Drugs 2009; 69 (8): 1077-1105

ADIS DRUG EVALUATION 0012-6667/09/0008-1077/$55.55/0

ª 2009 Adis Data Information BV. All rights reserved.

Omega-3 Ethylester Concentrate

A Review of its Use in Secondary Prevention
Post-Myocardial Infarction and the Treatment
of Hypertriglyceridaemia
Sheridan M. Hoy and Gillian M. Keating
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health,
Philadelphia, Pennsylvania, USA

Various sections of the manuscript reviewed by:

H.E. Bays, Louisville Metabolic and Atherosclerosis Research Center (L-MARC), Louisville, Kentucky, USA;
M.H. Davidson, Radiant Research, Chicago, Illinois, USA; R. Marchioli, Laboratory of Clinical Epidemiology
of Cardiovascular Disease, Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri
Sud, Santa Maria Imbaro, Italy; C. Von Schacky, Preventive Cardiology, Medizinische Klinik and Poliklinik
Innenstadt, University of Munich, Munich, Germany.

Data Selection
Sources: Medical literature published in any language since 1980 on ‘omega-3 ethylester’, identified using MEDLINE and EMBASE,
supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the
reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the
company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘omega-3 ethylester concentrate’ or ‘omega-3 acid ethyl esters’
or ‘Omacor’. Searches were last updated 22 May 2009.
Selection: Studies in patients with hypertriglyceridaemia or those with (or at risk of) myocardial infarction who received omega-3
ethylester concentrate. Inclusion of studies was based mainly on the methods section of the studies. When available, large, well controlled
studies with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Omega-3 ethylester concentrate, hypertriglyceridaemia, myocardial infarction, pharmacodynamics, pharmacoeconomics,
pharmacokinetics, therapeutic use, tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081
2.1 Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081
2.2 Effects on Lipid Levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082
2.3 Cardiovascular Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
2.4 Effects on Thrombosis and Haemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
2.5 Anti-Atherogenic and Anti-Inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
4.1 In Secondary Prevention Post-Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
4.1.1 Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
4.2 In the Treatment of Hypertriglyceridaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091
4.2.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092
4.2.2 In Combination with Simvastatin or Atorvastatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
1078 Hoy & Keating

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
7. Place of Omega-3 Ethylester Concentrate in Secondary Prevention Post-Myocardial Infarction
and the Treatment of Hypertriglyceridaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097

Summary
Abstract Oral omega-3 ethylester concentrate (omega-3 EEC) [Omacor; Lovaza] is in-
dicated as an adjuvant therapy in adult patients for secondary prevention post-
myocardial infarction (MI) and the treatment of hypertriglyceridaemia in the
majority of European countries, and for the treatment of hypertriglyceridaemia
(serum triglyceride levels ‡5.6 mmol/L [‡500 mg/dL]) in the US. Each 1000 mg
capsule of omega-3 EEC consists of 460 mg of ethyl eicosapentaenoic acid and
380 mg of ethyl docosahexaenoic acid.
The addition of omega-3 EEC 1000 mg/day to standard medical therapy in the
GISSI-Prevenzione study provided secondary prevention benefits in post-MI
adult patients. The benefits were attributable to reductions in death and cardio-
vascular death (including sudden death). Additional data examining the extent
and mechanisms of the cardiovascular benefit conferred by omega-3 EEC in
secondary prevention would be useful. As an adjunct to diet, monotherapy with
omega-3 EEC 4000 mg/day significantly reduced triglyceride levels in patients
with hypertriglyceridaemia, although limited data suggest it was less effective
than gemfibrozil. In addition, omega-3 EEC 4000 mg/day plus simvastatin
or atorvastatin reduced triglyceride, non-high-density lipoprotein cholesterol
(non-HDL-C) and/or very-low-density lipoprotein cholesterol (VLDL-C) levels
to a significantly greater extent than placebo plus simvastatin or atorvastatin.
Omega-3 EEC was generally well tolerated both as secondary prevention
post-MI and in the treatment of hypertriglyceridaemia. Thus, omega-3 EEC is
a useful option both in secondary prevention post-MI and the treatment of
hypertriglyceridaemia.
Pharmacological The proposed mechanisms of action for the triglyceride-lowering effects observed
Properties with omega-3 EEC are inhibition of acyl CoA:1,2-diacylglycerol acyltransferase
and elevation in hepatic peroxisomal b-oxidation, with upregulation of fatty acid
metabolism in the liver. Omega-3 fatty acids may also inhibit the secretion of
triglyceride-rich VLDL-C, increase the removal of triglycerides from circulating
VLDL and chylomicron particles via the upregulation of enzymes such as lipo-
protein lipase, and affect other nuclear receptors involved in the modulation of
triglyceride levels.
Various mechanisms have been proposed to explain the secondary preventive
effect of omega-3 EEC in patients with recent MI, including cardiovascular
effects, effects on thrombosis and haemostasis and antiatherogenic and anti-
inflammatory effects. The cardiovascular effects include reduced blood pressure
and heart rate, and antiarrhythmic effects (proposed mechanisms include
increased antiarrhythmic thresholds, effects on ion channels and effects on auto-
nomic balance) and augmentation of autonomic tone, both of which may
contribute to the reduced risk of sudden cardiac death seen in patients with recent
MI who received omega-3 EEC in the GISSI-Prevenzione study.

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review
Therapeutic Efficacy
ª 2009 Adis Data Information BV. All rights reserved.
1079
Antithrombotic effects have also been observed with omega-3 fatty acids, and
although omega-3 EEC does not appear to affect bleeding time, patients receiving
anticoagulant therapy and omega-3 EEC should be monitored and the anti-
coagulant dosage adjusted as necessary.
The effect of omega-3 EEC on the prevention of restenosis is equivocal; how-
ever, the drug may improve plaque stability. Omega-3 EEC appears to reduce the
levels of various markers of inflammation, including messenger RNA levels for a
number of matrix metalloproteinases and intercellular adhesion molecule-1, the
gene expression of platelet-derived growth factor-A and -B, endotoxin-stimulated
tumour necrosis factor-a production and reduce soluble E-selectin levels. In
general, omega-3 fatty acids did not affect C-reactive protein or interleukin-6
levels.
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are absorbed
following their oral administration as ethylesters to healthy volunteers and pa-
tients with hypertriglyceridaemia, with subsequent dose-dependent elevations in
plasma phospholipid EPA and DHA content. Age (<49 vs ‡49 years) did not
affect the uptake of EPA and DHA into serum phospholipids in omega-3 EEC
recipients, although the uptake of EPA in serum phospholipids tended to be
greater in women than in men.
Oral omega-3 EEC 1000 mg/day, as an adjuvant therapy to standard treatment
(e.g. ACE inhibitors, antiplatelet agents, b-adrenergic receptor antagonists,
HMG-CoA reductase inhibitors), demonstrated a secondary preventive effect in
patients with recent (<3 months) MI in the 42-month, randomized, nonblind
(endpoints validated by a blinded assessment committee), multicentre GISSI-
Prevenzione study. Omega-3 EEC-based therapy (omega-3 EEC 1000 mg/day and
omega-3 EEC 1000 mg/day plus tocopherol groups) significantly reduced the risk
of a primary composite efficacy endpoint (death plus nonfatal MI plus nonfatal
stroke) and various secondary or other endpoints (including death, cardiovas-
cular death and sudden death) versus non-omega-3 EEC-based therapy (the
tocopherol monotherapy and no treatment groups) in a two-way analysis of data.
Significant reductions versus control in the risk of death plus nonfatal MI plus
nonfatal stroke with omega-3 EEC monotherapy and omega-3 EEC plus toco-
pherol therapy, and in the risk of cardiovascular death plus nonfatal MI plus
nonfatal stroke with omega-3 EEC monotherapy were also demonstrated in a
four-way analysis. For the most part, omega-3 EEC therapy, with or without
tocopherol, and tocopherol monotherapy were significantly more effective than
no treatment in terms of secondary endpoints, with significant reductions
(of 20–45%) in the relative risk of various secondary endpoints observed across all
three active therapy groups versus no treatment.
According to preliminary data from the 12-month, randomized, double-blind,
placebo-controlled, multicentre OMEGA study, no significant difference in
the incidence of sudden cardiac death (primary endpoint) and the various sec-
ondary endpoints was observed between the omega-3 EEC and placebo groups in
patients with recent (3–14 days) MI. Of note, the observed incidence of sudden
cardiac death in both the omega-3 EEC and placebo groups was lower than
anticipated.
Data from a limited number of studies indicated that omega-3 EEC plus
standard therapy was predicted to be cost effective in secondary prevention post-
Drugs 2009; 69 (8)
1080 Hoy & Keating

MI relative to standard therapy in terms of cost per life-year or quality-adjusted

life-year gained.
Oral omega-3 EEC 4000 mg/day, as monotherapy or in combination with
simvastatin or atorvastatin, was generally effective as an adjunct to diet in
the treatment of hypertriglyceridaemia in adult patients. For the most part,
omega-3 EEC monotherapy demonstrated significantly greater reductions
from baseline than placebo in triglyceride, total cholesterol and VLDL-C levels,
and significantly greater elevations from baseline in HDL-C levels in a well
designed study. In contrast, significant elevations in low-density lipoprotein
cholesterol levels were observed in omega-3 EEC monotherapy versus placebo
recipients. Limited data suggest oral gemfibrozil was associated with significantly
greater reductions in serum triglyceride levels (primary endpoint) and sig-
nificantly greater increases in HDL-C levels than omega-3 EEC monotherapy.
However, no significant differences in total cholesterol and VLDL-C levels were
observed between the two treatment groups. In general, omega-3 EEC plus sim-
vastatin was an effective lipid-modifying therapy in patients with hypertrigly-
ceridaemia, inducing significantly greater reductions from baseline in triglyceride
and VLDL-C levels than placebo plus simvastatin in two well designed clinical
studies. In one study, the primary endpoint of non-HDL-C levels was reduced
by a significantly greater extent with omega-3 EEC plus simvastatin than with
placebo plus simvastatin. For the most part, improvements in the lipid profiles
of patients with hypertriglyceridaemia observed in the 24-week, double-blind
phase of one study were sustained with continued omega-3 EEC plus simvastatin
therapy in the 24-week, noncomparative extension phase. Preliminary data in-
dicated that omega-3 EEC plus atorvastatin was associated with significantly
greater reductions from baseline in non-HDL-C (primary endpoint), total cho-
lesterol, triglyceride and VLDL-C levels and significantly greater improvements
from baseline in HDL-C levels, than placebo plus atorvastatin in patients with
hypertriglyceridaemia.
Tolerability Oral omega-3 EEC was generally well tolerated by adult patients participating in
five randomized, multicentre studies of up to 42 months’ duration in secondary
prevention post-MI and the treatment of hypertriglyceridaemia. Treatment-
emergent adverse events associated with omega-3 EEC were generally gastro-
intestinal in nature and mild or minor in intensity. In the GISSI-Prevenzione
study, treatment-emergent gastrointestinal disturbances and nausea were ob-
served in 4.9% and 1.4% of patients receiving omega-3 EEC-based therapy, and in
2.9% and 0.4% of patients receiving tocopherol-based therapy (tocopherol
monotherapy and omega-3 EEC plus tocopherol groups). Therapy stopped
because of adverse events in 3.8% and 2.1% of patients in the respective treatment
groups.

