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

Primary Purpose

Coronary Heart Disease, Metabolic Syndrome

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Omega 3 acid ethyl esters
Sponsored by
Beth Israel Deaconess Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Coronary Heart Disease focused on measuring Coronary heart disease, metabolic syndrome, CT angiography

Eligibility Criteria

21 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

-

Sites / Locations

  • Beth Israel Deaconess Medical Center
  • South Shore Medical Group

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

Usual care

Lovaza (Omega 3 ethyl esters)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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
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.
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.
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.
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.
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?
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.
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.
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.

Full Information

First Posted
May 15, 2012
Last Updated
September 26, 2017
Sponsor
Beth Israel Deaconess Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Tufts Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT01624727
Brief Title
Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids
Acronym
HEARTS
Official Title
Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids (HEARTS)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Completed
Study Start Date
June 2009 (undefined)
Primary Completion Date
January 15, 2015 (Actual)
Study Completion Date
January 15, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beth Israel Deaconess Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Tufts Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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: 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronary Heart Disease, Metabolic Syndrome
Keywords
Coronary heart disease, metabolic syndrome, CT angiography

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
338 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Usual care
Arm Type
No Intervention
Arm Description
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.
Arm Title
Lovaza (Omega 3 ethyl esters)
Arm Type
Active Comparator
Intervention Type
Dietary Supplement
Intervention Name(s)
Omega 3 acid ethyl esters
Intervention Description
Lovaza 3.6 g daily
Primary Outcome Measure Information:
Title
The primary endpoint is change in coronary noncalcified plaque volume.
Description
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.
Time Frame
Baseline and 30 months
Secondary Outcome Measure Information:
Title
Coronary artery plaque assessment
Description
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.
Time Frame
Baseline and 30 months
Title
Effect of Lovaza on Physical Function, Pain, Stiffness and Exercise
Description
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
Time Frame
Baseline and 1 year
Title
Inflammatory markers
Description
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.
Time Frame
Baseline and 30 months
Title
Pericardial Fat
Description
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.
Time Frame
Baseline and 30 months
Title
Insulin Resistance
Description
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.
Time Frame
Baseline and 30 months
Title
Nonalcoholic steatohepatitis (NASH)
Description
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.
Time Frame
Baseline and 30 months
Title
Vitamin D Levels and coronary plaque progression
Description
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?
Time Frame
Baseline and 30 months
Title
Cognitive function
Description
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.
Time Frame
Baseline, 1 year and 30-months
Title
Exercise capacity and coronary plaque
Description
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.
Time Frame
Baseline
Title
Urinary microalbumin and coronary plaque
Description
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.
Time Frame
Baseline and 30-months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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) -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francine K Welty, MD, PhD
Organizational Affiliation
Beth Israel Deaconess Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
South Shore Medical Group
City
Milton
State/Province
Massachusetts
ZIP/Postal Code
02186
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33749913
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.
Results Reference
derived
PubMed Identifier
33675344
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.
Results Reference
derived
PubMed Identifier
32212910
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.
Results Reference
derived
PubMed Identifier
31055222
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.
Results Reference
derived
PubMed Identifier
29246960
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.
Results Reference
derived
PubMed Identifier
28710178
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.
Results Reference
derived

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Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids

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