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Figure.
Sales of Fish Oils or ω-3 Fatty Acids (FAs) in the United States, 2007 Through 2012
Sales of Fish Oils or ω-3 Fatty Acids (FAs) in the United States, 2007 Through 2012

Data are in millions of US dollars. Arrows indicate dates of publication of randomized clinical trials (solid arrows) or meta-analyses of randomized clinical trials (dashed arrows) of ω-3 FAs in high-impact medical journals between January 1, 2005, and December 31, 2012. Trials and meta-analyses with cardiovascular disease (CVD) end points are shown in the lower panel, and those with non-CVD end points are shown in the upper panel. a indicates the trials reporting a benefit of ω-3 FAs; NA, not available.

Table.  
RCTs and Meta-Analyses of RCTs Published in High-Impact Internal Medicine Journals From 2005 Through 2012
RCTs and Meta-Analyses of RCTs Published in High-Impact Internal Medicine Journals From 2005 Through 2012
1.
Prasad  V, Cifu  A, Ioannidis  JPA.  Reversals of established medical practices: evidence to abandon ship. JAMA. 2012;307(1):37-38.
PubMedArticle
2.
Kris-Etherton  PM, Harris  WS, Appel  LJ; American Heart Association, Nutrition Committee.  Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106(21):2747-2757.
PubMedArticle
3.
Studer  M, Briel  M, Leimenstoll  B, Glass  TR, Bucher  HC.  Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med. 2005;165(7):725-730.
PubMedArticle
4.
Raitt  MH, Connor  WE, Morris  C,  et al.  Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA. 2005;293(23):2884-2891.
PubMedArticle
5.
Hooper  L, Thompson  RL, Harrison  RA,  et al.  Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ. 2006;332(7544):752-760.
PubMedArticle
6.
Brouwer  IA, Zock  PL, Camm  AJ,  et al; SOFA Study Group.  Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA. 2006;295(22):2613-2619.
PubMedArticle
7.
Yokoyama  M, Origasa  H, Matsuzaki  M,  et al; Japan EPA Lipid Intervention Study (JELIS) Investigators.  Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis [published correction apperas in Lancet. 2007;370(9583):220]. Lancet. 2007;369(9567):1090-1098.
PubMedArticle
8.
Feagan  BG, Sandborn  WJ, Mittmann  U,  et al.  Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials. JAMA. 2008;299(14):1690-1697.
PubMedArticle
9.
Tavazzi  L, Maggioni  AP, Marchioli  R,  et al; GISSI-HF Investigators.  Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1223-1230.
PubMedArticle
10.
León  H, Shibata  MC, Sivakumaran  S, Dorgan  M, Chatterley  T, Tsuyuki  RT.  Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 2008;337:a2931. doi: 10.1136/bmj.a2931.
PubMedArticle
11.
Makrides  M, Gibson  RA, McPhee  AJ,  et al.  Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA. 2009;301(2):175-182.
PubMedArticle
12.
Carney  RM, Freedland  KE, Rubin  EH, Rich  MW, Steinmeyer  BC, Harris  WS.  Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: a randomized controlled trial. JAMA. 2009;302(15):1651-1657.
PubMedArticle
13.
Galan  P, Kesse-Guyot  E, Czernichow  S, Briancon  S, Blacher  J, Hercberg  S; SU.FOL.OM3 Collaborative Group.  Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ. 2010;341:c6273. doi: 10.1136/bmj.c6273.
PubMedArticle
14.
Makrides  M, Gibson  RA, McPhee  AJ, Yelland  L, Quinlivan  J, Ryan  P; DOMInO Investigative Team.  Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA. 2010;304(15):1675-1683.
PubMedArticle
15.
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;363(21):2015-2026.
PubMedArticle
16.
Kowey  PR, Reiffel  JA, Ellenbogen  KA, Naccarelli  GV, Pratt  CM.  Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010;304(21):2363-2372.
PubMedArticle
17.
Quinn  JF, Raman  R, Thomas  RG,  et al.  Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304(17):1903-1911.
PubMedArticle
18.
Rice  TW, Wheeler  AP, Thompson  BT, deBoisblanc  BP, Steingrub  J, Rock  P; NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators.  Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury [published correction appears in JAMA. 2012;307(6):563]. JAMA. 2011;306(14):1574-1581.
PubMedArticle
19.
Palmer  DJ, Sullivan  T, Gold  MS,  et al.  Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies in first year of life: randomised controlled trial. BMJ. 2012;344:e184.
PubMedArticle
20.
Andreeva  VA, Touvier  M, Kesse-Guyot  E, Julia  C, Galan  P, Hercberg  S.  B vitamin and/or ω-3 fatty acid supplementation and cancer: ancillary findings from the Supplementation With Folate, Vitamins B6 and B12, and/or Omega-3 Fatty Acids (SU.FOL.OM3) randomized trial. Arch Intern Med. 2012;172(7):540-547.
PubMedArticle
21.
Lok  CE, Moist  L, Hemmelgarn  BR,  et al; Fish Oil Inhibition of Stenosis in Hemodialysis Grafts (FISH) Study Group.  Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: a randomized controlled trial. JAMA. 2012;307(17):1809-1816.
PubMedArticle
22.
Bosch  J, Gerstein  HC, Dagenais  GR,  et al; ORIGIN Trial Investigators.  n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309-318.
PubMedArticle
23.
Chowdhury  R, Stevens  S, Gorman  D,  et al.  Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ. 2012;345:e6698.
PubMedArticle
24.
Kwak  SM, Myung  SK, Lee  YJ, Seo  HG; Korean Meta-analysis Study Group.  Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694.
PubMedArticle
25.
Rizos  EC, Ntzani  EE, Bika  E, Kostapanos  MS, Elisaf  MS.  Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024-1033.
PubMedArticle
26.
Mozaffarian  D, Marchioli  R, Macchia  A,  et al; OPERA Investigators.  Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012;308(19):2001-2011.
PubMedArticle
27.
Bailey  RL, Gahche  JJ, Miller  PE, Thomas  PR, Dwyer  JT.  Why US adults use dietary supplements. JAMA Intern Med. 2013;173(5):355-361.
PubMedArticle
28.
Messori  A, Fadda  V, Maratea  D, Trippoli  S.  ω-3 Fatty acid supplements for secondary prevention of cardiovascular disease: from “no proof of effectiveness” to “proof of no effectiveness.” JAMA Intern Med. 2013;173(15):1466-1468.
PubMedArticle
29.
Tatsioni  A, Bonitsis  NG, Ioannidis  JP.  Persistence of contradicted claims in the literature. JAMA. 2007;298(21):2517-2526.
PubMedArticle
30.
Council for Responsible Nutrition. The benefits of nutritional supplements. 2012. http://www.crnusa.org/benefits/. Accessed June 30, 2013.
Research Letter
March 2014

