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Rapid Responses: Rapid Responses published:
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biomarkers of omega-3 fatty acids intake
- Fumiaki Imamura (25 March 2006)
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Health benefits of omega 3 fats in doubt
- Johanna M Geleijnse, Ingeborg A. Brouwer, Edith J.M. Feskens (26 March 2006)
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Apples and Pears
- Johannes G. Scholl (27 March 2006)
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A few thoughts on Hooper's systematic review of omega-3 fats
- Ka He, Yiqing Song (27 March 2006)
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Excess Omega-6 Fats Thwart Health Benefits from Omega-3 Fats
- Evelyn f Tribole (27 March 2006)
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Fish is still healthy
- Arne Astrup, Jorn Dyerberg, Steen Stender (27 March 2006)
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Omega 3 fats and health - criteria for inclusion in the systematic review
- Eiliv Lund (27 March 2006)
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Fish oil supplements are not fish
- Richard J Schmidt (28 March 2006)
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Understanding the Risks and Benefits of Fish and Omega-3 Fatty Acid Intake
- Dariush Mozaffarian, David S. Siscovick, and Walter C. Willett (28 March 2006)
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A disservice to public health
- Ray Rice, MS., Ph.D., (28 March 2006)
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Looking through a limited lens.
- William Lands (28 March 2006)
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Meta-analysis of dietary interventions cannot be treated like drug trials
- Michael A Crawford (29 March 2006)
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Not ready for meta-analysis
- William S. Harris, Christie Ballantyne and Michael Davidson (31 March 2006)
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Heart disease, blood flow and omega-3 fatty acids.
- Leslie O Simpson. (31 March 2006)
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Clear benefit or no clear benefit, that is the question
- Eddie Vos (31 March 2006)
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Diet-gene interaction?
- Ivan Y Torshin (31 March 2006)
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Wrongly pooled
- Matti J. Tolonen, Matti Tolonen (1 April 2006)
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A little of what you fancy does you good.
- Alfred P J Lake (3 April 2006)
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High Quality Randomised Controlled Studies needed to determine risks and benefits of omega 3 fats
- Anthony Lwegaba (3 April 2006)
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Authors' reply - omega 3s and health
- Lee Hooper, Rudolph Riemersma, Paul Durrington, Carolyn Summerbell, Helen Moore, Rachel Thompson, Roger Harrison, Helen Worthington, Nigel Capps, Shah Ebrahim, and George Davey Smith (7 April 2006)
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Re: Authors' reply - omega 3s and health
- Eddie Vos (11 April 2006)
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On meta-analyses
- Roberto Marchioli, Luigi Tavazzi, Gianni Tognoni. (14 April 2006)
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Find the Pony
- Damien Downing (17 April 2006)
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Just a few concerns on this trial....
- stuart lloyd (18 April 2006)
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Risks and benefits of omega-3 fatty acids on cancer risk
- Shinkan Tokudome, Masayo Kojima, Chiho Goto, Nahomi Imaeda, Yuko Tokudome, Kiyonori Kuriki, Sadao Suzuki, Hiromitsu Ichikawa, Ryosuke Ando, Nami Hattori, and Harumi Okuyama (19 April 2006)
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Having your fish and eating it
- Christine M Williams (27 April 2006)
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The need of Antioxidants in omega-3 supplementation
- Mahabaleshwar V Hegde, Ulhas Wagh, (18 June 2006)
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a calculation mistake ?
- pascal huve (21 July 2006)
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Fumiaki Imamura, Ph.D Candidate MA, 02111, USA
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I read with great interest the paper on omega-3 fatty acids (FA) published by Hooper et al. On their criteria of selection of observational studies, I regard reconsideration needed. The following points are noteworthy, considering biomarkers of omega-3 FA represent dietary intake. First, as the authors focused on omega-3 FA intake, they excluded studies examining blood omega-3 FA levels. Albert et al., for example, demonstrated significant inverse association between omega-3 FA levels and fatal myocardial infarction, observing omega-3 FA in blood by nested case- control design (N Engl J Med 2002;346:1113-8). Albert et al. used the data from blood sampled at the baseline, obviously because of the high sensitivity of blood measure rather than dietary measure obtained by food frequency questionnaire. Use of dietary measure is known to attenuate the effect measure because of measurement error. One may argue poor comparability between blood level and intake level. Although they are not comparable without a valid regression equation, ranking individuals is expected to give a desired effect measure. Consequently, by unnecessarily excluding studies using biological measures of omega-3 FA, Hooper's meta- analysis of cohort studies is likely to have yielded significantly underestimated effect measure. Second, a retrospective study using adipose tissue marker can be included. A retrospective study (not nested one) may be unfavorable for causal inference, as Hooper et al. did not include. However, Guallar et al. compensated for the point, by collecting omega-3 FA levels of adipose tissue samples (N Engl J Med 2002;347:1746-1753). The biomarker represents long-term exposure to omega-3 FA intake and allows relatively unbiased assessment of the exposure. In fact, according to this plausibility, validity of estimates of omega-3 FA intake have been examined since over 20 years ago. Considering such nature of a biological marker, I assume that Hooper's systematic review excluded many useful retrospective studies by selecting only prospective sutdies looking at dietary intake. In summary, some observational studies used biomarkers of omega-3 FA for finer scientific inference, regarding limitations of dietary assessment and effect of measurement error. By excluding them, the estimated effect measure is likely to be biased. Further reviews are clearly needed in order to provide more reliable conclusion of the effect of omega-3 FA intake. Competing interests: None declared |
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Johanna M Geleijnse, Assistant professor Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, Ingeborg A. Brouwer, Edith J.M. Feskens
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Sir Hooper et al, in their systematic review of observational studies and randomized controlled trials (1), conclude that omega 3 fats do not have a clear effect on overall mortality, combined cardiovascular events and cancer. We do not agree with the approach by the authors to pool alpha- linolenic acid (which is of vegetable origin) with omega 3 fatty acids from fish. Furthermore, fatal and nonfatal cardiovascular events, as well as different types of (patient) populations, were pooled in this meta- analysis. On basis of previous reviews in this field, it is well known that each of these combinations could blur a clear view on the health effects of omega 3 fats. A number of previously conducted meta-analyses have shown a favourable effect of fish intake and intake of fish fatty acids on stroke and fatal coronary heart disease (2,3,4) For alpha- linolenic acid, the epidemiological evidence is less convincing and randomized controlled trials are lacking. As Hooper et al stated in their discussion, the trial by Burr et al (5) in patients with angina pectoris had a major impact on the pooled risk estimate for overall and cardiovascular mortality. This trial was performed in two phases, with a 12 month interruption due to lack of funding. In total, 1111 patients were enrolled during the first phase (1990-1992) and 2003 patients during the second phase (1993-1996). During the second phase of the study 462 patients of the fish advice group were subrandomized to receive fish oil capsules instead of dietary advice. It is unclear whether this group of patients actually consumed these fish oil capsules, and no data on compliance for this group were reported. Measurements of EPA levels in blood, a biological parameter of compliance to fish intake, was only measured in 68 patients during the first phase. Although plasma EPA levels increased after six months in the group that received fish advice (n=39), the confidence interval was very wide, which indicates large variation among subjects. Furthermore, the trial was not blinded. Regular fish consumption or use of fish oil capsules could possibly have influenced the patients or the physicians behaviour towards intake of medication or other issues related to diet and lifestyle. Data from many epidemiological studies and the GISSI-P trial suggest that omega 3 fats from fish protect against heart disease. Although the trial by Burr et al5 in angina patients should not be ignored, it is hard to interpret these adverse findings in light of previous studies. A different conclusion would be derived from the review by Hooper et al if these data are omitted, favoring a cardioprotective effect of omega 3 fats from fish. The pooled relative risk of 0.83 (95% confidence interval, 0.75 to 0.91) that would then be obtained is in line with the meta-analysis of Bucher et al (4). In conclusion, the majority of epidemiological studies and randomized controlled trials indicate a protective effect of omega 3 fatty acids from fish against fatal cardiovascular events. The advice for healthy people and myocardial infarction patients to consume oily fish on a regular basis does not confer adverse risks to health and is fully justified on the basis of currrent scientific evidence. References 1. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HL, et al. Risks and benefits of omega 3 for mortality, cardiovascular disease, and cancer: systematic review. BMJ Online, 24 March 2006. 2. He K, Song Y, Daviglus ML, Liu K, Van Horn, L, Dyer AR, Greenland P. Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation 2004;109:2705- 11. 3. Whelton SP, He J, Whelton PK, Muntner P. Meta-analysis of observational studies on fish intake and coronary heart disease. Am J Cardiol 2004;93:1119-23. 4. Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trial. Am J Med 2002:112:298-304. 5. 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. Competing interests: None declared |
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Johannes G. Scholl, physician, private practice 65385 Rdesheim, Germany
