Effects of High-dose n-3 Fatty Acids on Clinical Outcome and Serum Lipids - Omacor Following Acute Myocardial Infarction (OFAMI)

February 18, 2012 updated by: Helse Stavanger HF

Effects of a High-dose Concentrate of n-3 Fatty Acids or Corn Oil Introduced Early After an Acute Myocardial Infarction on Serum Triacylglycerol and High-density Lipoprotein (HDL)- Cholesterol

The object of this study was to evaluate the effect of a high-dose ethylester concentrate of of n-3 fatty acids administered early after an acute myocardial infarction on subsequent cardiac events and serum lipids.The second purpose of this study was to assess the impact of high-dose n-3 fatty acids on several markers of coagulation, inflammation, endothelial dysfunction and lipid peroxidation. Re-investigation was intended after a prolonged wash-out-period.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Results of epidemiologic studies and clinical trials indicate that moderate doses of n-3 unsaturated fatty acids reduce the risk of cardiovascular disease(CVD) and may improve prognosis. N-3 fatty acids have several beneficial cardiovascular properties (1-3), including antiatherothrombotic, antiarrhythmic, and antihypertensive effects, and are especially noted for their triacylglycerol-reducing ability (3-7). These effects may translate into an improved clinical outcome in patients with coronary artery disease (CAD) (8).

The pronounced effect obtained of moderate doses of n-3 fatty acids supplementation may suggest an even stronger effect of pharmacologic doses.

The object of this study was therefore to assess the effect of a high-dose ethylester concentrate of n-3 fatty acids as compared to corn oil administered early (4-8 days) after an acute myocardial infarction (MI), on fatal and non-fatal subsequent cardiac events (cardiac death, resuscitation, recurrent myocardial infarction (MI) or angina pectoris), during 2 ys follow-up (median 18 months). We hypothesized that a high-dose of n-3 fatty acids would improve serum lipids in this population, and beneficially influence several markers of coagulation, endothelial dysfunction and inflammation.

Three hundred patients with an acute myocardial infarction (MI) were recruited at one hospital center (Central Hospital in Rogaland, Stavanger, Norway) from September 1995 until December 1996. All patients were included between the fourth and the eighth day after an acute myocardial infarction (MI). All patients were randomly assigned to receive 2 gelatin capsules of Omacor-R (Pronova AS, Oslo) or corn oil twice a day. Each capsule contained either 850-882 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethylesters in the average ratio of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) of 1:2 or the same amount of corn oil. α-Tocopherol (4 mg) was added to all capsules. The capsules were administered in a double-blind manner over 12-24 months. A detailed patient history was recorded and a clinical examination was performed. The electrocardiogram was scrutinized for infarct location. The recent injury was classified as an anterior or inferior Q-wave infarction or any non-Q-wave infarction. Treatment was initiated immediately after inclusion and collection of baseline blood samples. The study was approved by the Regional Ethics Committee for Western Norway.

Clinical follow-up, including blood tests and electrocardiogram recordings, was repeated at 6 wk, 6 mo, 1 y, 18 mo, and, for some patients, 2 ys after the start of treatment. A deviation of 2 wk at the first follow-up and ≤1 mo at later follow-ups was allowed. All cardiac events and ongoing medication were recorded. Cardiac events were defined as cardiac death, resuscitation, recurrent myocardial infarction (MI), and unstable angina. Revascularization and death from other causes were also recorded. The study was closed at the end of 1997. The median follow-up time (ignoring events except deaths) was 1.5 y.