1. Introduction yield significant levels of eicosapentaenoic acid

Numerous epidemiological and clinical studies
have corroborated anecdotal evidence of the
benefits of a diet rich in fish on cardiovascular
disease (CVD).[1-5] Certain fish species (e.g. tuna)
(EPA) and docosahexaenoic acid (DHA), two
omega-3 fatty acids with a demonstrable cardio-
protective effect.[2-4,6]
Oral omega-3 ethylester concentrate, hereafter
referred to as omega-3 EEC, comprises the ethyles-

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review
Eicosapentaenoic acid ethylester
H3C
Docosahexaenoic acid ethylester
H3C
Fig. 1. Omega-3 ethylester concentrate.
ters of the omega-3 fatty acids EPA and DHA
(see figure 1).[7] Specifically, each 1000 mg cap-
sule of omega-3 EEC contains approximately
460 mg of the EPA ethylester and 380 mg of the
DHA ethylester.[7] This article reviews the phar-
macological properties of oral omega-3 EEC
(Omacor; Lovaza), focusing on its efficacy
and tolerability in secondary prevention post-
myocardial infarction (MI) and the treatment of
patients with hypertriglyceridaemia. Throughout
this article, lipid levels are reported in mmol/L;
to convert to mg/dL, triglyceride values should
be multiplied by 88.6 and total cholesterol, high-
density lipoprotein cholesterol (HDL-C), low-
density lipoprotein cholesterol (LDL-C) and
very-low-density lipoprotein cholesterol (VLDL-C)
values should be multiplied by 38.7.
2. Pharmacodynamic Properties
There are a plethora of data concerning the
pharmacodynamic effects of omega-3 fatty acids
when consumed as part of the diet or adminis-
tered as supplements.[1,8] This section focuses on
the pharmacodynamic properties of oral omega-3
EEC, where data pertaining to this specific
formulation are available, supplemented with
information relating to omega-3 fatty acids in
general. Studies used various dosages of omega-3
fatty acids; the maximum recommended daily
dose of omega-3 EEC is 4000 mg (section 6).
Apart from one noncomparative study,[9]
clinical studies discussed in this section were
randomized, with the majority double- or single-
blind. All but two studies (which were in healthy
ª 2009 Adis Data Information BV. All rights reserved.
1081
O
O CH3
O CH3
volunteers[10,11]) were conducted in patients with
cardiovascular disorders or hyperlipidaemia.
Most studies included <100 participants and had
a treatment period of £6 months. All but one[12] of
the studies with longer treatment periods (median
356–718 days[12-16] ) enrolled >100 participants.
Studies were fully published except for two ana-
lyses that were available as abstracts.[17,18]
Some of the data concerning the general
pharmacodynamic effects of omega-3 fatty acids
were obtained from large systematic reviews/
meta-analyses[8,19-22] or reviews.[23-31]
2.1 Mechanism of Action
The mechanism of action of omega-3 fatty
acids, including omega-3 EEC, is not fully un-
derstood.[32,33] Two main mechanisms have been
proposed to explain the triglyceride-lowering
effects of omega-3 fatty acids.[33] Firstly, the in-
hibition of acyl CoA:1,2-diacylglycerol acyl-
transferase by omega-3 fatty acids may reduce
the hepatic synthesis of triglycerides.[34] EPA and
DHA have high affinity for the enzymes involved
in triglyceride synthesis, but are poor substrates
for these enzymes.[7,34] Thus, the esterification
and release of other fatty acids is prevented.[7,34]
Secondly, omega-3 fatty acids have high affinity
for peroxisome proliferator-activated receptor
subtypes, thereby increasing hepatic peroxisomal
b-oxidation and upregulating fatty acid metabo-
lism in the liver.[35-37] This reduces the quantity of
free fatty acids available for triglyceride synthesis,
and reduces triglyceride levels; secretion of tri-
glyceride-rich VLDL is also inhibited.[7] Omega-3
Drugs 2009; 69 (8)
1082
fatty acids also affect other nuclear receptors in-
volved in the modulation of triglyceride levels
(e.g. liver X receptor, hepatocyte nuclear factor-
4a and farnesol X receptor)[38] and may increase
the removal of triglycerides from circulating
VLDL and chylomicron particles via the upre-
gulation of enzymes, such as lipoprotein
lipase.[39]
A number of mechanisms have been pro-
posed to explain the secondary preventive ef-
fect of omega-3 EEC in patients with recent MI
(section 4.1). These include cardiovascular effects
(section 2.3), effects on thrombosis and haemo-
stasis (section 2.4) and antiatherogenic and anti-
inflammatory effects (section 2.5).[27]
2.2 Effects on Lipid Levels
The triglyceride-lowering effects of omega-3
fatty acids are well established. Briefly, results
of a systematic review demonstrated dose-
dependent reductions in triglyceride levels with
omega-3 fatty acids in clinical studies; net reduc-
tions in triglyceride levels of 10–33% were seen in
most studies.[8] The effect of omega-3 fatty acids
tended to be greater in studies with higher tri-
glyceride levels at baseline.[8] Changes in total
cholesterol and HDL-C levels were generally not
significant, and small net increases occurred in
LDL-C levels.[8]
These data are supported in part by those
from studies in patients with hypertriglycer-
idaemia,[40-43] familial combined hyperlipidae-
mia[44] or mixed dyslipidaemia.[45] Significant
(p < 0.05 vs baseline and/or placebo) reductions
in plasma or serum triglyceride, total choles-
terol, non-HDL-C, VLDL-C, VLDL-triglyceride
and/or apolipoprotein-B levels, and signifi-
cant (p < 0.05) elevations in plasma or serum
HDL-C and/or LDL-C levels with omega-3 EEC
4000 mg/day, alone[40-44] or in combination with
simvastatin 20 mg/day,[45] were evident. However,
in contrast to a study[46] discussed in section 4.2,
no significant differences in the lipid parameters
measured (plasma triglycerides, total cholesterol,
HDL-C, LDL-C, VLDL-C and VLDL-triglyceride
levels) were observed between omega-3 EEC and
oral gemfibrozil 1200 mg/day.[40] Furthermore,
ª 2009 Adis Data Information BV. All rights reserved.
Hoy & Keating
no significant reductions from baseline in LDL-C
levels were observed between the omega-3 EEC
plus simvastatin 20 mg/day and the placebo plus
simvastatin 20 mg/day treatment groups.[45]
Elevations in LDL-C levels observed with
omega-3 EEC are believed to result from the
conversion of VLDL-C.[47] In a study in 24 obese
patients with dyslipidaemia, therapy with omega-3
EEC 4000 mg/day significantly (p < 0.05) reduced
triglyceride and VLDL-triglyceride levels and
the VLDL-apolipoprotein B production rate
compared with placebo.[48] Furthermore, the
mean conversion rate of VLDL-apolipoprotein B
to intermediate density lipoprotein (IDL)-
apolipoprotein B (from 28.6% to 42.6%) and
LDL-apolipoprotein B (from 22.7% to 39.2%)
and the mean conversion rate of IDL-apolipo-
protein B to LDL-apolipoprotein B (from 82.0%
to 92.9%) were significantly (p < 0.05 vs placebo)
elevated with omega-3 EEC therapy.[48]
The observed increase in LDL-C levels typically
reflects a shift to larger LDL particles, which may
be less atherogenic.[31] The direction of the shift in
LDL particle size seen with omega-3 EEC seemed
to depend on the triglyceride level (threshold
1.13–2.82 mmol/L) in patients with hypertriglycer-
idaemia (triglyceride levels of 2.3–5.6 mmol/L,
despite receiving simvastatin 40 mg/day) who
were randomized to receive omega-3 EEC
4000 mg/day or placebo for 8 weeks.[18] Overall,
median LDL particle size increased to a signifi-
cant extent with omega-3 EEC (from 19.9 to
20.2 nm; p = 0.007 vs placebo). In patients with
on-treatment triglyceride levels of <1.7, 1.7–2.2,
2.3–2.8 and ‡2.8 mmol/L, median changes from
baseline in LDL particle size were +0.60, +0.40,
+0.15 and -0.20 nm, respectively.[18] In the cor-
responding subgroups, LDL subfraction pat-
tern B (i.e. smaller particles) was present in
68%, 79%, 93% and 73% of patients at baseline
and 36%, 50%, 82% and 84% of patients at
endpoint.[18]
The increases in LDL particle size identified in
the Maki et al.[18] study with omega-3 EEC therapy
were also observed in a study in patients with mixed
lipidaemia: omega-3 EEC 4000 mg/day plus sim-
vastatin 20 mg/day induced a significant (p < 0.05)
increase from baseline in least-squares mean LDL
Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review
particle size (from 19.9 to 20.4 nm) compared
with placebo plus simvastatin 20 mg/day (from
19.9 to 20.2 nm).[45] However, there was no be-
tween-group difference in LDL particle con-
centration.[45] Significantly (p < 0.05) greater re-
ductions from baseline in VLDL particle size and
concentration were also observed between the
two treatment groups.[45]
Both oral omega-3 EEC 4000 mg/day and oral
gemfibrozil 1200 mg/day significantly (p < 0.05)
elevated the cholesterol content of the LDL-1,
LDL-2 and LDL-3 subfractions versus baseline
in patients with hypertriglyceridaemia, resulting
in a more buoyant, less atherogenic LDL subfrac-
tion profile.[40] No significant differences in the
LDL-4 and LDL-5 subfractions versus baseline
and no between-group differences in the cholesterol
levels of the LDL subfractions were observed.[40]
Average LDL particle size was unchanged
following omega-3 EEC therapy in patients with
familial combined hyperlipidaemia, although the
LDL-C : apolipoprotein-B ratio was elevated,
indicating an elevation in the more buoyant and
core-enriched LDL particles (LDL-1 and LDL-2
subfractions).[44]
Results from therapeutic efficacy studies
examining the effects of omega-3 EEC on lipid
levels in patients with hypertriglyceridaemia or
recent MI are discussed in section 4.
2.3 Cardiovascular Effects
Omega-3 fatty acids reduce BP, according to
the results of a meta-analysis.[20] Overall, a mean
systolic/diastolic BP reduction of 2.3/1.5 mmHg
occurred at a mean omega-3 fatty acid dosage of
4100 mg/day.[20] Subgroup analyses demon-
strated that BP was reduced to a greater extent
in older (age >45 years) versus younger partici-
pants and in hypertensive versus normotensive
participants.
The findings of this meta-analysis[20] were
supported by the results of studies in patients
with essential hypertension,[49,50] hypertriglycer-
idaemia[43] or combined hyperlipidaemia,[51,52]
patients who had undergone heart transplanta-
tion,[53] or hypertensive heart transplant recipi-
ents,[12] which generally showed significant
ª 2009 Adis Data Information BV. All rights reserved.
1083
(p < 0.05 vs baseline or controls) reductions in
systolic and/or diastolic BP with omega-3 EEC
2000–6000 mg/day. However, no significant
changes in BP were seen in healthy volunteers,[11]
post-MI patients[54] or patients with mild hyper-
tension[9] receiving omega-3 EEC 1000,[54] 3000[9]
or 4000[11] mg/day.
Omega-3 fatty acids reduce heart rate, accord-
ing to the results of another meta-analysis.[21]
Heart rate was significantly (p = 0.002 vs placebo)
reduced by 1.6 beats/minute by omega-3 fatty
acids (median dosage 3500 mg/day).[21] Sub-
group analysis revealed a significant (p < 0.001)
reduction of 2.5 beats/minute in patients with
a mean heart rate of ‡69 beats/minute at baseline,
with no significant change among those with a
mean heart rate of <69 beats/minute at baseline.[21]
The results of in vitro,[55] animal[56-60] and
some human[61] studies suggest that omega-3
fatty acids have antiarrhythmic effects. Various
mechanisms have been proposed to explain the
apparent antiarrhythmic effects of omega-3 fatty
acids, including incorporation of DHA and EPA
into membrane phospholipids (increasing
arrhythmic thresholds), effects on ion channels
(i.e. inhibition of fast voltage-dependent and late
sodium channels, L-type calcium channels and
delayed-rectifier potassium channels) and effects
on autonomic balance.[23,25,29,30,62-64]
An antiarrhythmic effect is one of the favoured
explanations for the reduced risk of sudden car-
diac death seen in patients with recent MI who
received omega-3 EEC in the GISSI (Gruppo
Italiano per lo Studio della Sopravvienze nell’In-
farto miocardico)-Prevenzione study[65]
[25,27]
(section 4). However, mixed results were seen
with omega-3 fatty acid supplementation in large,
well designed studies in patients with implantable
cardioverter defibrillators (ICDs).[13,15,16] Although
primary endpoints relating to the risk of ven-
tricular arrhythmias (ICD intervention for ven-
tricular fibrillation [VF], ventricular tachycardia
[VT][13,15,16] or death[13,15]) were not improved by
omega-3 fatty acids to a significant extent,[13,15,16]
omega-3 fatty acids had favourable effects in
certain subpopulations. For example, a signifi-
cant (p = 0.033) 31% reduction in the primary
endpoint was seen with omega-3 fatty acids when
Drugs 2009; 69 (8)
1084
probable events were also considered.[15] It
should be noted that these ICD patients comprise
a different population to those in the GISSI-
Prevenzione study[65] (sections 4 and 7). Omega-3
EEC has also demonstrated a preventative atrial
fibrillation effect in patients undergoing coro-
nary artery bypass graft surgery (CABG).[66]
Compared with control (usual care), omega-3
EEC 2000 mg/day plus usual care significantly
reduced the incidence of postoperative atrial
fibrillation (odds ratio [OR] 0.35; 95% CI 0.16,
0.76; p < 0.05) and length of hospital stay
(p < 0.05) in patients undergoing CABG.[66] Age
(OR 1.08; 95% CI 1.01, 1.15; p < 0.05) and ther-
apy with omega-3 EEC (OR 0.32; 95% CI 0.10,
0.98; p < 0.05) were both identified as significant
independent predictors of postoperative atrial
fibrillation.[66]
Another possible explanation for the reduc-
tion in sudden cardiac death seen with omega-3
EEC is an augmentation in autonomic tone.[23,29]
A positive correlation has been seen between
heart rate variability and the omega-3 fatty acid
content of cell membranes,[67] suggesting that
omega-3 fatty acid supplementation may increase
heart rate variability and protect against sudden
cardiac death. However, mixed results have
been obtained in terms of the effect of omega-3
fatty acids on heart rate variability.[9,54,68,69]
A significant (p < 0.05 vs controls) increase in
heart rate variability occurred in patients with
recent MI who received omega-3 fatty acids
5200 mg/day for 3 months.[68] In patients with
healed MI and left ventricular dysfunction, while
there was no improvement in overall heart rate
variability, omega-3 fatty acids 1500 mg/day sig-
nificantly improved heart rate variability in the
high-frequency band (p = 0.02 vs placebo) and
reduced heart rate after exercise to a significantly
greater extent than placebo (p < 0.05).[69] Omega-
3 EEC 1000[54] or 3000[9] mg/day for 3[54] or 4[9]
months did not alter heart rate variability indices
to a significant extent in patients with mild hy-
pertension[9] or post-MI.[54]
Improvements in endothelial function have
been reported in patients receiving omega-3 fatty
acids.[31] In patients with hypercholesterolaemia,
