Omega 3

Omega-3 Ethylester ConcentrateA Review of its Use in Secondary PreventionPost-Myocardial Infarction and the Treatmentof 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 Epidemiologyof Cardiovascular Disease, Department of Clinical Pharmacology and Epidemiology, Consorzio Mario NegriSud, Santa Maria Imbaro, Italy; C. Von Schacky, Preventive Cardiology, Medizinische Klinik and PoliklinikInnenstadt, 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 thereference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from thecompany developing the drug.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-3ethylester concentrate. Inclusion of studies was based mainly on the methods section of the studies. When available, large, well controlledstudies 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10781. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10802. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081

2.1 Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10812.2 Effects on Lipid Levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10822.3 Cardiovascular Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10832.4 Effects on Thrombosis and Haemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10842.5 Anti-Atherogenic and Anti-Inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085

3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10854. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086

4.1 In Secondary Prevention Post-Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10864.1.1 Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090

4.2 In the Treatment of Hypertriglyceridaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10914.2.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10924.2.2 In Combination with Simvastatin or Atorvastatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093

ADIS DRUG EVALUATIONDrugs 2009; 69 (8): 1077-1105

0012-6667/09/0008-1077/$55.55/0

ª 2009 Adis Data Information BV. All rights reserved.

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10956. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10977. Place of Omega-3 Ethylester Concentrate in Secondary Prevention Post-Myocardial Infarction

and the Treatment of Hypertriglyceridaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097

SummaryAbstract 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 ‡5.6mmol/L [‡500mg/dL]) in the US. Each 1000mg

capsule of omega-3 EEC consists of 460mg of ethyl eicosapentaenoic acid and

380mg of ethyl docosahexaenoic acid.

The addition of omega-3 EEC 1000mg/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 4000mg/day significantly reduced triglyceride levels in patients

with hypertriglyceridaemia, although limited data suggest it was less effective

than gemfibrozil. In addition, omega-3 EEC 4000mg/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.

PharmacologicalProperties

The proposed mechanisms of action for the triglyceride-lowering effects observed

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.

1078 Hoy & Keating

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

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.

Therapeutic Efficacy Oral omega-3 EEC 1000mg/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 1000mg/day andomega-3 EEC 1000mg/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-

Omega-3 Ethylester Concentrate: A Review 1079


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

life-year gained.Oral omega-3 EEC 4000mg/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

Numerous epidemiological and clinical studieshave corroborated anecdotal evidence of thebenefits of a diet rich in fish on cardiovasculardisease (CVD).[1-5] Certain fish species (e.g. tuna)

yield significant levels of eicosapentaenoic acid(EPA) and docosahexaenoic acid (DHA), twoomega-3 fatty acids with a demonstrable cardio-protective effect.[2-4,6]

Oral omega-3 ethylester concentrate, hereafterreferred to as omega-3 EEC, comprises the ethyles-

1080 Hoy & Keating


ters of the omega-3 fatty acids EPA and DHA(see figure 1).[7] Specifically, each 1000mg cap-sule of omega-3 EEC contains approximately460mg of the EPA ethylester and 380mg of theDHA ethylester.[7] This article reviews the phar-macological properties of oral omega-3 EEC(Omacor�; Lovaza�), focusing on its efficacyand tolerability in secondary prevention post-myocardial infarction (MI) and the treatment ofpatients with hypertriglyceridaemia. Throughoutthis article, lipid levels are reported in mmol/L;to convert to mg/dL, triglyceride values shouldbe multiplied by 88.6 and total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) andvery-low-density lipoprotein cholesterol (VLDL-C)values should be multiplied by 38.7.

2. Pharmacodynamic Properties

There are a plethora of data concerning thepharmacodynamic effects of omega-3 fatty acidswhen consumed as part of the diet or adminis-tered as supplements.[1,8] This section focuses onthe pharmacodynamic properties of oral omega-3EEC, where data pertaining to this specificformulation are available, supplemented withinformation relating to omega-3 fatty acids ingeneral. Studies used various dosages of omega-3fatty acids; the maximum recommended dailydose of omega-3 EEC is 4000mg (section 6).

Apart from one noncomparative study,[9]

clinical studies discussed in this section wererandomized, with the majority double- or single-blind. All but two studies (which were in healthy

volunteers[10,11]) were conducted in patients withcardiovascular disorders or hyperlipidaemia.Most studies included <100 participants and hada treatment period of £6 months. All but one[12] ofthe studies with longer treatment periods (median356–718 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 generalpharmacodynamic effects of omega-3 fatty acidswere 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 fattyacids, including omega-3 EEC, is not fully un-derstood.[32,33] Two main mechanisms have beenproposed to explain the triglyceride-loweringeffects of omega-3 fatty acids.[33] Firstly, the in-hibition of acyl CoA:1,2-diacylglycerol acyl-transferase by omega-3 fatty acids may reducethe hepatic synthesis of triglycerides.[34] EPA andDHA have high affinity for the enzymes involvedin triglyceride synthesis, but are poor substratesfor these enzymes.[7,34] Thus, the esterificationand release of other fatty acids is prevented.[7,34]

Secondly, omega-3 fatty acids have high affinityfor peroxisome proliferator-activated receptorsubtypes, thereby increasing hepatic peroxisomalb-oxidation and upregulating fatty acid metabo-lism in the liver.[35-37] This reduces the quantity offree fatty acids available for triglyceride synthesis,and reduces triglyceride levels; secretion of tri-glyceride-rich VLDL is also inhibited.[7] Omega-3

H3C

Docosahexaenoic acid ethylester

Eicosapentaenoic acid ethylester

O CH3

O

H3C

O CH3

O

Fig. 1. Omega-3 ethylester concentrate.