Analyses of serum triacylglycerols, total cholesterol and high-density lipoprotein (HDL)-cholesterol were performed at inclusion, 6 weeks, 6 and 12 months. In addition, analyses of markers of inflammation [high-sensitivity-C-reactive protein (CRP), CD-40 Ligand (CD40L)], coagulation [D-Dimer, fibrinogen, tissue factor, activated factor XII (FXIIa)], endothelial dysfunction [adhesion molecules such as E-selectin and Intra-Cellular Adhesion Molecule-1 (ICAM-1), homocysteine)], and Thiobarbituric Acid Reactive Substances (TBARS) as a marker of the oxidative burden of n-3 fatty acids, have been performed at different time points during follow-up, to evaluate the influence of n-3 fatty acids on these markers, and to assess their prognostic ability following a myocardial infarction (MI). Moreover, holo-transcobalamin (holoTC), methylmalonic acid (MMA), n-Terminal pro-Brain Natriuretic Peptide (NT-proBNP), matrix metalloproteinases-9 (MMP-9), Pregnancy-associated plasma protein A (PAPP-A), myeloperoxidase (MPO), and CD40 Ligand (CD40L) were measured also in order to evaluate their prognostic ability following a myocardial infarction (MI).

After closure of the main study, the purpose was to evaluate the prognosis of the study subjects after a prolonged wash-out period.

Publications from the study:

  1. Nilsen DWT, Albrektsen G, Landmark K, Moen S, Aarsland T, Woie L. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am J Clin Nutr 2001;74:50-6.
  2. Grundt H, Nilsen DW, Mansoor MA, Hetland Ø, Nordøy A. Reduction in homocysteine by n-3 polyunsaturated fatty acids after 1 year in a randomised double-blind study following an acute myocardial infarction: no effect on endothelial adhesion properties. Pathophysiol Haemost Thromb. 2003 Mar-Apr;33(2):88-95.
  3. Grundt H, Nilsen DW, Mansoor MA, Nordøy A. Increased lipid peroxidation during long-term intervention with high doses of n-3 fatty acids (PUFAs) following an acute myocardial infarction. Eur J Clin Nutr. 2003 Jun;57(6):793-800.
  4. Grundt H, Hetland Ø, Nilsen DW. Changes in tissue factor and activated factor XII following an acute myocardial infarction were uninfluenced by high doses of n-3 polyunsaturated fatty acids. Thromb Haemost. 2003 Apr;89(4):752-9.
  5. Grundt H, Nilsen DW, Hetland Ø, Mansoor MA. Clinical outcome and atherothrombogenic risk profile after prolonged wash-out following long-term treatment with high doses of n-3 PUFAs in patients with an acute myocardial infarction. Clin Nutr. 2004 Aug;23(4):491-500.
  6. Grundt H, Nilsen DW, Hetland Ø, Valente E, Fagertun HE. Activated factor 12 (FXIIa) predicts recurrent coronary events after an acute myocardial infarction. Am Heart J. 2004 Feb;147(2):260-6.
  7. Aarsetøy H, Brügger-Andersen T, Hetland Ø, Grundt H, Nilsen DW. Long term influence of regular intake of high dose n-3 fatty acids on CD40-ligand, pregnancy-associated plasma protein A and matrix metalloproteinase-9 following acute myocardial infarction. Thromb Haemost. 2006 Feb;95(2):329-36.
  8. Brügger-Andersen T, Aarsetøy H, Grundt H, Staines H, Nilsen DW. The long-term prognostic value of multiple biomarkers following a myocardial infarction.Thromb Res. 2008;123(1):60-6.
  9. Aarsetøy H, Valente E, Reine A, Mansoor MA, Grundt H, Nilsen DW. Holotranscobalamin and methylmalonic acid as prognostic markers following an acute myocardial infarction. Eur J Clin Nutr. 2008 Mar;62(3):411-8. Epub 2007 Mar 7.

Study Type

Interventional

Enrollment (Actual)

300

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Norway
      • Stavanger, Norway, 4011
        • Central Hospital in Rogalanad

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Verified an acute myocardial infarction (MI) by World Health Organization criteria
  • Age above 18 years
  • Discontinuation of a regular supplementation of other fish-oil products
  • Signed informed consent

Exclusion Criteria:

