Nutrition, Metabolism & Cardiovascular Diseases (2014) 24, 470e475

Available online at www.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases

journal homepage: www.elsevier.com/locate/nmcd

META-ANALYSIS

Effects of Omega-3 fatty acid on major cardiovascular events and

mortality in patients with coronary heart disease: A meta-analysis
of randomized controlled trials
Y.T. Wen a,1, J.H. Dai b,1, Q. Gao a,*
a
Center for Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
b
Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China

Received 31 August 2013; received in revised form 10 December 2013; accepted 11 December 2013
Available online 25 December 2013

KEYWORDS Abstract Aim: There is considerable discrepancy regarding the protective effects of Omega-3
Coronary heart polyunsaturated fatty acids (Omega-3 PUFAs) in patients with coronary heart disease (CHD) from
disease; the early-phase clinical randomized controlled trials (RCTs). We conducted a meta-analysis of
Major cardiovascular RCTs to address this issue.
events; Data synthesis: Pubmed, the Cochrane Central Register of Controlled Trials, and EMBASE data-
Meta-analysis; bases (wMay 2013) were systematically searched. Odds ratios (OR) and associated 95% CI were
Omega-3 retrieved by using random-effect model according to heterogeneity. A total of 14 RCTs involving
polyunsaturated fatty 16,338 individuals in the Omega-3 PUFAs group and 16,318 in the control group were identified.
acids; Patients assigned to Omega-3 PUFAs did not demonstrate satisfactory improvements on major
cardiovascular events (OR, 0.93; 95% CI, 0.86 to 1.01; P Z 0.08; I2 Z 46%). By contrast, the
Randomized
reduced risks of death from cardiac causes, sudden cardiac death and death from all causes
controlled trials
(OR, 0.88; 95% CI, 0.80 to 0.96; P Z 0.003; I2 Z 0%; OR, 0.86; 95% CI, 0.76 to 0.98; P Z 0.03;
I2 Z 29%; and OR, 0.92; 95% CI, 0.85 to 0.99; P Z 0.02; I2 Z 6%; respectively) were shown.
Conclusions: Supplement of Omega-3 PUFAs in patients with CHD is not associated with a protec-
tive effect on major cardiovascular events, while it does exert beneficial effects in reducing death
from cardiac causes, sudden cardiac death and death from all causes. However, with currently
available cardio-protective therapies, whether dietary supplementation with Omega-3 PUFAs
should be still considered in patients with CHD is currently debated.
ª 2013 Elsevier B.V. All rights reserved.

Introduction community, and has been long recommended by health

Intake of long chain Omega-3 polyunsaturated fatty acids
(Omega-3 PUFAs) derived from marine sources, including
eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA) [1], is widely consumed as supplements within the
* Corresponding author. Center of Translational Medicine, Nanjing
University Medical School, 22 Hankou Road, Nanjing 210093, China.
Tel./fax: þ86 25 83595103.
E-mail addresses: qian_gao@nju.edu.cn, gaoqiannju@hotmail.com
(Q. Gao).
1
These two authors contributed equally to this paper.
authorities to provide cardiovascular protection for the
management of patients with coronary heart disease
(CHD). For example, World Health Organization recom-
mended an adequate intake of PUFAs in the range 6e10%
of daily energy intake for patients with cardiovascular
diseases (CVD) [2]. American Heart Association recom-
mended w1 g of EPA and DHA (combined) per day for
patients with documented CHD [3]. These recommenda-
tions were made on the basis of numerous large ran-
domized controlled trials (RCTs) demonstrating that
Omega-3 PUFAs supplementation leads to a marked

