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Rapid response to:


Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review

BMJ 2006; 332 doi: (Published 30 March 2006) Cite this as: BMJ 2006;332:752

Rapid Response:

Understanding the Risks and Benefits of Fish and Omega-3 Fatty Acid Intake

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-

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 individual’s 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

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-

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

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,

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-

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.

Competing interests:
None declared

Competing interests: No competing interests

28 March 2006
Dariush Mozaffarian
Instructor of Medicine
David S. Siscovick, and Walter C. Willett
Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School