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 increasethe removal of triglycerides from circulatingVLDL and chylomicron particles via the upre-gulation of enzymes, such as lipoproteinlipase.[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-3fatty acids are well established. Briefly, resultsof a systematic review demonstrated dose-dependent reductions in triglyceride levels withomega-3 fatty acids in clinical studies; net reduc-tions in triglyceride levels of 10–33% were seen inmost studies.[8] The effect of omega-3 fatty acidstended to be greater in studies with higher tri-glyceride levels at baseline.[8] Changes in totalcholesterol and HDL-C levels were generally notsignificant, and small net increases occurred inLDL-C levels.[8]

These data are supported in part by thosefrom 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) reductionsin plasma or serum triglyceride, total choles-terol, non-HDL-C, VLDL-C, VLDL-triglycerideand/or apolipoprotein-B levels, and signifi-cant (p < 0.05) elevations in plasma or serumHDL-C and/or LDL-C levels with omega-3 EEC4000mg/day, alone[40-44] or in combination withsimvastatin 20mg/day,[45] were evident. However,in contrast to a study[46] discussed in section 4.2,no significant differences in the lipid parametersmeasured (plasma triglycerides, total cholesterol,HDL-C, LDL-C, VLDL-C andVLDL-triglyceridelevels) were observed between omega-3 EEC andoral gemfibrozil 1200mg/day.[40] Furthermore,

no significant reductions from baseline in LDL-Clevels were observed between the omega-3 EECplus simvastatin 20mg/day and the placebo plussimvastatin 20mg/day treatment groups.[45]

Elevations in LDL-C levels observed withomega-3 EEC are believed to result from theconversion of VLDL-C.[47] In a study in 24 obesepatients with dyslipidaemia, therapywith omega-3EEC 4000mg/day significantly (p < 0.05) reducedtriglyceride and VLDL-triglyceride levels andthe VLDL-apolipoprotein B production ratecompared with placebo.[48] Furthermore, themean conversion rate of VLDL-apolipoprotein Bto intermediate density lipoprotein (IDL)-apolipoprotein B (from 28.6% to 42.6%) andLDL-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 typicallyreflects a shift to larger LDL particles, which maybe less atherogenic.[31] The direction of the shift inLDL particle size seen with omega-3 EEC seemedto depend on the triglyceride level (threshold1.13–2.82mmol/L) in patients with hypertriglycer-idaemia (triglyceride levels of 2.3–5.6mmol/L,despite receiving simvastatin 40mg/day) whowere randomized to receive omega-3 EEC4000mg/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 to20.2 nm; p= 0.007 vs placebo). In patients withon-treatment triglyceride levels of <1.7, 1.7–2.2,2.3–2.8 and ‡2.8mmol/L, median changes frombaseline 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 in68%, 79%, 93% and 73% of patients at baselineand 36%, 50%, 82% and 84% of patients atendpoint.[18]

The increases in LDL particle size identified intheMaki et al.[18] study with omega-3 EEC therapywere also observed in a study in patients withmixedlipidaemia: omega-3 EEC 4000mg/day plus sim-vastatin 20mg/day induced a significant (p< 0.05)increase from baseline in least-squares mean LDL

1082 Hoy & Keating


particle size (from 19.9 to 20.4 nm) comparedwith placebo plus simvastatin 20mg/day (from19.9 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 andconcentration were also observed between thetwo treatment groups.[45]

Both oral omega-3 EEC 4000mg/day and oralgemfibrozil 1200mg/day significantly (p < 0.05)elevated the cholesterol content of the LDL-1,LDL-2 and LDL-3 subfractions versus baselinein patients with hypertriglyceridaemia, resultingin amore buoyant, less atherogenic LDL subfrac-tion profile.[40] No significant differences in theLDL-4 and LDL-5 subfractions versus baselineand no between-group differences in the cholesterollevels of the LDL subfractions were observed.[40]

Average LDL particle size was unchangedfollowing omega-3 EEC therapy in patients withfamilial combined hyperlipidaemia, although theLDL-C : apolipoprotein-B ratio was elevated,indicating an elevation in the more buoyant andcore-enriched LDL particles (LDL-1 and LDL-2subfractions).[44]

Results from therapeutic efficacy studiesexamining the effects of omega-3 EEC on lipidlevels in patients with hypertriglyceridaemia orrecent MI are discussed in section 4.

2.3 Cardiovascular Effects

Omega-3 fatty acids reduce BP, according tothe results of a meta-analysis.[20] Overall, a meansystolic/diastolic BP reduction of 2.3/1.5mmHgoccurred at a mean omega-3 fatty acid dosage of4100mg/day.[20] Subgroup analyses demon-strated that BP was reduced to a greater extentin older (age >45 years) versus younger partici-pants and in hypertensive versus normotensiveparticipants.

The findings of this meta-analysis[20] weresupported by the results of studies in patientswith 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

(p < 0.05 vs baseline or controls) reductions insystolic and/or diastolic BP with omega-3 EEC2000–6000mg/day. However, no significantchanges 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 fattyacids (median dosage 3500mg/day).[21] Sub-group analysis revealed a significant (p < 0.001)reduction of 2.5 beats/minute in patients witha mean heart rate of ‡69 beats/minute at baseline,with no significant change among those with amean heart rate of <69beats/minute at baseline.[21]

The results of in vitro,[55] animal[56-60] andsome human[61] studies suggest that omega-3fatty acids have antiarrhythmic effects. Variousmechanisms have been proposed to explain theapparent antiarrhythmic effects of omega-3 fattyacids, including incorporation of DHA and EPAinto membrane phospholipids (increasingarrhythmic thresholds), effects on ion channels(i.e. inhibition of fast voltage-dependent and latesodium channels, L-type calcium channels anddelayed-rectifier potassium channels) and effectson autonomic balance.[23,25,29,30,62-64]