endothelium-dependent, flow-mediated dilata-
ª 2009 Adis Data Information BV. All rights reserved.
Hoy & Keating
tion increased from baseline to a significantly
(p < 0.05) greater extent with omega-3 EEC
4000 mg/day (from 0.05 to 0.12 mm) than with
placebo (from 0.03 to 0.04 mm).[70]
2.4 Effects on Thrombosis and Haemostasis
EPA was incorporated into platelets in a dose-
dependent manner in healthy volunteers re-
ceiving omega-3 EEC 1000–4000 mg/day.[10] In
addition, omega-3 fatty acids have shown in-
hibitory effects on thrombosis in in vitro studies
(e.g. reducing platelet aggregation[71-73] and pla-
telet thromboxane B2 response[73]), suggesting a
potential cardioprotective mechanism.[24]
However, across clinical studies, omega-3 fat-
ty acids did not show a consistent effect on hae-
mostatic variables, such as levels of fibrinogen,
factor VII or VIII, or von Willebrand factor.[8,28]
Moreover, changes in the levels of fibrinogen,
factor VII or VIII, or von Willebrand factor
generally did not differ significantly between re-
cipients of omega-3 EEC 1000–6000 mg/day
and controls in studies involving healthy volun-
teers,[11] post-MI patients,[74] patients with mild
hypertension,[9] patients with combined hyper-
lipidaemia[75] or patients undergoing CABG
surgery.[76]
Concern has been raised that an antithrombo-
tic effect could potentially increase the risk of
clinically significant bleeding in patients receiv-
ing omega-3 fatty acids.[24,26] However, omega-3
EEC 6000 mg/day did not affect bleeding time at
rest QJ;in patients with familial hypercholester-
olaemia, although exercise-induced shortening of
the bleeding time was inhibited (p < 0.05 vs base-
line).[77] No significant between-group differences
were seen with omega-3 EEC 6000 mg/day and
controls in terms of platelet numbers or bleed-
ing times[76] or omega-3 EEC 4000 mg/day and
placebo in the incidence of bleeding episodes[14]
in patients undergoing CABG,[14,76] some of
whom also received warfarin or aspirin. Regard-
less, patients receiving anticoagulant therapy
should be monitored (e.g. the prothrombin
time should be monitored in patients receiving
Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review
warfarin) and the anticoagulant dosage adjusted
as necessary in patients receiving omega-3 EEC.[7]
2.5 Anti-Atherogenic and
Anti-Inflammatory Effects
Meta-analyses have suggested that omega-3
fatty acids may prevent restenosis following coro-
nary angioplasty.[19,22] However, treatment with
omega-3 EEC 6000 mg/day for 6 months did not
reduce the incidence of restenosis in patients who
had undergone coronary angioplasty.[78]
EPA and DHA were incorporated into the
atherosclerotic plaques of patients who received
omega-3 fatty acids prior to undergoing carotid
endarterectomy, potentially improving plaque
stability.[79] Similarly, plaque phospholipid EPA
content was significantly (p < 0.0001) higher in
patients who received omega-3 EEC 2000 mg/day
versus placebo prior to carotid endarter-
ectomy.[17] Moreover, plaque from patients re-
ceiving omega-3 EEC expressed significantly
(p < 0.05) lower messenger RNA (mRNA) levels
for matrix metalloproteinase (MMP)-7, MMP-9,
MMP-12 and intercellular adhesion molecule
(ICAM)-1 than plaque from placebo recipients,
although there was no significant between-group
difference in mRNA levels of MMP-3, MMP-8 or
MMP-13.[17]
In patients with hypertriglyceridaemia, soluble
E-selectin (sE-selectin) levels were increased from
baseline to a significantly greater extent with
omega-3 EEC 4000 mg/day than with placebo
after 6 weeks’ therapy (+11% vs -2%; p = 0.01),
although after more than 6 months’ treatment,
significant decreases from baseline in sE-selectin
levels of 16% (p < 0.0001) and in soluble ICAM-1
levels of 9% (p = 0.02) were observed.[42]
In addition, gene expression of platelet-de-
rived growth factor-A and -B was down regulated
in mononuclear cells from healthy volunteers
who received omega-3 EEC 7000 mg/day for
6 weeks.[80]
In terms of inflammatory markers, there
was a significant (p = 0.02) reduction from base-
line in endotoxin-stimulated tumour necrosis
factor (TNF)-a production in peripheral blood
mononuclear cells from patients with severe
ª 2009 Adis Data Information BV. All rights reserved.
1085
heart failure who received omega-3 fatty acids
8000 mg/day for 18 weeks.[81] However, no sig-
nificant change from baseline in TNFa levels was
observed in obese patients with dyslipidaemia
who received omega-3 EEC 4000 mg/day for
6 weeks.[82]
Interleukin-6 levels were not altered to a sig-
nificant extent with omega-3 EEC 1000 mg/day
versus control in post-MI patients[74] or with
omega-3 EEC 4000 mg/day versus baseline in
obese patients with dyslipidaemia.[82]
In general, omega-3 fatty acids did not affect
C-reactive protein (CRP) levels;[8,69] no signifi-
cant change in CRP levels versus baseline was
observed with omega-3 EEC 4000 mg/day ther-
apy in obese patients with dyslipidaemia.[82]
3. Pharmacokinetic Properties
Animal studies demonstrated that oral
omega-3 EEC is completely hydrolyzed, after
which EPA and DHA are absorbed and in-
corporated into plasma phospholipids and cho-
lesterol esters.[7] Indeed, EPA and DHA were
absorbed following their oral administration as
ethylesters to healthy volunteers[32,33,83,84] and
patients with hypertriglyceridaemia.[32]
In healthy volunteers receiving omega-3
EEC 1000, 2000 or 4000 mg/day for 12 weeks,
significant (p < 0.05 vs baseline) dose-dependent
increases were seen in plasma phospholipid
EPA and DHA content.[10] Omega-3 EEC
4000 mg/day also significantly (p < 0.05 vs base-
line and/or controls) increased plasma/serum
phospholipid EPA and DHA content in various
patient populations, including patients with se-
vere hypertriglyceridaemia,[85] combined hy-
perlipidaemia[51] or essential hypertension[49] and
hypertensive heart transplant recipients.[12] In
patients with coronary heart disease (CHD) re-
ceiving omega-3 EEC 2000 mg twice daily, mean
serum phospholipid EPA and DHA concentra-
tions increased 361% and 52% after 12 months of
therapy (see section 4 for study details).[86] The
EPA and DHA concentrations in plasma phos-
pholipids correspond to the EPA and DHA in-
corporated into cell membranes.[7]
Drugs 2009; 69 (8)
1086
Omega-3 fatty acids are metabolized via three
main pathways during and after absorption.[7]
Fatty acids are initially transported to the liver
for incorporation into lipoproteins, after which
they are channelled to peripheral lipid stores.[7]
Secondly, cell membrane phospholipids are re-
placed by lipoprotein phospholipids allowing
fatty acids to act as precursors for eicosanoids.[7]
Finally, the majority of omega-3 fatty acids are
oxidised to meet energy requirements.[7]
Age (<49 vs ‡49 years) did not affect the up-
take of EPA and DHA into serum phospholipids
in omega-3 EEC recipients.[32] The uptake of
EPA in serum phospholipids tended to be greater
in women than in men.[32]
Undetectable concentrations (<1 mmol/L) of
the free forms of EPA and DHA are present in
the circulation, meaning that clinically signifi-
cant inhibition of cytochrome P450 (CYP) en-
zymes is not expected to occur.[32] In vitro, a free
fatty acid-albumin conjugate (concentration
of 23 mmol/L) inhibited CYP2A6, CYP2C19,
CYP2D6 and CYP3A by <20%, with 68% in-
hibition of CYP2E1.[32]
The concomitant administration of omega-3
EEC did not alter the steady-state pharmaco-
kinetics of atorvastatin (and its major active
metabolites 2-hydroxyatorvastatin and 4-hydro-
xyatorvastatin),[87] rosuvastatin[88] or simvastatin
(and its major active metabolite b-hydroxy
simvastatin)[89] in healthy volunteers.
4. Therapeutic Efficacy
4.1 In Secondary Prevention
Post-Myocardial Infarction
The comparative efficacy of omega-3 EEC, as
monotherapy or in combination with tocopherol,
versus tocopherol monotherapy or no treatment
in secondary prevention post-MI in adult
patients (n = 11 324) has been assessed in the
fully published randomized, nonblind (endpoints
were assessed by a blinded endpoint validation
committee of cardiologists and neurologists),
multicentre GISSI-Prevenzione study.[65]
ª 2009 Adis Data Information BV. All rights reserved.
Hoy & Keating
A randomized, double-blind, placebo-controlled,
multicentre study (OMEGA; n = 3851) [currently
available only as an oral presentation] that com-
pared omega-3 EEC with placebo in secondary
prevention post-MI patients is also discussed.[90]
Data from three post hoc subanalyses[91-93] of the
GISSI-Prevenzione study[65] and supplementary
design details[94] for the OMEGA study[90] are
also available.
Eligibility criteria included a recent (within the
previous 3–14 days[90] or 3 months[65]) MI. The
studies were conducted in male (85.3%[65] and
74.4%[90]) and female (14.7%[65] and 25.6%[90])
patients with a mean age of 59[65] and 64[90] years
(16% of patients in the GISSI-Prevenzione study
were aged >70 years[65]), a mean body mass index
(BMI) of 26.5 kg/m2[65] and an ejection frac-
tion of £0.30 (2.6% of patients), 0.31–0.40 (11.1%)
or >0.40 (86.3%) in the GISSI-Prevenzione
study,[65] and <0.45 (24.1%) and ‡0.45 (75.9%) in
the OMEGA study.[90] Patients were diagnosed
with concomitant arterial hypertension (35.6%
of patients),[65] claudication (4.4%),[65] diabetes
mellitus (14.8%[65] and 27.0%[90]), renal failure
(1.8%)[90] and/or ventricular arrhythmias (19.3%);[65]
42.4% of patients were smokers[65] and 28.9% has a
positive exercise-stress test.[65] Randomization in
the GISSI-Prevenzione study occurred a median of
16 days following MI.[65]
Patients were randomized to receive
omega-3 EEC 1000 mg/day (n = 2836), omega-3
EEC 1000 mg/day plus tocopherol 300 mg/day
(n = 2830), tocopherol 300 mg/day (n = 2830) or
no treatment (n = 2828) for 42 months in the
GISSI-Prevenzione study[65] or omega-3 EEC
1000 mg/day (n = 1940) or placebo (n = 1911) for
12 months in the OMEGA study.[90,94]
At baseline, patients were receiving ACE
inhibitor (46.9%[65] and 69.5%[90] of patients),
antiplatelet (including aspirin, clopidogrel and
glycoprotein IIb/IIIa antagonists[90]) [91.7%[65]
and £94.4%[90]] b-adrenergic receptor anta-
gonist (b-blocker) [44.3%[65] and 85.7%[90]]
and/or lipid-lowering (including HMG-CoA
reductase inhibitor [statin][90]) [4.7%[65] and
81.5%[90]] therapy; those receiving aspirin,
b-blockers and/or ACE inhibitors were per-
Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review
mitted to continue concomitant therapy through-
out the study.[65] Patients in the OMEGA study
received standard therapy (not defined).[90] At
hospital discharge, 83.3%, 95.3%, 94.1%, 88.4%
and 94.2% of patients in the OMEGA study were
receiving ACE inhibitor, aspirin, b-blocker, clopi-
dogrel and/or statin therapy, respectively.[90] By the
end of the GISSI-Prevenzione study, 39.0%,
82.8%, 38.5% and 45.5% of patients were receiving
ACE inhibitor, antiplatelet, b-blocker and/or lipid-
lowering therapy, respectively.[65]
The primary composite efficacy endpoints for
the GISSI-Prevenzione study were the cumula-
tive rate of all-cause death, nonfatal MI and
nonfatal stroke, and the cumulative rate of car-
diovascular death, nonfatal MI and nonfatal
stroke.[65] Secondary endpoints included the in-
dividual components of the primary endpoints
and the major causes of death.[65] The primary
endpoint for the OMEGA study was sudden
cardiac death; secondary endpoints included
arrhythmic events, death, reinfarction, revascu-
larization (percutaneous coronary intervention
and/or CABG) and stroke.[90,94]
A prespecified two-way factorial analysis of
data compared the efficacy of omega-3 EEC-
based therapy (omega-3 EEC monotherapy and
omega-3 EEC plus tocopherol groups) with that
of non-omega-3 EEC-based therapy (tocopherol
monotherapy and no treatment groups) and the
efficacy of tocopherol-based therapy (tocopherol
monotherapy and omega-3 EEC plus tocopherol
groups) versus non-tocopherol-based therapy
(omega-3 EEC monotherapy and no treatment)
over 42 months in the GISSI-Prevenzione
study.[65] A prespecified four-way analysis of data
compared the efficacy of omega-3 EEC mono-
therapy, tocopherol monotherapy and omega-3
EEC plus tocopherol with that of the no treat-
ment group over the same time period; the effi-
cacy of omega-3 EEC plus tocopherol was also
compared with omega-3 EEC monotherapy and
tocopherol monotherapy.[65]
Data are reported for the intent-to-treat[65]
and per-protocol[90] populations.
Oral omega-3 EEC demonstrated a secondary
preventive effect in patients with recent MI in the
GISSI-Prevenzione study.[65] The risk of death
ª 2009 Adis Data Information BV. All rights reserved.
1087
plus nonfatal MI plus nonfatal stroke (coprimary
composite efficacy endpoint) at study end was
significantly reduced with omega-3 EEC-based
therapy versus non-omega-3 EEC-based ther-
apy but not with tocopherol-based therapy
versus non-tocopherol-based therapy, according
to a two-way analysis of data (figure 2).[65]
However, there were no significant differences in
the risk of cardiovascular death plus nonfatal MI
plus nonfatal stroke (coprimary composite effi-
cacy endpoint) for either of these therapy groups
(figure 2).[65]
Of the individual events contributing to the
primary endpoints, significant reductions in
the relative risk of death, cardiovascular death
and fatal CHD plus nonfatal MI occurred in
patients receiving omega-3 EEC-based therapy
relative to those receiving non-omega-3 EEC-
based therapy (figure 2).[65] No significant dif-
ferences were observed between these two groups
with regard to nonfatal cardiovascular events
or fatal plus nonfatal stroke (figure 2).[65] The risk
of cardiac death (4.0% vs 5.2%), coronary death
(3.8% vs 4.7%) and sudden death (2.2% vs 2.9%)
with omega-3 EEC-based therapy relative to that
with non-omega-3 EEC-based therapy was sig-
nificantly reduced by 22% (relative risk [RR]
0.78; 95% CI 0.65, 0.92), 20% (RR 0.80; 95% CI
0.67, 0.96) and 26% (RR 0.74; 95% CI 0.58, 0.93),
respectively, at study end (secondary end-
points).[65] No significant reductions in the risk of
the events contributing to the primary endpoints
(figure 2) or the risk of cardiac death (4.4% vs
4.8%; RR 0.91; 95% CI 0.76, 1.08), coronary
death (4.0% vs 4.4%; RR 0.91; 95% CI 0.76, 1.09)
and sudden death (2.3% vs 2.7%; RR 0.86; 95%
CI 0.68, 1.08) were observed with tocopherol-
based therapy relative to non-tocopherol-based
therapy.[65]
Compared with no treatment, the four-way
analysis of data demonstrated significant reduc-
tions at study end in the risk of death plus non-
fatal MI plus nonfatal stroke with omega-3
EEC as monotherapy or in combination with
tocopherol and in the risk of cardiovascular
death plus nonfatal MI plus nonfatal stroke
with omega-3 EEC monotherapy (table I).[65]
No significant reductions in the risk of these copri-
Drugs 2009; 69 (8)
1088 Hoy & Keating

