Alpha Omega Trial: Study of Omega-3 Fatty Acids and Coronary Mortality

• ClinicalTrials.gov Identifier: NCT00127452
• Recruitment Status: Completed
• First Posted: August 5, 2005
• Last Update Posted: July 7, 2010
• Sponsor: Wageningen University
• Collaborators: Netherlands Heart Foundation; National Heart, Lung, and Blood Institute (NHLBI); Unilever R&D
• Information provided by: Wageningen University

Tracking Information

• First Submitted Date: August 3, 2005
• First Posted Date: August 5, 2005
• Last Update Posted Date: July 7, 2010
• Study Start Date: April 2002
• Actual Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: December 21, 2009): Major cardiovascular events, which comprises fatal cardiovascular diseases (CVD), non-fatal myocardial infarction, non-fatal cardiac arrest, non-fatal stroke and cardiac interventions (PCI and CABG) [ Time Frame: monitored during intervention ]
• Original Primary Outcome Measures (submitted: August 3, 2005): Coronary mortality during 3 years of follow-up

Current Secondary Outcome Measures (submitted: April 15, 2010)

• Incident CVD, which comprises fatal CVD, non-fatal myocardial infarction, non-fatal cardiac arrest and non-fatal stroke [ Time Frame: monitored during intervention ]
• Fatal CVD, which comprises mortality from ischaemic heart disease, fatal cardiac arrest, sudden death undefined, mortality from heart failure and fatal stroke [ Time Frame: monitored during intervention ]
• Fatal CHD, which comprises mortality from ischaemic heart disease, mortality from cardiac arrest, and sudden death undefined [ Time Frame: monitored during intervention ]
• All-causes mortality [ Time Frame: monitored during intervention ]
• The composite of sudden death undefined and nonfatal and fatal cardiac arrest [ Time Frame: monitored during intervention ]
• The composite of sudden death undefined, nonfatal and fatal cardiac arrest, and self-reported placement of any implantable cardioverter-defibrillator, verified in medical records [ Time Frame: monitored during intervention ]

Original Secondary Outcome Measures (submitted: August 3, 2005)

• Cardiovascular mortality during 3 years of follow-up
• All cause mortality during 3 years of follow-up
• Sudden cardiac death during 3 years of follow-up

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Alpha Omega Trial: Study of Omega-3 Fatty Acids and Coronary Mortality
• Official Title: Alpha Omega Trial: A Randomised, Placebo Controlled, Double Blind Intervention Study of the Effect of Low Doses of Omega-3 Fatty Acids on Cardiovascular Diseases in Patients With a History of Myocardial Infarction

Brief Summary

The Alpha Omega Trial is a randomized, placebo-controlled, double-blind dietary intervention study in 4837 postmyocardial infarction patients in the Netherlands to examine whether incidence of cardiovascular diseases during 40 months of follow-up can be prevented by low doses of omega-3 polyunsaturated fatty acids. The key objectives are:

• to examine the effect of low-dose supplementation (400 mg/day) of eicosapentaenoic acid and docosahexaenoic acid on incidence of cardiovascular diseases; and
• to examine the effect of low-dose supplementation (2 g/day) of alpha-linolenic acid on incidence of cardiovascular diseases.