An antiarrhythmic effect is one of the favouredexplanations for the reduced risk of sudden car-diac death seen in patients with recent MI whoreceived omega-3 EEC in the GISSI (GruppoItaliano per lo Studio della Sopravvienze nell’In-farto miocardico)-Prevenzione study[65]

(section 4).[25,27] However, mixed results were seenwith omega-3 fatty acid supplementation in large,well designed studies in patients with implantablecardioverter defibrillators (ICDs).[13,15,16] Althoughprimary 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 byomega-3 fatty acids to a significant extent,[13,15,16]

omega-3 fatty acids had favourable effects incertain subpopulations. For example, a signifi-cant (p= 0.033) 31% reduction in the primaryendpoint was seen with omega-3 fatty acids when



probable events were also considered.[15] Itshould be noted that these ICD patients comprisea different population to those in the GISSI-Prevenzione study[65] (sections 4 and 7). Omega-3EEC has also demonstrated a preventative atrialfibrillation effect in patients undergoing coro-nary artery bypass graft surgery (CABG).[66]

Compared with control (usual care), omega-3EEC 2000mg/day plus usual care significantlyreduced the incidence of postoperative atrialfibrillation (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 significantindependent predictors of postoperative atrialfibrillation.[66]

Another possible explanation for the reduc-tion in sudden cardiac death seen with omega-3EEC is an augmentation in autonomic tone.[23,29]

A positive correlation has been seen betweenheart rate variability and the omega-3 fatty acidcontent of cell membranes,[67] suggesting thatomega-3 fatty acid supplementation may increaseheart rate variability and protect against suddencardiac death. However, mixed results havebeen obtained in terms of the effect of omega-3fatty acids on heart rate variability.[9,54,68,69]

A significant (p < 0.05 vs controls) increase inheart rate variability occurred in patients withrecent MI who received omega-3 fatty acids5200mg/day for 3 months.[68] In patients withhealed MI and left ventricular dysfunction, whilethere was no improvement in overall heart ratevariability, omega-3 fatty acids 1500mg/day sig-nificantly improved heart rate variability in thehigh-frequency band (p = 0.02 vs placebo) andreduced heart rate after exercise to a significantlygreater 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 indicesto a significant extent in patients with mild hy-pertension[9] or post-MI.[54]

Improvements in endothelial function havebeen reported in patients receiving omega-3 fattyacids.[31] In patients with hypercholesterolaemia,endothelium-dependent, flow-mediated dilata-

tion increased from baseline to a significantly(p < 0.05) greater extent with omega-3 EEC4000mg/day (from 0.05 to 0.12mm) than withplacebo (from 0.03 to 0.04mm).[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 1000–4000mg/day.[10] Inaddition, 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 apotential 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 factorgenerally did not differ significantly between re-cipients of omega-3 EEC 1000–6000mg/dayand controls in studies involving healthy volun-teers,[11] post-MI patients,[74] patients with mildhypertension,[9] patients with combined hyper-lipidaemia[75] or patients undergoing CABGsurgery.[76]

Concern has been raised that an antithrombo-tic effect could potentially increase the risk ofclinically significant bleeding in patients receiv-ing omega-3 fatty acids.[24,26] However, omega-3EEC 6000mg/day did not affect bleeding time atrest QJ;in patients with familial hypercholester-olaemia, although exercise-induced shortening ofthe bleeding time was inhibited (p< 0.05 vs base-line).[77] No significant between-group differenceswere seen with omega-3 EEC 6000mg/day andcontrols in terms of platelet numbers or bleed-ing times[76] or omega-3 EEC 4000mg/day andplacebo in the incidence of bleeding episodes[14]

in patients undergoing CABG,[14,76] some ofwhom also received warfarin or aspirin. Regard-less, patients receiving anticoagulant therapyshould be monitored (e.g. the prothrombintime should be monitored in patients receiving

1084 Hoy & Keating


warfarin) and the anticoagulant dosage adjustedas necessary in patients receiving omega-3 EEC.[7]

2.5 Anti-Atherogenic andAnti-Inflammatory Effects

Meta-analyses have suggested that omega-3fatty acids may prevent restenosis following coro-nary angioplasty.[19,22] However, treatment withomega-3 EEC 6000mg/day for 6 months did notreduce the incidence of restenosis in patients whohad undergone coronary angioplasty.[78]

EPA and DHA were incorporated into theatherosclerotic plaques of patients who receivedomega-3 fatty acids prior to undergoing carotidendarterectomy, potentially improving plaquestability.[79] Similarly, plaque phospholipid EPAcontent was significantly (p < 0.0001) higher inpatients who received omega-3 EEC 2000mg/dayversus 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) levelsfor 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-groupdifference inmRNA levels ofMMP-3,MMP-8 orMMP-13.[17]

In patients with hypertriglyceridaemia, solubleE-selectin (sE-selectin) levels were increased frombaseline to a significantly greater extent withomega-3 EEC 4000mg/day than with placeboafter 6 weeks’ therapy (+11% vs -2%; p= 0.01),although after more than 6 months’ treatment,significant decreases from baseline in sE-selectinlevels of 16% (p < 0.0001) and in soluble ICAM-1levels of 9% (p = 0.02) were observed.[42]

In addition, gene expression of platelet-de-rived growth factor-A and -B was down regulatedin mononuclear cells from healthy volunteerswho received omega-3 EEC 7000mg/day for6 weeks.[80]

In terms of inflammatory markers, therewas a significant (p = 0.02) reduction from base-line in endotoxin-stimulated tumour necrosisfactor (TNF)-a production in peripheral bloodmononuclear cells from patients with severe

heart failure who received omega-3 fatty acids8000mg/day for 18 weeks.[81] However, no sig-nificant change from baseline in TNFa levels wasobserved in obese patients with dyslipidaemiawho received omega-3 EEC 4000mg/day for6 weeks.[82]

