Clinical trial NCT01624727: Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids
Official title: Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids (HEARTS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Coronary Heart Disease
Metabolic Syndrome
Keywords: Coronary heart disease
metabolic syndrome
CT angiography
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Tufts Medical Center
First posted: 2012-06-21
Enrollment: 338
Sex: ALL
Minimum age (years): 21
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

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Primary outcomes:
measure: The primary endpoint is change in coronary noncalcified plaque volume.
timeFrame: Baseline and 30 months
Secondary outcomes:
measure: Coronary artery plaque assessment
timeFrame: Baseline and 30 months
measure: Effect of Lovaza on Physical Function, Pain, Stiffness and Exercise
timeFrame: Baseline and 1 year
measure: Inflammatory markers
timeFrame: Baseline and 30 months
measure: Pericardial Fat
timeFrame: Baseline and 30 months
measure: Insulin Resistance
timeFrame: Baseline and 30 months
measure: Nonalcoholic steatohepatitis (NASH)
timeFrame: Baseline and 30 months
measure: Vitamin D Levels and coronary plaque progression
timeFrame: Baseline and 30 months
measure: Cognitive function
timeFrame: Baseline, 1 year and 30-months
measure: Exercise capacity and coronary plaque
timeFrame: Baseline
measure: Urinary microalbumin and coronary plaque
timeFrame: Baseline and 30-months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Milton
country: United States
facility: South Shore Medical Group
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Francine K Welty, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Welty FK, Schulte F, Alfaddagh A, Elajami TK, Bistrian BR, Hardt M. Regression of human coronary artery plaque is associated with a high ratio of (18-hydroxy-eicosapentaenoic acid + resolvin E1) to leukotriene B4. FASEB J. 2021 Apr;35(4):e21448. doi: 10.1096/fj.202002471R.
citation: Malik A, Ramadan A, Vemuri B, Siddiq W, Amangurbanova M, Ali A, Welty FK. omega-3 Ethyl ester results in better cognitive function at 12 and 30 months than control in cognitively healthy subjects with coronary artery disease: a secondary analysis of a randomized clinical trial. Am J Clin Nutr. 2021 May 8;113(5):1168-1176. doi: 10.1093/ajcn/nqaa420.
citation: Malik A, Kanduri JS, Asbeutah AAA, Khraishah H, Shen C, Welty FK. Exercise Capacity, Coronary Artery Fatty Plaque, Coronary Calcium Score, and Cardiovascular Events in Subjects With Stable Coronary Artery Disease. J Am Heart Assoc. 2020 Apr 7;9(7):e014919. doi: 10.1161/JAHA.119.014919. Epub 2020 Mar 26.
citation: Alfaddagh A, Elajami TK, Saleh M, Mohebali D, Bistrian BR, Welty FK. An omega-3 fatty acid plasma index >/=4% prevents progression of coronary artery plaque in patients with coronary artery disease on statin treatment. Atherosclerosis. 2019 Jun;285:153-162. doi: 10.1016/j.atherosclerosis.2019.04.213. Epub 2019 Apr 13.
citation: Alfaddagh A, Elajami TK, Ashfaque H, Saleh M, Bistrian BR, Welty FK. Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial. J Am Heart Assoc. 2017 Dec 15;6(12):e006981. doi: 10.1161/JAHA.117.006981.
citation: Elajami TK, Alfaddagh A, Lakshminarayan D, Soliman M, Chandnani M, Welty FK. Eicosapentaenoic and Docosahexaenoic Acids Attenuate Progression of Albuminuria in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease. J Am Heart Assoc. 2017 Jul 14;6(7):e004740. doi: 10.1161/JAHA.116.004740.