0939-4753/$ - see front matter ª 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.numecd.2013.12.004
Effects of Omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease
reduction in cardiovascular events and mortality in diverse
patient populations [4e6]. By contrast, some large RCTs
reported no additional protection provided by Omega-3
PUFAs application over guideline-adjusted treatment in
patients with myocardial infarction (MI) or at high risk
for CVD [7e9]. The conflicting findings reported added
notable controversy to the common belief of Omega-3
PUFAs supplement in the management of CHD.
Given the inconsistency of prior trials assessing the
potential impact of Omega-3 PUFAs on clinical outcomes,
in the present study, we performed a meta-analysis of
RCTs to analyze the effects of Omega-3 PUFAs in prevent-
ing major cardiovascular events and mortality compared
with controls in patients with CHD.
Methods
Literature search and including criteria
Pubmed, the Cochrane Central Register of Controlled Tri-
als, and EMBASE databases (from inception to May 2013)
were systematically searched for relative RCTs. Search al-
gorithm was “(Omega 3 OR PUFA OR fish oil OR marine oil
OR cod liver oil OR n-3 fatty acid OR polyunsaturated fatty
acid OR eicosapentaenoic acid OR docosahexaenoic acid
OR EPA OR DHA) AND (cardiac death OR coronary heart
disease OR heart disease OR myocardial infarction OR
angina OR heart failure OR cardiovascular disease) AND
(random*)” following database-appropriate terms. The
reference lists and related links of retrieved articles were
also examined for studies potentially eligible for inclusion.
Inclusion criteria were: a) prospective RCTs published in
English; b) Omega-3 PUFAs or placebo orally administered
through supplements for patients with ischemic CHD
(including established atherosclerosis in native coronary
arteries, angina, CAD, MI and ischemic heart failure (HF));
c) Omega-3 PUFAs dosing duration >4 weeks; and d)
reporting safety or cardiovascular events during follow-up.
Although plant-derived a-linolenic acid (ALA) can be
enzymatically converted to EPA and DHA in human, the
process is inefficient (as low as 0.04%e2.84%) [10]. As a
result, trials using ALA was excluded. Studies using diet
supplements of fish were excluded, too. Studies pertained
to patients with other cardiovascular diseases such as
stroke, arrhythmias and non-ischemic heart failure were
excluded. When there were several reports conducting the
same patients’ population at different follow-up periods,
the longest follow-up was retained.
Data extraction and quality assessment
Study selection, data extraction, and quality assessment
were completed in duplicate and independently by two
reviewers (Y. W. and J. D.) by using a standardized proto-
col. In the case of disagreement, a third reviewer inde-
pendently assessed the data for consensus. Serious
cardiovascular events (such as cardiac death, recurrent
myocardial infarction, additional coronary revasculariza-
tion procedures, and stroke) and neoplasm during follow-
471
up were collected. Methodological quality of the included
studies and the risk of bias conferred were evaluated.
Statistical analysis
All data were analyzed by using RevMan software version
5 (Cochrane Collaboration, 2011) and Stata software
version 12.0 (Stata Corporation, College Station, TX). The
primary outcomes examined were major cardiovascular
events (comprising fatal and nonfatal cardiovascular
events and the cardiac interventions percutaneous coro-
nary intervention and coronary-artery bypass grafting).
The secondary outcomes were all cause mortality, sudden
cardiac death and death from cardiac causes. As dichoto-
mous results, Odds ratios (OR) and their associated 95%
confidence interval (CI) were retrieved. The extent of the
observed heterogeneity was explored by using I2 (a value
of 0% indicates limited heterogeneity, and larger values
demonstrate increasing heterogeneity). A random-effect
model was chosen for analysis in the case of significant
heterogeneity among trials (I2  50%, P < 0.1) [11]. Planned
subgroup analyses according to the severity of CHD (MI vs.
coronary atherosclerosis), Omega-3 PUFAs dosage (1 g/
d vs. > 1 g/d) and duration (<2 y vs. > 2 y) were conducted
for treatment subgroup interactions by using random-
effect model. The sensitivity analysis was done by
excluding one trial at a time. The presence of publication
bias was assessed by visual examination of Funnel plots of
the primary outcome and quantified by the Begg’s and
Egger’s Tests (on outcomes which were reported in over 9
RCTs). P values equal or less than 0.05 were considered to
be statistically significant.
Results
Study characteristics and quality assessment
The flow diagram of article selection was shown in Fig. 1.
14 RCTs [4e8,12e20] were included in the meta-analysis,
comprising a total of 16,338 individuals in the Omega-3
PUFAs group and 16,318 in the placebo one
(Supplementary Table 1). Patients treated in these RCTs
had CHD such as CAD, AMI, post-MI and heart failure, etc.
2 of these 14 studies supplied the Omega-3 PUFAs or
placebo for less than 3 months [12,14], 3 for 6 months
[13,15,16], and the other 9 for more than 1 year