Clinical Trial Evidence and Use of Fish Oil Supplements

Author Affiliations
  • 1Department of Medicine, University of Auckland, Auckland, New Zealand
JAMA Intern Med. 2014;174(3):460-462. doi:10.1001/jamainternmed.2013.12765

Randomized clinical trials (RCTs) with “hard” end points and meta-analyses of these trials should influence clinical practice because they represent the highest level of evidence. Health care behaviors based on less robust evidence are often established before such RCTs are conducted. If the results of high-quality RCTs contradict established practice, numerous barriers exist to their acceptance and implementation.1 ω-3 Fatty acid (FA) supplements are commonly used for the management of cardiovascular, neurocognitive, ophthalmic, and inflammatory disorders. In 2002, their use in the secondary prevention of heart disease was endorsed by the American Heart Association.2 Recently, their health effects have been studied in several RCTs and meta-analyses, many of which were reported in high-impact journals. Here, we report the relationship between these publications in influential journals and the use of ω-3 FAs.

Methods

Data on annual sales of fish oils and ω-3 FAs from 2007 through 2012 were obtained from Euromonitor International (http://www.euromonitor.com/). Using MEDLINE and Factiva, we identified RCTs or meta-analyses of RCTs of ω-3 FAs and accompanying editorials, published in the top-ranking internal medicine journals (New England Journal of Medicine, The Lancet, JAMA, PLoS Medicine, JAMA Internal Medicine, British Medical Journal, and Annals of Internal Medicine),326 between January 1, 2005, and December 31, 2012, and news reports generated within 2 weeks of each publication. We independently assessed editorial disposition toward the use of ω-3 FAs using a scale from 1 (clearly unfavorable) to 5 (clearly favorable).

