Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids

Not Applicable

Completed

• Conditions: Metabolic Syndrome; Coronary Heart Disease
• Interventions: Dietary Supplement: Omega 3 acid ethyl esters

• Registration Number: NCT01624727
• Lead Sponsor: Beth Israel Deaconess Medical Center

Brief Summary

The purpose of the study is to target inflammation to reduce progression of noncalcified plaque in the coronary arteries using omega-3 fatty acid supplementation compared to standard of care.

Detailed Description

Study Design: This is a randomized, parallel study design with a usual care control group. 278 subjects with coronary heart disease (CHD) are being randomized to omega-3 supplementation or standard of care (139 in each arm).

Multidetector computed tomographic angiography (MDCTA) is performed at baseline to quantitate the amount of noncalcified and calcified coronary plaque and again at 30 month follow-up to determine if there has been a change in the volume of noncalcified or total plaque. The primary endpoint is change in coronary noncalcified plaque volume during the 30 months of intervention between active and standard of care.

Hypothesis: Percent change in progression of coronary plaque volume will be less for the omega-3 fatty acid intervention compared to standard of care.

Secondary endpoints include plasma levels of inflammatory markers, lipids and measures of insulin sensitivity.

Secondary outcomes include testing the hypothesis that targeting inflammation with omega-3 fatty acids will be associated with:

1. Change in total plaque volume per patient.

2. improvement in physical function and exercise and reduction in pain and stiffness as measured by the WOMAC questionnaire

3. Reduction of mediators of inflammation in the circulation including CRP, PAI-1, serum amyloid A, MMP-9 and fibrinogen, pro-inflammatory cytokines including IL-6, TNF-a and IL-1b, the adhesion molecules VCAM-1 and ICAM-1, increase in adiponectin and reduction in serum nitrotyrosine as a marker of oxidative stress.

4. Reduction of insulin resistance assessed by fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR).

5. Reduction of inflammation in the liver associated with nonalcoholic steatohepatitis (NASH), a newly recognized component of the metabolic syndrome, and reduction of fatty liver quantitated by computerized tomography and levels of AST and ALT as markers of liver inflammation related to NASH.

6. Investigation of the relationship between vitamin D status and coronary plaque progression as well as with insulin resistance (HOMA-IR), beta-cell function (HOMA-%beta) and inflammatory cytokines.

7. Determination of whether baseline vitamin D levels predict clinical response to the omega-3 fatty acid intervention, and whether hypovitaminosis D is associated with plaque progression.

Study Timeline

• Study Start: 2009-06
• Study First Submitted: 2012-05-15
• Study First Submitted QC: 2012-06-19
• Study First Posted: 2012-06-21
• Primary Completion: 2015-01-15
• Study Completion: 2015-01-15
• Status Verified: 2017-09
• Last Update Submitted: 2017-09-26
• Last Update Posted: 2017-09-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 338

Inclusion Criteria

1. coronary artery disease
2. previous myocardial infarction
3. angioplasty (> 6 months ago)
4. previous coronary bypass surgery (> 12 months ago)
5. stable angina
6. non-calcified plaque on prior CT
7. abnormal exercise tolerance test
8. aged 21- 80 years
9. BMI ≥ 27 kg/m2 and ≤ 35 kg/m2 if female and ≤ 40 kg/m2 if male (a BMI > 24.5 for subjects from Asian origin)
10. stable dose of statin for 1 month at screening or unable to tolerate a statin
11. normal renal function - estimated creatinine clearance calculated using Cockcroft-Gault (CG) equation ≥60 at screening [eCrCLCG (ml/min) = [(140 - age) x weight (kg)]/[SCr(mg/dl) x 72] x [0.85 if female] or serum Cr < 1.3
12. ALT, AST) < 3 times upper limits of normal)
13. normal thyroid function or on stable dose replacement therapy
14. an ETT performed within 12 months prior

Exclusion criteria

1. unstable angina (increase in frequency or severity of anginal episodes or development of chest pain at rest)
2. significant obstructive disease in left main coronary artery, ostial LAD or newly diagnosed three-vessel disease since prior cardiac catheterization by MDCTA
3. significant heart failure (NYHA class III and IV)
4. Current atrial fibrillation or Wolf-Parkinson-White (WPW) syndrome
5. allergy to beta-blocker in subjects with resting heart rate > 65 bpm
6. systolic blood pressure > 160 mm Hg
7. diastolic BP > 100 mm Hg
8. persons with allergies to iodinated contrast material or shellfish
9. allergy to nitroglycerin
10. history of asthma only if unable to tolerate beta-blockers
11. BMI > 35 kg/m2 if female and > 40 kg/m2 if male
12. body weight > 350 lbs
13. Use of drugs for weight loss [eg Xenical (orlistat), Meridia (sibutramine), Acutrim (phenylpropanolamine) or similar over-the-counter medications] within three months of screening
14. surgery within 30 days of screening
15. history of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)
16. poor mental function or history of dementia/Alzheimer's Disease or on medications used for treatment of dementia [e.g. Tacrine (Cognex), Rivastigmine (Exelon), Galantamine (Razadyne, Reminyl), Donepezil (Aricept), Memantine (Namenda)] or any other reason to except patient difficulty in complying with the requirements of the study
17. medicine for erectile dysfunction within 72 hours prior to MDCTA
18. Prior stroke with residual cognitive deficit or functional deficit preventing any type of exercise
19. Current chemotherapy or radiation for malignancy
20. Current weekly alcohol consumption > 21 units/week (1 unit = 1 beer, 1 glass of wine, 1 mixed cocktail containing 1 ounce of alcohol)