Omega-3 EEC-based therapy

Non-omega-3 EEC-based therapy
a
RR 0.90*†
16
(0.82, 0.99)
14 RR 0.89
(0.80, 1.01) RR 0.86†
Incidence (% of patients)

12 (0.76, 0.97) RR 0.87†

(0.76, 0.99)
10
RR 0.83†
8 (0.71, 0.97) RR 0.98
(0.83, 1.15)
6
RR 1.21
4 (0.91, 1.63)

al +
th

h
ro I

en al
ro al

ro d
st l M

at
ea

st an
at D
ev fat
st at

I
de

M
ke

ts
ke

ke
nf H
al ta

al nf

V n

al l
no l C

at ta
C No
at fa

at o

V
nf + n

nf Fa
C
nf on

ta
Fa
no + n

no th
I + ea
th

M Vd

no
ea
D
+

Tocopherol-based therapy
Non-tocopherol-based therapy
b RR 0.95
16 (0.86, 1.05)

14 RR 0.98
(0.87, 1.10) RR 0.92
Incidence (% of patients)

12 (0.82, 1.04) RR 1.00

(0.88, 1.14)
10
RR 0.94
8 (0.81, 1.10) RR 1.04
(0.88, 1.22)

6
RR 0.87
4 (0.65, 1.17)

0
th

al +
h
ro I

ro al

en al

ro d
st l M

at
ea

at D

st an
st at

ev fat

I
de
ke

ke

M
ts

ke
nf H
al nf
al ta

V n

al l
no l C

at ta
at o
at fa

C No
V
nf + n

nf Fa
nf on

t a
Fa
no n

no th
+ h+

I + ea
t

M Vd

no
ea
D

Fig. 2. Comparative efficacy of oral omega-3 ethylester concentrate (omega-3 EEC) in secondary prevention post-myocardial infarction (MI)
in adult patients. Results from the randomized, nonblind (endpoints validated by blinded assessment committee), multicentre GISSI-
Prevenzione study; analyses are of intent-to-treat data.[65] Patients received omega-3 EEC 1000 mg/day, omega-3 EEC 1000 mg/day plus
tocopherol 300 mg/day, tocopherol monotherapy 300 mg/day or no treatment for 42 months.[65] In this two-way factorial analysis, (a) omega-3
EEC-based therapy consisted of the omega-3 EEC monotherapy and the omega-3 EEC plus tocopherol groups (n = 5666) and non-omega-3
EEC-based therapy consisted of the tocopherol monotherapy and no treatment groups (n = 5668); and (b) tocopherol-based therapy consisted
of the omega-3 EEC plus tocopherol and the tocopherol monotherapy groups (n = 5666) and non-tocopherol-based therapy consisted of the
omega-3 EEC monotherapy and no treatment groups (n = 5668). The primary composite efficacy endpoints were the cumulative rate of all-
cause death, nonfatal MI and nonfatal stroke, and the cumulative rate of cardiovascular (CV) death, nonfatal MI and nonfatal stroke. 95% CI
values are shown in parentheses. CHD = coronary heart disease; RR = relative risk; - indicates significant results. * p = 0.048.

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review 1089

Table I. Comparative efficacy of oral omega-3 ethylester concentrate (omega-3 EEC) in secondary prevention post-myocardial infarction (MI)
in adult patients. Summary of a prespecified four-way analysis of data from the randomized, nonblind (endpoints validated by blinded as-
sessment committee), multicentre GISSI-Prevenzione study; analyses are of intent-to-treat data.[65,92] Patients received omega-3 EEC
monotherapy 1000 mg/day (n = 2836), omega-3 EEC 1000 mg/day plus tocopherol 300 mg/day (n = 2830), tocopherol monotherapy 300 mg
(n = 2830) or control (no treatment) [n = 2828] for 42 months[65]
Endpoint Incidence (% of patients) RR (95% CI) [active therapy vs control]a
omega-3 omega-3 tocopherol control omega-3 EEC omega-3 EEC + tocopherol
EEC EEC + tocopherol
tocopherol
Primary composite
Death + nonfatal 12.3 12.7 13.1 14.6 0.85* (0.74, 0.98)- 0.86 (0.74, 0.99)- 0.89 (0.77, 1.03)
MI + nonfatal stroke
CV death + nonfatal 9.2 10.1 10.1 11.4 0.80*** (0.68, 0.95)- 0.88 (0.75, 1.03) 0.88 (0.75, 1.04)
MI + nonfatal stroke
Secondary
Death 8.3 8.3 8.9 10.4 0.80** (0.67, 0.94)- 0.80 (0.67, 0.95)- 0.86 (0.72, 1.02)
CV death 4.8 5.5 5.5 6.8 0.70 (0.56, 0.87)- 0.80 (0.65, 0.99)- 0.80 (0.65, 0.99)-
- -
cardiac death 3.8 4.2 4.5 5.8 0.65 (0.51, 0.82) 0.72 (0.57, 0.91) 0.77 (0.61, 0.97)-
- -
coronary death 3.5 4.0 4.0 5.3 0.65 (0.51, 0.84) 0.75 (0.59, 0.96) 0.75 (0.59, 0.96)-
** - -
sudden death 1.9 2.4 2.3 3.5 0.55 (0.40, 0.76) 0.67 (0.49, 0.92) 0.65 (0.48, 0.89)-
Nonfatal CV events 4.9 5.0 5.2 5.1 0.96 (0.76, 1.21) 1.01 (0.80, 1.27) 1.02 (0.81, 1.28)
Other
Fatal CHD + nonfatal MI 6.9 8.1 8.0 9.2 0.75 (0.62, 0.90)- 0.87 (0.73, 1.04) 0.87 (0.73, 1.04)
Fatal and nonfatal stroke 1.9 1.6 1.4 1.5 1.30 (0.87, 1.96) 1.06 (0.70, 1.63) 0.95 (0.61, 1.47)
a p-Values were not stated for all comparisons.
CHD = coronary heart disease; CV = cardiovascular; RR = relative risk; - indicates significant results. * p = 0.023; ** p = 0.01; *** p = 0.008.

mary endpoints were observed following tocopherol
monotherapy versus no treatment (table I).[65]
In general, omega-3 EEC monotherapy, ome-
ga-3 EEC plus tocopherol combination therapy
and tocopherol monotherapy were all signifi-
cantly more effective than control in terms of
secondary endpoints in the four-way analysis
(table I).[65] Significant reductions (of 20–45%) in
the risk of these endpoints were observed across
all three active therapy groups versus control,
with the exception of death in the tocopherol
monotherapy group and nonfatal cardiovascular
events in all three active therapy groups (table I).[65]
In contrast, no significant reductions in the risk
of fatal CHD plus nonfatal MI and fatal plus
nonfatal stroke (other endpoints) were observed
in active therapy groups, apart from a significant
25% reduction in the risk of fatal CHD plus
nonfatal MI in omega-3 EEC monotherapy ver-
sus no treatment recipients (table I).[65]
No evidence of an interaction effect between
omega-3 EEC and tocopherol was observed fol-
lowing an analysis of the coprimary composite
efficacy endpoints and one secondary endpoint
(death).[65] The risk of death plus nonfatal
MI plus nonfatal stroke (coprimary composite
efficacy endpoint) was not significantly reduced
in omega-3 EEC plus tocopherol combina-
tion therapy versus omega-3 EEC monotherapy
(RR 1.01; 95% CI 0.87, 1.17) or tocopherol
monotherapy (RR 0.96; 95% CI 0.83, 1.12)
recipients.[65]
Analyses of the individual components of the
coprimary composite efficacy endpoints indicated
that significant reductions in the relative risk of
death, cardiovascular death and sudden death
following therapy with omega-3 EEC accounted
for the observed reductions in the risk of the co-
primary composite efficacy endpoints (table I)[65]
and suggested an antiarrhythmic/antifibrillatory
effect.[91] A post hoc time-course subanalysis[91] of the
GISSI-Prevenzione study[65] suggested that omega-3
EEC-based therapy was associated with early (from
month 9 for the coprimary endpoints, and from