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The systematic review of risks and benefits of omega-3-fats compares - as we say in Germany - apples with pears. Neither was the trial design in GISSI-Prevenzione the same as in DART-2 nor did these studies use the same type of dietary supplement. GISSI-Prevenzione used a purified n-3-supplement containing 850-882 mg EPA/DHA within a 1 g capsule, whereas Dart-2 "recommended" the use of a "Fish-Oil supplement" containing only 600 mg EPA/DHA within a 2 g capsule. Fish-oil capsules are not made of free-living fish like wild salmon, but mainly of farmed fish. Food for farmed fish contains grains and other starchy foods and is very different from what these fishes would eat in "real wildlife", e.g. the n-3- to n-6-ratio is fourfold lower in farmed than in wild salmon, the latter being leaner and containing much more n-3-fats (data derived from the U.S. Nutrient database). Fish-oil capsules instead deliver large amounts of n-6-fatty acids, too, not only n-3-fatty acids, for which they are heavily marketed. As there is a competition between n-3- and n-6-fats for incorporation into the myocellular membrane, which influences myocardial susceptibility for arrhythmias especially in the case of myocardial ischemia, one should not expect the same effect from a fish-oil capsule that one can expect from a purified n-3-supplement. Why then combine studies of such a different approach (dietary advice or randomised trial) and different interventions (n-3- or fish-oil supplement) like GISSI-P and DART-2 into a meta-analysis? DART-2 is the cause of confusion in the n-3-debate. Has anyone mentioned yet, that it may have used the wrong supplement? In the times of aquacultured fish, Hooper should have distinguished studies better, because fish may be different from fish, and fish-oil capsules definetely are different from purified n-3-supplements. In my view, for patients after myocardial infarction there is still good evidence to take a n-3-supplement, because the methodological quality of GISSI-P is superior to a systematic review like Hoopers, that compares "apples with pears". I declare, that I have no conflict of interest, that I do not market and never have marketed or sold n-3-supplements. Dr. med. Johannes Scholl Prevention First - Clinic for Preventive Medicine Rdesheim Germany scholl@preventionfirst.de Competing interests: None declared |
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Ka He, Assistant Professor Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Yiqing Song
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To the editor, Hooper et al1 in their meta-analysis conclude that omega-3 fats have no effect on total mortality, combined cardiovascular events, or cancer. However, we think that their results need to be interpreted cautiously and their conclusions are somewhat misleading based on the following grounds: First, their null findings could be in part explained by the use of the composite endpoints. The context presented by Hooper et al ignores strong biological evidence for the potentially disease-specific effects of omega-3 fat. The underlying hypotheses for this study are not clearly stated for their main analyses. For example, systemic review on long-chain omega-3 polyunsaturated fatty acids in randomized controlled trials2 and fish in prospective cohort studies3 in relation to coronary heart disease (CHD) mortality have been published previously. Significant risk reductions have been observed. Also, previous studies suggest that long- chain omega-3 fatty acids may have different effects on fatal and non- fatal CHD as well as on ischemic stroke and hemorrhagic stroke. The findings would be different according to the ratio of fatal / non-fatal CHD and ischemic stroke / hemorrhagic stroke in the outcome. Second, the authors focus primarily on the summary estimates from heterogeneous studies. Certainly, a large amount of unexplained heterogeneity across studies presents a difficult challenge for their quantitative approach. Of note, their results of combining trials are mainly driven by Burr et al,4 a diet advice intervention study among male angina patients, which is different from other randomized placebo controlled trials. Although Burr et al is the longest trial included in Hooper et al, the compliance has been questioned.5, 6 In fact, blood EPA is measured in only 2% of participants for determining the compliance in Burr et al. Third, Hooper et al exclude 108 potential cohorts that have no omega- 3 assessment. Dietary intake of long-chain omega-3 fatty acids assessed by dietary instruments is more likely to be a surrogate marker of fish consumption. The effects of dietary long-chain omega-3 fatty acid intake cannot be isolated from fish intake. Thus, in observational studies, fish consumption rather than long-chain omega-3 fatty acid intake should be focused on. Also, in their meta-analysis of cohort studies, the authors compare the most exposed quantile with the least exposed quantile. Since the amounts of omega-3 intake substantially varied between these two extreme groups across individual studies, the combined results may differ depending on the range of omega-3 intake and number of exposure groups in the primary studies. Fourth, the authors do not provide data for exploring any dose-response relation or possible threshold for the effects of omega-3 fats on different endpoints of interest. Also they provide no further evidence to justify the sufficiency and robustness of their results. Finally, their study does not distinguish between primary prevention and secondary prevention by omega-3 fatty acids. Mixing them together could lead to misinterpretation of the results. Ka He, MD, ScD Assistant Professor Northwestern University Feinberg School of Medicine Yiqing Song, MD, ScD Instructor Brigham and Womens Hospital Harvard Medical School Reference: 1. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HL, et al. Risks and benefits of omega 3 for mortality, cardiovascular disease, and cancer: systematic review. BMJ Online, 24 March 2006. 2. Bucher HC, Hengstler P, Schindler C, and Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2002; 112: 298-304. 3. He K, Song Y, Daviglus ML, Liu K, Van Horn L, Dyer AR, and Greenland P. Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation. 2004; 109: 2705-2711. 4. Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, Zotos PC, Haboubi NA, and 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. 5. Hamazaki T. The first randomized clinical trial of 2 y to prevent reinfarction with fish oil. Eur J Clin Nutr. 2004; 58: 1557. 6. Kris-Etherton PM, and Harris WS. Adverse effect of fish oils in patients with angina? Curr Atheroscler Rep. 2004; 6: 413-414. Competing interests: None declared |
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Evelyn f Tribole, Consulting Nutritionist 15615 Alton Pkwy, Suite 450, Irvine, CA 92618 USA
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Conducting a meta-analysis study on the effectiveness of omega-3 fats for mortality, cardiovascular disease and cancer, without considering the impact of excess omega-6 fat in the diet, is akin to reviewing the efficacy of a healthy diet without factoring the effects of smoking. Excess omega-6 fats interfere with the health benefits of omega-3 fats because they compete for the same rate-limiting enzymes. A high proportion of omega-6 to omega-3 fat in the diet shifts the physiological state of the body toward the pathogenesis of many diseases: prothrombotic, proinflammatory and proconstrictive (1). Chronic excessive production of omega-6 eicosanoids is associated with heart attacks, thrombotic stroke, arrhythmia, arthritis, osteoporosis, inflammation and cancer. Furthermore, coronary heart disease mortality has been demonstrated to be proportional to plasma levels of long chain omega -6 fat. (2) Prior to industrialization, no population has been exposed to the current high levels of omega-6 polyunsaturated fats in westernized diets. Today we eat fat that did not exist 100 years ago, such as cottonseed oil (3). Humans evolved on a diet with a balanced ratio of omega-6 to omega-3 fats of about 1:1. Today, that ratio in westernized countries is near 17:1. The Greenland Inuit Eskimos are famous for their high omega-3 fat diet, but just as importantly, their diet was also low in omega-6 fat. The Lyon Diet Heart study illustrated the significant impact of a Mediterranean diet, with a striking reduction in all-cause mortality and coronary heart disease; this diet was low in omega-6 fat (4). Cultures that suddenly increase their omega-6 fat intake experience markedly higher mortality rates and health problems. When Okinawans tripled their omega-6 fat intake, they experienced a rise in cancer and cardiovascular disease, which Japanese researchers called excess linoleic acid syndrome (5). Notably, this syndrome occurred in the presence of consuming fatty fish. Israel embraced a high polyunsaturated fat diet (at the expense of saturated fats). Consequently, they now have one of the highest omega-6 fat intakes in the world, along with an unexpected high incidence of chronic western diseases, which researchers term the Israeli paradox (6). Eating an adequate amount of long chain omega-3 fats, whether through regular fish consumption or fish oil supplements is only half of the health picture. Omega-3 fats provide little if any benefit if there are excessive dietary omega-6 fats. Its puzzling that the authors did not address this issue as a limitation of their study, especially when the international scientific community has published guidelines addressing the need to balance omega -6 and omega-3 fats, by decreasing the former while increasing the latter (7). 1. Simopoulus, AP and Cleland LG. Omega-6/Omega-3 Essential Fatty acid ratio: the scientific evidence. World Review of Nutrition and Dietetics. (2003): 92:1-174. 2. Lands EM. Dietary fat and health: the evidence and the politics of prevention. Annal New York Academy of Sciences (2005). 1055:179-192. 3.Cordain, L et al. Origins and evolution of the Western diet: health implications for the 21st century. American Journal of Clinical Nutrition (2005).81:341-354. De Lorgeril et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction; final report of the Lyon Diet Heart Study. Circulation (1999)99;779-785. Okuyama, H et al. Dietary fatty acidsthe n-6/n-3 balance and chronic elderly diseases: excess linoleic acic and relative n-3 deficiency syndrome seen in Japan. Prog. Lipid. Res (1997); 35(4):409-457. Dubnov G. and Berry EM. Omega-6/omega-3 fatty acid ratio: The Israeli Paradox. World Review of Nutrition and Dietetics. (2003):92:81-91. Simopoulos AP, Leaf A, Salem Jr N. Workshop statement on the essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids. Prostaglandins, Leukot Essential Fatty Acids (2000) 63:119-121. Competing interests: None declared |
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Arne Astrup, Director of the Department of Human Nutrition The Royal Veterinary and Agricultural University, Rolighedsvej 30, 1958 Frederiksberg C, Denmark, Jorn Dyerberg, Steen Stender
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Editor Hooper et als condensed version (1) of their 2004 Cochrane omega 3 review up to February 2002 (2) concluded that it is not clear that omega 3 fats alter total mortality, combined cardiovascular events or cancer in people with, or at high risk of, cardiovascular disease or in the general population. We do not believe that this conclusion rests on solid evidence (1). The conclusion of the meta-analysis is changed from clear benefit to no benefit by the inclusion of one single study (DART-2), which should probably not been included, and in particular not be allowed to be the decisive one. The inclusion of the DART-2 study (3) gave rise to a statistically significant heterogeneity i.e. evidence of the study was an outlier. Excluding this study resulted in a reduced relative risk (RR) of death of 0.83 (95% confidence interval (CI) 0.75 to 0.91), and the heterogeneity disappeared. To us this is no surprise as the DART-2 study had a poor quality, and this view is supported by The U.S. Department of Health and Human Services Evidence Report from 2005: The methodological quality of this trial was poor (4). This authority published a report based on the literature 1966-2003, and concluded that the overall evidence from the primary and secondary prevention studies supports the hypothesis that consumption of omega 3 fatty acids, fish, and fish oil reduces all-cause mortality and various cardiovascular disease outcomes (4). This conclusion is consistent with a meta-analysis of observational studies up to May 2003 that found that intake of fish was associated with a RR of 0.83 for fatal CHD (95% CI 0.76 to 0.90; p<0.005) and a RR of 0.86 for total CHD (0.81 to 0.92; p<0.005) (5). In the DART-2 study dietary instructions were only given at study start and after 6 months. No further reinforcement was done during the rest of the study of 9 years. The methodological poor quality of the DART- 2 study and the above data raises concern on the conclusions of the Cochrane review and give in our opinion a solid basis to continue to advise the public to increase the intake of fish. Jorn Dyerberg, professor MD, Steen Stender professor MD, Arne Astrup professor MD 1. Hooper L, Thompson RL, Harrison RA, et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ, doi:10.1136/bmj.38744.366331.2F (published 24 March 2006) 2. Hooper L, Thompson RL, Harrison RA et al. Omega 3 fatty acids for prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev 2004;4:CD003177 3. Burr ML, Ashfield-Watt PAL, Dunstan FDJ, et al. Lack of benefit of dietary advice to men with angina:results of a controlled trial. Eur J Clin Nutr 2003;57:193-200 4. Effects of omega-3 fatty acids on cardiovascular disease. http://www.ahcpr.gov/clinic/epcsums/o3cardsum.htm/dec.2004 5. Whelton SP, He J, Whelton PK, et al. Meta-analysis of observational studies on fish intake and coronary heart disease. Am J Cardiol 2004;93:1119-23 Competing interests: None declared |