[4e8,17e20]. The longest treatment duration was 4.6 years
[6]. The comparison arms of the included trials got regular
medical therapy with/without placebos such as corn oil,
soybean oil, olive oil, oleic acid and aluminum hydroxide,
etc. Notably, there were RCTs with relatively small sample
sizes (range, 59e551 patients) [11e20] and relatively big
ones (range, 3664e11,324 patients) [4e8]. The character-
istics and the primary endpoint/outcomes of the studies
included in meta-analysis are shown in Supplementary
Table 1.
Of the 14 trials included (Supplementary Table 1), two
trials [4,7] are a four-arm comparison. One [7] compared
Omega-3 PUFAs and/or plant-derived alpha-linolenic acid
472
Figure 1 Flow diagram of article selection. RCT, randomized
controlled trial.
(ALA) with control, the other [4] compared Omega-3
PUFAs and/or Vitamin E with placebo. To be included in
the analysis, these 2 RCTs were stratified into arms with/
without Omega-3 PUFAs as the original RCTs did in their
results.
The methodological quality of the RCTs included was
described in Supplementary Table 2. All the 14 RCTs ran-
domized their participants, but only 9 described an
adequate method of generating randomized sequences,
and 6 of them failed to describe allocation concealment.
All the 14 trials blinded outcome assessors and reported
details of withdrawn patients.
Effect of Omega-3 PUFAs supplement on major
cardiovascular events and deaths
Compared with controls, patients assigned to Omega-3
PUFAs demonstrated a trend of improvements on major
cardiovascular events during follow-up, but without sta-
tistical significance (OR, 0.93; 95% CI, 0.86 to 1.01;
P Z 0.08; I2 Z 46%) (Fig. 2A). Overall, compared with
placebo, Omega-3 PUFAs supplementation significantly
associated with reduced risks of death from cardiac causes
(OR, 0.88; 95% CI, 0.80 to 0.96; P Z 0.003; I2 Z 0%),
reduced sudden cardiac death (OR, 0.86; 95% CI, 0.76 to
0.98; P Z 0.03; I2 Z 29%), and reduced death from all
causes (OR, 0.92; 95% CI, 0.85 to 0.99; P Z 0.02; I2 Z 6%)
(Fig. 2BeD).
Among these major cardiovascular events occurred in
those trials during follow-up, Omega-3 PUFAs supple-
mentation significantly reduced the incidence of MI (OR,
Y.T. Wen et al.
0.85; 95% CI, 0.73 to 1.00; P Z 0.04; I2 Z 13%), but had no
effects on the incidence of revascularization (OR, 0.91; 95%
CI, 0.81 to 1.02; P Z 0.11; I2 Z 0%), unstable angina (OR,
0.63; 95% CI, 0.36 to 1.11; P Z 0.11; I2 Z 71%) and stroke
(OR, 1.21; 95% CI, 0.99 to 1.47; P Z 0.07; I2 Z 0%)
(Fig. 3AeD). When including the 4 trials [4,5,8,20]
reporting neoplasm, there was no obvious evidence that
Omega-3 PUFAs supplement increased the risk of tumor-
igenesis (OR, 1.05; 95% CI, 0.89 to 1.25; P Z 0.55; I2 Z 28%)
(Fig. 3E).
Subgroup analysis
To evaluate the influence of CHD severity on the effects of
Omega-3 PUFAs supplement, trials were firstly divided
into two subgroups according to clinical scenario: com-
parisons that treated patients with coronary atheroscle-
rosis and comparisons that did those with MI (Table 1).
And then the efficacy of Omega-3 PUFAs supplement on
incidence of major cardiovascular events in CHD patients
was then discussed with Omega-3 PUFAs given in different
dosage (1 g/d vs. >1 g/d) and duration (<2 years vs. >2
years) (Table 1). Test of interaction showed significance for
the subgroup differences according to clinical scenario
(P Z 0.05) and Omega-3 PUFAs’ dosage (P Z 0.03), but not
significant according to duration of Omega-3 PUFAs’ usage
(P Z 0.74).
In separate analysis, the incidence of major cardiovas-
cular events was reduced in patients with coronary
atherosclerosis after Omega-3 PUFAs supplement (OR,
0.49; 95% CI, 0.25 to 0.96; P Z 0.04; I2 Z 0%), while it was
not statistically reduced in those with MI (OR, 0.98; 95% CI,
0.84 to 1.15; P Z 0.85; I2 Z 55%) (Table 1). We extracted
data with higher Omega-3 dosage (>1 g/d), which showed
a significantly reduced incidence of major cardiovascular
events (OR, 0.78; 95% CI, 0.65 to 0.93; P Z 0.006; I2 Z 0%).
Meta-analysis of the trials applying lower Omega-3 dosage
(1 g/d) did not substantially change this estimate (1.01,
0.86e1.20) (Table 1). The benefits of Omega-3 supple-
mentation were similar in patients who got less or more
than 2 years treatment, although the incidence of major
cardiovascular events was reduced in the latter, although
did not reach statistical significance (Table 1).
Sensitivity analysis and publication bias
By excluding one trial at a time and computing meta-
analysis estimates for the remaining studies, it showed
that exclusion of the Alpha Omega Trial [7] or the Omega
Trial [8] led to the statistical reduction of major cardio-
vascular events, suggesting the high weight of these
studies. After visual inspections of funnel plots of major
cardiovascular events (the primary outcome), there was no
obvious evidence to suggest the presentence of publication
bias (Supplementary Fig. 1). Both the Begg’s and Egger’s
Tests of the outcomes such as major cardiovascular events
(the primary outcome), death from cardiac causes, all
death and MI, also showed no publication bias among the
analyzed studies (Supplementary Table 3).
Effects of Omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease 473