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
1090
Table II. Effect of oral omega-3 ethylester concentrate (omega-3 EEC) on lipid levels in adult patients with recent myocardial infarction.
Summary of the randomized, nonblind (endpoints validated by blinded assessment committee), multicentre GISSI-Prevenzione study after
6 months’ therapy; analyses are of intent-to-treat data.[65] Patients received omega-3 EEC monotherapy 1000 mg/day, omega-3 EEC
1000 mg/day plus tocopherol 300 mg/day, tocopherol monotherapy 300 mg or control (no treatment) for 42 months[65]
Treatment No. of pts
Omega-3 EEC 2836
Omega-3 EEC + tocopherol 2830
Tocopherol 2830
Control 2828
HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride;
*
p < 0.0001 vs control.
months 3–8 for the secondary and other end-
points), sustained and significant (p < 0.05) re-
ductions in the risk of the mortality endpoints,
apart from coronary death, versus non-omega-3
EEC-based therapy. Results for the morbidity
endpoints were mixed.[91]
An exploratory, post hoc analysis of data from
the GISSI-Prevenzione study[65] indicated that
omega-3 EEC was effective in patients with
(n = 4324) or without (n = 5306; ejection fraction
>50%) left ventricular systolic dysfunction
(LVSD) and suggested that the beneficial effects
of therapy may increase with worsening LVSD.[93]
However, prospective randomized studies are
required to confirm this.
At 6 months, no clinically relevant changes from
baseline in total cholesterol, LDL-C and HDL-C
levels (table II), fibrinogen and glycaemia (no
data reported for these parameters) were ob-
served in omega-3 EEC monotherapy, tocopher-
ol monotherapy or omega-3 EEC plus tocopherol
treatment groups.[65] However, a statistically
significant reduction in triglyceride levels was
observed in patients receiving omega-3 EEC
monotherapy versus no treatment (table II).[65]
No significant difference in the incidence of
sudden cardiac death (primary endpoint) was ob-
served between the omega-3 EEC (1.5% [29/1919]
of patients) and placebo (1.5% [28/1885]) groups,
according to preliminary data from the OMEGA
study.[90] Furthermore, no significant differences
were observed between these two groups with
regard to the secondary endpoints, including
arrhythmic events (1.1% of omega-3 EEC re-
cipients and 0.7% of placebo recipients), death
ª 2009 Adis Data Information BV. All rights reserved.
Hoy & Keating
Mean change from baseline in lipid level (%) [mean baseline level; mmol/L]
TG TC LDL-C HDL-C
-3.4* [1.79] +7.9 [5.47] +9.9 [3.57] +8.8 [1.08]
-0.9 [1.76] +8.9 [5.48] +10.8 [3.59] +8.9 [1.08]
+2.9 [1.80] +7.1 [5.49] +7.2 [3.59] +9.4 [1.07]
+1.4 [1.78] +7.1 [5.50] +7.4 [3.60] +9.2 [1.08]
(4.6% and 3.7%), reinfarction (4.5% and 4.1%),
revascularization (27.7% and 29.1%) and stroke
(1.4% and 0.7%).[90] Of note, the observed in-
cidence of sudden cardiac death in both the ome-
ga-3 EEC and placebo groups (1.5% vs 1.5%) was
lower than anticipated; the OMEGA study was
designed assuming a sudden cardiac death rate of
1.9% in omega-3 EEC recipients and 3.5% in
placebo recipients.[90]
4.1.1 Pharmacoeconomic Considerations
This section focuses on the findings from two
fully published, well designed pharmacoeconomic
modelling studies,[95,96] both primarily based
on data from the GISSI-Prevenzione study[65]
and conducted from a healthcare payer per-
spective,[65] in secondary prevention post-MI.
A summary of the design and results of the two
analyses is presented in table III.
Omega-3 EEC plus standard therapy was pre-
dicted to be a cost-effective option in secondary
prevention post-MI relative to standard therapy
alone, according to two analyses conducted in
several countries (Australia, Belgium, Canada,
Germany and Poland)[95] or the UK[96] (table III).
The incremental cost-effectiveness ratio per life-
year gained[95,96] or per quality-adjusted life-year
gained[96] was favourable in relation to com-
monly accepted thresholds for cost effectiveness
(table III). In the UK analysis, the cost per death
avoided over the 48-month time horizon was
estimated to be d31 768 (2004 value).[96]
Sensitivity analyses suggested that the results in
both the multi-national[95] and UK[96] studies were
robust to variations in key parameters. Furthermore,
omega-3 EEC was estimated to be cost effective in
Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review 1091

93% of simulations in Poland, and in >98% of
simulations in Australia, Belgium, Canada and
Germany, according to a second-order Monte-
Carlo simulation based on the 95% confidence
intervals obtained from the GISSI-Prevenzione
study (assuming the country-specific willingness-
to-pay thresholds).[95] However, pharmacoeco-
nomic analyses of omega-3 EEC, in common with
all pharmacoeconomic analyses, are subject to a
number of limitations. Pharmacoeconomic ana-
lyses based on clinical studies extrapolate the re-
sults of relatively short-term studies to long-term
results in the general population; however, pa-
tient populations, rates of compliance and major
outcomes in clinical studies may differ from those
observed in real-life practice. Modelled analyses,
such as those presented in this section, rely on a
number of assumptions and use data from a
variety of sources. Results of pharmacoeconomic
analyses may not be applicable to other geogra-
phical regions because of differences in healthcare
systems, medical practice and unit costs.
4.2 In the Treatment
of Hypertriglyceridaemia
The therapeutic efficacy of oral omega-3 EEC
in the treatment of adult patients with hyper-
triglyceridaemia has been evaluated in five random-
ized, double-blind, multicentre clinical studies of
8–24 weeks’ duration,[46,85,86,97,98] with the 12-week
monotherapy study[46] utilizing a double-dummy
design. All of the studies have been fully pub-
lished apart from one,[98] which is currently avail-
able only as an abstract. These studies assessed the
efficacy of omega-3 EEC as monotherapy[46,85]
(section 4.2.1) or in combination with simvasta-
tin[86,97] or atorvastatin[98] (section 4.2.2).

Table III. Cost effectiveness of omega-3 ethylester concentrate (omega-3 EEC) plus standard therapy (ST) relative to ST alone in secondary
prevention post-myocardial infarction. Design and base-case results of fully published cost-effectiveness analyses conducted from the per-
spective of a healthcare payer (direct medical costs related to acute care[95] or acute plus preventative care[96]) in Australia, Belgium, Canada,
Germany and Poland[95] or the UK.[96] Analyses assumed patients aged 59 y received omega-3 EEC 1000 mg/day for 42 or 48 mo, and
incorporated data from the GISSI-Prevenzione study[65] (see section 4.1), the literature and country-specific cost databases (year of costing
2004). Cost and benefits were discounted at 3.5%[96] or 5%[95] per 12 mo
Time horizon Country Incremental results (omega-3 EEC + ST vs ST)
costs LYG QALY gained Cost per LYGa Cost per QALY
gainedb
Lamotte et al.[95] (decision tree model)
42 mo Australiac h959 0.284 NA h3371 NA
Belgium h1439 0.282 NA h5097 NA
Canadac h787 0.282 NA h2788 NA
Germany h1169 0.278 NA h4204 NA
Poland h1258 0.261 NA h4825 NA
Lifetime Australiac h1598 0.284 NA h5619 NA
Belgium h2554 0.282 NA h9048 NA
Canadac h1509 0.282 NA h5346 NA
Germany h2311 0.278 NA h8315 NA
Poland h1521 0.261 NA h5834 NA
Quilici et al.[96] (Markov with nine health states and a cycle length of 12 mo)
48 mo UK d649 005 54 43 d12 011 d15 189
Lifetime UK d770 336 274 207 d2812 d3723
a Commonly accepted thresholds for cost effectiveness per LYG are: Australia, h47 000; Belgium, h20 000; Canada, h30 000; Germany,
h20 000; Poland, h10 640.[95]
b The National Institute of Health and Clinical Excellence threshold for the approval of a new therapy is d20 000–30 000 per QALY gained.[96]
c Values in local currency not reported.
LYG = life-year gained; NA = not available; QALY = quality-adjusted life-year.

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
1092
Eligible patients were aged 18–75,[85]
18–79[97,98] or £75[86] years and had mean[97]
fasting[46,97] serum triglyceride levels >2.3,[86]
>4.5,[46] ‡2.3 to <5.6,[97] ‡5.7 to <22.6[85] or ‡2.8
to <6.76[98] mmol/L (serum triglyceride levels
‡5.6 mmol/L [‡500 mg/dL] are considered by
the National Cholesterol Education Program
Adult Treatment Panel III [NCEP ATP III][99]
to be ‘very high’). Where stated, patients had
mean LDL-C levels below, or within 10% of, the
NCEP ATP III goal;[97] had non-HDL-C levels
>4.13 mmol/L;[98] were receiving stable therapy
with simvastatin 10–40 mg/day for at least the
previous 3 months[86] or stable statin therapy for
at least the previous 8 weeks;[97] had established
CHD;[86] and were in good health (as assessed by
medical history, physical examination, ECG and
laboratory tests).[97]
Dietary advice/assessment was provided prior
to[46,85,86,97,98] and throughout[46,85,86,97] the ac-
tive therapy phase.
In the monotherapy studies,[46,85] patients
were randomized to receive oral omega-3 EEC
4000 mg once daily or a comparator (placebo[85]
or oral gemfibrozil 1200 mg/day[46]) for 12[46] or
16[85] weeks. In the combination therapy stu-
dies,[86,97,98] patients were randomized to receive
oral omega-3 EEC 2000 mg twice daily or place-
bo, both in combination with oral simvastatin
10–40 mg/day for 24 weeks,[86] omega-3 EEC
4000 mg once daily or placebo, both in com-
bination with oral simvastatin 40 mg/day, for
8 weeks,[97] or omega-3 EEC 4000 mg once daily
or placebo, both in combination with oral ator-
vastatin (10, 20 then 40 mg/day over 8, 4 and
4 weeks, respectively) for 16 weeks.[98]
Patients in the 8-week combination therapy
study underwent a simvastatin 40 mg/day[97]
run-in period of 8 weeks; only those who were
assessed as ‡80% compliant with simvastatin
therapy, with mean triglyceride levels ‡2.2 to
<5.6 mmol/L and LDL-C levels £10% above
the NCEP ATP III goal, were randomized to
omega-3 EEC plus simvastatin or placebo plus
simvastatin therapy.[97] In the 24-week, combi-
nation therapy study, patients received stable
therapy with simvastatin 10–40 mg/day for at
ª 2009 Adis Data Information BV. All rights reserved.
Hoy & Keating
least 3 months prior to study commencement.[86]
Compliance was 80% in all but three patients.[86]
Patients from the 24-week study were invited to
participate in a 24-week, noncomparative exten-
sion phase during which they received omega-3
EEC 2000 mg twice daily.[86]
Where reported, antihyperlipidaemics (other
than simvastatin[86,97]) were discontinued at least
4–8 weeks prior to study commencement or ac-
tive therapy.[46,85,86,97]
Patients had a mean age of 45–60.3 years and a
mean BMI of 27.5–31.5 kg/m2.[46,85,86,97] Where
stated, patients had pre-existing CVD (20%),[46]
diabetes (3%;[46] 25%[86]) and hypertension
(15%).[46] In the 8-week, combination therapy
study, 75% and 68% of patients in the omega-3
EEC plus simvastatin (n = 122) and placebo
(n = 132) treatment groups were at their non-
HDL-C treatment goal at baseline.[97]
Where stated, the primary endpoints included
the percentage changes from baseline in serum tri-
glyceride,[46,86] non-HDL-C[97,98] and VLDL-C[86]
levels. Secondary or other endpoints included the
changes from baseline in serum total cholester-
ol,[46,86,97,98] triglyceride,[97,98] HDL-C,[46,86,97,98]
VLDL-C[46,86,97,98] and LDL-C,[86,97,98] apolipo-
protein[46] A-I,[86,98] B[86,97,98] and C-III,[98] free
fatty acid[46] and lipoprotein-associated phos-
pholipase A2[98] levels. Endpoints were not spe-
cified as primary or secondary in the 16-week
monotherapy study[85] and included changes in
serum triglyceride, total cholesterol, VLDL-C,
HDL-C, LDL-C and apolipoprotein A-I levels.
Endpoints in the 16-week combination therapy
study[98] were determined at week 8 of therapy.
Where specified, data are reported for the
modified intent-to-treat[97] and per-protocol[85,86]
populations.
4.2.1 Monotherapy
For the most part, monotherapy with oral ome-
ga-3 EEC 4000 mg/day demonstrated greater tri-
glyceride-lowering efficacy than placebo in patients
with hypertriglyceridaemia.[85] Significantly greater
reductions from baseline in triglyceride (mean per-
centage change 45%), total cholesterol (15%) and
VLDL-C (32%) levels and significantly greater ele-
Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review 1093

