Clinical trial NCT01422317: Effects of High-dose n-3 Fatty Acids on Clinical Outcome and Serum Lipids - Omacor Following Acute Myocardial Infarction
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Coronary Disease
Myocardial Infarction
Keywords: n-3 fatty acids
randomized double-blind study
coronary events
serum lipids
antithrombotic effects of omega-3 fatty acids
anti-inflammatory effects of omega-3 fatty acids
prognostic biomarkers in myocardial infarction (MI)-patients
Lead sponsor: Helse Stavanger HF
Sponsor class: OTHER_GOV
Collaborators: name: University of Bergen
name: University of Oslo
name: Pharmacia and Upjohn
name: Pronova BioPharma
First posted: 2011-08-23
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Fatal and non-fatal cardiac events
timeFrame: 2 years
Secondary outcomes:
measure: Serum lipids
timeFrame: One year
measure: Inflammation markers
timeFrame: One year
measure: Coagulation markers
timeFrame: One year
measure: Endothelial dysfunction
timeFrame: One year
measure: Oxidative stress
timeFrame: One year
Other outcomes:
Locations:
city: Stavanger
country: Norway
facility: Central Hospital in Rogalanad
Study officials:
affiliation: Department of Medicine, the Division of Cardiology, the Central Hospital in Rogaland, Norway, and the University of Bergen, Norway
name: Dennis WT Nilsen, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Connor SL, Connor WE. Are fish oils beneficial in the prevention and treatment of coronary artery disease? Am J Clin Nutr. 1997 Oct;66(4 Suppl):1020S-1031S. doi: 10.1093/ajcn/66.4.1020S.
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citation: Bonaa KH, Bjerve KS, Straume B, Gram IT, Thelle D. Effect of eicosapentaenoic and docosahexaenoic acids on blood pressure in hypertension. A population-based intervention trial from the Tromso study. N Engl J Med. 1990 Mar 22;322(12):795-801. doi: 10.1056/NEJM199003223221202.
citation: Harris WS. Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review. J Lipid Res. 1989 Jun;30(6):785-807.
citation: Eritsland J, Arnesen H, Seljeflot I, Hostmark AT. Long-term metabolic effects of n-3 polyunsaturated fatty acids in patients with coronary artery disease. Am J Clin Nutr. 1995 Apr;61(4):831-6. doi: 10.1093/ajcn/61.4.831.
citation: Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study. Circulation. 1998 Mar 24;97(11):1029-36. doi: 10.1161/01.cir.97.11.1029.
citation: Naesgaard PA, Grundt H, Nordoy AF, Staines H, Nilsen DWT. Vitamin D Uptake in Patients Treated with a High-Dosed Purified Omega-3 Compound in a Randomized Clinical Trial Following an Acute Myocardial Infarction. Front Cardiovasc Med. 2017 Jul 24;4:41. doi: 10.3389/fcvm.2017.00041. eCollection 2017.