Figure 2 Forest plot of odds ratio (OR), with 95% confidence interval (CI) on (A) major cardiovascular events; (B) death from cardiac causes; (C)
sudden cardiac death; and (D) death from all causes in patients with coronary heart disease treated with Omega-3 polyunsaturated fatty acids
compared with controls.

Discussion effect of Omega-3 PUFAs. However, all these previous

The biological effects of Omega-3 PUFAs in CHD and its
complications are wide ranging, including effects on lipids,
blood pressure, cardiac and vascular function, prostanoids,
concoagulation and immunological responses [21,22]. The
recent published meta-analysis on Omega-3 PUFAs mainly
included populations with cardiovascular risk factors or
atherosclerotic vascular disease, instead of documental
CHD. In a meta-analysis implemented in primary or sec-
ondary CVD prevention settings [23], Omega-3 PUFAs
supplementation was not associated with a lower risk of
all-cause mortality, cardiac death, sudden death, myocar-
dial infarction, or stroke based on relative and absolute
measures of association. When including a diverse group
of populations with CAD, AMI, implantable cardiac defi-
brillation (ICD), and hypercholesterolaemia [24], supple-
ment with Omega-3 PUFAs was associated with a
significant reduction in deaths from cardiac causes but had
no effect on arrhythmias or all cause mortality. In two
meta-analyses [25,26] of patients with CVD including CHD,
lower limb atherosclerosis, ICD, stroke and hyper-
cholesterolaemia, there was discrepancy on the protective
meta-analysis targeted on either populations with car-
diovascular risk factors or patients with all kinds of
atherosclerotic vascular disease. These combined types of
participants or condition may result in potential statistical
heterogeneity. In this study, we have limited our analysis
to documental CHD and have evaluated the importance of
early usage of Omega-3 PUFAs at the stage of coronary
atherosclerosis, before MI and HF, on the risk of major
cardiovascular events.
An impressive feature indicated by our meta-analysis is
that Omega-3 PUFAs supplements in patients with CHD is
associated with a significant reduction of the risks of death
from cardiac causes, sudden cardiac death and death from
all causes. Although there is insufficient evidence of a
preventive effect of Omega-3 PUFAs supplements against
major cardiovascular events in patients with CHD, sub-
group analysis demonstrates a reduced incidence of major
cardiovascular events in the setting of coronary athero-
sclerosis. This underlines the fact that Omega-3 PUFAs
supplements should primarily focus on patients with less
severe CHD such as coronary atherosclerosis; however,
cautions in interpretation are required because of the