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Eiliv Lund, professor in epidemiology University of Troms, 9013 Troms, Norway
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Dear Editor, in their paper (1) Hooper et al. describe the method for selecting papers for the systematic review of risk and benefits of omega 3 fats given mainly as dietary supplements. They conclude in the review that omega 3 fats have no effect on total mortality, cancer or cardiovascular events. The findings of no effect are mainly due to the inclusion of the study by Burr et al (2), and differ from most previous reviews which have concluded with an positive effect on cardiovascular conditions. However, the inclusion of the clinical trial by Burr et al. violates their own inclusion criterias twice. First, the Burr article was published one year after the date of the last systematic search of relevant articles (February 2002). Secondly, they stated that all studies with multifactorial interventions were excluded. The Burr trial was in fact multifactorial having a 2X2 design including both fish or fish oil and fruit. In addition, it was stopped and then restarted with another design. The credibility of the review would improve if all published papers in 2002-2003 (if any) had been incorporated in the analysis on equal terms, and all trials with multifactorial design also had been counted. 1. Hooper L et al. Risks and benefits om omega 3 fats for mortality, cardiovascular disease, and cancer: a systematic review. BMJ 2. Burr ML et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003; 57; 193-200 Competing interests: None declared |
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Richard J Schmidt, Locum community pharmacist [Various]
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One ideal that researchers strive to achieve in designing an experiment is to reduce the number of variables to just one. Clearly this is impossible in clinical research because each subject / patient will [usually] be genetically dissimilar to every other. This confounding factor is magnified by the fact that each subject / patient will eat different foods in differing quantities. So, in trials involving fish oil supplements, one question that needs to be asked, and probably never has been is: "What else has the subject been eating?" I haven't had the benefit of reading all the background literature to which Hooper et al. (2006) refer, but I think it is a safe bet that dietary sodium and potassium intake has not been taken into account and controlled in any of the reviewed trials. Perhaps patients were also taking diuretics that have a direct effect on (sodium / potassium) electrolyte balance? I have corresponded with the Food Standards Agency on the subject of food labelling, questioning why there is no requirement to declare both sodium AND potassium levels in nutrition information labels. Their response was essentially that this would serve only to confuse consumers. Yet, there is an extensive literature dating back to the 1920s on this subject from which it is safe to conclude that it is meaningless to declare just the sodium level in a food. This literature has been recognised by sports scientists, by those who dabble in fundamental toxicology, and most recently by those studying intra- and extracellular water structure ... but seems to have been overlooked by those involved in nutrition. Fish are an important dietary source of potassium. There is no potassium in fish oil. Potassium has long been recognised as an "antidote" to the toxicity of sodium. And because plant material is also a major source of dietary potassium, this probably explains at least in part the health benefits of "5 fruit and veg a day". Wine and milk are also rich in potassium. It is reasonable to hypothesise that the variability of responses to fish oil supplements is a function of overall potassium / sodium intake. High dietary sodium intake (coupled with low dietary potassium intake) is after all a recognised cause of cardiovascular disease. On this basis, it can be argued that all the trials carried out to date on fish oil supplements are invalidated by the fact that dietary sodium and potassium intake was not controlled!? Competing interests: None declared |
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Dariush Mozaffarian, Instructor of Medicine Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, David S. Siscovick, and Walter C. Willett
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Hooper et al. have reported a review of effects of n-3 fatty acids on total mortality, combined cardiovascular events, and cancer, very similar to their prior report in 2004.1 Observational, clinical trial, and experimental data indicate that the strongest effects of marine omega-3 fatty acids are on fatal coronary heart disease (CHD) events, particularly arrhythmic death or sudden death.2-7 Fish or fish oil intake is unlikely to affect other causes of mortality. Thus, the endpoint of total mortality unsurprisingly would demonstrate effects closer to the null, with significant reductions in CHD death (25-40%)8 diluted by minimal effects on other causes of death. Given that CHD deaths would account for between one-quarter to one-half of all deaths in the populations studied (middle-aged and older adults with CHD risk factors or established CHD), fish or fish oil intake would be expected to reduce total mortality by between ~6% (25% reduction x 25% CHD deaths) to 20% (40% reduction x 50% CHD deaths), or an average of 13% overall. This is consistent with the authors findings in randomized trials of a 13% reduction in mortality overall (RR=0.87, 95% CI=0.73-1.03), largely driven by the 14% reduction in mortality in trials using marine n-3 fatty acids (RR=0.86, 95% CI=0.70- 1.04). The absence of a major effect on total cardiovascular events is also unsurprising. The effects of n-3 fatty acid intake on fatal vs. nonfatal CHD events are distinct, due to heterogeneity of dose-responses and clinical time-courses of effects on different CHD risk factors. With modest doses (e.g., < 1-2 g/d) and over shorter durations of follow-up (e.g., < 3-4 years), fish or fish oil intake would be unlikely to affect progression of atherosclerosis or plaque rupture. Instead, anti- arrhythmic effects (direct or indirect) would predominate, reducing the risk of fatal arrhythmia in response to plaque rupture or ischemia. Consequently, in most trial designs, an individuals risk for acute myocardial infarction would not be lessened, but they would be more likely to survive the event. Thus, total cardiovascular events would not be greatly affected, but mortality from these events would be substantially reduced. Much emphasis is given to clinical trials, even though such studies may have serious limitations related to enrollment, lack of blinding, noncompliance, and loss to follow-up (e.g., DART-2 suffered from many of these limitations). Additionally, because most of the reduction in CHD mortality likely occurs at relatively low intakes (e.g., 300-500 mg/d), limited additional benefits may be seen in clinical trials due to consumption of fish in the control group.9 For this reason, one would expect to see stronger associations in observational studies because such analyses can evaluate effects compared to individuals with little to no fish intake. The authors exclusion of numerous observational studies evaluating fish intake is puzzling and markedly limits their cohort meta- analyses. In the few studies they did include, the estimates of n-3 fatty acid intake were directly derived from data on fish intake; it makes little sense to value only the secondary estimates and not the primary data. Other, more complete meta-analyses of prospective cohort studies demonstrate clear associations between fish intake and reduced risk of CHD death8 and ischemic stroke.10 The authors also did not include observational studies evaluating blood or membrane n-3 fatty acid levels, which effectively remove bias due to errors in reported dietary intake and have demonstrated marked inverse associations between marine n-3 fatty acid levels of risk of sudden death2, 11 and CHD death.6 Few other interventions lifestyle, pharmacologic, or surgical have levels of evidence or magnitudes of health benefits approaching those of fish consumption. For example, in a meta-analysis of 14 randomized trials of statin therapy, considered by many a pharmacologic panacea, total mortality was reduced by 12% (RR=0.88, 95% CI=0.84-0.91),12 similar to the estimate in the Hooper et al. analysis. Prevention of CHD death, the leading cause of mortality in most countries, is of great public health importance, and intake of n-3 fatty acids from fish should play a major role in prevention efforts. 1. Hooper L, Thompson RL, Harrison RA, et al. Omega 3 fatty acids for prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev. 2004:CD003177. 2. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995;274:1363-1367. 3. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI- Prevenzione trial. Lancet. 1999;354:447-455. 4. McLennan PL. Myocardial membrane fatty acids and the antiarrhythmic actions of dietary fish oil in animal models. Lipids. 2001;36 Suppl:S111- 114. 5. Mozaffarian D, Lemaitre RN, Kuller LH, Burke GL, Tracy RP, Siscovick DS. Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study. Circulation. 2003;107:1372 -1377. 6. Lemaitre RN, King IB, Mozaffarian D, Kuller LH, Tracy RP, Siscovick DS. n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am J Clin Nutr. 2003;77:319-325. 7. Mozaffarian D, Ascherio A, Hu FB, et al. Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation. 2005;111:157-164. 8. He K, Song Y, Daviglus ML, et al. Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation. 2004;109:2705-2711. 9. Yokoyama M, Origasu H, Matsuzaki M, et al. Effects of eicosapentaenoic acid (EPA) on major cardiovascular events in hypercholesterolemic patients: The Japan EPA Lipid Intervention Study (JELIS). Paper presented at: American Heart Association Scientific Sessions; Nov 17, 2005; Dallas, TX. 10. He K, Song Y, Daviglus ML, et al. Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke. 2004;35:1538-1542. 11. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n- 3 fatty acids and the risk of sudden death. N Engl J Med. 2002;346:1113- 1118. 12. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278. Competing interests: None declared |
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Ray Rice, MS., Ph.D.,, Scientific Consultant P.O.Box 24,Tiverton,Devon,EX16 4QQ, UK.