• Detailed Description: Whether dietary omega-3 (or n-3) polyunsaturated fatty acids are causally related to risk of cardiovascular diseases (CVD) is a major, unresolved question in preventive cardiology. Essential n-3 fatty acids are eicosapentaenoic acid (EPA; C20:5, n-3) and docosahexaenoic acid (DHA; C22:6, n-3) on one hand, and their parent compound alpha-linolenic acid (ALA; C18:3, n-3) on the other hand. The intake of n-3 fatty acids is below recommended levels in most Western populations. The Alpha Omega Trial is a randomized, double-blind, placebo-controlled study of the effect of low-dose supplementation of ALA and EPA-DHA on CVD. A total of 4837 Dutch men and women aged 60-80 years who had a myocardial infarction in the past 10 years are randomly allocated to 2 g/d of ALA, 400 mg/d of EPA-DHA, 2 g/d ALA + 400 mg/d EPA-DHA, or placebo, for 40 months. Increased intake of n-3 fatty acids is achieved through daily use of 20 g of margarine on bread. Margarines for all treatment groups are similar in taste and appearance. The primary outcome of the trial is 'major cardiovascular events', which comprises incident CVD and cardiac interventions (PCI and CABG) during follow-up. Secondary endpoints are incident CVD, fatal CVD, fatal CHD and all-causes mortality. Complete follow-up for vital status is achieved. Cause-specific mortality is coded by an independent Endpoint Adjudication Committee. Physical examination, blood sampling and data collection on diet and lifestyle are performed in all subjects at baseline, in 810 randomly selected subjects after 20 months of intervention, and in 58% of the cohort at the end of follow-up. Cardiovascular health, serious adverse events, lifestyle, fish intake and margarine use are monitored in all subjects by yearly telephone interviews. Compliance is continuously monitored by registration of margarine tubs. An objective biomarker of compliance (i.e. plasma n-3 fatty acids) is obtained in randomly selected subjects at baseline and after 20 and 40 months of intervention. The Alpha Omega Trial could provide a sound scientific basis for dietary recommendations on intake of ALA and EPA-DHA, in order to reduce the burden of cardiovascular diseases.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Cardiovascular Diseases

Intervention

Dietary Supplement: margarine spread

Daily use of margarine spread (approximately 20 grams) during 40 months

Study Arms

• Experimental: EPA + DHA
  Margarine spread that yields 400 mg of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) per day for average margarine use of 20 grams per day
  Intervention: Dietary Supplement: margarine spread
• Experimental: ALA
  Margarine spread that yields 2 grams of alpha-linolenic acid (ALA) per day for average margarine use of 20 grams per day
  Intervention: Dietary Supplement: margarine spread
• Experimental: EPA + DHA plus ALA
  Margarine spread that yields 400 mg of EPA + DHA per day plus 2 grams of ALA per day, for average margarine use of 20 grams per day
  Intervention: Dietary Supplement: margarine spread
• Placebo Comparator: Placebo
  Margarine spread that contains no EPA, DHA or ALA (exchanged for oleic acid)
  Intervention: Dietary Supplement: margarine spread