Results

Between January 1, 2005, and December 31, 2012, a total of 18 RCTs (primary end points: 10 cardiovascular, 4 neurocognitive, 1 cancer, 1 immune, 1 gastrointestinal, and 1 respiratory) and 6 meta-analyses of RCTs (all cardiovascular primary end points) of ω-3 FAs were published in the high-impact journals326 (Table). Only 2 publications reported benefit of the intervention on the primary end point.3,7 The median (range) editorial score was 4 (1.5-5), indicating overall enthusiasm for the use of ω-3 FAs (Table). The median (range) number of news reports per publication was 11 (0-27). Between 2007 and 2012, sales of fish oils and ω-3 FA supplements in the United States increased steadily, from $425 to $1043 million (Figure). The median (range) year-on-year increase was $124 (104-150) million. Similar patterns of sales were observed in the United Kingdom and Australasia (data not shown).

Discussion

This analysis suggests that publications in prominent medical journals of RCTs and meta-analyses of RCTs of ω-3 FAs have had little effect on the use of these supplements. Sales of ω-3 FAs steadily increased despite contemporaneous accrual of high-level evidence that the supplements lack efficacy across a range of health outcomes for which their use is advocated. Since 10% of adults in the United States take an ω-3 FA or fish oil supplement, most commonly for heart health or to lower cholesterol,27 the null results of 9 of the 10 RCTs and 5 of the 6 meta-analyses studying cardiovascular disease might have been expected to influence use. It remains to be seen whether a recently published trial sequential analysis, which reports proof of no efficacy of ω-3 FAs in the secondary prevention of cardiovascular disease, alters use of the supplements.28

For prescribed interventions, numerous factors, including academic and/or medical specialists’ biases, contribute to resistance to the translation into clinical practice of robust evidence that contradicts established behaviors.29 The editorialists’ positive views on ω-3 FAs may have influenced the responses of health practitioners to the results of the source trials. However, only 10% of those who take ω-3 FAs do so on the advice of a health care professional.27 Additional factors that may contribute to increasing use of a nonprescribed intervention despite accumulating evidence of its ineffectiveness include anecdotal evidence, low cost, ready availability, assumptions of safety, supportive news reports, and selective presentation of evidence by the supplements industry.30

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Article Information

Corresponding Author: Andrew Grey, MD, Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand (a.grey@auckland.ac.nz).

Published Online: December 16, 2013. doi:10.1001/jamainternmed.2013.12765.

Author Contributions: Dr Grey had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Both authors.

Acquisition of data: Grey.

Analysis and interpretation of data: Both authors.

Drafting of the manuscript: Grey.

Critical revision of the manuscript for important intellectual content: Bolland.

Conflict of Interest Disclosures: None reported.

Funding/Support: The Health Research Council of New Zealand.