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The editor, BMJ I write to respond to the publication last week of the Hooper et al (1) review of risks and benefits of omega-3 fats. As scientific adviser to a consortium of omega-3 interests I last year coordinated an application to the Joint Health Claims Initiative (JHCI)for a label claim supporting the role of long chain omega-3 polyunsaturates in respect of cardiovascular health. The process involved a literature search and review. Our conclusions were quite different. The conclusions were endorsed by the independent Expert panel of assessors appointed by JHCI. The Cochrane review process has previously been questioned (2) over its suitability for use in nutrition studies of this sort. The fact that previous Cochrane reviews by Hooper have concluded that there was no evidence to support the hypothesis that reducing dietary salt intake decreased blood pressure, or that reducing saturated fat intake decreased heart disease risks seems to me to make the point very eloquently. The Hooper review is flawed by the indiscriminate combination of primary and secondary prevention studies, and the consequent failure to compare like with like. They also dismiss as unreliable, cohort studies involving many thousands of subject-years, on the grounds that there is a risk of confounding. But then they include studies such as the Burr 2003 (3) study, the authors of which accept there may be confounding issues. They conclude that with a RR of 0.86 and a 95% CI of 0.70 to 1.04 in the 12 RCT studies involving fish or fish oil in CV mortality, that there is no clear evidence of benefit. With a RR of 0.65 and 95% CI of 0.48 to 0.88 from like-with-like cohort studies, I submit that to put out the message that there is no clear evidence to support a reduction in risk of CV death from long chain omega-3 usage is highly irresponsible. When Bucher et al (4) reviewed this subject in 2002, they surveyed the literature, drew up their criteria and carried out a meta analysis of the 11 RCT studies published at the time, and concluded that eating more omega-3 significantly reduced risk of death by 25-30%. The Burr 2003 study was included in the Hooper review, but not Bucher, primarily because it was not published at the time. In conducting the search and review for the JHCI application process, I carried out an update of the Bucher process, with a closing date of September 2003. The search revealed a small number of relevant papers, which met the Bucher inclusion criteria. Interestingly, the Burr 2003 study did not meet the Bucher criteria, as I confirmed with the lead author, Professor Burr in a personal communication. I submitted the additional data to a statistician, and included the results in the JHCI submission (5). The Burr 2003 study is anomalous for a number of reasons, and is at odds with the very extensive published literature in this field. There are significant uncertainties in this trial, which the author and others have pointed out. To use it uncritically as Hooper et al did, is not science. To claim long chain omega-3 does not offer any protection from heart disease based on an uncritical interpretation of selected papers is a gross disservice to the communication of science, and to the health of UK citizens and others. To publish this flawed study, as the BMJ chose to do, is a similar disservice. I urge the authors and the BMJ to correct this situation by retraction. References 1.Hooper L,Thompson RL,Harrison RA,Summerbell CD,Ness AR, Moore HJ, et al. Risks and benefits of omega3 fats for mortality, cardiovascular disease and cancer: a systematic review. BMJ 2006. [Epub ahead of print; doi = 10.1136/bmj.38755.366331. 2F]. 2.Truswell A.S. Some problems with Cochrane reviews of diet and chronic disease. Eur.J.Clin.Nutr. 2005,59; Suppl 1:S150-154. 3. Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, Zotos PC, Haboubi NA, and 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. Bucher HC, Hengstler P, Schindler C, & Meier| G. N-3 Polyunsaturated Fatty Acids in Coronary Disease: A Meta-Analysis of Randomized Controlled Trials. Am.J.Med., 2002, 112:298-304. 5. www.jhci.co.uk/approv/omega.htm Competing interests: Scientific Consultant to the Omega-3 Group (A consortium of organisations involved in the marketing of fish) |
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William Lands, retired 6100 Westchester park Drive, College Park, MD 20740 USA
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A very limited view of evidence for an effect of long chain and shorter chain omega-3 fatty acids produced an incorrect conclusion that long chain and shorter chain omega-3 fats do not have a clear effect on total mortality, combined cardiovascular events or cancer (1). The bias came from evaluating only randomized clinical trials (RCTs), omitting large amounts of published evidence (2) on how dietary omega-3 fats compete with omega-6 fats as they maintain healthy tissues and prevent disease processes. The biased view failed to interpret the reported estimates of omega-3 fat intakes in relation to existing levels of competing omega-6 fat intakes, a balance readily seen with gas chromatographic analyses of blood lipids (3). Such analytical biomarker information would show whether the reported efforts of the various RCT interventions had actually succeeded in sufficiently shifting tissue proportions of omega-3 and omega-6 fatty acids to the extent intended (and whether all subjects complied with the intended dietary intervention). An RCT in which tissue proportions of long chain omega-3 and omega-6 fats changed very little has little merit in forming a useful conclusion. The authors shed little light on such evidence, which is needed for a truly sound interpretation. The absence of tissue proportions and of known evidence about n-6 eicosanoids mediating inflammation, thrombosis and arrhythmia might lead readers to apply Macbeths description to this "meta-analysis": it is a tale told by an idiot, full of sound and fury, signifying nothing. 1 Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, et al. Risks and benefits of omega3 fats for mortality, cardiovascular disease and cancer: a systematic review. BMJ 2006. [Epub ahead of print; doi = 10.1136/ bmj.38755.366331.2F]. 2 Lands WE. Fish, Omega-3 and Human Health 2005 AOCS Press, Champaign 3 Lands WE. Dietary fat and health: the evidence and the politics of prevention: careful use of dietary fats can improve life and prevent disease. Ann N Y Acad Sci. 2005 Dec; 1055: 179-92. Competing interests: The author is a non-employee member of the Board of Directors of Omega Protein. |
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Michael A Crawford, Director of research Institue of Brain Chemistry and Human Nutrition, N7 8DB
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Comment on Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review Lee Hooper et al BMJ, doi:10.1136/bmj.38755.366331.2F (published 24 March 2006) Sir- All diagrams purporting to support the conclusion of Hooper et al (BMJ 24th March 2006) are based on relative risk - favours high or favours low omega 3 - which like a drug trial assumes the variable is only the omega 3 dose. This falsifies the review.. Efficacy of a fatty acid depends on which fatty acid(s), position in the glyceride, in the specific family or indeed the nature of a product (e.g phosphoglycerides, triglyceride, enteric) , dietary prehistory of individuals and importantly, on other fats in the diet which compete for receptors. Moreover, it is DART II that skews the data. It was a stop start affair and used MAXEPA capsules. MAXEPA is an EPA rich oil derived from but not a fish oil! The alternative was advice, which is notorious for non compliance. To put it bluntly, advice to eat fish if taken could be translated in different ways. Cardiff has good fish and chip shops or did they eat farmed salmon in butter and mayonnaise sauce and mashed potatoes cooked with margarine, to soak up the fats? Or did they eat raw salmon (Norwegian Gravidlax perhaps) , lightly grilled tuna or swordfish with a mixed salad and plain boiled potatoes or rice? Did they use olive oil or sunflower oil? These menus would have quite different effects. Careful validation with full reporting would be required to reach any degree of scientific acceptability. In an attempt at validation DART II reports plasma levels of EPA in only 39 test compared to 29 control after 6 months fish advice = 4.58 (3.54) compared to no fish advice 3.03 (1.34) mg/dl. The standard deviation of the test is larger than the mean of the alleged control. Are these really different (no statistics are given)?. Of critical importance, they do not report docosahexaenoic acid (DHA). Is that because there was no difference or maybe less? DHA is the principle cell membrane omega 3 fatty acid of the endothelium, smooth muscle cells, heart, immune, neural and other cells. The receptors are in the membrane and that is where you would want to see a difference if your measure was effective. There is relatively little EPA in the receptor sites. What is in the plasma can be very different to what is around the membrane receptors. Moreover control levels of EPA seem far higher than others report so maybe they are not measuring EPA at all. This is simply not a credible study and even its authors had concerns. There is an abundant and robust science showing that other fatty acids in the diet (e.g saturated fats, linoleic, arachidonic acid) will affect differentially the utilisation of omega 3 fatty acids e.g. alpha- linolenic, stearodonic, eicosapentaenoic, docosapentaenoic or docosahexaenoic acids. Little attempt has been made by Hooper et al to control for these confounders. To illustrate the point, there is a recent review of long standing data (1) which concludes "that eicosapentaenoic acid and docosahexaenoic acid have differing haemodynamic and anti- atherogenic properties. The effects of the two fatty acids may also differ depending on the target population". There is a lack of understanding in this review possibly because it is not the lead authors field. However, that is no excuse. A meta- analysis which makes no attempt to control for these basic and varied metabolic and dietary confounding factors is simply valueless and likely to be misleading. 1. Mori TA, Woodman RJ. The independent effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans. Curr Opin Clin Nutr Metab Care. 2006 Mar;9(2):95-104 Competing interests: The health of the Nation |
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William S. Harris, Professor of Medicine University of Missouri-Kansas City, Christie Ballantyne and Michael Davidson
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The meta-analysis by Hooper et al.(1) concluding that omega-3 fatty acids do not have a clear effect on total or coronary heart disease (CHD) mortality is of concern from several perspectives. Most importantly, the very attempt to perform a meta-analysis in this area is problematic owing to the lack of high quality, randomized controlled trials (RCTs). Absent these, meta-analyses can be more harmful than helpful. Nevertheless, this report by Hooper et al. merits careful scrutiny for several reasons: 1) the excellent reputation of the Cochrane group, 2) the prior publication of other such summaries, particularly that from the Agency for Healthcare Research and Quality (2), 3) the existence of recommendations for increased fish/omega-3 fatty acid intake by national and international bodies, and 4) the recent publication of conflicting studies on the effects of omega-3 fatty acids on the susceptibility to arrhythmias in patients with implanted cardioversion defibrillators (3,4). One troubling aspect of the Hooper meta-analysis was the pooling of diet studies (i.e. fish intake advice) with supplementation trials (using either generic fish oil capsules or highly concentrated prescription omega -3 preparations). The former required replacement of some foods with others (leaving open the possibility that the omitted items contributed to the observed outcomes), whereas the latter did not. In addition, commingling studies with differing doses, background diets, patient populations, and follow-up periods adds markedly to sample heterogeneity. Perhaps the most significant problem with the Hooper report is the inclusion of one, large and negative study (5) that trumped all the other studies included in the analysis. Due, in some measure, to forces beyond the control of the investigators, the study by Burr et al. suffered from sub-optimal design and execution. [Its difficulties have been discussed by the authors in detail (5,6)]. By including this study, Hooper et al. found a non-significant (95% CI 0.7-1.04) 14% relative reduction in risk for death in the high omega-3 group relative to controls. Without this study, the 17% risk reduction seen in the remaining studies was statistically significant 0.83 (0.75-0.91) and thus the conclusions would be markedly different. The strongest evidence we have for a clear benefit of long chain omega-3 fatty acids in secondary prevention of CHD death is the GISSI Prevenzione study (7). Although utilizing an open-label design, this randomized, controlled study of 11, 324 post-MI patients who were given 1 g/d of highly concentrated prescription omega-3 fatty acid convincingly showed a 21% reduction in total mortality (95% CI 0.66-0.93). In this trial, the risk of sudden cardiac death was reduced by 45%. The combination of a weak and diverse dataset in the Hooper meta- analysis, and the inclusion of one large and particularly problematic negative study have conspired to confuse and complicate this emerging research arena where the promise of benefit is great and the risk for harm is minimal. Nevertheless, we concur with the authors that we need more high quality RCTs. In the meantime, the strongest data available suggest that the current recommendations for omega-3 intake are reasonable. References 1. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ. 2006. 2. Wang, C., Chung, M., Lichtenstein, A. H., Balk, E., Kupelnick, B., DeVine, D., Lawrence, A., and Lau, J. Effects of omega-3 fatty acids on cardiovascular disease. No. 04-E009-2 (Prepared by the Tufts-New England Medical Center Evidence-based Practice Center, under contract No. 290-02- 0022), 1-122. 2004. Rockville, MD, Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment. 3. Leaf A, Albert CM, Josephson M, Steinhaus D, Kluger J, Kang JX et al. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation. 2005;112:2762-8. 4. Raitt MH, Connor WE, Morris C, Kron J, Halperin B, Chugh SS et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 2005;293:2884-91. 5. Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003;57:193-200. 6. Burr ML, Dunstan FD, George CH. Is fish oil good or bad for heart disease? Two trials with apparently conflicting results. J Membr.Biol. 2005;206:155-63. 7. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R 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;105:1897-903. Competing interests: All three authors serve as consultants and speakers for a variety of pharmaceutical companies, including Reliant Pharmaceuticals which markets Omacor in the US. |
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Leslie O Simpson., retired medical research worker Dunedin, New Zealand, 9001
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The Hooper et al meta-analysis has generated many rapid reponses, yet not one responder has referred to what specific role omega-3 fatty acids play in reducing the risk of heart disease. Eicosapentaenoic acid improves the flow properties of blood and lowers blood viscosity by increasing the fluidity of the red cell membrane, thus improving red cell deformability and enhancing capillary blood flow. Until the importance of the physical properties of red cells in blood flow are recognised, it is unlikely that the benefits of those agents which improve red cell deformability will gain general acceptance. Nor will the role of omega-3 fatty acids be understood. Competing interests: None declared |
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Eddie Vos, maintains health-heart.org Sutton (Qc) Canada J0E 2K0
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The Hooper
et al exclusion criteria underpinning the sweeping conclusion that
".. omega-3 fats have no clear [sic] effect on total mortality,.."
needs to be questioned if only because they allowed the inclusion of the MARGARIN trial [Bemelmans,
2002] while excluding the larger Lyon
trial on which the former was 'inspired' and that was halted early because of a mortality benefit from a high omega-3, low omega-6 canola oil margarine. Lyon was supported by analysis of blood fatty acids demonstrating the targeted efficacy of its omega-3 canola (rapeseed) based intervention and with other fatty acids changing less than 11% up or down.