Interleukin-6 levels were not altered to a sig-nificant extent with omega-3 EEC 1000mg/dayversus control in post-MI patients[74] or withomega-3 EEC 4000mg/day versus baseline inobese patients with dyslipidaemia.[82]

In general, omega-3 fatty acids did not affectC-reactive protein (CRP) levels;[8,69] no signifi-cant change in CRP levels versus baseline wasobserved with omega-3 EEC 4000mg/day ther-apy in obese patients with dyslipidaemia.[82]

3. Pharmacokinetic Properties

Animal studies demonstrated that oralomega-3 EEC is completely hydrolyzed, afterwhich EPA and DHA are absorbed and in-corporated into plasma phospholipids and cho-lesterol esters.[7] Indeed, EPA and DHA wereabsorbed following their oral administration asethylesters to healthy volunteers[32,33,83,84] andpatients with hypertriglyceridaemia.[32]

In healthy volunteers receiving omega-3EEC 1000, 2000 or 4000mg/day for 12 weeks,significant (p < 0.05 vs baseline) dose-dependentincreases were seen in plasma phospholipidEPA and DHA content.[10] Omega-3 EEC4000mg/day also significantly (p < 0.05 vs base-line and/or controls) increased plasma/serumphospholipid EPA and DHA content in variouspatient populations, including patients with se-vere hypertriglyceridaemia,[85] combined hy-perlipidaemia[51] or essential hypertension[49] andhypertensive heart transplant recipients.[12] Inpatients with coronary heart disease (CHD) re-ceiving omega-3 EEC 2000mg twice daily, meanserum phospholipid EPA and DHA concentra-tions increased 361% and 52% after 12 months oftherapy (see section 4 for study details).[86] TheEPA and DHA concentrations in plasma phos-pholipids correspond to the EPA and DHA in-corporated into cell membranes.[7]



Omega-3 fatty acids are metabolized via threemain pathways during and after absorption.[7]

Fatty acids are initially transported to the liverfor incorporation into lipoproteins, after whichthey are channelled to peripheral lipid stores.[7]

Secondly, cell membrane phospholipids are re-placed by lipoprotein phospholipids allowingfatty acids to act as precursors for eicosanoids.[7]

Finally, the majority of omega-3 fatty acids areoxidised to meet energy requirements.[7]

Age (<49 vs ‡49 years) did not affect the up-take of EPA and DHA into serum phospholipidsin omega-3 EEC recipients.[32] The uptake ofEPA in serum phospholipids tended to be greaterin women than in men.[32]

Undetectable concentrations (<1 mmol/L) ofthe free forms of EPA and DHA are present inthe circulation, meaning that clinically signifi-cant inhibition of cytochrome P450 (CYP) en-zymes is not expected to occur.[32] In vitro, a freefatty acid-albumin conjugate (concentrationof 23 mmol/L) inhibited CYP2A6, CYP2C19,CYP2D6 and CYP3A by <20%, with 68% in-hibition of CYP2E1.[32]

The concomitant administration of omega-3EEC did not alter the steady-state pharmaco-kinetics of atorvastatin (and its major activemetabolites 2-hydroxyatorvastatin and 4-hydro-xyatorvastatin),[87] rosuvastatin[88] or simvastatin(and its major active metabolite b-hydroxysimvastatin)[89] in healthy volunteers.

4. Therapeutic Efficacy

4.1 In Secondary PreventionPost-Myocardial Infarction

The comparative efficacy of omega-3 EEC, asmonotherapy or in combination with tocopherol,versus tocopherol monotherapy or no treatmentin secondary prevention post-MI in adultpatients (n = 11 324) has been assessed in thefully published randomized, nonblind (endpointswere assessed by a blinded endpoint validationcommittee of cardiologists and neurologists),multicentre GISSI-Prevenzione study.[65]

A randomized, double-blind, placebo-controlled,multicentre study (OMEGA; n= 3851) [currentlyavailable only as an oral presentation] that com-pared omega-3 EEC with placebo in secondaryprevention post-MI patients is also discussed.[90]

Data from three post hoc subanalyses[91-93] of theGISSI-Prevenzione study[65] and supplementarydesign details[94] for the OMEGA study[90] arealso available.

Eligibility criteria included a recent (within theprevious 3–14 days[90] or 3 months[65]) MI. Thestudies were conducted in male (85.3%[65] and74.4%[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 studywere 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-Prevenzionestudy,[65] and <0.45 (24.1%) and ‡0.45 (75.9%) inthe OMEGA study.[90] Patients were diagnosedwith concomitant arterial hypertension (35.6%of patients),[65] claudication (4.4%),[65] diabetesmellitus (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 apositive exercise-stress test.[65] Randomization inthe GISSI-Prevenzione study occurred a median of16 days following MI.[65]

Patients were randomized to receiveomega-3 EEC 1000mg/day (n = 2836), omega-3EEC 1000mg/day plus tocopherol 300mg/day(n = 2830), tocopherol 300mg/day (n = 2830) orno treatment (n = 2828) for 42 months in theGISSI-Prevenzione study[65] or omega-3 EEC1000mg/day (n = 1940) or placebo (n = 1911) for12 months in the OMEGA study.[90,94]

At baseline, patients were receiving ACEinhibitor (46.9%[65] and 69.5%[90] of patients),antiplatelet (including aspirin, clopidogrel andglycoprotein 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-CoAreductase inhibitor [statin][90]) [4.7%[65] and81.5%[90]] therapy; those receiving aspirin,b-blockers and/or ACE inhibitors were per-