Role of the Sponsor: The Health Research Council of New Zealand had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Prasad  V, Cifu  A, Ioannidis  JPA.  Reversals of established medical practices: evidence to abandon ship. JAMA. 2012;307(1):37-38.
PubMedArticle
2.
Kris-Etherton  PM, Harris  WS, Appel  LJ; American Heart Association, Nutrition Committee.  Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106(21):2747-2757.
PubMedArticle
3.
Studer  M, Briel  M, Leimenstoll  B, Glass  TR, Bucher  HC.  Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med. 2005;165(7):725-730.
PubMedArticle
4.
Raitt  MH, Connor  WE, Morris  C,  et al.  Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA. 2005;293(23):2884-2891.
PubMedArticle
5.
Hooper  L, Thompson  RL, Harrison  RA,  et al.  Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ. 2006;332(7544):752-760.
PubMedArticle
6.
Brouwer  IA, Zock  PL, Camm  AJ,  et al; SOFA Study Group.  Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA. 2006;295(22):2613-2619.
PubMedArticle
7.
Yokoyama  M, Origasa  H, Matsuzaki  M,  et al; Japan EPA Lipid Intervention Study (JELIS) Investigators.  Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis [published correction apperas in Lancet. 2007;370(9583):220]. Lancet. 2007;369(9567):1090-1098.
PubMedArticle
8.
Feagan  BG, Sandborn  WJ, Mittmann  U,  et al.  Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials. JAMA. 2008;299(14):1690-1697.
PubMedArticle
9.
Tavazzi  L, Maggioni  AP, Marchioli  R,  et al; GISSI-HF Investigators.  Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1223-1230.
PubMedArticle
10.
León  H, Shibata  MC, Sivakumaran  S, Dorgan  M, Chatterley  T, Tsuyuki  RT.  Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 2008;337:a2931. doi: 10.1136/bmj.a2931.
PubMedArticle
11.
Makrides  M, Gibson  RA, McPhee  AJ,  et al.  Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA. 2009;301(2):175-182.
PubMedArticle
12.
Carney  RM, Freedland  KE, Rubin  EH, Rich  MW, Steinmeyer  BC, Harris  WS.  Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: a randomized controlled trial. JAMA. 2009;302(15):1651-1657.
PubMedArticle
13.
Galan  P, Kesse-Guyot  E, Czernichow  S, Briancon  S, Blacher  J, Hercberg  S; SU.FOL.OM3 Collaborative Group.  Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ. 2010;341:c6273. doi: 10.1136/bmj.c6273.
PubMedArticle
14.
Makrides  M, Gibson  RA, McPhee  AJ, Yelland  L, Quinlivan  J, Ryan  P; DOMInO Investigative Team.  Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA. 2010;304(15):1675-1683.
PubMedArticle
15.
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;363(21):2015-2026.
PubMedArticle
16.
Kowey  PR, Reiffel  JA, Ellenbogen  KA, Naccarelli  GV, Pratt  CM.  Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010;304(21):2363-2372.
PubMedArticle
17.
Quinn  JF, Raman  R, Thomas  RG,  et al.  Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304(17):1903-1911.
PubMedArticle
18.
Rice  TW, Wheeler  AP, Thompson  BT, deBoisblanc  BP, Steingrub  J, Rock  P; NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators.  Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury [published correction appears in JAMA. 2012;307(6):563]. JAMA. 2011;306(14):1574-1581.
PubMedArticle
19.
Palmer  DJ, Sullivan  T, Gold  MS,  et al.  Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies in first year of life: randomised controlled trial. BMJ. 2012;344:e184.
PubMedArticle
20.
Andreeva  VA, Touvier  M, Kesse-Guyot  E, Julia  C, Galan  P, Hercberg  S.  B vitamin and/or ω-3 fatty acid supplementation and cancer: ancillary findings from the Supplementation With Folate, Vitamins B6 and B12, and/or Omega-3 Fatty Acids (SU.FOL.OM3) randomized trial. Arch Intern Med. 2012;172(7):540-547.
PubMedArticle
21.
Lok  CE, Moist  L, Hemmelgarn  BR,  et al; Fish Oil Inhibition of Stenosis in Hemodialysis Grafts (FISH) Study Group.  Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: a randomized controlled trial. JAMA. 2012;307(17):1809-1816.
PubMedArticle
22.
Bosch  J, Gerstein  HC, Dagenais  GR,  et al; ORIGIN Trial Investigators.  n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309-318.
PubMedArticle
23.
Chowdhury  R, Stevens  S, Gorman  D,  et al.  Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ. 2012;345:e6698.
PubMedArticle
24.
Kwak  SM, Myung  SK, Lee  YJ, Seo  HG; Korean Meta-analysis Study Group.  Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694.
PubMedArticle
25.
Rizos  EC, Ntzani  EE, Bika  E, Kostapanos  MS, Elisaf  MS.  Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024-1033.
PubMedArticle
26.
Mozaffarian  D, Marchioli  R, Macchia  A,  et al; OPERA Investigators.  Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012;308(19):2001-2011.
PubMedArticle
27.
Bailey  RL, Gahche  JJ, Miller  PE, Thomas  PR, Dwyer  JT.  Why US adults use dietary supplements. JAMA Intern Med. 2013;173(5):355-361.
PubMedArticle
28.
Messori  A, Fadda  V, Maratea  D, Trippoli  S.  ω-3 Fatty acid supplements for secondary prevention of cardiovascular disease: from “no proof of effectiveness” to “proof of no effectiveness.” JAMA Intern Med. 2013;173(15):1466-1468.
PubMedArticle
29.
Tatsioni  A, Bonitsis  NG, Ioannidis  JP.  Persistence of contradicted claims in the literature. JAMA. 2007;298(21):2517-2526.
PubMedArticle
30.
Council for Responsible Nutrition. The benefits of nutritional supplements. 2012. http://www.crnusa.org/benefits/. Accessed June 30, 2013.
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