Unlike Lyon, the MARGARIN study was confounded by a massive intake of omega-6 linoleic acid and predictably no effect was found; indeed, Figure 2 of the Hooper et al analysis shows the odd ball nature of that trial. Excluding MARGARIN and including Lyon instead, the virtually significant mortality reduction of 14% might well have become so and I propose that anyone should be enthused by the finding of such nutrient rather than drug-based finding of even this meta analysis. Plant and fish based omega-3 fatty acids have important and complementary roles supported by many avenues of research and supplement based marine omega-3's have the added advantage of not necessarily depleting fish stocks and thus being a sustainable source of such fatty acids. Competing interests: None declared |
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Ivan Y Torshin, Dir of Bioinformatics Consulting, LLC 125239, Moscow, Russia
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Concering the paper [1]: generally, if there is a negative result, a researcher usually more carefully analyzes stratification of the data. For instance, in a forthcoming book [2], there are a few examples of such 'negative reports' which, after more careful inspection, turned out to be quite reliable associations (with P<0.001). Specifically, the following points concerning the paper [1] completely baffled me: -What about a consistent stratification of the data by population? The genetic predispositions to dietary factors are very different among different populations (sorry for this truism), even among Caucasian sub- populations. -What about discussing (let alone analyzing) the genetic background? Polymorphisms in APOC3 and other lipoproteins are known for the diet-gene interactions. By the way, these polymorphisms can have very different frequencies among Caucasian sub-populations. -Hopefully, it's not a trend in primitivization of the medical science that sometimes researchers restrict stratification mostly to age, gender and, at best, smoking and alcohol (in addition to the variables of interest). Even in a meta-analysis more stratifications can be usefully analyzed, especially when there is such a large group as in this study. -I didn't get the point of "electronic databases searched to Feb 2002"- is it really a scientific criterion for selection of the most reliable data? I would question the underlying assumption of equalling validity of a study with its date. Or, of course, it could be just the date of 1st april so we do not need, actually, to analyze the negative report [1] in greater detail... References [1] Hooper et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ 2006; 332: 752- 760 [2] Torshin IY. Bioinformatics in post-genomic era. Volume I: physiology and medicine (Nova Sci, NY, in press). Competing interests: None declared |
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Matti J. Tolonen, Dr, med, docent Biomedicus S.L. E-29640 Espain, Matti Tolonen
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Hooper et al may have overlooked that commercial fish oil preparations contain roughly half omega-3, the rest being other fatty acids (about 50) many of which antagonise each other, like arachidonic acid (AA) and eicosapentaenoic acid (EPA). The latter may be the most important omega-3 for cardiovascular health, as suggested by the largest fish oil study sofar, JELIS. http://www.americanheart.org/presenter.jhtml?identifier=3035468 As stressed by prof. Yokoyamas team, arteriosclerosis is an inflammatory condition. Charles Serhans team at Harvard discovered that EPA turns in the body to Resolvin E1, a potent antiinflamatory nanomolecule. Gao et al have found that EPA forms F3-isoprostanes, which fight proinflammatory F2-isoprostanes, and this might be of special importance in cardiovascular diseases. Taken together, Hoopert el al may have thrown the baby with the wash water by pooling together studies using different types of fish and fish oil preparations. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan CN. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005;201(5):713-22 Gao L, Yin H, Milne GL, et al. Formation of F-ring ispoprostane-like compounds(F3-isoprostanes) in vivo from eicosapentaenoic acid. J Biol Chem. 2006 Mar 28; [Epub ahead of print] Competing interests: I have helped launch of the first commercial E-EPA preparations in the European market. |
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Alfred P J Lake, Consultant in Anaesthesia and Pain Management Glan Clwyd Hospital, Rhyl LL18 5UJ.
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Long chain and shorter chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer; should we be surprised? Toxic compounds found in oily fish and fish oils may be a factor but do we need to invoke methylmercury and the like when it is more likely to be, as the authors state, that its beneficial effect is limited to a specific group? The decision to expose a patient to any intervention whatsoever should be based upon two premises: first, that every actual prescription is a clinical trial (1) and, secondly, that the evidence used should relate to the best decision for the patient in front of you and not necessarily that applicable in the group setting which ignores individuals who are therein subsumed (2). We are reminded that all clinicians and researchers should first do no harm (3) and this should also resonate without the arena of RCTs. Prescribing a drug or suggesting any other intervention represents a trade -off between its benefits and harms, which point I always make to patients attending my pain clinic, and, increasingly, we are exhorted to individualise the patients treatment and consider the benefit harm ratio; indeed, the new consent process in respect of surgery, for example, requires it. Response by the patient to a medicine or any other intervention is always (except twins) individual, we are not Sprague-dawley rats. Treatment options need to be considered with appropriate outcome measures to enable the better identification of those individuals or groups of patients who may respond to also avoid denying safe and effective treatments which should continue to be available for those who may derive benefit therefrom (2). For the general public some omega 3 fat is good for health (4) but, of course, that some is good does not necessarily mean that more is better and, likewise, in a different context, that if less is good it does not necessarily mean that even less is better. Acting against the realisation of all these simple premises are lined up medical practitioners, epidemiologists, statisticians and the pharmaceutical industry is it any wonder that the patient may lose out? When big business, big money and influence are involved there can be a risk of the eye being taken off the ball as may have happened in the recent trial disaster (5). Cholesterol is an integral part of lipid metabolism and homeostasis, involved in the continuous turnover of cells but what is the right level? Who can say, but we do know absolutely (and intuitively) that it will be individual. Statins are, of course, big money and this means a big push (with mega-dose therapy now proposed) to reduce the level of cholesterol to one which may, in fact, be bad for many individuals. Peripheral neuropathy as a recognised complication of use may be just the tip of an iceberg which may well include chronic pain either exacerbated or de novo in this association and the beginning of other problems related to cellular turnover and requiring a patient specific level (6). We ought to be more concerned that an individuals inbuilt checks upon their own intake of dietary constituents (including salt) are being bypassed by food technology in particular and issues covered up with the connivance of the pharmaceutical industry rather than properly addressed. All things in moderation 1. Lake APJ. Every Prescription is a clinical trial. Br Med J 2004; 329: 1346. 2. Lake APJ. EBM for the future. J Eval Clin Pract (in press: accepted 25.01.05). 3. Godlee F. Count the harms. BMJ 2006; 332, doi:10.1136/bmj.332.7543.0-f 4. BMJ, doi:10.1136/bmj.38798.680185.47 (published 24 March 2006) 5. Goodyear M. Learning from the TGN1412 trial. BMJ 2006; 332: 677-8. 6. Lake APJ. JACK SPRAT WOULD EAT NO FAT. Pain for the future? http://bja.oxfordjournals.org/cgi/qa-display/short/brjana_el;595 Competing interests: None declared |
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Anthony Lwegaba, Lecturer, Public Health School of Clinical Medicine and Research, UWI, Barbados, WI
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On the recommendations for high quality RTCs, long duration with allocation concealment and masking to study the effects of omega 3 fats by Lee Hooper et al should be added: Determine the time it takes for the effects to be detected. The (induction) time for such effects on mortality, cardiovascular events and cancer would theoretically be longer than present studies indicate. Even though measurements in the control group would ensure detection of difference, knowing the induction period for omega 3 fats related effects would refine what studies to include in systematic reviews. Bearing in mind the complexity of the metabolism of food nutrients, include arms of participants exposed to potently enhancing factors as probably occurs in nature when people eat fish; because our chief interest is to find an intervention that helps people whether omega 3 alone or in combination. Competing interests: None declared |
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Lee Hooper, Lecturer School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, UK, Rudolph Riemersma, Paul Durrington, Carolyn Summerbell, Helen Moore, Rachel Thompson, Roger Harrison, Helen Worthington, Nigel Capps, Shah Ebrahim, and George Davey Smith
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Thank you all for your comments about our systematic review on the effects of oily fish and fish oils on mortality, cardiovascular disease and cancers.(1) Our findings We did not report that long chain omega-3 does not offer any protection from heart disease, that omega-3 fats have no effect on total mortality, combined cardiovascular events, or cancer or that omega 3 fats are of no benefit - this is not what we found, or what we reported (despite our being misquoted in much of the press). The overall result from the meta-analysis was a relative risk suggesting benefit of omega 3 intake on mortality, but a confidence interval including unity (total mortality RR 0.87, 95% CI 0.73 to 1.03 with significant heterogeneity) so that we are not quite so sure. This raises the possibility that the protective effect of omega 3s may have been overestimated OR the heterogeneity may imply that omega 3s may be helpful in some people and less so (or even harmful) in others (perhaps men with angina or people with higher omega 6 intakes?). If the first is the case, this is not a big issue, and general advice on therapeutic doses of omega 3 fats should probably not alter. If the second is the case then we owe it to our patients to watch the unfolding evidence very carefully so we can react fast and alter our advice for specific groups if it proves necessary. Apples, pears and different outcomes Many of you suggest that if we kept different types of studies separate, or separated out specific outcomes, the results of our meta- analysis would have been different. This is not the case, we did run most of the subgroupings and individual outcomes that you suggest in the original Cochrane review.