Figure 3 Forest plot of Odds Ratio with 95% confidence interval (CI) in (A) myocardial infarction, (B) revascularization, (C) unstable angina, (D)
stroke, and (E) neoplasm in patients with coronary heart disease treated with Omega-3 polyunsaturated fatty acids compared with controls.
474
Table 1 Subgroup analysis examining the impact of Omega-3 PUFAs supplement on the incidence of major cardiovascular events compared with
controls.
Subgroup Number of RCTs
Clinical scenario
Myocardial infarction 6 [5,7,8,14,17,19]
Coronary atherosclerosis 4 [12,16,18,20]
Supplement duration
<2 y 5 [8,12,14,16,19]
>2 y 6 [4,6,7,17,18,20]
Omega-3 PUFAs dosage
1 g/d 4 [4,7,8,14]
>1 g/d 7 [6,12,16e20]
Abbreviations; CI, confidence interval; PUFAs, polyunsaturated fatty acids; RCT, randomized controlled trial.
a
With statistical difference.
small sample size in the 4 RCTs conducting this patients’
population [12,16,18,20]. It seemed Omega-3 PUFAs had no
effects on the incidence of unstable angina and stroke; but
this conclusion was based on the limited trials included (4
RCTs reporting unstable angina and 2 reporting stroke). A
more robust outcome should be incorporated in future
trials with larger sample size.
In our study, it showed that exclusion of the Alpha
Omega Trial [7] or the Omega Trial [8] led to the statistical
reduction of major cardiovascular events when computing
meta-analysis estimates for the remaining studies. For the
Alpha Omega Trial [7], on one hand, it enrolled patients
with diagnosed MI of median 3.7 y. During this period, the
patients received sustained anti-MI therapy. On the other
hand, it should be pointed out that the patients in this trial
only took approximately 400 mg of EPAeDHA every day,
which was the lowest dosage of Omega-3 PUFAs supple-
ment among the 14 RCTs enrolled in our meta-analysis.
For the Omega Trial [8], the patients with AMI received
considerably improved guideline-adjusted therapy
compared to the previous ones. These characters of the
single trial may be important for several reasons. Firstly,
the discrepancy among the findings of the Alpha Omega
Trial, the Omega Trial and the previous ones may be
comprehensible, which is in consistent with the hypoth-
esis that Omega-3 PUFAs may not have large benefits in
patients receiving modern medical and interventional
therapies [27,28]. In this circumstance, with contemporary
cardioprotective therapies, whether Omega-3 PUFAs sup-
plementation is still worthy recommendation to further
improve CHD prognosis is debatable. Secondly, dosage and
supplement duration are also an important determinant of
patient outcome. Higher doses of Omega-3 PUFAs (for
example, 2e4 g EPA þ DHA/day) provide cardiovascular
benefit on longer treatment duration [29e31]. Our sub-
group analysis also provided evidence of a more signifi-
cant reduction of major cardiovascular events in patients
who got >1 g/d Omega-3 PUFAs; while longer supple-
mentary duration (>2 years) did not show a more pro-
nounced benefit than a shorter one (<2 years). It is
conceivable that, patients with less severe CHD such as
coronary atherosclerosis might especially profit from
Y.T. Wen et al.
Major cardiovascular events
OR (95% CI, %) P I2, % P for subgroup
differences
0.98 (0.84, 1.15) 0.85 55 0.05a
0.49 (0.25, 0.96) 0.04a 0
0.82 (0.47, 1.42) 0.48 60 0.74
0.90 (0.80, 1.02) 0.11 28
1.01 (0.86, 1.20) 0.88 67 0.03a
0.78 (0.65, 0.93) 0.006a 0
therapy with higher Omega-3 PUFAs’ dosage. On the basis
of the above considerations, further large RCTs with pro-
tocols integrate lessons learned from the first wave of
trials are warranted.
Omega-3 PUFAs supplement is relatively safe in the 14
RCTs included. Miscellaneous adverse events were found
during follow-up, mostly mild gastrointestinal discomfort,
prolonged bleeding, diarrhea or nausea, infections and
allergic reaction. Their frequency did not differ signifi-
cantly between groups. The OMEGA trial reported slightly
higher incidence of neoplasm in the treatment group [8].
There were concerns about the association between high
intake of ALA and prostate cancer [32]. However, as to the
Omega-3 PUFAs, there are even indications that it may
protect against a range of cancer types such as prostate
cancer and colorectal cancer [33e36]. Pooled data from
the 4 trials [4,5,8,20] reporting neoplasm did not support
the tumorigenesis potential of the Omega-3 PUFAs. How-
