Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids

Study Overview
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Brief Summary
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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
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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: Change in total plaque volume per patient. improvement in physical function and exercise and reduction in pain and stiffness as measured by the WOMAC questionnaire 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. Reduction of insulin resistance assessed by fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR). 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. 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. 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.

Official Title
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Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids (HEARTS)

Conditions
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Coronary Heart Disease, Metabolic Syndrome

Intervention / Treatment
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* Dietary Supplement: Omega 3 acid ethyl esters


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: coronary artery disease previous myocardial infarction angioplasty (> 6 months ago) previous coronary bypass surgery (> 12 months ago) stable angina non-calcified plaque on prior CT abnormal exercise tolerance test aged 21- 80 years 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) stable dose of statin for 1 month at screening or unable to tolerate a statin 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 ALT, AST) < 3 times upper limits of normal) normal thyroid function or on stable dose replacement therapy an ETT performed within 12 months prior Exclusion criteria unstable angina (increase in frequency or severity of anginal episodes or development of chest pain at rest) significant obstructive disease in left main coronary artery, ostial LAD or newly diagnosed three-vessel disease since prior cardiac catheterization by MDCTA significant heart failure (NYHA class III and IV) Current atrial fibrillation or Wolf-Parkinson-White (WPW) syndrome allergy to beta-blocker in subjects with resting heart rate > 65 bpm systolic blood pressure > 160 mm Hg diastolic BP > 100 mm Hg persons with allergies to iodinated contrast material or shellfish allergy to nitroglycerin history of asthma only if unable to tolerate beta-blockers BMI > 35 kg/m2 if female and > 40 kg/m2 if male body weight > 350 lbs Use of drugs for weight loss [eg Xenical (orlistat), Meridia (sibutramine), Acutrim (phenylpropanolamine) or similar over-the-counter medications] within three months of screening surgery within 30 days of screening history of acquired immune deficiency syndrome or human immunodeficiency virus (HIV) 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 medicine for erectile dysfunction within 72 hours prior to MDCTA Prior stroke with residual cognitive deficit or functional deficit preventing any type of exercise Current chemotherapy or radiation for malignancy 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: Transient cavity dilation More than one vascular territory involved with reversible defect (multiple defects) 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) -

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Usual care<br>Those randomized to usual care will continue to follow the care provided by their cardiologist. They will have all the follow-up phone calls, visits and testing which the intervention group has. | |
| Active Comparator: Lovaza (Omega 3 ethyl esters)<br> | Dietary Supplement: Omega 3 acid ethyl esters<br>* Lovaza 3.6 g daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is change in coronary noncalcified plaque volume. | 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. | Baseline and 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coronary artery plaque assessment | Percent atheroma volume calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque and total atheroma volume, normalized to segment length. Maximum percent diameter stenosis and minimal luminal diameter. Number of subjects with categorical variables of maximal stenosis >50% and number with 3-vessel disease >20%. Number of subjects with stenosis of 0-29%, 30-49%, 50-69% and >70% stenosis at baseline compared to 30 months. Change in remodeling index - ratio of plaque volume at the most diseased site compared to the least diseased site. | Baseline and 30 months | 
| Effect of Lovaza on Physical Function, Pain, Stiffness and Exercise | 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 | Baseline and 1 year | 
| Inflammatory markers | 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. | Baseline and 30 months | 
| Pericardial Fat | 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. | Baseline and 30 months | 
| Insulin Resistance | 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. | Baseline and 30 months | 
| Nonalcoholic steatohepatitis (NASH) | 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. | Baseline and 30 months | 
| Vitamin D Levels and coronary plaque progression | Investigation of the relationship between vitamin D status and coronary plaque progression, insulin resistance (HOMA-IR), beta-cell function (HOMA-%beta) and inflammatory cytokines Do baseline vitamin D levels predict response to omega-3 fatty acid supplementation? | Baseline and 30 months | 
| Cognitive function | 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. | Baseline, 1 year and 30-months | 
| Exercise capacity and coronary plaque | 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. | Baseline | 
| Urinary microalbumin and coronary plaque | 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. | Baseline and 30-months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary heart disease, metabolic syndrome, CT angiography