Publications *

• Geleijnse JM, Giltay EJ, Schouten EG, de Goede J, Oude Griep LM, Teitsma-Jansen AM, Katan MB, Kromhout D; Alpha Omega Trial Group. Effect of low doses of n-3 fatty acids on cardiovascular diseases in 4,837 post-myocardial infarction patients: design and baseline characteristics of the Alpha Omega Trial. Am Heart J. 2010 Apr;159(4):539-546.e2. doi: 10.1016/j.ahj.2009.12.033.
• Pertiwi K, Wanders AJ, Harbers MC, Kupers LK, Soedamah-Muthu SS, de Goede J, Zock PL, Geleijnse JM. Plasma and Dietary Linoleic Acid and 3-Year Risk of Type 2 Diabetes After Myocardial Infarction: A Prospective Analysis in the Alpha Omega Cohort. Diabetes Care. 2020 Feb;43(2):358-365. doi: 10.2337/dc19-1483. Epub 2019 Nov 14.
• Sijtsma FP, Soedamah-Muthu SS, de Goede J, Oude Griep LM, Geleijnse JM, Giltay EJ, de Boer MJ, Jacobs DR Jr, Kromhout D. Healthy eating and lower mortality risk in a large cohort of cardiac patients who received state-of-the-art drug treatment. Am J Clin Nutr. 2015 Dec;102(6):1527-33. doi: 10.3945/ajcn.115.112276. Epub 2015 Oct 21.
• Hoogeveen EK, Geleijnse JM, Kromhout D, Stijnen T, Gemen EF, Kusters R, Giltay EJ. Effect of omega-3 fatty acids on kidney function after myocardial infarction: the Alpha Omega Trial. Clin J Am Soc Nephrol. 2014 Oct 7;9(10):1676-83. doi: 10.2215/CJN.10441013. Epub 2014 Aug 7.
• Hoogeveen EK, Geleijnse JM, Kromhout D, van't Sant P, Gemen EF, Kusters R, Giltay EJ. No effect of n-3 fatty acids supplementation on NT-proBNP after myocardial infarction: the Alpha Omega Trial. Eur J Prev Cardiol. 2015 May;22(5):648-55. doi: 10.1177/2047487314536694. Epub 2014 May 30.
• Brouwer IA, Geleijnse JM, Klaasen VM, Smit LA, Giltay EJ, de Goede J, Heijboer AC, Kromhout D, Katan MB. Effect of alpha linolenic acid supplementation on serum prostate specific antigen (PSA): results from the alpha omega trial. PLoS One. 2013 Dec 11;8(12):e81519. doi: 10.1371/journal.pone.0081519. eCollection 2013.
• Hoogeveen EK, Geleijnse JM, Kromhout D, Giltay EJ. No effect of n-3 fatty acids on high-sensitivity C-reactive protein after myocardial infarction: the Alpha Omega Trial. Eur J Prev Cardiol. 2014 Nov;21(11):1429-36. doi: 10.1177/2047487313494295. Epub 2013 Jun 17.
• Eussen SR, Geleijnse JM, Giltay EJ, Rompelberg CJ, Klungel OH, Kromhout D. Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction. Eur Heart J. 2012 Jul;33(13):1582-8. doi: 10.1093/eurheartj/ehr499. Epub 2012 Feb 1.
• Kromhout D, Geleijnse JM, de Goede J, Oude Griep LM, Mulder BJ, de Boer MJ, Deckers JW, Boersma E, Zock PL, Giltay EJ. n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes. Diabetes Care. 2011 Dec;34(12):2515-20. doi: 10.2337/dc11-0896.
• Giltay EJ, Geleijnse JM, Kromhout D. Effects of n-3 fatty acids on depressive symptoms and dispositional optimism after myocardial infarction. Am J Clin Nutr. 2011 Dec;94(6):1442-50. doi: 10.3945/ajcn.111.018259. Epub 2011 Oct 26.
• Geleijnse JM, Giltay EJ, Kromhout D. Effects of n-3 fatty acids on cognitive decline: a randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients. Alzheimers Dement. 2012 Jul;8(4):278-87. doi: 10.1016/j.jalz.2011.06.002. Epub 2011 Oct 2.
• Kromhout D, Giltay EJ, Geleijnse JM; Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010 Nov 18;363(21):2015-26. doi: 10.1056/NEJMoa1003603. Epub 2010 Aug 28.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 21, 2009): 4837
• Original Enrollment (submitted: August 3, 2005): 4000
• Actual Study Completion Date: June 2010
• Actual Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Men and women
• Aged 60 through 80 y
• Verified clinically diagnosed myocardial infarction up to 10 y before randomization
• Written informed consent

Exclusion criteria:

• Living in a nursing home or other institution
• Participation in another scientific study
• Habitual margarine intake < 10 g per day
• Habitual fish intake > 150 g per day
• Habitual alcohol intake > 6 drinks per day
• Use of fish oil capsules or other supplements containing omega-3 fatty acids
• Presence of cancer with < 1 y of life expectancy
• Cognitive impairment, as indicated by the Mini Mental State Examination (score <= 21)
• Unintended weight loss > 5 kg in the past year
• Lack of facilities for cooled margarine storage at home
• Inability or unwillingness to comply with study procedures

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT00127452
• Other Study ID Numbers: METC-ZWH 0552; NHF-2000T401; L01.049; 5R01HL076200 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Daan Kromhout, Wageningen University
• Original Responsible Party: Not Provided
• Current Study Sponsor: Wageningen University
• Original Study Sponsor: Same as current

Collaborators

• Netherlands Heart Foundation
• National Heart, Lung, and Blood Institute (NHLBI)
• Unilever R&D

Investigators

• Principal Investigator: Daan Kromhout, PhD MPH; Wageningen University, The Netherlands

• PRS Account: Wageningen University
• Verification Date: July 2010