(2) However, there was no space to present all these results in the BMJ version of this review. The full Cochrane review can be found on the Cochrane Library at: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003177/pdf_fs.html. (The Cochrane Library is free to those from the UK and some other countries, for others it is by subscription.) Analyses that some of you requested (see Cochrane review table 04 and forest plots): Subgrouping by oily fish advice vs. supplementation with fish oil: RR of total mortality in trials where dietary advice to eat more oily fish was given 0.91 (95% CI 0.57 to 1.44, 3 trials, 4727 participants, 664 deaths highly heterogeneous), RR of total mortality in trials where fish oil supplements, capsules or oil were provided 0.90 (95% CI 0.76 to 1.07, 39 trials, 32641 participants, 1569 deaths) Subgrouping by plant vs. fish source: see BMJ paper, subgrouping results are reported within or below all of the forest plots, none are statistically significant Sudden death or fatal MI rather than total mortality: RR of sudden death in all trials with data 0.85 (95% CI 0.49 to 1.48, 6 trials, 416 deaths highly heterogeneous), RR of fatal MI in all trials with data 0.86 (95% CI 0.60 to 1.25, 8 trials, 390 deaths). Primary vs. secondary prevention: RR of total mortality in trials where participants have existing CVD 0.84 (95% CI 0.70 to 1.02, 18 trials, 20002 participants, 1907 deaths), RR of total mortality in trials where participants have strong risk factors but not diagnosed CVD 1.04 (95% CI 0.04 to 24.53, 9 trials, 1564 participants, 5 deaths), RR of total mortality in trials where participants are at low initial risk of CVD 1.07 (95% CI 0.70 to 1.64, 17 trials, 14599 participants, 83 deaths). Unfortunately there are virtually no data from the trials on genetic factors so further analysis will need new trials. We did run a meta- regression of fish-based omega 3 dose (combination of EPA, DHA and DPA where known) vs. total mortality (see the Cochrane review) we did not find a statistically significant relationship. We did not break down the results into individual fatty acids. Including the Burr 2003 paper We accept that the Burr 2003 trial(3) was not perfect, but neither were the other two very large trials (and many of the smaller ones) that contribute most of the data to the analysis. The DART trial(4) was similar in methodology to the later Burr trial. The GISSI-P trial,(5) the largest, was also imperfect as it did not provide a placebo. We find it hard to understand how one could justify including DART and GISSI-P (and these trials are included as star evidence within most reviews that cite the effectiveness of omega 3s) without including Burr 2003 you would need to write your exclusion criteria to specifically exclude it. The strength of the Cochrane Systematic Review process is that it aims to remove any bias during the meta-analysis and precludes post-hoc exclusions. A couple of points to note about Burr 2003 there is evidence from weighed dietary records of 1202 subjects (38.6% of the total) that fish advice increased the intake of EPA (from fish and capsules) and decreased total fat and saturated fat intake. Also, around 50% of the men with chronic stable angina had had a myocardial infarction in the past, so the populations in Burr 2003 and DART may not have been very dissimilar. The main difference is that DART recruited patients immediately post MI. When we excluded studies at moderate or high risk of bias (in sensitivity analysis) the relative risk of death was 0.98, 95% CI 0.70 to 1.36, including only 138 deaths (see figure 2 of the long BMJ version). Because of the low number of events, the confidence interval does not preclude a beneficial effect, nor does it exclude a detrimental effect, but the closeness of the point estimate to unity lends weight to the idea that we may have overestimated the protective effect of omega 3 fats. Also, the evidence could change rapidly when data from further RCTs at low risk of bias become available. It is interesting to note that the point estimate of each of the three largest studies (DART, GISSI-P and Burr 2003) lies within the confidence intervals of the sensitivity analysis we could be seeing natural variability around a negligible effect size. Inclusion criteria As stated in both the BMJ paper and the Cochrane review, the Burr 2003 paper was included before publication (Andy Ness, one of our review authors, was working with Michael Burr and we included a manuscript which had been submitted for publication). We also wrote to all authors of included studies asking whether they knew of unpublished studies, and would have included more if they had been relevant. This was stated clearly in the review protocol. We also stated in our published protocol that we would exclude studies of multiple risk factor interventions unless the effect of diet or supplementation could be separated out from the other interventions, to ensure that any effect could be more clearly attributed to omega 3. The Lyon Heart study was therefore excluded as the effect of alpha-linolenic acid could not be separated from changes in the consumption of many other foods (for example, fruit and vegetable intake rose and saturated fat and linoleic acid intake fell in the intervention arm).(6) However, factorial trials were included as it is clearly possible to separate out the effects of the different interventions. GISSI-P and DART were both factorial trials, not just Burr 2003. It might be possible to use these factorial designs to assess the effects of omega 3 with regard to omega 6 intake interactions were not seen between the dietary fat arm (which advised and achieved an increase in the P/S ratio) and the oily fish arm (increasing omega 3) of DART. This tends not to support the idea that omega 3 fats work better when omega 6 intakes are lower. Inclusion of specific cohort studies We did include prospective cohort studies that assessed either dietary intake or biomarkers (and used biomarker analyses for preference where both types of analysis of a single cohort were available). The reason we included cohorts was that adverse effects might be observed in observational but not in relatively short-term randomised controlled trials. Of the 41 analyses of 26 cohort studies included in our review intake of omega 3 (varying combinations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, along with linolenic acid, supplemental fish oils, or dietary oily fish) was assessed by dietary and biochemical means in two cohorts, dietary means only in 18, and biochemical means only in 10. The Albert(9) analysis of the Physicians Health Study (PHS) was indeed one of the 5 analyses of the PHS cohort relevant to the review which we included. The Morris 1995 paper(10) provided the most useful data on cardiovascular events and stroke for the PHS study and is seen in these forest plots in the review (for details please see the references to included studies provided on the BMJ website). We excluded cohort studies which assessed general fish intake (rather than oily fish or fish oil intake, or biomarkers of omega 3 intake) as we were interested in the effect of omega 3 fats, not fish, on health. We agree that white fish consumption may have health effects other than those we have studied, but this was not our interest. He has conducted this analysis and there is not much point in our repeating it.(11) Relying on cohort studies to inform us The problem with reliance on cohort evidence for assessing the effects on health of omega 3 fats is that in all cohorts we examined, where there were data on socioeconomic and lifestyle characteristics, participants consuming more omega 3 fats (or with higher body levels) were better off, better educated, had better social support, were more interested in health (as evidenced by them taking more vitamin supplements of various types), ate less saturated fats, more fruit and vegetables, more fibre, smoked less and took more physical activity than those taking less omega 3. Adjusting for this level of confounding is difficult and our analysis demonstrates that adjustments are often not adequate. We should remember that claims based on observational studies about the health benefits of beta-carotene, folate and vitamin E (for example) have been shown to be incorrect following randomised controlled trials.(7, 8) While observational data are interesting clues to the health effects of foods, we need to rely on high quality trial evidence to fully understand the health benefits of increasing our intake of oily fish or fish oil supplements. Overall Like many of you, we had anticipated that our review would provide a simple comprehensive conclusion that omega-3s are protective against cardiovascular disease. In fact this is not the case. Surely, however, it is more important to have a balanced and objective analysis of existing evidence so that we can be certain about what we do not know and be clear about what future trials should be designed to answer? Our review has not questioned UK healthy eating advice suggesting that the public eat two portions of fish per week, one of which should be oily. This seems very sensible given the essentiality of omega 3 fats and evidence of wide ranging benefits of fish. It also suggests that low dose fish oil supplements in those not eating oily fish (the sorts of doses taken to help with arthritic symptoms for example) would cause no harm. However we are less sure about the higher, therapeutic, doses of omega 3 - three or more large portions of oily fish each week or 1g+ of omega 3 fats daily. The evidence here is less clear. If high doses of omega 3 are not helpful for some people, or are even harmful for some groups of people, it is important that we recognise this and make sure that only the right people get the advice to take more oily fish or fish oil supplements. We need to keep watching the evidence as it emerges and adjust our advice as appropriate, for the best health of people everywhere. 1. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. British Medical Journal 2006;332:752-60. 2. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Moore H, Worthington HV, et al. Omega 3 fatty acids for prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev 2004;4:CD003177. 3. Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. European Journal of Clinical Nutrition 2003;57:193- 200. 4. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effects of changes in fat, fish and fibre intakes on death and myocardial reinfarction:diet and reinfarction trial (DART). Lancet 1989;ii:757-61. 5. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI- Prevenzione trial. Lancet 1999;354:447-55. 6. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343(8911):1454-9. 7. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomised placebo- controlled trial. Lancet 2002;360:7-22. 8. Davey Smith G, Ebrahim SBJ. Folate supplementation and cardiovascular disease. Lancet 2005;366:1679-81. 9. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. New England Journal of Medicine 2002;346(15):1113-8. 10. Morris MC, Manson JE, Rosner B, Buring JE, Willett WC, Stampfer MJ. Fish consumption and cardiovascular disease in the physician's health study: a prospective study. American Journal of Epidemiology 1995;142(2):166-175. 11. He K, Song Y, Daviglus ML, Liu K, Van Horn L, Dyer AR, et al. Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation 2004;109:2705- 11. Competing interests: As shown in the published paper. |
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Eddie Vos, maintains health-heart.org Sutton (Qc) Canada J0E 2K0
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One problem with the Hooper analysis and response is the inclusion of trials without full understanding of what was done. The odd ball MARGARIN trial was confounded with a truly massive amount of omega-6 yet included, and Lyon is characterized in the current eBMJ response as a 'multiple risk factor intervention' which it was not by any stretch of the imagination. What really happened in Lyon, this city 500 km from Paris and another 300 km to the Mediterranean? The control group was left alone under regular doctor's care while the 'experimental' group of n=302 got high omega-3 canola-based margarine, 'free for the entire family', as well as yearly [sic] dietary 'advice'. Dietary advice has historically not changed eating patterns and indeed here is what happened: Converted into food items (tables 3 & 5 from Lancet (343)1994-6- 11: 1456), in experimentals after 1-4 year followup, per day vs. controls: * 10% fewer calories but only 0.1 less weight gain (Body Mass Index); * 0.6 slices more bread but 1/6th less servings of cereals; * 10 more beans/day and 10% more veggies (the weight of a small carrot); * 20% more fruits [1/2 a small 5 cm (2") apple]; * a sliver (7 g) less 'delicatessen'; * 13% less meat + poultry (14 g); 10% less cheese (3 g); * 15% more fish (6 grams, an anchovy fillet); * Zero difference in total fat intake from butter + margarine + cream + oil; * Experimentals ingested 1/2 'egg-equivalents' less cholesterol. Clearly this was not a 'diet' study considering these tiny global food intake and zero blood cholesterol changes. One can see why NEJM refused (private communication) to publish these dramatic results (such as a 76% reduction in adjusted cardiac deaths), results that were subsequently published in Lancet 1994; medline 7911176, AJCN 1995; medline 7754988, and free: Circulation 1999 (medline 9989963, with editorial [medline 9989956]. Dietitians understandably have never been able to change the global eating patterns of 300 seniors from Lyon, Birmingham or anywhere else for that matter, and show clinical benefit. What people WILL do is take free margarine and replace regular omega-6 margarine and butter with it; the difference evidently is the omega-3. Simple comme bonjour! Indeed, to explain these 'impossible' dogma defying results one has to look at the plasma fatty acid analysis of 280 subjects at 1 year follow-up (Lancet, as above, table 4) where experimentals had a 67% higher level of alpha-linolenic acid (ALA, from canola margarine), a 35% increase of C20:5n3 EPA, the first and main ALA 'daughter', and less than 11% differences in either omega-6, mono or saturated fatty acids. Lyon's failing was allowing critique by including once yearly dietary advise, Hooper's failing was not understanding the fundamentals of this excellent study and thus excluding it. vos{at}health-heart.org Competing interests: None declared |
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Roberto Marchioli, Head, Laboratory of Clinical Epidemiology of Cardiovascular Disease 66030 Santa Maria Imbaro, Italy, Luigi Tavazzi, Gianni Tognoni.