Exclusions based on nuclear imaging:

1. Transient cavity dilation
2. More than one vascular territory involved with reversible defect (multiple defects)
3. Reversible defects involving the anterior wall, septum or apex (LAD territory)

Exclusions based on echocardiography imaging:

1. More than one vascular territory involved with inducible wall motion abnormalities (multiple defects) 2. Inducible wall motion abnormalities involving the anterior wall, septum or apex (LAD territory)

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lovaza (Omega 3 ethyl esters)	Omega 3 acid ethyl esters	-

Primary Outcome Measures

Name	Time	Method
The primary endpoint is change in coronary noncalcified plaque volume.	Baseline and 30 months	MDCTA is performed at baseline to quantitate the amount of noncalcified and calcified coronary plaque and again at 30 month follow-up to determine if there has been a change in the volume of noncalcified or total plaque. The primary endpoint is change in coronary noncalcified plaque volume during the 30 months of intervention between active and standard of care. The hypothesis is that those on Lovaza will have less progression of coronary plaque compared to those in usual care.

Secondary Outcome Measures

Name	Time	Method
Effect of Lovaza on Physical Function, Pain, Stiffness and Exercise	Baseline and 1 year	Those on Lovaza will have better physical function and less pain and stiffness as assessed by the WOMAC questionnaire and more minutes of exercise per week compared to control
Nonalcoholic steatohepatitis (NASH)	Baseline and 30 months	Reduction of inflammation in the liver associated with nonalcoholic steatohepatitis (NASH), a component of the metabolic syndrome, and reduction of fatty liver quantitated by computerized tomography and levels of AST and ALT as markers of liver inflammation related to NASH.
Coronary artery plaque assessment	Baseline and 30 months	1. Percent atheroma volume calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque and total atheroma volume, normalized to segment length.; 2. Maximum percent diameter stenosis and minimal luminal diameter.; 3. Number of subjects with categorical variables of maximal stenosis \>50% and number with 3-vessel disease \>20%.; 4. Number of subjects with stenosis of 0-29%, 30-49%, 50-69% and \>70% stenosis at baseline compared to 30 months.; 5. Change in remodeling index - ratio of plaque volume at the most diseased site compared to the least diseased site.
Inflammatory markers	Baseline and 30 months	Compared to usual care, those on Lovaza will have reduction of mediators of inflammation in the circulation, including CRP, PAI-1, serum amyloid A, MMP-9 and fibrinogen, pro-inflammatory cytokines including IL-6, TNF-a and IL-1b, the adhesion molecules VCAM-1 and ICAM-1, increase in adiponectin and reduction in serum nitrotyrosine as a marker of oxidative stress. Additional inflammatory markers may be identified in the future and measured.
Pericardial Fat	Baseline and 30 months	The amount of pericardial fat will be quantitated by CT at baseline and 30-month follow-up. The percent change between the two time-frames will be measured. Those on Lovaza and/or those who have lost weight will have a reduction (or lack of increase) in pericardial fat at 30-months compared to those in usual care.
Insulin Resistance	Baseline and 30 months	Insulin resistance will be assessed by fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) at baseline and 30-months in the two study groups.
Vitamin D Levels and coronary plaque progression	Baseline and 30 months	1. Investigation of the relationship between vitamin D status and coronary plaque progression, insulin resistance (HOMA-IR), beta-cell function (HOMA-%beta) and inflammatory cytokines; 2. Do baseline vitamin D levels predict response to omega-3 fatty acid supplementation?
Exercise capacity and coronary plaque	Baseline	To determine if exercise capacity correlates with coronary plaque measurements. The hypothesis is that those with better exercise capacity will have lower amounts of coronary plaque.
Urinary microalbumin and coronary plaque	Baseline and 30-months	At baseline, subjects with lower urinary microalbumin will have lower amounts of coronary plaque. Those taking Lovaza will have less increase in urinary microalbmumin at 30-month follow-up compared to those in usual care.
Cognitive function	Baseline, 1 year and 30-months	To determine if those on Lovaza have less decline in cognitive function at 1 year and 30 months of follow-up compared to those in the usual care group.

Trial Locations

Locations (2)

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

South Shore Medical Group; 🇺🇸 Milton, Massachusetts, United States