JELIS results discussion in pre-eminent LANCET journal
Discussion
Our results show that EPA treatment reduced the
frequency of major coronary events. The composite
frequency of the primary endpoint in all patients for the
EPA group was 19% lower than in controls. The risks of
unstable angina and non-fatal coronary events were
also substantially reduced, by 24% and 19%, respectively.
The benefi cial eff ects of EPA seemed much the same in
both the secondary prevention and the primary
prevention subgroups, although they were signifi cant
only in the EPA group because of greater numbers of
events.
We showed that the reduced risk associated with EPA
treatment was confi ned to non-fatal coronary events.
However, the reduced risk did not apply to coronary
death or sudden cardiac death in any of our study
populations or secondary prevention subgroup studies.
This fi nding diff ers from the results of previous
interventional and observational studies.29 Most
observational studies report that fi sh intake only once
or twice a week or a small intake of fi sh about 30–60 g
per day is associated with a 30–60% reduction in the
risk of fatal coronary events or sudden cardiac deaths,
but not of non-fatal coronary events.1,3–5,7 Secondary
prevention trials for coronary heart disease report that a
modest intake of fatty fi sh (200–400 g/week) or
supplemental intake of EPA plus DHA (1 g/d) reduces
coronary mortality by about 20–30% in patients who
have already had a myocardial infarction.8,9 Experimental
and epidemiological studies suggest that fi sh oil at low
doses might prevent sudden cardiac death by an
antiarrhythmic eff ect.30
Our fi ndings accord with a cohort study by the Japan
Public Health Centre, which used a food-frequency
questionnaire.31 Iso and co-workers31 reported that,
compared with a small intake of fi sh (once a week or
about 20 g per day), a high intake (eight times per week,
or about 180 g per day) was associated with a substantially
reduced risk of coronary heart disease, especially nonfatal
cardiac events, in middle-aged Japanese men and
women. This fi nding suggests that two protective
mechanisms of EPA or n-3 polyunsaturated fatty acids
aff ect the risk of coronary events: reduction of mortality
from coronary artery disease and sudden cardiac death
with a low intake of n-3 polyunsaturated fatty acid, and
reduction of all coronary events with a high intake of
n-3 polyunsaturated fatty acids. Our patients could
possibly all have had intakes of fi sh that were above the
threshold for prevention of fatal coronary events or
sudden cardiac death.4 One potential explanation for
the strong inverse association with non-fatal coronary
events in our study population, but not in other study
populations of non-Japanese patients, is that EPA might
aff ect risk only at very high levels of fi sh intake, such as
those common in Japan.
n-3 polyunsaturated fatty acids have antiarrhythmic
eff ects and other benefi cial eff ects,32,33 such as reduced
platelet aggregation,10,11 vasodilation,12,13 anti proli feration,
14 plaque-stabilisation,15 and a reduction in lipid
action.16,17 One clinical study examined the morphology of
endoatherectomised carotid specimens and showed that
fi sh-oil supplementation increased the stability of
atherosclerotic plaque.15,34 Atherosclerotic plaque is
vulnerable to rupture because it has a thin fi brous cap
that covers a large lipid core, and an increased number of
infl ammatory cells such as macrophages. n-3 polyunsaturated
fatty acids reduce the expression of adhesion
molecules on endothelial cells35 and macrophages.36
Dietary fi sh oil reduces the production of chemoattractants,
including leukotriene B4,37 platelet-derived growth
factor,38 and monocyte chemoattractant protein-1.39 These
mechanisms reduce the passage of monocytes and
macrophages into the plaque. Thus, EPA and DHA
reduce the numbers of macrophages in the atherosclerotic
plaque. Thrombus formation in the ruptured plaque
leads to acute cardiovascular events.
Our study has some specifi c characteristics. First, we
used highly purifi ed EPA rather than n-3 polyunsaturated
fatty acids or fi sh oils. This trial is a pharmacological
intervention rather than a food-based or nutrient trial.
Nutritional data are diffi cult to extrapolate to
pharmacological intervention because fi sh oil contains
many fatty acids other than EPA and DHA. Although
both EPA and DHA are biologically active, we do not
know whether they have diff erential eff ects on
cardiovascular protection. Second, our population was
exclusively Japanese. In Japan, death from coronary
artery disease is rare and the average dietary intake of
fi sh is about fi ve times higher than that in other
countries.28 We did not use a food-frequency questionnaire
to measure fi sh intake; instead, at baseline, we
measured plasma fatty acid concentrations that indicate
fi sh consumption and EPA intake. Plasma EPA was
2·9 mol% at baseline in our study population, which is
similar to reports by Iso and co-workers40 that serum
EPA composition was 4·1 mol% in rural Japanese and
2·4 mol% in urban Japanese; these values are much
higher than those recorded in the USA, which are about
0·3 mol%
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