Table IV. Efficacy of oral omega-3 ethylester concentrate (omega-3 EEC) monotherapy in adult patients (pts) with hypertriglyceridaemia.
Summary of two randomized, double-blind, multicentre studies comparing omega-3 EEC with placebo (PL)[85] or gemfibrozil (GEM).[46] Pts
received omega-3 EEC 4000 mg once daily or a comparator (PL[85] or oral GEM 1200 mg/day[46]) for 12[46] or 16[85] weeks. Dietary ad-
vice/assessment was provided prior to and throughout the active therapy phase.[46,85] All baseline, endpoint and percentage change from
baseline values are means. Where specified, data are reported for the per-protocol population[85]
Study Treatment No. of TG (mmol/L) TC (mmol/L) VLDL-C (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L)
pts baseline endpoint baseline endpoint baseline endpoint baseline endpoint baseline endpoint
[%D] [%D] [%D] [%D] [%D]
Comparison with PL
Harris Omega-3 22 10.38 5.71 6.94 5.91 4.12 2.33 2.05 2.69 0.78 0.88
et al.[85] EEC [-45---] [-15--] [-32--] [+32] [+13-]
PL 20 9.91 11.38 7.80 7.64 4.59 4.56 2.49 2.36 0.73 0.73
[+16] [NRzzz]
Comparison with GEM
van Dam Omega-3 45 12.36 7.82**** 8.81 7.61**** 3.82 2.92** 3.28 3.66 0.81 0.75 [+1]
et al.[46] EEC [-29]a [-10] [-11]
GEM 44 11.55 5.22**** 8.41 6.82*** 3.55 2.07*** 3.59 4.60* 0.83 0.95
[-51zz]a [-13] [-19] [+28z]
a Primary endpoint.
%D = percentage change from baseline; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NR = not
reported; TC = total cholesterol; TG = triglyceride; VLDL-C = very-low-density lipoprotein cholesterol; * p < 0.05, ** p < 0.01, *** p £ 0.005,
****
p < 0.0001 vs baseline; - p < 0.05, -- p £ 0.001, --- p < 0.0001 vs PL; z p < 0.05, zz p < 0.01, zzz p < 0.005 vs omega-3 EEC.

vations from baseline in HDL-C levels (13%)
were observed with omega-3 EEC monotherapy
than with placebo (table IV).[85] A ‡35% reduc-
tion in triglyceride levels from baseline was
achieved by 18 of 22 (81.8%) patients of those
patients receiving omega-3 EEC monotherapy;
the remaining four patients achieved a £15% re-
duction.[85] In contrast, significant elevations in
LDL-levels were observed in omega-3 EEC ver-
sus placebo recipients (table IV).[85]
Significant (p < 0.001) reductions from baseline
in the ratio of total cholesterol : HDL-C were ob-
served in patients receiving omega-3 EEC mono-
therapy (mean percentage change from baseline
-20%; baseline 10.5) versus those receiving
placebo (mean percentage change not reported;
baseline 11.2).[85] No significant between-group
difference was observed in the LDL-C : HDL-C
ratio (3.3 [baseline 2.9] vs 3.2 [baseline 3.4]).[85]
No significant difference in serum apolipo-
protein A-I levels was observed between the
omega-3 EEC and placebo groups (1.31 vs
1.26 g/L; baseline: 1.32 vs 1.28 g/L).[85]
Gemfibrozil was associated with significantly
greater reductions from baseline in serum trigly-
ceride levels (primary endpoint) and significantly
greater elevations from baseline in HDL-C levels
than omega-3 EEC in a randomized, double-
blind, double-dummy, multicentre study in pa-
tients with hypertriglyceridaemia (table IV).[46]
Changes from baseline in total cholesterol and
VLDL-C levels did not significantly differ be-
tween the two treatment groups (table IV).[46]
4.2.2 In Combination with Simvastatin
or Atorvastatin
In general, omega-3 EEC plus simvastatin was
an effective lipid-modifying therapy in patients
with hypertriglyceridaemia, inducing signifi-
cantly greater reductions from baseline in trigly-
ceride and VLDL-C levels than placebo plus
simvastatin in two well designed clinical studies
(table V).[86,97,98] Significant between-group dif-
ferences in triglyceride and VLDL-C levels were
observed from week 12 in the 24-week study.[86]
Omega-3 EEC plus simvastatin was also asso-
ciated with significantly greater reductions from
baseline in total cholesterol levels and significantly
greater elevations from baseline in HDL-C levels
than placebo plus simvastatin in the 8-week study
(table V).[97] No significant between-group differ-

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
ª 2009 Adis Data Information BV. All rights reserved.

1094
Table V. Efficacy of oral omega-3 ethylester concentrate (omega-3 EEC) plus simvastatin (SIM) in adult patients (pts) with hypertriglyceridaemia. Summary of two randomized,
double-blind, multicentre studies comparing omega-3 EEC 2000 mg twice daily (bid)[86] or 4000 mg once daily (od)[97] with placebo (PL),[86,97] both in combination with SIM 10–40[86]
or 40[97] mg/day, for 8[97] or 24[86] weeks. Pts in the 8-week study underwent a SIM 40 mg/day run-in period of 8 weeks;[97] pts in the 24-week study received stable SIM therapy
10–40 mg/day for at least 3 months prior to study commencement.[86] Dietary advice/assessment was provided prior to and throughout the active therapy phase.[86,97] All baseline,
endpoint and percentage change from baseline values are means. Analyses are of modified intent-to-treat[97] or per-protocol[86] data
Study Treatment No. of Timepoint TG (mmol/L) TC (mmol/L) VLDL-C (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Non-HDL-C (mmol/L)
(mg/day) pts (wk) baseline endpoint baseline endpoint baseline endpoint baseline endpoint baseline endpoint baseline endpoint
[%D] [%D] [%D] [%D] [%D] [%D]
Davidson Omega-3 122 8 3.2 2.3 4.7 4.5 1.4 1.0 2.3 2.3 [+3.4] 1.2 1.3 3.5 3.2
et al.[97] EEC 4000 [-28.2--] [-4.7--] [-23.8--] [+4.1--] [-7.9-- c]
od + SIM 40

PL + SIM 40 132 8 3.2 3.1 [-3.5] 4.8 4.7 [-1.5] 1.4 1.3 [-4.8] 2.4 2.3 [-1.9] 1.2 1.1 [-1.1] 3.7 3.6 [-1.5c]

Durrington Omega-3 30 12 4.6 3.3*** 5.6 4.9*b 1.0 0.6** 3.5 3.1b 1.1 1.2b
et al.[86] EEC 2000 [-22.8-a] [-34.2-a]
bid + SIM
10–40

PL + SIM 27 12 3.8 3.9 6.2 6.3b 0.9 0.8 4.2 4.2b 1.1 1.2b
10–40 [+12.8a] [-2.8a]

Omega-3 29 24 4.6 3.5*** 5.6 5.0*b 1.0 0.6** 3.5 3.3b 1.1 1.0b
EEC 2000 [-18.6-a,c] [-31.4-a,c]
bid + SIM
10–40

PL + SIM 26 24 3.8 3.9 6.2 6.4b 0.9 0.8 4.2 4.4b 1.1 1.3b
10–40 [+4.2c] [-10.0a,c]
a Value derived from a graph.
Drugs 2009; 69 (8)