ever, based on the limited RCTs focusing on neoplasm,
special attentions on long-term safety are still warranted
in the future epidemiologic studies.
In conclusion, our meta-analysis indicates that supple-
ment of Omega-3 PUFAs in patients with CHD is not
associated with a protective effect on major cardiovascular
events, probably due to the improved cardio-protective
treatment. However, Omega-3 PUFAs exert beneficial ef-
fects in reducing death from cardiac causes, sudden cardiac
death and death from all causes. Several issues remain to
be elucidated in further studies. First, the optimal dosage of
Omega-3 PUFAs, the ratios of DHA to EPA and the supple-
ment duration is yet to be determined. Second, whether
coronary atherosclerosis, MI, or even HF is the target of
Omega-3 PUFAs is still under discussion. Last but not least,
when receiving contemporary cardio-protective therapies,
are Omega-3 PUFAs still worthy recommendation for pa-
tients with CHD? The final word is being waiting.
Fundings
This work was supported by the National Natural Science
Foundation of China (81100386, 81030013), the New
Teachers’ Fund for Doctor Stations, Ministry of Education
Effects of Omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease
of China (20110091120031), and the National Ministry of
Science and Technology (2009CB918704).
Competing interests
The authors state no conflict of interest.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.numecd.2013.12.004.
References
[1] Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the
anti-inflammatory potential of long-chain omega-3 fatty acids.
Nutr Rev 2010;68:280e9.
[2] World Health Organization. Diet, nutrition and the prevention of
chronic diseases. Report of the Joint WHO/FAO Expert Consulta-
tion; 2013 [accessed 23.06.13], http://www.who.int/
dietphysicalactivity/publications/trs916/download/en/.
[3] Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and
cardiovascular disease: new recommendations from the American
Heart Association. Arterioscler Thromb Vasc Biol 2003;23:151e2.
[4] GISSI-Prevenzione Investigators. Dietary supplementation with n-
3 polyunsaturated fatty acids and vitamin E after myocardial
infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano
per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet
1999;354:447e55.
[5] Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG,
Latini R, et al. Effect of n-3 polyunsaturated fatty acids in patients
with chronic heart failure (the GISSI-HF trial): a randomised,
double-blind, placebo-controlled trial. Lancet 2008;372:1223e30.
[6] Matsuzaki M, Yokoyama M, Saito Y, Origasa H, Ishikawa Y,
Oikawa S, et al. Incremental effects of eicosapentaenoic acid on
cardiovascular events in statin-treated patients with coronary
artery disease. Circ J 2009;73:1283e90.
[7] Kromhout D, Giltay EJ, Geleijnse JM. n-3 fatty acids and cardio-
vascular events after myocardial infarction. N Engl J Med 2010;
363:2015e26.
[8] Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, et al.
OMEGA, a randomized, placebo-controlled trial to test the effect of
highly purified omega-3 fatty acids on top of modern guideline-
adjusted therapy after myocardial infarction. Circulation 2010;122:
2152e9.
[9] Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, et al. n-3
fatty acids and cardiovascular outcomes in patients with dysgly-
cemia. N Engl J Med 2012;367:309e18.
[10] Burdge GC, Finnegan YE, Minihane AM, Williams CM, Wootton SA.
Effect of altered dietary n-3 fatty acid intake upon plasma lipid
fatty acid composition, conversion of [13C]alpha-linolenic acid to
longer-chain fatty acids and partitioning towards beta-oxidation
in older men. Br J Nutr 2003;90:311e21.
[11] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring incon-
sistency in meta-analyses. BMJ 2003;327:557e60.
[12] Carney RM, Freedland KE, Rubin EH, Rich MW, Steinmeyer BC,
Harris WS. Omega-3 augmentation of sertraline in treatment of
depression in patients with coronary heart disease: a randomized
controlled trial. J Am Med Assoc 2009;302:1651e7.
[13] Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K,
Khan MA, et al. An omega-3 polyunsaturated fatty acid concen-
trate administered for one year decreased triglycerides in simva-
statin treated patients with coronary heart disease and persisting
hypertriglyceridaemia. Heart 2001;85:544e8.
[14] Gajos G, Rostoff P, Undas A, Piwowarska W. Effects of poly-