  • Assumed noncompliance to protocol
  • Expected survival < 2 y because of severe heart failure (New York Heart Association class IV), malignancy, or other reasons
  • Ongoing gastrointestinal bleeding or verified stomach ulcer
  • Thrombocytopenia or blood platelets < 100 x 10'9/L
  • Liver insufficiency
  • Participation in any other study
  • Residence outside the recruitment area of this study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: n-3 fatty acids
Two gelatine capsules of Omacor-R (Pronova AS, Oslo) twice a day, each capsule containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethylesters, in the average ratio of EPA to DHA of 1:2. Alpha-Tocopherol (4 mg) was added to each capsule.
Drug: EPA / DHA / Alpha-Tocopherol
Two gelatine capsules of Omacor-R (Pronova AS, Oslo) twice a day, each containing 850-882 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethylesters in the average ratio of EPA to DHA of 1:2. Alpha-Tocopherol (4 mg) was added to each capsule.
Other Names:
  • Omacor-R
Active Comparator: Corn Oil
Two gelatine capsules twice a day, each containing 1 gram of corn oil. Alpha-Tocopherol (4 mg) was added to each capsule.
Drug: EPA / DHA / Alpha-Tocopherol
Two gelatine capsules of Omacor-R (Pronova AS, Oslo) twice a day, each containing 850-882 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethylesters in the average ratio of EPA to DHA of 1:2. Alpha-Tocopherol (4 mg) was added to each capsule.
Other Names:
  • Omacor-R
Drug: Corn Oil / Alpha-Tocopherol (4 mg)
Two gelatine capsules twice a day. Each capsule contains 1g Corn Oil and 4 mg Alpha-Tocopherol
Other Names:
  • Corn oil

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fatal and non-fatal cardiac events
Time Frame: 2 years
Cardiac events were defined as cardiac death, resuscitation, recurrent myocardial infarction (MI) and unstable angina pectoris, presented as single or combined cardiac events. Revascularizations and death from other causes were also recorded.
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum lipids
Time Frame: One year
Blood specimen were harvested at baseline [3-5 days post myocardial infarction (MI)] and repeated at 6 weeks, at 6 and 12 months follow-up. Serum cholesterol, high-density lipoprotein (HDL) - cholesterol and triacylglycerol were evaluated during follow-up.
One year
Inflammation markers
Time Frame: One year
Blood specimen were harvested at baseline [3-5 days post myocardial infarction (MI)] and repeated at 6 weeks, at 6 and 12 months follow-up. Several markers of inflammation [high-sensitivity C-Reactive Protein (CRP), CD40-Ligand] were evaluated during follow-up.
One year
Coagulation markers
Time Frame: One year
Blood specimen were harvested at baseline [3-5 days post myocardial infarction (MI)] and repeated at 6 weeks, at 6 and 12 months follow-up. Several markers of coagulation (fibrin monomer, fibrinogen, tissue factor, activated factor XII) were evaluated during follow-up.
One year
Endothelial dysfunction
Time Frame: One year
Blood specimen were harvested at baseline [3-5 days post myocardial infarction (MI)] and repeated at 6 weeks, at 6 and 12 months follow-up. Several markers of endothelial dysfunction (adhesion molecules, homocysteine) were evaluated during follow-up.
One year
Oxidative stress
Time Frame: One year
Blood specimen were harvested at baseline [3-5 days post myocardila infraction (MI)] and repeated at 6 weeks, at 6 and 12 months follow-up. Thiobarbituric acid Reactive Substances(TBARS), a marker of the oxidative burden of n-3 fatty acids, was evaluated during follow-up.
One year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Helse Stavanger HF

Collaborators

University of Oslo
University of Bergen
Pronova BioPharma
Pharmacia and Upjohn

Investigators

  • Principal Investigator: Dennis WT Nilsen, PhD, Department of Medicine, the Division of Cardiology, the Central Hospital in Rogaland, Norway, and the University of Bergen, Norway

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 1995

Primary Completion (Actual)

December 1, 1997

Study Completion (Actual)

December 1, 2002

Study Registration Dates

First Submitted

August 18, 2011

First Submitted That Met QC Criteria

August 22, 2011

First Posted (Estimate)

August 23, 2011

Study Record Updates

Last Update Posted (Estimate)

February 22, 2012

Last Update Submitted That Met QC Criteria

February 18, 2012

Last Verified

February 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OFAMI1995

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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