1086 Hoy & Keating


mitted to continue concomitant therapy through-out the study.[65] Patients in the OMEGA studyreceived standard therapy (not defined).[90] Athospital discharge, 83.3%, 95.3%, 94.1%, 88.4%and 94.2% of patients in the OMEGA study werereceiving ACE inhibitor, aspirin, b-blocker, clopi-dogrel and/or statin therapy, respectively.[90] By theend of the GISSI-Prevenzione study, 39.0%,82.8%, 38.5% and 45.5% of patients were receivingACE inhibitor, antiplatelet, b-blocker and/or lipid-lowering therapy, respectively.[65]

The primary composite efficacy endpoints forthe GISSI-Prevenzione study were the cumula-tive rate of all-cause death, nonfatal MI andnonfatal stroke, and the cumulative rate of car-diovascular death, nonfatal MI and nonfatalstroke.[65] Secondary endpoints included the in-dividual components of the primary endpointsand the major causes of death.[65] The primaryendpoint for the OMEGA study was suddencardiac death; secondary endpoints includedarrhythmic events, death, reinfarction, revascu-larization (percutaneous coronary interventionand/or CABG) and stroke.[90,94]

A prespecified two-way factorial analysis ofdata compared the efficacy of omega-3 EEC-based therapy (omega-3 EEC monotherapy andomega-3 EEC plus tocopherol groups) with thatof non-omega-3 EEC-based therapy (tocopherolmonotherapy and no treatment groups) and theefficacy of tocopherol-based therapy (tocopherolmonotherapy and omega-3 EEC plus tocopherolgroups) versus non-tocopherol-based therapy(omega-3 EEC monotherapy and no treatment)over 42 months in the GISSI-Prevenzionestudy.[65] A prespecified four-way analysis of datacompared the efficacy of omega-3 EEC mono-therapy, tocopherol monotherapy and omega-3EEC 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 alsocompared with omega-3 EEC monotherapy andtocopherol 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 theGISSI-Prevenzione study.[65] The risk of death

plus nonfatal MI plus nonfatal stroke (coprimarycomposite efficacy endpoint) at study end wassignificantly reduced with omega-3 EEC-basedtherapy versus non-omega-3 EEC-based ther-apy but not with tocopherol-based therapyversus non-tocopherol-based therapy, accordingto a two-way analysis of data (figure 2).[65]

However, there were no significant differences inthe risk of cardiovascular death plus nonfatal MIplus nonfatal stroke (coprimary composite effi-cacy endpoint) for either of these therapy groups(figure 2).[65]

Of the individual events contributing to theprimary endpoints, significant reductions inthe relative risk of death, cardiovascular deathand fatal CHD plus nonfatal MI occurred inpatients receiving omega-3 EEC-based therapyrelative to those receiving non-omega-3 EEC-based therapy (figure 2).[65] No significant dif-ferences were observed between these two groupswith regard to nonfatal cardiovascular eventsor fatal plus nonfatal stroke (figure 2).[65] The riskof 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 thatwith 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% CI0.67, 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 ofthe events contributing to the primary endpoints(figure 2) or the risk of cardiac death (4.4% vs4.8%; RR 0.91; 95% CI 0.76, 1.08), coronarydeath (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-basedtherapy.[65]

Compared with no treatment, the four-wayanalysis of data demonstrated significant reduc-tions at study end in the risk of death plus non-fatal MI plus nonfatal stroke with omega-3EEC as monotherapy or in combination withtocopherol and in the risk of cardiovasculardeath plus nonfatal MI plus nonfatal strokewith omega-3 EEC monotherapy (table I).[65]

No significant reductions in the risk of these copri-



0

2

4

6

8

10

12

14

16

Death

+ non

fatal

MI

+ non

fatal

strok

e

CV dea

th + n

onfat

al

MI + n

onfat

al str

oke Dea

th

CV dea

th

Nonfat

al

CV even

ts

Fata

l CHD +

nonfa

tal M

I

Fata

l and

nonfa

tal s

troke

Inci

denc

e (%

of p

atie

nts)

RR 0.90*†(0.82, 0.99)

RR 0.89(0.80, 1.01) RR 0.86†

(0.76, 0.97)

0

2

4

6

8

10

12

14

16

Death

+ non

fatal

MI

+ non

fatal

strok

e

CV dea

th + n

onfat

al

MI + n

onfat

al str

oke Dea

th

CV dea

th

Nonfat

al

CV even

ts

Fata

l CHD +

nonfa

tal M

I

Fata

l and

nonfa

tal s

troke

Inci

denc

e (%

of p

atie

nts)

RR 0.83†(0.71, 0.97) RR 0.98

(0.83, 1.15)

RR 0.87† (0.76, 0.99)

RR 1.21(0.91, 1.63)

RR 0.95(0.86, 1.05)b

a

RR 0.98(0.87, 1.10) RR 0.92

(0.82, 1.04)

RR 0.94 (0.81, 1.10) RR 1.04

(0.88, 1.22)

RR 1.00(0.88, 1.14)

RR 0.87(0.65, 1.17)

Omega-3 EEC-based therapyNon-omega-3 EEC-based therapy

Tocopherol-based therapyNon-tocopherol-based therapy

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 plustocopherol 300 mg/day, tocopherol monotherapy 300 mg/day or no treatment for 42 months.[65] In this two-way factorial analysis, (a) omega-3EEC-based therapy consisted of the omega-3 EEC monotherapy and the omega-3 EEC plus tocopherol groups (n = 5666) and non-omega-3EEC-based therapy consisted of the tocopherol monotherapy and no treatment groups (n = 5668); and (b) tocopherol-based therapy consistedof the omega-3 EEC plus tocopherol and the tocopherol monotherapy groups (n = 5666) and non-tocopherol-based therapy consisted of theomega-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% CIvalues are shown in parentheses. CHD = coronary heart disease; RR = relative risk; - indicates significant results. * p = 0.048.

