Statin Therapy in Heart Failure: Potential Mechanisms of Benefit

• Sponsor: University of California, Los Angeles (Other)
• Overall Status: Completed
• CT.gov ID: NCT00233480
• Collaborator: Pfizer (Industry), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 27
• Location: 1
• Arms: 2
• Duration (Months): 42.1
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Heart Failure, Congestive	Drug: atorvastatin; Drug: placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Study Start Date: Aug 1, 2005
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: active treatment atorvastatin 10mg QD x 3 months	Drug: atorvastatin; atorvastatin 10mg PO QD; Other Names: lipitor
Placebo Comparator: placebo matched placebo QD x 3 months	Drug: placebo; matched placebo Qd x 3 months

Outcome Measures

Primary Outcome Measures

1. LVEF (Left Ventricular Ejection Fraction) [baseline and three months]

   Left ventricular ejection fraction was assessed by transthoracic echocardiography according to Simpson's rule (biplane method of disks).

2. Muscle Sympathetic Nerve Activity (by Sympathetic Microneurography) [Baseline and three months]

Secondary Outcome Measures

1. Left Ventricular End-diastolic Dimension (LVEDD) [Baseline and three months]

   The end-diastolic dimension of the left ventricle (in mm) was measured with 2D echocardiography performed by experienced technicians using Acuson Sequoia Echocardiography System

2. Cardiac Biomarker Level BNP [Baseline, 3 months]

   B-type natriuretic peptide, measured pg/mL at baseline and post-treatment

3. High-sensitivity C-reactive Protein (hsCRP) as a Cardiac Biomarker [Baseline, Three months]

4. Cardiac Troponin I (cTnI) [Baseline, Three months]

   Participants with cTnI ≥0.04 ng/mL

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Ahmanson-UCLA Cardiomyopathy Center	Los Angeles	California	United States	90095

Sponsors and Collaborators

• University of California, Los Angeles
• Pfizer
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Tamara B Horwich, MD, UCLA Division of Cardiology

Study Documents (Full-Text)

None provided.

More Information

Publications

• Horwich TB, MacLellan WR. Atorvastatin and statins in the treatment of heart failure. Expert Opin Pharmacother. 2007 Dec;8(17):3061-8. Review.
• Horwich TB, Middlekauff HR. Potential autonomic nervous system effects of statins in heart failure. Heart Fail Clin. 2008 Apr;4(2):163-70. doi: 10.1016/j.hfc.2008.01.004.

• Responsible Party: Tamara Horwich, Tamara Horwich, MD, MS, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT00233480
• Other Study ID Numbers: UCLA IRB #04-12-007-01; 1K23HL085097-01A1
• First Posted: Oct 5, 2005
• Last Update Posted: Mar 20, 2020
• Last Verified: Mar 1, 2020

• Keywords provided by Tamara Horwich, Tamara Horwich, MD, MS, University of California, Los Angeles: Randomized Controlled Trial; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Sympathetic Nervous System; Ventricular Remodeling; Chemokines
• Additional relevant MeSH terms: Heart Failure; Atorvastatin

Study Results

Participant Flow

Arm/Group Title	Active Treatment	Placebo
Arm/Group Description	atorvastatin 10mg QD x 3 months	matched placebo QD x 3 months
Period Title: Overall Study
STARTED	14	13
COMPLETED	14	12
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Active Treatment	Placebo	Total
Arm/Group Description	atorvastatin 10mg QD x 3 months	matched placebo QD x 3 months	Total of all reporting groups
Overall Participants	14	12	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	12 100%	26 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47 (14)	49 (17)	48 (15)
Sex: Female, Male (Count of Participants)
Female	8 57.1%	2 16.7%	10 38.5%
Male	6 42.9%	10 83.3%	16 61.5%
Region of Enrollment (participants) [Number]
United States	14 100%	12 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	LVEF (Left Ventricular Ejection Fraction)
Description	Left ventricular ejection fraction was assessed by transthoracic echocardiography according to Simpson's rule (biplane method of disks).
Time Frame	baseline and three months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Treatment	Placebo
Arm/Group Description	atorvastatin 10mg QD x 3 months	matched placebo QD x 3 months
Measure Participants	14	12
Baseline LVEF	24 (6)	28 (7)
3 month LVEF	25 (6)	24 (7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	paired t test
	Comments

2. Primary Outcome

Title	Muscle Sympathetic Nerve Activity (by Sympathetic Microneurography)
Time Frame	Baseline and three months

Outcome Measure Data

Analysis Population Description

Eighteen subjects had baseline and final sympathetic microneurographic tracings that were technically adequate for analysis. Reasons for inadequate microneurographic tracing were: 1) inability of investigators to locate sympathetic nerve on baseline or final study; or 2) inability of patient to tolerate discomfort of the procedure.

Arm/Group Title	Active Treatment	Placebo
Arm/Group Description	atorvastatin 10mg daily for three months	matched placebo daily for three months
Measure Participants	9	9
Baseline	43 (3)	39 (3)
Three months	36 (5)	38 (3)

3. Secondary Outcome

Title	Left Ventricular End-diastolic Dimension (LVEDD)
Description	The end-diastolic dimension of the left ventricle (in mm) was measured with 2D echocardiography performed by experienced technicians using Acuson Sequoia Echocardiography System
Time Frame	Baseline and three months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Treatment	Placebo
Arm/Group Description	atorvastatin 10mg daily for three months	matched placebo daily for three months
Measure Participants	14	12
Baseline LVEDD	65 (12)	28 (7)
Three months LVEDD	25 (6)	24 (7)

4. Secondary Outcome

Title	Cardiac Biomarker Level BNP
Description	B-type natriuretic peptide, measured pg/mL at baseline and post-treatment
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Treatment	Placebo
Arm/Group Description	atorvastatin 10mg QD x 3 months	matched placebo QD x 3 months
Measure Participants	14	12
Baseline	175	66
Three Months	107	67

5. Secondary Outcome

Title	High-sensitivity C-reactive Protein (hsCRP) as a Cardiac Biomarker
Time Frame	Baseline, Three months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Treatment	Placebo
Arm/Group Description	atorvastatin 10mg daily for three months	matched placebo daily for three months
Measure Participants	14	12
Baseline	1.6	1.9
Three months	1.9	3.4

6. Secondary Outcome

Title	Cardiac Troponin I (cTnI)
Description	Participants with cTnI ≥0.04 ng/mL
Time Frame	Baseline, Three months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Treatment	Placebo
Arm/Group Description	atorvastatin 10mg daily for three months	matched placebo daily for three months
Measure Participants	14	12
Baseline	8 57.1%	21 175%
Three Months	0 0%	15 125%

Adverse Events

Time Frame	3 months
Arm/Group Title	Active Treatment		Placebo
Arm/Group Description	atorvastatin 10mg QD x 3 months		matched placebo QD x 3 months
All Cause Mortality
	Active Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Active Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Active Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.