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Sir, Hooper et al. recently published in the journal a Cochrane Database Systematic Review on risk and benefits of omega 3 fats (1). They concluded that omega 3 fats do not have a clear effect on total mortality, cardiovascular events, or cancer. The two main trials included in the meta -analysis were: a) GISSI-Prevenzione (2,3) testing the effect of a daily administration of 850 mg omega 3 fats given with 1 capsule of a highly purified and concentrated form in 11323 post-MI patients, 1031 deaths, duration 3.5 years, relative risk 0.86, 95% confidence interval 0.77 to 0.97); b) DART II (4) testing the effect of eating two portions of oily fish each week (or to take up to 3 g of fish oil as a partial or total substitute of fatty fish meals) in 3,114 patients with angina, 525 deaths, duration about 8 years, relative risk 1.15, 95% confidence interval 0.98 to 1.34) trials. Therefore, 1,556 out of 1,995 total deaths occurred in two trials with opposite results. From a conceptual (and substantial) point of view, Hoopers et al article is closer to a head-to-head comparison of two trials than to a meta-analysis aimed at summarizing properly the evidence on this issue. While there are some concerns about the use of qualitative assessments of trials on the base of appropriate concealment of allocation to the study arms when applied to meta-analyses including not concealable therapies like dietary interventions, most of our concern for this meta-analysis pertains the inclusion of DART II results. As the authors acknowledge in their paper, the inclusion/exclusion of DART II can change profoundly the results of the meta-analysis. To highlight this issue, it is worth considering that the course of DART II was rugged by many difficulties. Its recruitment phase lasted from 1990 to 1996 and was hampered by an interruption of funding in 1992-93 that made recruitment of patients to be ceased and then restarted one-year later. This second phase of the trial allowed the recruitment of 2,003 additional patients, but major changes to the research protocol were required to curtail costs (e.g., contacts between dieticians and patients, collection of dietary and pharmacologicical data during follow- up, ascertainment of incident myocardial infarction by examining hospital notes). In addition a subrandomization was added among the patients allocated fish advice who could receive omega 3 fats through either dietary or pharmacological intervention (5). The shortage of funds causing the lack of proper follow-up, the length of the study follow-up, the temporary stop of the trial, the sensitive nature of dietary intervention requiring constant reinforcement of the message to be delivered to the study participants, the added randomization to three large capsules daily in the second phase of the study, all could have hampered the compliance of patients to the experimental intervention as well as to pharmacological therapies known to be effective in the prevention of cardiovascular disease, thus causing a higher than expected rate of events in the experimental arm and eventually an unexpectedly higher mortality rate in patients allocated omega 3 fats intervention. GISSI-Prevenzione was a pragmatic trial that adopted a PROBE format (Prospective Randomized Open Blinded Endpoint adjudication) like the Hypertension Optimal Treatment study (6). Because of its design, GISSI- Prevenzione was (wrongly) considered as a weak study and this explains the results of the sensitivity analysis that was carried out after excluding studies at moderate or high risk of bias. Last but not least, it is somewhat strange to have a meta-analysis published in 2006 dealing with trials published up to February 2002. A number of new, relevant clinical trials a) are currently available in the literature, b) have been recently presented in medical meetings, and c) are going to be presented shortly. Was this a truly systematic overview including all available evidence in this field? Did we need it ? 1) Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore H, Worthington HV, Durrington, PN, Higgins JPT, Capps NE, Riemersma RA, Ebrahim SBJ, Davey Smith G. Risk and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: a systematic review. BMJ 2006. [Epub ahead of print; doi = 10.1136/bmj.38755.366331.2F] 2) GISSI Prevenzione Investigators. Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447455. 3) Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio DDMR, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marfisi RM, Mastrogiussepe G, Minnini N, Nicolosi GL, Santini M, Schweiger C, Tavazzi L, Tognoni G, Tucci C, Valagussa F. 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. 4) Burr ML, Ashfield-Watt PAL, Dunstan FDJ, Fehily AM, Breay P, Ashton T, Zotos PC, Haboubi NAA, Elwood PC. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003:57:1932003. 5) Burr ML, Dunstan FDJ, George CH. Is Fish Oil Good or Bad for Heart Disease? Two Trials with Apparently Conflicting Results. J Membrane Biol 2005:206,155163. 6) Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood- pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351:1755-62. Competing interests: GISSI-Prevenzione co-ordinator |
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Damien Downing, Ecological physician, journal editor Journal of Nutritional and Environmental Medicine
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The BMJ must have known that this paper would lead to headlines such as Debunked! (Independent) and The benefits of fish and linseed oils as elixir of life are another health myth (Times) statements that are unjustified, but useful to the pharmaceutical industry even though the paper does not claim to show this (the abstract says ...omega 3 fats do not have a clear effect...), and the accompanying editorial hardly condemns omega 3 supplementation. Richard Smith has written on this (1), as has Richard Horton (2). Mind you, the BMJ did publish the manual on how to do it (3) and yes, I do know it was humorous, but I think most of this paper comes under FPSU (Find the Pony Statistical Unit); Execute sub-n-group analysis where n=keep going until you find a statistically significant effect in your favour. Meta-analysis (which the media always describes as new research does nobody in biomedical publication worry about that?) is being debased as a tool to discredit non-pharmaceutical treatments. In the last 3 years there has been a series of such studies, each declared as new research, and each arguably a variation on Find the Pony. The problem of course is that to adequately peer-review a meta-analysis it is necessary to peer-review all the papers it uses, AND those it excludes, in order to judge the selection criteria. The selection process in Hooper et al has already been extensively criticised here by others. Any analysis of the effects of increasing omega 3 intake alone contributes to the medicalisation of nutrition; while the drug model of intervention requires a single intervention to yield an effect, nutrition is an integrative approach involving all aspects of diet and lifestyle. Nobody who understands this would expect taking omega 3s to over-ride the effects of smoking, eating high- calorie junk food and trans-fats, being overweight and taking insufficient exercise etc. On the basis of cui bono? it is noteworthy that the only stated competing interest in the Hooper paper is the receipt of fees from Solvay Heathcare, who market Omacor the first ever prescription-only fish oil. In September 2005, Solvay and Pronova Biocare signed a licensing agreement for exclusive distribution rights on Omacor. Whether intentionally or not, this paper will help to persuade patients to shun OTC fish-oil supplements, ignore nutritional and lifestyle recommendations, and elect for the prescription- only version. 1. Smith R, Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLOS Medicine 2 (5): e138 2. Horton R (2004) The dawn of McScience. New York Rev Books 51(4): 79 3. Sackett DL, Oxman AD (2003) HARLOT plc: An amalgamation of the world's two oldest professions. BMJ 327: 14421445 Competing interests: I help patients with diets and supplements |
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stuart lloyd, student UCLAN, Preston
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I have a big issue when the effects of fish consumption are linked to the effects of the long-chain omega-3 fatty acids. Sure, fish is the best natural source of the long-chain omega-3 fatty acids, but our fish supply is also tainted with mercury, lead, pesticide residues, and other harmful compounds. Mercury has been known to increase the risk of cardiovascular disease. While fish oils may protect against heart disease, is the benefit of eating fish counteracted by a higher intake of mercury? Apparently not as results from another study published in the New England Journal of Medicine show that while higher body levels EPA and DHA were associated with a decreased risk for heart attacks, the higher the body mercury level the greater risk of a heart attack (Gualler et al, 2002). Researchers concluded that the high mercury content of fish may diminish the protective effect of fish intake against heart disease. So, it is entirely inappropriate to lump fish consumption into the analysis of the health benefits of the long-chain omega-3 fatty acids. Another mistake, surely, is pooling the data with both the long-chain omega-3 fatty acids from fish oils with the short-chain omega-3 fatty acids alpha- linolenic acid. While the data on the beneficial effects of the long-chain omega-3 fatty acids is quite solid, for alpha- linolenic acid the evidence is less convincing and randomized controlled trials are lacking. One of the studies included in the analysis that should not have been was conducted not on fish oil, but rather a margarine containing alpha-linolenic acid (ALA) - that's the omega 3 found in flax versus a margarine with linoleic acid (an omega-6 fatty acid) (Bemelmans et al, 2002). Again, including this study appears inappropriate and its exclusion may have changed the picture entirely. Finally, it has been stated that conducting a meta-analysis study on the effectiveness of omega-3 fats for mortality, cardiovascular disease and cancer, without considering the impact of excess omega-6 fat in the diet, is akin to reviewing the efficacy of a healthy diet without factoring the effects of smoking (Tribole EF, 2006). In other words, a high omega-6 to omega-3 fatty acid ratio would counteract the impact of an increased omega-3 fatty acid intake and make the results difficult to interpret. The reason omega-6 fatty acids counteract the effects of the omega-3 fatty acids relates to the production of eicosanoids (prostaglandins, thromboxanes, and leukotrienes) from omega-6 fatty acids. Chronic excessive production eicosanoids derived from omega-6 fatty acids is associated with an increased risk heart attacks, thrombotic stroke, arrhythmia, arthritis, osteoporosis, inflammation and cancer. The overall benefits of a higher intake of omega-3 fatty acids appears to be related to reducing the omega-6 to omega-3 fatty acid ratio and availability of omega-6 fatty acids for eicosanoid synthesis. REFERENCES: 1. Guallar E, Sanz-Gallardo MI, van't Veer P, Bode P, et al. Mercury, fish oils, and the risk of myocardial infarction. N Engl J Med 2002;347:1747-54. 2. Bemelmans WJ, Broer J, Feskens EJ, et al. Effect of an increased intake of alpha-linolenic acid and group nutritional education on cardiovascular risk factors: the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study. Am J Clin Nutr. 2002 Feb;75(2):221-7. 3. Tribole EF. Excess Omega-6 Fats Thwart Health Benefits from Omega- 3 Fats. BMJ.com March 27, 2006 Competing interests: None declared |
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Shinkan Tokudome, Professor Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan, Masayo Kojima, Chiho Goto, Nahomi Imaeda, Yuko Tokudome, Kiyonori Kuriki, Sadao Suzuki, Hiromitsu Ichikawa, Ryosuke Ando, Nami Hattori, and Harumi Okuyama