1088 Hoy & Keating


mary endpoints were observed following tocopherolmonotherapy versus no treatment (table I).[65]

In general, omega-3 EEC monotherapy, ome-ga-3 EEC plus tocopherol combination therapyand tocopherol monotherapy were all signifi-cantly more effective than control in terms ofsecondary endpoints in the four-way analysis(table I).[65] Significant reductions (of 20–45%) inthe risk of these endpoints were observed acrossall three active therapy groups versus control,with the exception of death in the tocopherolmonotherapy group and nonfatal cardiovascularevents in all three active therapy groups (table I).[65]

In contrast, no significant reductions in the riskof fatal CHD plus nonfatal MI and fatal plusnonfatal stroke (other endpoints) were observedin active therapy groups, apart from a significant25% reduction in the risk of fatal CHD plusnonfatal MI in omega-3 EEC monotherapy ver-sus no treatment recipients (table I).[65]

No evidence of an interaction effect betweenomega-3 EEC and tocopherol was observed fol-

lowing an analysis of the coprimary compositeefficacy endpoints and one secondary endpoint(death).[65] The risk of death plus nonfatalMI plus nonfatal stroke (coprimary compositeefficacy endpoint) was not significantly reducedin omega-3 EEC plus tocopherol combina-tion therapy versus omega-3 EEC monotherapy(RR 1.01; 95% CI 0.87, 1.17) or tocopherolmonotherapy (RR 0.96; 95% CI 0.83, 1.12)recipients.[65]

Analyses of the individual components of thecoprimary composite efficacy endpoints indicatedthat significant reductions in the relative risk ofdeath, cardiovascular death and sudden deathfollowing therapy with omega-3 EEC accountedfor the observed reductions in the risk of the co-primary composite efficacy endpoints (table I)[65]

and suggested an antiarrhythmic/antifibrillatoryeffect.[91] A post hoc time-course subanalysis[91] of theGISSI-Prevenzione study[65] suggested that omega-3EEC-based therapy was associated with early (frommonth 9 for the coprimary endpoints, and from

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

EEC

omega-3

EEC +tocopherol

tocopherol control omega-3 EEC omega-3 EEC +tocopherol

tocopherol

Primary composite

Death + nonfatal

MI + nonfatal stroke

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)

CV death + nonfatal

MI + nonfatal stroke

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)

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.



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-3EEC-based therapy. Results for the morbidityendpoints were mixed.[91]

An exploratory, post hoc analysis of data fromthe GISSI-Prevenzione study[65] indicated thatomega-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 effectsof therapymay increase with worsening LVSD.[93]

However, prospective randomized studies arerequired to confirm this.

At 6months, no clinically relevant changes frombaseline in total cholesterol, LDL-C and HDL-Clevels (table II), fibrinogen and glycaemia (nodata reported for these parameters) were ob-served in omega-3 EEC monotherapy, tocopher-ol monotherapy or omega-3 EEC plus tocopheroltreatment groups.[65] However, a statisticallysignificant reduction in triglyceride levels wasobserved in patients receiving omega-3 EECmonotherapy versus no treatment (table II).[65]

No significant difference in the incidence ofsudden 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 OMEGAstudy.[90] Furthermore, no significant differenceswere observed between these two groups withregard to the secondary endpoints, includingarrhythmic events (1.1% of omega-3 EEC re-cipients and 0.7% of placebo recipients), death

(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%) waslower than anticipated; the OMEGA study wasdesigned assuming a sudden cardiac death rate of1.9% in omega-3 EEC recipients and 3.5% inplacebo recipients.[90]

4.1.1 Pharmacoeconomic Considerations

This section focuses on the findings from twofully published, well designed pharmacoeconomicmodelling studies,[95,96] both primarily basedon 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 twoanalyses is presented in table III.

Omega-3 EEC plus standard therapy was pre-dicted to be a cost-effective option in secondaryprevention post-MI relative to standard therapyalone, according to two analyses conducted inseveral 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-yeargained[96] was favourable in relation to com-monly accepted thresholds for cost effectiveness(table III). In the UK analysis, the cost per deathavoided over the 48-month time horizon wasestimated to be d31 768 (2004 value).[96]

Sensitivity analyses suggested that the results inboth the multi-national[95] and UK[96] studies wererobust to variations in key parameters. Furthermore,omega-3 EEC was estimated to be cost effective in

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 Mean change from baseline in lipid level (%) [mean baseline level; mmol/L]

TG TC LDL-C HDL-C

Omega-3 EEC 2836 -3.4* [1.79] +7.9 [5.47] +9.9 [3.57] +8.8 [1.08]

Omega-3 EEC + tocopherol 2830 -0.9 [1.76] +8.9 [5.48] +10.8 [3.59] +8.9 [1.08]

Tocopherol 2830 +2.9 [1.80] +7.1 [5.49] +7.2 [3.59] +9.4 [1.07]

Control 2828 +1.4 [1.78] +7.1 [5.50] +7.4 [3.60] +9.2 [1.08]

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride;* p < 0.0001 vs control.

1090 Hoy & Keating


93% of simulations in Poland, and in >98% ofsimulations in Australia, Belgium, Canada andGermany, according to a second-order Monte-Carlo simulation based on the 95% confidenceintervals obtained from the GISSI-Prevenzionestudy (assuming the country-specific willingness-to-pay thresholds).[95] However, pharmacoeco-nomic analyses of omega-3 EEC, in commonwithall pharmacoeconomic analyses, are subject to anumber of limitations. Pharmacoeconomic ana-lyses based on clinical studies extrapolate the re-sults of relatively short-term studies to long-termresults in the general population; however, pa-tient populations, rates of compliance and majoroutcomes in clinical studies may differ from thoseobserved in real-life practice. Modelled analyses,such as those presented in this section, rely on anumber of assumptions and use data from avariety of sources. Results of pharmacoeconomic

analyses may not be applicable to other geogra-phical regions because of differences in healthcaresystems, medical practice and unit costs.