Hoy & Keating

b Percentage change from baseline not reported.
c Primary endpoint.
%D = percentage change from baseline; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride;
VLDL-C = very-low-density lipoprotein cholesterol; * p < 0.05, ** p < 0.005, *** p < 0.0005 vs baseline; - p < 0.005, -- p £ 0.001 vs PL + SIM.
Omega-3 Ethylester Concentrate: A Review
ence in LDL-C levels was observed between
omega-3 EEC plus simvastatin and placebo plus
simvastatin recipients (table V).[97] The propor-
tion of omega-3 EEC plus simvastatin recipients
achieving their LDL-C treatment goal in the
8-week study remained constant (93%).[97]
No quantitative data on the percentage chan-
ges from baseline in total cholesterol, HDL-C
and LDL-C levels were reported in the 24-week
study; however, significantly greater reductions
in total cholesterol levels versus baseline were
observed in omega-3 EEC recipients.[86]
Non-HDL-C levels were reduced to a sig-
nificantly greater extent with omega-3 EEC plus
simvastatin than with placebo plus simvastatin in
patients with hypertriglyceridaemia (table V).[97]
In the same study, 84% of omega-3 EEC plus
simvastatin recipients and 70% of placebo plus
simvastatin recipients reached their non-HDL-C
treatment goal at study end; 52% (16 of 31 pa-
tients) and 24% (10 of 42) of patients in the re-
spective treatment groups who were not at their
non-HDL-C treatment goal at baseline had
reached it by study end.[97]
In general, improvements in the lipid profiles
of patients with hypertriglyceridaemia observed
in the 24-week, double-blind phase of one study
were sustained with continued omega-3 EEC plus
simvastatin therapy in the 24-week, non-
comparative extension phase.[86] Furthermore,
patients who switched to omega-3 EEC from
placebo achieved lipid levels that were generally
similar to those observed in patients initially
treated with omega-3 EEC (figure 3).
Preliminary data indicate that oral omega-3
EEC plus atorvastatin improved the lipid profile
to a significantly greater extent than placebo plus
atorvastatin in patients with hypertriglycer-
idaemia.[98] At week 8, significantly greater reduc-
tions from baseline in non-HDL-C (median
percentage change from baseline: -40.2% vs
-33.7%; p < 0.0005) [primary endpoint], triglycer-
ide (-45.4% vs -26.9%; p < 0.0001), total choles-
terol (-31.5% vs -27.4%; p < 0.005) and VLDL-C
(-54.3% vs -37.0%; p < 0.0001) levels and sig-
nificantly greater improvements from baseline in
HDL-C levels (+12.4% vs +10.0%; p < 0.01) were
observed with omega-3 EEC 4000 mg/day plus
ª 2009 Adis Data Information BV. All rights reserved.
1095
atorvastatin 10 mg/day (n = 122) than with place-
bo plus atorvastatin 10 mg/day (n = 121).[98] No
significant difference in the median percentage
change from baseline in LDL-C levels was observed
in patients receiving omega-3 EEC 4000 mg/day
plus atorvastatin 10 mg/day (-29.3%) versus those
receiving placebo plus atorvastatin 10 mg/day
(-31.5%).[98] Non-HDL-C levels and various
other endpoints (not stated) were also sig-
nificantly improved versus baseline with omega-3
EEC plus atorvastatin 20 mg/day (weeks 9–12)
and omega-3 EEC plus atorvastatin 40 mg/day
(weeks 12–16) therapy (no data reported).[98]
5. Tolerability
This section focuses on the tolerability
data derived from the clinical studies discussed in
section 4;[46,65,85,86,97,98] supplementary data from
one post hoc analysis[92] of the GISSI-
Prevenzione study[65] are also discussed.
Oral omega-3 EEC was generally well tolerated
in secondary prevention post-MI patients and in
the treatment of patients with hypertriglycer-
idaemia.[46,65,85,86,97] Where reported, treatment-
Originally randomized to omega-3 EEC + SIM (n = 25)
Originally randomized to PL (n = 21)
6.0
Mean lipid levels (mmol/L)
5.0 **
4.0
*** ***
3.0 *
2.0
1.0 ** **
0
TG TC VLDL-C LDL-C HDL-C
Fig. 3. Efficacy of extended oral omega-3 ethylester concentrate
(omega-3 EEC) plus simvastatin (SIM) therapy in adult patients with
hypertriglyceridaemia. Mean serum triglyceride (TG), total choles-
terol (TC), very-low-density lipoprotein cholesterol (VLDL-C), low-
density lipoprotein cholesterol (LDL-C) and high-density lipoprotein
cholesterol (HDL-C) levels after 24 weeks’ therapy with omega-3
EEC 2000 mg twice daily plus SIM 10–40 mg/day in the non-
comparative extension phase of a randomized, double-blind, multi-
centre, 24-week study.[86] Data are for the per-protocol population.
PL = placebo; * p < 0.05, ** p < 0.005, *** p < 0.0005 vs baseline.
Drugs 2009; 69 (8)
1096
emergent adverse events associated with
omega-3 EEC were generally gastrointes-
tinal in nature[65,85] and mild[46] or minor[86]
in intensity.
Treatment-emergent gastrointestinal distur-
bances and nausea were observed in 4.9% and
1.4% of patients receiving omega-3 EEC 1000 mg/
day-based therapy and in 2.9% and 0.4% of pa-
tients receiving tocopherol 300 mg/day-based
therapy in studies of secondary prevention post-
MI in adult patients (see figure 2 for defini-
tions).[65] In the same study, a few patients
receiving omega-3 EEC monotherapy, omega-3
EEC plus tocopherol therapy, tocopherol mono-
therapy or no treatment developed cancer (2.2–2.7%),
including non-fatal cancer (0.9–1.5%).[65] Among
omega-3 EEC and tocopherol recipients, 11.6%
and 7.3% of patients discontinued therapy at
12 months and 28.5% and 26.2% of patients dis-
continued therapy at 42 months;[92] therapy was
stopped because of adverse events in 3.8% of
patients receiving omega-3 EEC and 2.1% of
patients receiving tocopherol.[65]
Monotherapy with omega-3 EEC
4000 mg/day was generally well tolerated in
patients with hypertriglyceridaemia.[46,85] In the
16-week study, 18.2% and 15.0% of patients ran-
domized to receive omega-3 EEC 4000 mg/day
(n = 22) or placebo (n = 20) experienced a gastro-
intestinal disturbance.[85] In the 12-week study,
treatment-emergent adverse events were experi-
enced by two patients in the omega-3 EEC
4000 mg/day group (n = 45) and three patients in
the oral gemfibrozil 1200 mg/day treatment
group (n = 44), with all the events classified as
mild.[46] No patient in either study permanently
discontinued therapy because of adverse
events[46,85] and no serious drug-related adverse
events were reported in the 16-week study.[85]
Combination therapy with omega-3 EEC
2000 mg twice daily[86] or 4000 mg once daily[97]
plus simvastatin 10–40[86]or 40[97] mg/day was
generally well tolerated in patients with hyper-
triglyceridaemia.[86,97] No significant difference in
the incidence of treatment-emergent adverse
events between those patients receiving omega-3
EEC 4000 mg/day (n = 122) or placebo (n = 132)
ª 2009 Adis Data Information BV. All rights reserved.
Hoy & Keating
plus simvastatin 40 mg/day was reported in the
8-week study (41.8% vs 47.7%).[97] Furthermore,
there were no significant between-group differ-
ences in the incidence of individual treatment-
emergent adverse events reported by ‡1% of
patients (and occurring more frequently in
omega-3 EEC 4000 mg/day plus simvastatin
40 mg/day recipients than in the control group);
these included nasopharyngitis (3.3% vs 2.3%),
upper respiratory tract infection (3.3% vs 0.8%),
diarrhoea (2.5% vs 2.3%), dyspepsia (2.5% vs
2.3%), bronchitis (1.6% vs 1.5%), cystitis (1.6% vs
0.8%) and gastroenteritis (1.6% vs 0%).[97] In the
24-week study, treatment-emergent adverse events
were observed in 73.3% of patients receiving
omega-3 EEC 4000 mg/day plus simvastatin
10–40 mg/day (n = 30) compared with 58.6% of
patients receiving placebo plus simvastatin
10–40 mg/day (n = 29) [no statistical analysis re-
ported], with the majority of events classified as
minor.[86] Few patients in either treatment group
withdrew because of adverse events (3.3% vs
3.4%).[86]
Serious adverse events in the 8-week, combi-
nation therapy study (none of which were drug-
related) were observed in 3.3% of omega-3
EEC 4000 mg/day plus simvastatin 40 mg/day
and 0.8% of placebo plus simvastatin 40 mg/day
recipients.[97] There were no reports of myopathy
or rhabdomyolysis in omega-3 EEC 4000 mg/day
plus simvastatin 40 mg/day and placebo plus
simvastatin 40 mg/day recipients in the 8-week,
combination therapy study.[97] No serious
drug-related adverse events were reported in the
16-week, combination therapy study.[98]
In general, laboratory parameters (e.g. levels
of ALT,[85] AST,[85] creatine phosphokinase,[97]
creatinine,[85,97] fasting blood glucose,[86] fibrino-
gen,[86] fructosamine,[97] glucose,[85] haematocrit,[85]
haemoglobin,[85] HbA1c,[85,86] homocysteine[97]
or uric acid[85]) were not altered to a signi-
ficant extent in patients receiving omega-3 EEC,
either alone[85] or in combination with simvasta-
tin.[86,97] Although no patient in the 8-week,
combination therapy study developed a clini-
cally significant increase in transaminase levels,
mildly elevated ALT levels occurred in 1.6% of
omega-3 EEC 4000 mg/day plus simvas-
Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review
tatin 40 mg/day recipients and 0.8% of placebo
plus simvastatin 40 mg/day recipients, with sig-
nificantly greater increases in ALT (+5.7 vs
-0.7 U/L; p < 0.001) and AST (+1.9 vs +0.2 U/L;
p < 0.032) levels occurring in omega-3 EEC plus
simvastatin recipients than in placebo plus sim-
vastatin recipients.[97] Fasting blood glucose le-
vels also increased to a significantly greater extent
with omega-3 EEC plus simvastatin than with
placebo plus simvastatin (+5.5 vs -0.1 mg/dL).[97]
6. Dosage and Administration
Oral omega-3 EEC is indicated in the majority
of European countries,[100] including the UK,[7]
as an adjuvant therapy to standard treat-
ment (e.g. ACE inhibitors, anti-platelet agents,
b-blockers, statins) for secondary prevention in
post-MI adult patients. It is also indicated for use
as an adjunct to diet in the treatment of hyper-
triglyceridaemia, either as monotherapy (type IV
hypertriglyceridaemia) or in combination with
statins (type IIb/III hypertriglyceridaemia when
triglyceride control is insufficient), in adult
patients who have not responded to dietary
measures.[7] In the US, omega-3 EEC is indi-
cated as an adjunct to diet in the treatment of
hypertriglyceridaemia (serum triglyceride levels
‡5.6 mmol/L [‡500 mg/dL]) in adult patients.[32]
Each 1000 mg capsule of omega-3 EEC consists
of ethyl EPA 460 mg and ethyl DHA 380 mg.[7]
The recommended omega-3 EEC dosage regimen
for secondary prevention post-MI is 1000 mg/day.
In patients with hypertriglyceridaemia, the re-
commended dosage regimen is 2000 mg/day in the
UK, increasing to 4000 mg/day if an adequate re-
sponse is not achieved,[7] and 4000 mg/day in the
US.[32] The capsule(s) may be administered with
food to avoid gastrointestinal disturbances.[7]
The regular monitoring of hepatic function
(ALT and AST levels) is necessary in patients
with hepatic impairment, particularly those re-
ceiving omega-3 EEC 4000 mg/day.[7] Patients at
high risk of haemorrhage (e.g. those undergoing
surgery or receiving anticoagulant therapy)
require monitoring (see section 2.4). Local pre-
scribing information should be consulted for de-
tailed information, including contraindications,
ª 2009 Adis Data Information BV. All rights reserved.
1097
drug interactions, precautions and use in special
patient populations.
7. Place of Omega-3 Ethylester
Concentrate in Secondary Prevention
Post-Myocardial Infarction and the
Treatment of Hypertriglyceridaemia
The interaction of multiple risk factors,
such as physical inactivity, smoking and an un-
healthy diet, contributes to the occurrence of
CVD.[101,102] Modifying these risk factors has
been shown to reduce CVD morbidity and mor-
tality, particularly in high-risk patients; thus,
effective risk management should target all
modifiable risk factors.[101]
The 2006 update of the American College
of Cardiology/American Heart Association
(ACC/AHA) guidelines for the secondary pre-
vention of coronary and other atherosclerotic
vascular disease[103] and the Fourth Joint Task
Force guidelines on CVD prevention in clinical
practice[101] provide a range of risk reduction
recommendations for the prevention of CVD,
including lifestyle modification and drug ther-
apy (e.g. anticoagulants, antihyperglycaemics,
antiplatelets, b-blockers, fibric acid deriva-
tives, statins, niacin, omega-3 fatty acids, renin-
aldosterone system inhibitors) in order to achieve
adequate BP and diabetes control, modify lipid
levels and provide cardioprotection.
The NCEP ATP III has identified elevated
LDL-C levels as a major risk factor for CHD and
the primary target for lipid-lowering therapy.[99]
Thus, a goal for patients with CHD or CHD risk
equivalents is a reduction in LDL-C levels to
<2.6 mmol/L (<100 mg/dL).[99,104] Elevated tri-
glyceride levels have recently been identified as an
independent risk factor for CHD, suggesting that
some triglyceride-rich lipoproteins are athero-
genic.[99] Factors leading to hypertriglyceridaemia
include obesity, physical inactivity, smoking,
excess alcohol intake, high carbohydrate diet, dis-
eases such as type 2 diabetes and chronic renal
failure, some drugs (e.g. corticosteroids) and
certain genetic disorders (e.g. familial hyper-
triglyceridaemia).[99] Hypertriglyceridaemia is
also associated with the metabolic syndrome.[99]
Drugs 2009; 69 (8)
1098
The treatment strategy for hypertriglycer-
idaemia is dependent upon the cause and severity
of the triglyceride elevation.[99] The primary aim
of therapy in patients with hypertriglyceridaemia
is to achieve the target LDL-C level.[99] In pa-
tients with triglyceride levels of 1.70–2.25 mmol/L
(150–199 mg/dL), the emphasis is placed on weight
management and physical activity.[99] For pa-
tients with triglyceride levels of 2.26–5.63 mmol/L
(200–499 mg/dL), non-HDL-C becomes a sec-
ondary therapy target.[99] Fibric acid derivatives
and niacin can also be administered.[99,105]
The presence of a high level of CHD risk or the
failure of lifestyle modification to lower LDL-C
levels warrants the utilization of drug ther-
apy;[105] the majority of patients with CHD will
require drug therapy to lower LDL-C levels.[99]
Statins are generally the first-line treatment op-
tion for lowering LDL-C levels, in conjunction
with lifestyle modification (a healthy diet, physi-
cal activity and weight management).[99,101,105]
However, triglyceride reduction is only a sec-
ondary benefit of statins.[105] Furthermore, addi-
tional lipid-lowering therapy targeting factors
other than LDL-C levels may also be warranted,
as some patients require combination lipid-
lowering therapy to achieve the various treatment
goals.[101] Non-lipid risk factors may also require
modification.[99]
Epidemiological data have demonstrated an
inverse relationship between fish consumption
and cardiovascular morbidity and mortality;[106]
the omega-3 fatty acids EPA and DHA are
mainly derived from oily fish.[5] The pharmaco-
dynamic and cardiovascular effects of omega-3