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Risks and benefits of omega-3 fatty acids on cancer risk Editor - Hooper et al1 systematically reviewed cohort studies and randomized controlled trials to examine whether intake of omega-3 fatty acids (FAs) or n-3 polyunsaturated fatty acids (PUFAs) is beneficial for prevention of cardiovascular disease and cancer, and concluded that n-3 PUFAs have little effects for reducing the risk of cancer. We here would like to discuss most frequently probed associations between consumption of n-3 PUFAs and risk of colorectal cancer. Seven articles cited as negative effects, except one, of n-3 PUFAs on colorectal carcinogenesis were reported from the USA (3 articles), Norway (2 articles), Sweden (1 article) and the Netherlands (1 article).1 Consumption of total FAs and saturated FAs seemed greater in those people than that in Japanese, but no differences for the intake of arachidonic acid (AA) and alpha-linolenic acid. Intake of highly unsaturated FAs (n-3 HUFAs) or fish FAs in Japanese, on the other hand, was far greater than those people, indicating that the consumption of n-3 HUFAs by those people is only approximately 1/10th of Japanese. Because n- 3 PUFAs compete with n-6 PUFAs (or AA) in various metabolic processes, the absolute intake of n-3 PUFAs (or n-3 HUFAs) may be crucial for colorectal carcinogenesis.2 Consumption of n-3 HUFAs in those people appears insufficient to exert pharmacologic influence. The ratio of n-3 PUFAs/n-6 PUFAs (or specifically n-3 HUFAs/AA) may also be critical. The ratios in those people appear to be far less than those in Japanese. Plasma concentration of phospholipids in those people would be expected to be highly saturated with n-6 PUFAs, linoleic acid and AA, in particular, and the concentrations of n-3 PUFAs and n-3 HUFAs might not effectively compete in the arachidonate cascade.3 As seen in our observational study4 and randomized controlled trial,5 omega-3 FAs, n-3 PUFAs and/or n-3 HUFAs may indeed be favorable for the prevention of colorectal adenomas/tumors in populations, including Japanese, who consume appreciable amounts of fish and marine foods. (317 words) Shinkan Tokudome,1 Masayo Kojima,1 Chiho Goto,2 Nahomi Imaeda,3 Yuko Tokudome,2 Kiyonori Kuriki,4 Sadao Suzuki,1 Hiromitsu Ichikawa,1 Ryosuke Ando,1 Nami Hattori,1 and Harumi Okuyama5 1Department of Health Promotion and Preventive Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, 2School of Health and Human Life, Nagoya-bunri University, Inazawa, Japan, 3Faculty of Human Life and Environmental Sciences, Nagoya Womenfs University, Mizuho-ku, Nagoya, Japan, 4Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan, 5Kinjogakuin University College of Pharmacy, Moriyama-ku, Nagoya, Japan References 1. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ, 2006; 332: 752 -60. 2. Nkondjock A, Shatenstein B, Maisonneuve P, Ghardirian P. Specific fatty acids and human colorectal cancer: an overview. Cancer Detect Prev, 2003; 27: 55-66. 3. Lands WEM, Libelt B, Morris A, Kramer NC, Prewitt TE, Bowen P, et al. Maintenance of lower proportions of (n-6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n-3) fatty acids. Biochim Biophys Acta, 1992; 1180: 147-62. 4. Kojima M, Wakai K, Tokudome S, Suzuki K, Tamakoshi K, Watanabe Y, et al. Serum levels of polyunsaturated fatty acids and risk of colorectal cancer: a prospective study. Am J Epidemiol, 2005; 161: 462-71. 5. Cheng JL, Ogawa K, Kuriki K, Yokoyama Y, Kamiya T, Seno K, et al. Increased intake of n-3 polyunsaturated fatty acids elevates the level of apoptosis in the normal sigmoid colon of patients polypectomized for adenomas/tumors. Cancer Lett, 2003; 193: 17-24. Competing interests: None declared |
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Christine M Williams, Professor of Human Nutrition University of Reading,UK RG6 6AO
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I wish to add additional comment on the paper by Lee Hooper et al which undertook a systematic review of randomised controlled trials and prospective cohort studies of the effects of long and short chain omega-3 fats on cardiovascular disease, cancer and bleeding events. As far as possible I have not repeated comments made by other contributors but focus on reasons why this review has drawn different conclusions from a previous meta-analyses (1) and from a review of the Scientific Advisory Committee on Nutrition (SACN) and the Committee on Toxicity (COT) of the benefits and risks of consumption of fish (2). The main reason for these differences was the inclusion of the data from Burr et al. (3) in the pooled analysis for risk of death in high risk subjects, in the report from Lee Hooper and colleagues. In the methods section of their paper the authors refer to use of two specific quality criteria (concealment of study arms and masking of participants, providers and outcome assessors) in judging studies at potential risk of bias. The authors do not appear to have taken account of (or acknowledged) the fact that concealment of study arms and masking of participants and providers are design characteristic that cannot be applied in dietary intervention trials in which individual advice on food intake forms part of the study protocol. However many other aspects of study design are used to evaluate the quality of evidence used to guide policy and public health advice in the area of diet and these were not used in judging the quality of the papers included in this latest meta-analysis. The risk assessment protocol applied by SACN/COT, concluded that the study of Burr et al contained a number of significant flaws that reduced the reliability of the data. These have also been fully addressed in the previous correspondence. The SACN/COT review group were provide with a copy of the Cochrane review which formed the basis of the present meta-analysis and concluded that a meta-analytical approach, without consideration of wider study design issues, was inappropriate for use in their overall assessment of the evidence. A critique of the use of Cochrane reviews in assessing the reliability of knowledge about diet and chronic disease has recently been published (4). It clearly illustrates why meta- analysis cannot be considered a gold standard for evaluating dietary intervention trials and is in direct conflict with the authors view that their data provides high quality evidence to guide policy and practice. The explanations put forward by the authors to explain differences between the findings of Burr et al and other large long chain omega-3 intervention trials, appear to be unlikely. They suggest the study to be the longest follow up of all the long chain omega -3 trials and consider the findings may reflect cumulative adverse effects of methylmercury in fish and fish oils. However, the adverse impacts were largely confined to the second phase which represented subjects whose follow up (36 months maximum) was shorter than phase one (72 months) and shorter than the 42 month follow up in the GISSI trial. The possibility that fish or fish oils have different effects in men with angina than in those who have had a recent myocardial infarction (MI) is also an unlikely explanation given that many of the post MI patients in the GISSI-P and the DART I trial were likely to be suffering angina. Burr et al suggested a possible explanation lay in the differential behaviour of men given fish oil capsules, as opposed to dietary advice. If so, this illustrates precisely why design factors other than concealment to study arms and masking, are essential in controlled intervention trials involving diet. Whilst the size of the study conducted by Burr et al. provides a potentially important contribution to the literature in this area, the authors themselves have been extremely transparent concerning the limitations of their study and fully discuss these in their paper, and also in communications with the SACN/COT review group. However, despite acknowledging the important contribution made by the Burr et al paper to the conclusion drawn from their meta-analysis, Lee Hooper and colleagues have failed to give any consideration to these quality issues in the discussion of their findings, and as a consequence, have exaggerated the strength of the findings from Burr et al. During the significant media coverage which followed the publication of the review, one of the authors was quoted as supporting the recommendations of the SACN/COT fish report. The SACN/COT review group could not have made these general population recommendations had they concluded their advice to be hazardous to a significant proportion of the adult population (angina sufferers), since this is contrary to the basic tenets of sound public health policy and practice. On this basis, it would seem the authors wish to have their fish and eat it. Because of the media coverage given to the findings of this study and the damage done to the clarity of public health policy on diet and heart disease, it is hoped that this response will be given equal coverage, and by doing so, will elevate the level of debate concerning the evaluation of science in the area of diet and health. Competing interests: None declared |
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Mahabaleshwar V Hegde, Scientific Advisor IRSHA, Bharati Vidyapeeth medical College Campus Pune 411043, India, Ulhas Wagh,
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The findings and conclusions drawn from the analysis being contrary, to general belief that omega-3 fatty acids are beneficial to cardiovascular patients, naturally it has been severally criticized and the validity of the conclusions questioned. I have read the numerous rapid responses and one very vital point missed in these comments is about the importance of antioxidants in omega-3 fatty acid supplementation. It has been suggested (1) that it might be possible to reduce the extent of damage caused by free radicals through three dietary changes: i) reducing energy intake (i.e., lowering the level of free radical reactions arising in the course of normal metabolism, ii) minimizing dietary components that increase the level of free radical reactions (e.g., poly unsaturated fats), and iii) supplement the diet with one or more free radical- reactions inhibitors (antioxidants) Both essential omega-6 and omega-3 fatty acids are polyunsaturated, and increase the free radical load on the body with its consequent harmful effects on the body. Therefore it is very important to check the lipid peroxidation, the chain reactions initiated by free radicals to reap the beneficial effects of omega-3 fatty acids (2) It has been noted by us and observed by others, that the oxidative stress are usually high in patients and their omega-3 levels are lower than the controls. Therefore the above strategy of combining antioxidants, in omega-3 fatty acid supplementation, may be effective in the treatment of CVD patients. With respect to the clinical trials, following additional suggestions can be made: i) Just as the initial omega-3 and omega-6 levels are necessary to know in the patients recruited, their oxidative stress levels, total antioxidant capacity must also be ascertained. ii) It is also important to provide good amount of antioxidants along with omega-3 fatty acids to minimize its adverse effects. References 1. Harold E. Seifried, Darrel E. Anderson, Barbara C.Sorkin and Rebecca B.Costello., Free radicals: The Pros and Cons of Antioxidants, xecutive Summary report, J Nutr. 134: 3143S-3163S, 2004. 2. Meena Arvindakshan, Madhav Ghate, Prabhakar K Ranjekar, Denise R Evans, Sahebrao P Mahadik, Supplementation with a combination of omega-3 fatty acids and antioxidants ( vitamin E and C) improves the outcome of schizophrenia, Schizophrenia Research, 62, 195-204, 2003. Competing interests: We at Interactive Research School for Health Affairs(IRSHA) Bharati Vidyapeeth Medical college Campus Pune 411043, India, are investigating i)the role of omega-3 fatty acids and antioxidants in the desease outcome, ii) Enrichment of omega-3 fatty acids, in egg, fish and milk,and iii) Flax agriculture for human health and IQ. |
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pascal huve, medical journalist 152 av malakoff 75116 Paris France
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Sir, I dont know if this would change the author's conclusions on the non clear benefit of omega 3 but I draw your attention on a simple calculation (or editing) mistake that might be relevant : in fig 2, "Effect of omega 3 fatty acids on mortality", in the subcategory "RCT data, a linolenic acid only", the total events for low omega 3 /control should be 68, not 58, which makes the 72 events in the high omega 3 group look not as bad. Best regards Competing interests: None declared |
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