4.2 In the Treatmentof Hypertriglyceridaemia

The therapeutic efficacy of oral omega-3 EECin the treatment of adult patients with hyper-triglyceridaemia has been evaluated in five random-ized, double-blind, multicentre clinical studies of8–24 weeks’ duration,[46,85,86,97,98] with the 12-weekmonotherapy study[46] utilizing a double-dummydesign. 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 theefficacy 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.



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 ‡2.8to <6.76[98] mmol/L (serum triglyceride levels‡5.6mmol/L [‡500mg/dL] are considered bythe National Cholesterol Education ProgramAdult Treatment Panel III [NCEP ATP III][99]

to be ‘very high’). Where stated, patients hadmean LDL-C levels below, or within 10% of, theNCEP ATP III goal;[97] had non-HDL-C levels>4.13mmol/L;[98] were receiving stable therapywith simvastatin 10–40mg/day for at least theprevious 3 months[86] or stable statin therapy forat least the previous 8 weeks;[97] had establishedCHD;[86] and were in good health (as assessed bymedical history, physical examination, ECG andlaboratory tests).[97]

Dietary advice/assessment was provided priorto[46,85,86,97,98] and throughout[46,85,86,97] the ac-tive therapy phase.

In the monotherapy studies,[46,85] patientswere randomized to receive oral omega-3 EEC4000mg once daily or a comparator (placebo[85]

or oral gemfibrozil 1200mg/day[46]) for 12[46] or16[85] weeks. In the combination therapy stu-dies,[86,97,98] patients were randomized to receiveoral omega-3 EEC 2000mg twice daily or place-bo, both in combination with oral simvastatin10–40mg/day for 24 weeks,[86] omega-3 EEC4000mg once daily or placebo, both in com-bination with oral simvastatin 40mg/day, for8 weeks,[97] or omega-3 EEC 4000mg once dailyor placebo, both in combination with oral ator-vastatin (10, 20 then 40mg/day over 8, 4 and4 weeks, respectively) for 16 weeks.[98]

Patients in the 8-week combination therapystudy underwent a simvastatin 40mg/day[97]run-in period of 8 weeks; only those who wereassessed as ‡80% compliant with simvastatintherapy, with mean triglyceride levels ‡2.2 to<5.6mmol/L and LDL-C levels £10% abovethe NCEP ATP III goal, were randomized toomega-3 EEC plus simvastatin or placebo plussimvastatin therapy.[97] In the 24-week, combi-nation therapy study, patients received stabletherapy with simvastatin 10–40mg/day for at

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 toparticipate in a 24-week, noncomparative exten-sion phase during which they received omega-3EEC 2000mg twice daily.[86]

Where reported, antihyperlipidaemics (otherthan simvastatin[86,97]) were discontinued at least4–8 weeks prior to study commencement or ac-tive therapy.[46,85,86,97]

Patients had a mean age of 45–60.3 years and amean BMI of 27.5–31.5 kg/m2.[46,85,86,97] Wherestated, patients had pre-existing CVD (20%),[46]

diabetes (3%;[46] 25%[86]) and hypertension(15%).[46] In the 8-week, combination therapystudy, 75% and 68% of patients in the omega-3EEC 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 includedthe 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 thechanges 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] freefatty acid[46] and lipoprotein-associated phos-pholipase A2[98] levels. Endpoints were not spe-cified as primary or secondary in the 16-weekmonotherapy study[85] and included changes inserum triglyceride, total cholesterol, VLDL-C,HDL-C, LDL-C and apolipoprotein A-I levels.Endpoints in the 16-week combination therapystudy[98] were determined at week 8 of therapy.

Where specified, data are reported for themodified 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 4000mg/day demonstrated greater tri-glyceride-lowering efficacy than placebo in patientswith hypertriglyceridaemia.[85] Significantly greaterreductions from baseline in triglyceride (mean per-centage change 45%), total cholesterol (15%) andVLDL-C (32%) levels and significantly greater ele-

1092 Hoy & Keating


vations from baseline in HDL-C levels (13%)were observed with omega-3 EEC monotherapythan with placebo (table IV).[85] A ‡35% reduc-tion in triglyceride levels from baseline wasachieved by 18 of 22 (81.8%) patients of thosepatients receiving omega-3 EEC monotherapy;the remaining four patients achieved a £15% re-duction.[85] In contrast, significant elevations inLDL-levels were observed in omega-3 EEC ver-sus placebo recipients (table IV).[85]

Significant (p< 0.001) reductions from baselinein 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 receivingplacebo (mean percentage change not reported;baseline 11.2).[85] No significant between-groupdifference was observed in the LDL-C :HDL-Cratio (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 theomega-3 EEC and placebo groups (1.31 vs1.26 g/L; baseline: 1.32 vs 1.28 g/L).[85]

Gemfibrozil was associated with significantlygreater reductions from baseline in serum trigly-ceride levels (primary endpoint) and significantly

greater elevations from baseline in HDL-C levelsthan 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 andVLDL-C levels did not significantly differ be-tween the two treatment groups (table IV).[46]

4.2.2 In Combination with Simvastatinor Atorvastatin

In general, omega-3 EEC plus simvastatin wasan effective lipid-modifying therapy in patientswith hypertriglyceridaemia, inducing signifi-cantly greater reductions from baseline in trigly-ceride and VLDL-C levels than placebo plussimvastatin in two well designed clinical studies(table V).[86,97,98] Significant between-group dif-ferences in triglyceride and VLDL-C levels wereobserved from week 12 in the 24-week study.[86]

