicalTrials.gov Identifier:	NCT00233480

Purpose

The goal of the investigators' study is to further understand the potentially beneficial effects of statin therapy in patients with heart failure. It is hypothesized that statins will 1) increase the heart's pumping ability 2) improve functioning of the sympathetic nervous system and 3) decrease immune activation in heart failure.

Condition	Intervention	Phase
Heart Failure, Congestive	Drug: atorvastatin Drug: placebo	Phase IV

MedlinePlus related topics: Heart Failure Statins

Drug Information available for: Atorvastatin Atorvastatin calcium

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study
Official Title:	A Double-Blind Randomized, Placebo-Controlled, Single-Center Study to Assess the Impact of Statins on the Autonomic Nervous System and Cardiac Structure/Function in Non-Ischemic Heart Failure

Further study details as provided by University of California, Los Angeles:

Primary Outcome Measures:

Left Ventricular Ejection Fraction (by echocardiography) [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
Muscle Sympathetic Nerve Activity (by sympathetic microneurography [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Circulating cytokine and chemokine levels, as well as cytokine and chemokine receptor expression [ Time Frame: 3 months ] [ Designated as safety issue: No ]
Secondary indices of autonomic nervous system function: [ Time Frame: 3 months ] [ Designated as safety issue: No ]
echocardiography (all patients):LV mass, MPI, diastolic and systolic volume index, wall thickness [ Time Frame: 3 months ] [ Designated as safety issue: No ]
cardiac MRI (subgroup without pacemaker or ICD): LV mass, diastolic and systolic volume index, wall thickness, sphericity index, pulmonary arteriovenous transit time, cardiac output/index, regional wall motion, and subendocardial scar [ Time Frame: 3 months ] [ Designated as safety issue: No ]
Established cardiac biomarkers: BNP, cTnI, hs-CRP [ Time Frame: 3 months ] [ Designated as safety issue: No ]
Symptoms: NYHA class (assessed by blinded physician or nurse), QOL questionnaire [ Time Frame: 3 months ] [ Designated as safety issue: No ]
Arrhythmia frequency on 24 hour Holter: ventricular ectopy, non-sustained ventricular tachycardia, sustained ventricular tachycardia, atrial fibrillation. [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	50
Study Start Date:	August 2005
Estimated Study Completion Date:	March 2009
Estimated Primary Completion Date:	March 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
active treatment: Experimental atorvastatin 10mg QD x 3 months	Drug: atorvastatin atorvastatin 10mg PO QD
placebo: Placebo Comparator matched placebo QD x 3 months	Drug: placebo matched placebo Qd x 3 months

Detailed Description:

Recent evidence suggests that HMG-Coenzyme A (statin) therapy may be associated with improved survival in both ischemic and non-ischemic heart failure (HF). Large, randomized outcome studies of statins in HF are currently underway, but these trials will not address underlying mechanisms. The aim of the study is to investigate statins' potentially beneficial mechanisms of action in HF, focusing on: 1) sympathetic nervous system activation and 2) myocardial remodeling, and 3) immune activation in heart failure.

Fifty patients with systolic HF of non-ischemic etiology from a single center will be randomized in a double-blinded fashion to 3 months of atorvastatin 10mg QD (25 subjects) vs matching placebo QD (25 subjects). The following exams will be performed at baseline (pre-treatment) and at end of study (post-treatment): sympathetic microneurography, echocardiography, and peripheral blood chemokine analysis. Sympathetic microneurography at the peroneal nerve will directly quantify changes in sympathetic nerve activity (bursts/minute). Echocardiography (with the addition of MRI in a subset of subjects without pacemakers or implantable defibrillators) will be used to track changes in cardiac structure and function; indices of remodeling will include measurement of left ventricular mass index, left ventricular volume indices, left ventricular ejection fraction, and subendocardial scar quantification (MRI only). Immune activation will be characterized by circulating cytokines and chemokines. Additionally, quantification of established cardiac biomarkers (cardiac troponin, B-type natriuretic peptide, and C-reactive Protein), Holter monitor/heart rate variability studies, and quality of life and global clinical assessment will be performed pre- and post- treatment.

Neither sympathetic microneurography nor MRI have been previously utilized to assess statins' effects in humans with HF. The impact of statin therapy on inflammatory chemokine activation in HF also has not been studied. The knowledge gained from our proposed investigations may serve as a basis for understanding how statin therapy has potential to improve clinical outcomes in HF, and may ultimately lead to new therapeutic strategies for HF.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age≥18 years old
LVEF ≤ 35%, as documented by echocardiography, radionuclide ventriculography, gated SPECT, or contrast ventriculography within past 6 months
Symptomatic HF (NYHA II-IV) or current NYHA I with history of symptomatic HF within the last year
Stable doses of optimal HF medical therapy, unless documented contraindication.

Exclusion Criteria:

Ischemic etiology of HF, defined as the presence of at least one of the following four criteria; angiographic evidence of > 50% lesion in 1 or more of the 3 major epicardial vessels; history of myocardial infarction; history of revascularization procedure; evidence of significant perfusion defect in the setting of ischemic symptoms.
Clinical indication for statin treatment - coronary artery, cerebrovascular, or peripheral vascular disease
Major cardiovascular event or surgical procedure within past 8 weeks
LDL<70 mg/dL
HF secondary to congenital heart disease or uncorrected valvular disease
Treatment with statin within past 2 months
Pregnancy
Contraindication to statin: moderate liver disease, AST/ALT > 150 U/ L, known hypersensitivity
Likely to receive heart transplant within 3 months
Known peripheral or autonomic neuropathy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00233480

Locations

United States, California
Ahmanson-UCLA Cardiomyopathy Center
Los Angeles, California, United States, 90095

Sponsors and Collaborators

University of California, Los Angeles

Pfizer

Investigators

Principal Investigator:

Tamara B Horwich, MD

UCLA Division of Cardiology

More Information

Publications:

Horwich TB, Middlekauff HR. Potential autonomic nervous system effects of statins in heart failure. Heart Fail Clin. 2008 Apr;4(2):163-70.

Horwich TB, MacLellan WR. Atorvastatin and statins in the treatment of heart failure. Expert Opin Pharmacother. 2007 Dec;8(17):3061-8. Review.

Responsible Party:	University of California, Los Angeles ( Tamara Horwich, MD, MS / Assistant Professor )
Study ID Numbers:	UCLA IRB #04-12-007-01, 1K23HL085097-01A1
Study First Received:	October 4, 2005
Last Updated:	February 13, 2009
ClinicalTrials.gov Identifier:	NCT00233480 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by University of California, Los Angeles:

Randomized Controlled Trial
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Sympathetic Nervous System
Ventricular Remodeling
Chemokines

Study placed in the following topic categories:

Antimetabolites
Heart Failure
Heart Diseases
Antilipemic Agents

Anticholesteremic Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Atorvastatin

Additional relevant MeSH terms:

Antimetabolites
Heart Failure
Heart Diseases
Molecular Mechanisms of Pharmacological Action
Therapeutic Uses
Antilipemic Agents

Enzyme Inhibitors
Cardiovascular Diseases
Anticholesteremic Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pharmacologic Actions
Atorvastatin

ClinicalTrials.gov processed this record on May 07, 2009