unsaturated omega-3 fatty acids on responsiveness to dual anti-
platelet therapy in patients undergoing percutaneous coronary
intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to
modify responsiveness to dual antiplatelet therapy) study. J Am
Coll Cardiol 2010;55:1671e8.
475
[15] Johansen O, Brekke M, Seljeflot I, Abdelnoor M, Arnesen H. N-3
fatty acids do not prevent restenosis after coronary angioplasty:
results from the CART study. Coronary Angioplasty Restenosis
Trial. J Am Coll Cardiol 1999;33:1619e26.
[16] Leaf A, Jorgensen MB, Jacobs AK, Cote G, Schoenfeld DA, Scheer J,
et al. Do fish oils prevent restenosis after coronary angioplasty?
Circulation 1994;90:2248e57.
[17] Nilsen DW, Albrektsen G, Landmark K, Moen S, Aarsland T, Woie L.
Effects of a high-dose concentrate of n-3 fatty acids or corn oil
introduced early after an acute myocardial infarction on serum
triacylglycerol and HDL cholesterol. Am J Clin Nutr 2001;74:50e6.
[18] Sacks FM, Stone PH, Gibson CM, Silverman DI, Rosner B,
Pasternak RC. Controlled trial of fish oil for regression of human
coronary atherosclerosis. HARP Research Group. J Am Coll Cardiol
1995;25:1492e8.
[19] Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M.
Randomized, double-blind, placebo-controlled trial of fish oil and
mustard oil in patients with suspected acute myocardial infarc-
tion: the Indian experiment of infarct survivale4. Cardiovasc
Drugs Ther 1997;11:485e91.
[20] von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H. The
effect of dietary omega-3 fatty acids on coronary atherosclerosis. A
randomized, double-blind, placebo-controlled trial. Ann Intern
Med 1999;130:554e62.
[21] Mori TA, Beilin LJ. Long-chain omega 3 fatty acids, blood lipids and
cardiovascular risk reduction. Curr Opin Lipidol 2001;12:11e7.
[22] Kromhout D, Yasuda S, Geleijnse JM, Shimokawa H. Fish oil and
omega-3 fatty acids in cardiovascular disease: do they really
work? Eur Heart J 2012;33:436e43.
[23] Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association
between omega-3 fatty acid supplementation and risk of major
cardiovascular disease events: a systematic review and meta-
analysis. J Am Med Assoc 2012;308:1024e33.
[24] Leon H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T,
Tsuyuki RT. Effect of fish oil on arrhythmias and mortality: sys-
tematic review. BMJ 2008;337:a2931.
[25] Kwak SM, Myung SK, Lee YJ, Seo HG. Efficacy of omega-3 fatty acid
supplements (eicosapentaenoic acid and docosahexaenoic acid) in
the secondary prevention of cardiovascular disease: a meta-
analysis of randomized, double-blind, placebo-controlled trials.
Arch Intern Med 2012;172:686e94.
[26] Marik PE, Varon J. Omega-3 dietary supplements and the risk of
cardiovascular events: a systematic review. Clin Cardiol 2009;32:
365e72.
[27] Ferrari R. Revising common beliefs in the management of stable
CAD. Nat Rev 2013;10:65e6.
[28] Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular
disease: effects on risk factors, molecular pathways, and clinical
events. J Am Coll Cardiol 2011;58:2047e67.
[29] Laufs U, Schirmer SH. Margarines supplemented with low dose n-
3 fatty acids are not effective in secondary prevention. Eur Heart J
2012;33:1555e7.
[30] Christensen JH, Christensen MS, Dyerberg J, Schmidt EB. Heart rate
variability and fatty acid content of blood cell membranes: a dose-
response study with n-3 fatty acids. Am J Clin Nutr 1999;70:331e7.
[31] Mozaffarian D, Geelen A, Brouwer IA, Geleijnse JM, Zock PL,
Katan MB. Effect of fish oil on heart rate in humans: a meta-
analysis of randomized controlled trials. Circulation 2005;112:
1945e52.
[32] Brouwer IA, Katan MB, Zock PL. Dietary alpha-linolenic acid is
associated with reduced risk of fatal coronary heart disease, but
increased prostate cancer risk: a meta-analysis. J Nutr 2004;134:
919e22.
[33] Augustsson K, Michaud DS, Rimm EB, Leitzmann MF, Stampfer MJ,
Willett WC, et al. A prospective study of intake of fish and marine
fatty acids and prostate cancer. Cancer Epidemiol Biomarkers Prev
2003;12:64e7.
[34] Fabian CJ, Kimler BF. Marine-derived omega-3 fatty acids. Am Soc
Clin Oncol Educ Book 2013;2013:97e101.
[35] Cockbain AJ, Toogood GJ, Hull MA. Omega-3 polyunsaturated fatty
acids for the treatment and prevention of colorectal cancer. Gut
2012;61:135e49.
[36] Vaughan VC, Hassing MR, Lewandowski PA. Marine poly-
unsaturated fatty acids and cancer therapy. Br J Cancer 2013;108:
486e92.