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The JAMA Omega-3 Meta-analayis was Flawed

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By William S. Harris, PhD

The most recent meta-analysis of omega-3 fatty acids and CVD was published in September 2012 by Rizos et al.1 These authors included 20 randomized controlled studies that primarily used omega-3 capsules whether placebo-controlled or open label. They also included the two dietary advice studies from Burr et al.2,3  This was an improvement on an earlier meta-analysis in 20124 that did not include four major non-placebo controlled trials.2,3,5,6 Nevertheless, Rizos et al. concluded that there was no statistically significant effect of omega-3 supplements on risk for cardiovascular disease. The primary reason why they reached this conclusion was because they inflated the critical value for significance to 0.006 instead of the standard 0.05. With this statistical maneuver, their conclusion – which should have been that fish oil supplementation significantly reduced risk for cardiac death by 9% (relative risk reduction of 0.91; 95% CI, 0.85 to 0.98; p=0.01) - was that there was no effect of fish oil on cardiovascular disease. The authors justified this on the basis of needing to correct for “multiple testing,” a practice rarely done in meta-analyses. In fact, 16 meta-analyses 1,7-21 were published in JAMA during the first 9 months of 2012, and Rizos et al. was the only one to adjust for multiple testing and the only one to not use the standard 95% confidence interval to draw their conclusions. Why the rules changed for this analysis is not clear, but what is clear is that their conclusion driven by a subjective interpretation of the data, not by standard statistical practices, that turned a favorable effect into a non-effect.

Even if their conclusions had been statistically sound, they should have been much more nuanced in their conclusions. They said, “Our findings do not justify the use of omega-3 as a structured intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFA administration” (and here they referenced the 2002 American Heart Association guidelines22). A more accurate and less sweeping conclusion should have been something like, “In patients of average age 63, with existing cardiovascular disease and under optimal medical care, the administration of about 1 g of EPA+DHA for about 2 years [median duration in their analysis] did not significantly reduce risk for major clinical outcomes.” Their study does not show that treating with a higher dose for a longer period of time, or treating patients earlier in the disease process or those who are not receiving “optimal medical therapy” will not be beneficial.

Other problems with their conclusions included the fact that very few people are actually “on optimal medical therapy,” with non-compliance rates around 50% within a year of getting a prescription23. So the findings of research trials cannot always be extrapolated to the real world. Finally, 84% of the subjects in the Rizos meta-analysis were taking ethyl esters. It is now becoming clear that taking ethyl esters on an empty stomach (as opposed to with a meal) results in very poor absorption24. So the true dose may have been even smaller than the average of 1 g that characterized these studies.

In summary, Rizos et al. were too conservative in their analysis and they were not circumspect in drawing their conclusions. It may be true that nowadays 1 g of EPA+DHA does not have the marked impact on heart disease risk that we came to expect after GISSI-Prevenzione, but it is still the nutritional factor with the strongest evidence for cardioprotection.


William S. Harris, PhD President, OmegaQuant Analytics 2329 N. Career Ave, Ste 113 Sioux Falls, SD 57107 (605) 271-6917 (913) 302-9433 (cell) bill@omegaquant.com Professor of Medicine Sanford School of Medicine University of South Dakota Sioux Falls, SD


Reference List

(1)     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;308:1024-1033.

(2)     Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757-761.

(3)     Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, Zotos PC, Haboubi NA, Elwood PC. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003;57:193-200.

(4)     Kwak SM, Myung SK, Lee YJ, Seo HG. 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.

(5)     Marchioli R, Barzi F, Bomba E, Chieffo C, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105:1897-1903.

(6)     Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-1098.

(7)     Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307:1302-1309.

(8)     Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, Pollono EN, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 2012;308:898-908.

(9)     Den Ruijter HM, Peters SA, Anderson TJ, Britton AR, et al. Common carotid intima- media thickness measurements in cardiovascular risk prediction: a meta-analysis. JAMA 2012;308:796-803.

(10)   Mustafic H, Jabre P, Caussin C, Murad MH, Escolano S, Tafflet M, Perier MC, Marijon E, Vernerey D, Empana JP, Jouven X. Main air pollutants and myocardial infarction: a systematic review and meta-analysis. JAMA 2012;307:713-721.

(11)   Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 2012;307:1736-1745.

(12)   Preiss D, Tikkanen MJ, Welsh P, Ford I, et al. Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. JAMA 2012;308:804-811.

(13)   Hempel S, Newberry SJ, Maher AR, Wang Z, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012;307:1959-1969.

(14)   Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 2012;307:382-390.

(15)   Ekelund U, Luan J, Sherar LB, Esliger DW, Griew P, Cooper A. Moderate to vigorous physical activity and sedentary time and cardiometabolic risk factors in children and adolescents. JAMA 2012;307:704-712.

(16)   Januel JM, Chen G, Ruffieux C, Quan H, et al. Symptomatic in-hospital deep vein thrombosis and pulmonary embolism following hip and knee arthroplasty among patients receiving recommended prophylaxis: a systematic review. JAMA 2012;307:294-303.

(17)   Chico RM, Mayaud P, Ariti C, Mabey D, Ronsmans C, Chandramohan D. Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub- Saharan Africa: a systematic review. JAMA 2012;307:2079-2086.

(18)   Matsushita K, Mahmoodi BK, Woodward M, Emberson JR, et al. Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA 2012;307:1941-1951.

(19)   Udell JA, Wang CS, Tinmouth J, FitzGerald JM, Ayas NT, Simel DL, Schulzer M, Mak E, Yoshida EM. Does this patient with liver disease have cirrhosis? JAMA 2012;307:832-842.

(20)   Reddy M, Gill SS, Wu W, Kalkar SR, Rochon PA. Does this patient have an infection of a chronic wound? JAMA 2012;307:605-611.

(21)   Nishijima DK, Simel DL, Wisner DH, Holmes JF. Does this adult patient have a blunt intra-abdominal injury? JAMA 2012;307:1517-1527.

(22)   Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-2757.

(23)   Frishman WH. Importance of medication adherence in cardiovascular disease and the value of once-daily treatment regimens. Cardiol Rev 2007;15:257-263.

(24)   Davidson MH, Kling D, Maki KC. Novel developments in omega-3 fatty acid-based strategies. Curr Opin Lipidol 2011;22:437-444.


Articolo pubblicato in Sistema cardiovascolare, Malattie cardiovascolari ed è stato taggato con

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