fatty acids have also been widely studied; taken
together, these data indicate that omega-3 fatty
acids have cardioprotective effects,[1,25,29,107]
with an inverse correlation observed between the
risk of coronary artery disease events and the
quantity of DHA in plasma and cellular phos-
pholipids (which is closely linked to the DHA
content of the myocardium).[108] Despite this, it is
not yet known whether DHA, EPA or the com-
bination of both contributes to the cardiopro-
tective effect observed with omega-3 fatty acid
therapy.[109]
ª 2009 Adis Data Information BV. All rights reserved.
Hoy & Keating
The consumption of large quantities of fish
has prompted concern regarding the levels of
contaminants, particular dioxins, mercury and
polychlorinated biphenyls, in certain fish spe-
cies.[24,107] However, current evidence suggests
that the benefits of moderate fish consumption
outweigh the potential risks among adults.[107]
Oral omega-3 EEC is the only omega-3 fatty
acid product approved in Europe and the US.
Omega-3 EEC 1000 mg/day was generally effec-
tive as an adjuvant therapy to standard treat-
ment (e.g. ACE inhibitors, anti-platelet agents,
b-blockers, statins) for secondary prevention
in post-MI adult patients (section 4.1). In the
GISSI-Prevenzione study, omega-3 EEC-based
therapy significantly reduced the risk of the pri-
mary composite endpoint of death plus nonfatal
MI plus nonfatal stroke as well as various sec-
ondary or other endpoints (including death, car-
diovascular death and sudden death). However,
there was no significant difference in the risk of
cardiovascular death plus nonfatal MI plus non-
fatal stroke (coprimary composite efficacy end-
point) with omega-3 EEC- versus non-omega-3
EEC-based therapy.
Individual component and post hoc time-
course analyses suggest that the reductions in the
risk of death and cardiovascular death follow-
ing omega-3 EEC monotherapy contribute to
the significant reductions observed in the risk of
the coprimary composite efficacy endpoints
(section 4.1). However, the 45% reduction in the
risk of sudden death (secondary endpoint) was
the major component in the reduction in the risk
of death. Another post hoc analysis has suggested
that omega-3 EEC therapy may have benefits in
the subgroup of post-MI patients with LVSD
(section 4.1); however, randomized studies are
required to assess this further.
Differing results were observed in the OME-
GA study, with no significant difference in
the incidence of sudden cardiac death (primary
endpoint) and the various secondary endpoints
seen between the omega-3 EEC and placebo
treatment groups (section 4.1). Of note, the
observed incidence of sudden cardiac death
in both the omega-3 EEC and placebo groups
(1.5% vs 1.5%) was lower than anticipated,
Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review
with the OMEGA study design assuming a sud-
den cardiac death rate of 1.9% in omega-3 EEC
recipients and 3.5% in placebo recipients, thus
preventing robust conclusions from being drawn.
The 12-month OMEGA study (n = 3851) in-
cluded only those patients who had experienced a
MI within the previous 3–14 days, while the 42-
month GISSI-Prevenzione study (n = 11 324) in-
cluded those who had experienced a MI within
the previous 3 months. With only preliminary
data from the OMEGA study currently available,
further findings are awaited with interest.
Oral omega-3 EEC, as monotherapy or in
combination with simvastatin or atorvastatin,
was generally effective as an adjunct to diet in the
treatment of hypertriglyceridaemia in adult pa-
tients (section 4.2). Omega-3 EEC monotherapy
demonstrated significantly greater reductions
from baseline than placebo in triglyceride, total
cholesterol and VLDL-C levels, and significantly
greater elevations from baseline in HDL-C levels
in a small study (section 4.2.1). In another study,
oral gemfibrozil was associated with significantly
greater reductions in serum triglyceride levels
(primary endpoint) and significantly greater in-
creases in HDL-C levels than omega-3 EEC
monotherapy (section 4.2.1). However, no sig-
nificant differences in total cholesterol and
VLDL-C levels were observed between the two
treatment groups. It should be noted that the
results from this study[46] are at variance with
those from Stalenhoef et al.[40] (section 2.2);
however, Stalenhoef et al.[40] was not powered to
determine any between-treatment differences.
Additional studies would be of interest.
In general, omega-3 EEC plus simvastatin was
an effective lipid-modifying therapy in patients
with hypertriglyceridaemia, inducing signifi-
cantly greater reductions from baseline in trigly-
ceride and VLDL-C levels than placebo plus
simvastatin in two clinical studies (section 4.2.2).
For the most part, improvements in the lipid
profiles of patients with hypertriglyceridaemia
observed in the 24-week, double-blind phase of
one study were sustained with continued omega-3
EEC plus simvastatin therapy in the 24-week,
noncomparative extension phase (section 4.2.2).
Preliminary data indicate that omega-3 EEC plus
ª 2009 Adis Data Information BV. All rights reserved.
1099
atorvastatin is associated with significantly
greater reductions from baseline in non-HDL-C
(primary endpoint), total cholesterol, triglyceride
and VLDL-C levels and significantly greater
improvements from baseline in HDL-C levels
than placebo plus atorvastatin in patients with
hypertriglyceridaemia.
The precise mechanisms of action of omega-3
EEC, in terms of both its triglyceride-lowering
effect and its secondary preventive effect in
patients with recent MI, are not yet fully under-
stood (section 2.1). It has been suggested that
the early protection against sudden cardiac
death conferred by omega-3 EEC in the GISSI-
Prevenzione study[65] (section 4.1) was due to an
antiarrhythmic effect.[91] Indeed, evidence for an
antiarrhythmic effect of omega-3 fatty acids
comes from various sources, such as epidemio-
logical studies examining fish consumption[30]
and preclinical studies (section 2.3). However,
results in clinical studies have been mixed
(section 2.3).[30] There are a number of possible
explanations for the disparity in results, including
differences in background diet, the source and
amount of omega-3 fatty acids administered
and the patient population.[30] For example,
patients in the GISSI-Prevenzione study[65]
had experienced recent MI and were most
likely experiencing ischaemic VF,[16] unlike
patients in ICD studies (which showed mixed re-
sults; section 2.3). Thus, it has been suggested
that the antiarrhythmic effects of omega-3 fatty
acids may be greatest in the setting of acute
ischaemia and VF, and that the mechanism of
benefit may not involve suppression of re-entrant
VF or VT.[16,110]
Other factors purported to contribute to the
cardioprotective effects of omega-3 fatty acids
include antithrombotic, antiatherogenic and
anti-inflammatory effects. Improvements in re-
levant parameters have been reported in some
studies, although the effects are inconsistent
(sections 2.4 and 2.5). Thus, it seems that in
patients with CHD, the most important con-
tributor to the reduction in sudden cardiac death
is likely to be the effect of omega-3 fatty acids on
the physiology of the cardiac and/or autonomic
nervous systems.[69]
Drugs 2009; 69 (8)
1100
Currently, the efficacy of omega-3 EEC
1000 mg/day is being assessed in cardiovascular
disease prevention in a randomized, open-label,
multicentre, factorial design study in dysgly-
caemic patients with impaired fasting glucose,
impaired glucose tolerance or diabetes (ORIGIN
[Outcome Reduction with an Initial Glargine
Intervention]).[111] In addition, two recently
published, randomized, double-blind, placebo-
controlled, clinical studies[112,113] have evaluated
the efficacy of omega-3 EEC 1000[113] and
2000[112] mg/day in cardiovascular disease pre-
vention in patients with type 2 diabetes who were
not receiving lipid-lowering therapy (AFORRD
[Atorvastatin in Factorial with Omega-3 EE
(EthylEster)90 Risk Reduction in Diabetes])[112]
and in the treatment of patients with chronic
heart failure (GISSI-HF [GISSI-Heart Fail-
ure]).[113] GISSI-HF observed a beneficial effect
with omega-3 EEC therapy in terms of the co-
primary efficacy endpoints of all-cause mortality
(adjusted hazard ratio [HR] 0.91; 95.5% CI 0.833,
0.998) and all-cause mortality or hospitaliza-
tions for cardiovascular reasons (adjusted HR
0.92; 99% CI 0.849, 0.999) in patients with
heart failure, suggesting an effect by omega-3
EEC on the mechanisms leading to heart failure
progression.[113]
Pharmacoeconomic analyses of omega-3
EEC in the treatment of patients with hyper-
triglyceridaemia are currently lacking; however, a
limited number of pharmacoeconomic analyses
in secondary prevention post-MI are available
(section 4.1.1). Data predict that omega-3 EEC
plus standard therapy is cost effective in second-
ary prevention post-MI relative to standard
therapy. However, further long-term, robust
pharmacoeconomic studies are required to
fully establish the cost effectiveness of omega-3
EEC.
Oral omega-3 EEC was generally well toler-
ated in secondary prevention post-MI and the
treatment of hypertriglyceridaemia (section 5).
Treatment-emergent adverse events associated
with omega-3 EEC were generally gastrointes-
tinal in nature and mild or minor in intensity.
Given that omega-3 fatty acids have demon-
strated inhibitory effects on thrombosis in vitro,
ª 2009 Adis Data Information BV. All rights reserved.
Hoy & Keating
there is a concern that omega-3 EEC therapy
may elevate the risk of bleeding (section 2.4).
However, current clinical evidence indicates
a negligible risk of bleeding with omega-3
EEC therapy.[24,26] Regardless, monitoring
(with possible adjustments in the anticoagulant
dosage) following the concurrent administration
of omega-3 EEC and anticoagulant therapy is
recommended, particularly with the utilization of
high (4000 mg/day) oral omega-3 EEC dosages
(sections 2.4 and 6).[7]
Oral omega-3 EEC is indicated in the majority
of European countries,[100] including the UK,[7]
as an adjuvant therapy to standard treatment
(e.g. ACE inhibitors, anti-platelet agents, b-block-
ers, statins) for secondary prevention in post-MI
adult patients. It is also indicated for use as
an adjunct to diet in the treatment of hyper-
triglyceridaemia, either as monotherapy (type IV
hypertriglyceridaemia) or in combination with
statins (type IIb/III hypertriglyceridaemia when
triglyceride control is insufficient), in adult
patients who have not responded to dietary
measures.[7] In the US, omega-3 EEC is indi-
cated as an adjunct to diet in the treatment of
hypertriglyceridaemia (serum triglyceride levels
‡5.6 mmol/L [‡500 mg/dL]) in adult patients.[32]
The ACC/AHA[103] and the UK National In-
stitute of Health and Clinical Excellence[114]
guidelines both recommend an increase in the
consumption of omega-3 fatty acids, in the form
of fish or omega-3 EEC capsules (1000 mg/day)
for secondary prevention post-MI, with higher
doses indicated for the treatment of hyper-
triglyceridaemia.[103] Current literature, including
the GISSI-Prevenzione study,[65] has served as the
foundation for the recommendation of omega-3
fatty acid therapy in the treatment guidelines.[115]
However, a previous Cochrane review[116] and
recent meta-analysis[117] on the use of omega-3
fatty acids for the prevention and treatment of
CVD concluded that it was unclear whether diet-
ary or supplemental omega-3 fatty acids altered
the rates of total death, combined cardiovascular
events or cancer in patients with, or at high risk
of, CVD or in the general population and that fur-
ther study was required. The Cochrane review[116]
analysed 48 randomized controlled studies
Drugs 2009; 69 (8)
Omega-3 Ethylester Concentrate: A Review
(36 913 patients) and 41 cohort studies, and
found no strong evidence of a reduction in the
risk of total mortality (RR 0.87; 95% CI 0.73,
1.03) or combined cardiovascular events (RR
0.95; 95% CI 0.82, 1.12) in omega-3 fatty acid
recipients.[116,117] Following publication of the
Cochrane review, however, debate has ensued
regarding the inclusion of the DART (Diet and
Reinfarction Trial) II in the analysis;[115,118,119]
upon excluding DART II from the Cochrane
analysis, the RR of total death was 0.83 (95% CI
0.75, 0.91).[116] Exclusion of DART II did not,
however, result in a significant reduction in the
risk of cardiovascular events following omega-3
fatty acid therapy.[116]
Of interest, a recent meta-analysis of 12 studies
involving >30 000 patients concluded that omega-3
fatty acid therapy demonstrated no beneficial
effect on the coprimary (arrhythmic) endpoints of
implantable cardiac defibrillation intervention
(OR 0.90; 95% CI 0.55, 1.46) and sudden cardiac
death (OR 0.81; 95% CI 0.52, 1.25) or on the sec-
ondary endpoint of all-cause mortality (OR 0.92;
95% CI 0.82, 1.03), but a significant reduction in
the secondary endpoint of mortality from cardiac
causes was seen (OR 0.80; 95% CI 0.69, 0.92).[120]
The potential mechanism behind this beneficial
effect remains to be elucidated.[120] Thus, while the
balance of evidence suggests that omega-3 fatty
acids reduce cardiovascular risk,[119] further well
designed studies would be of use in clarifying
the extent to which omega-3 fatty acids reduce
cardiovascular morbidity and mortality and the
mechanisms behind this beneficial effect.[115,118]
In conclusion, the addition of omega-3 EEC
1000 mg/day to standard medical therapy in the
GISSI-Prevenzione study provided secondary
prevention benefits in post-MI adult patients.
The benefits were attributable to reductions in
death and cardiovascular death (including sud-
den death). Additional data examining the extent
and mechanisms of the cardiovascular benefit
conferred by omega-3 EEC in secondary pre-
vention would be useful. As an adjunct to diet,
monotherapy with omega-3 EEC 4000 mg/day
significantly reduced triglyceride levels in patients
with hypertriglyceridaemia, although limited
data suggest it was less effective than gemfibrozil.
ª 2009 Adis Data Information BV. All rights reserved.
1101
In addition, omega-3 EEC 4000 mg/day plus
simvastatin or atorvastatin reduced triglyceride,
non-HDL-C and/or VLDL-C levels to a signifi-
cantly greater extent than placebo plus simvas-
tatin. Omega-3 EEC was generally well tolerated
both as secondary prevention post-MI and in
the treatment of hypertriglyceridaemia. Thus,
omega-3 EEC is a useful option both in second-
ary prevention post-MI and the treatment of
hypertriglyceridaemia.
Disclosure
The preparation of this review was not supported by any
external funding. During the peer review process, the manu-
facturer of the agent under review was offered an opportunity
to comment on this article. Changes resulting from comments
received were made on the basis of scientific and editorial merit.
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