Omega-3 EEC plus simvastatin was also asso-ciated with significantly greater reductions frombaseline in total cholesterol levels and significantlygreater elevations from baseline in HDL-C levelsthan placebo plus simvastatin in the 8-week study(table V).[97] No significant between-group differ-

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

[%D]

baseline endpoint

[%D]

baseline endpoint

[%D]

baseline endpoint

[%D]

baseline endpoint

[%D]

Comparison with PL

Harris

et al.[85]

Omega-3

EEC

22 10.38 5.71

[-45---]

6.94 5.91

[-15--]

4.12 2.33

[-32--]

2.05 2.69

[+32]

0.78 0.88

[+13-]

PL 20 9.91 11.38

[+16]

7.80 7.64 4.59 4.56 2.49 2.36

[NRzzz]

0.73 0.73

Comparison with GEM

van Dam

et al.[46]

Omega-3

EEC

45 12.36 7.82****

[-29]a8.81 7.61****

[-10]

3.82 2.92**

[-11]

3.28 3.66 0.81 0.75 [+1]

GEM 44 11.55 5.22****

[-51zz]a8.41 6.82***

[-13]

3.55 2.07***

[-19]

3.59 4.60* 0.83 0.95

[+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.



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

(mg/day)

No. of

pts

Timepoint

(wk)

TG (mmol/L) TC (mmol/L) VLDL-C (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Non-HDL-C (mmol/L)

baseline endpoint

[%D]

baseline endpoint

[%D]

baseline endpoint

[%D]

baseline endpoint

[%D]

baseline endpoint

[%D]

baseline endpoint

[%D]

Davidson

et al.[97]

Omega-3

EEC 4000

od + SIM 40

122 8 3.2 2.3

[-28.2--]

4.7 4.5

[-4.7--]

1.4 1.0

[-23.8--]

2.3 2.3 [+3.4] 1.2 1.3

[+4.1--]

3.5 3.2

[-7.9-- c]

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

et al.[86]

Omega-3

EEC 2000

bid + SIM

10–40

30 12 4.6 3.3***

[-22.8-a]

5.6 4.9*b 1.0 0.6**

[-34.2-a]

3.5 3.1b 1.1 1.2b

PL + SIM

10–40

27 12 3.8 3.9

[+12.8a]

6.2 6.3b 0.9 0.8

[-2.8a]

4.2 4.2b 1.1 1.2b

Omega-3

EEC 2000

bid + SIM

10–40

29 24 4.6 3.5***

[-18.6-a,c]

5.6 5.0*b 1.0 0.6**

[-31.4-a,c]

3.5 3.3b 1.1 1.0b

PL + SIM

10–40

26 24 3.8 3.9

[+4.2c]

6.2 6.4b 0.9 0.8

[-10.0a,c]

4.2 4.4b 1.1 1.3b

a Value derived from a graph.

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.

1094H

oy&

Keatin

g

ª2009

Ad

isD

ata

Info

rma

tion

BV

.A

llrigh

tsre

serv

ed

.D

rug

s2009;69

(8)

ence in LDL-C levels was observed betweenomega-3 EEC plus simvastatin and placebo plussimvastatin recipients (table V).[97] The propor-tion of omega-3 EEC plus simvastatin recipientsachieving their LDL-C treatment goal in the8-week study remained constant (93%).[97]

No quantitative data on the percentage chan-ges from baseline in total cholesterol, HDL-Cand LDL-C levels were reported in the 24-weekstudy; however, significantly greater reductionsin total cholesterol levels versus baseline wereobserved in omega-3 EEC recipients.[86]

Non-HDL-C levels were reduced to a sig-nificantly greater extent with omega-3 EEC plussimvastatin than with placebo plus simvastatin inpatients with hypertriglyceridaemia (table V).[97]

In the same study, 84% of omega-3 EEC plussimvastatin recipients and 70% of placebo plussimvastatin recipients reached their non-HDL-Ctreatment 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 theirnon-HDL-C treatment goal at baseline hadreached it by study end.[97]

In general, improvements in the lipid profilesof patients with hypertriglyceridaemia observedin the 24-week, double-blind phase of one studywere sustained with continued omega-3 EEC plussimvastatin therapy in the 24-week, non-comparative extension phase.[86] Furthermore,patients who switched to omega-3 EEC fromplacebo achieved lipid levels that were generallysimilar to those observed in patients initiallytreated with omega-3 EEC (figure 3).

Preliminary data indicate that oral omega-3EEC plus atorvastatin improved the lipid profileto a significantly greater extent than placebo plusatorvastatin in patients with hypertriglycer-idaemia.[98] At week 8, significantly greater reduc-tions from baseline in non-HDL-C (medianpercentage 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 inHDL-C levels (+12.4% vs +10.0%; p< 0.01) wereobserved with omega-3 EEC 4000mg/day plus

atorvastatin 10mg/day (n= 122) than with place-bo plus atorvastatin 10mg/day (n= 121).[98] Nosignificant difference in the median percentagechange frombaseline in LDL-C levels was observedin patients receiving omega-3 EEC 4000mg/dayplus atorvastatin 10mg/day (-29.3%) versus thosereceiving placebo plus atorvastatin 10mg/day(-31.5%).[98] Non-HDL-C levels and variousother endpoints (not stated) were also sig-nificantly improved versus baseline with omega-3EEC plus atorvastatin 20mg/day (weeks 9–12)and omega-3 EEC plus atorvastatin 40mg/day(weeks 12–16) therapy (no data reported).[98]

5. Tolerability

This section focuses on the tolerabilitydata derived from the clinical studies discussed insection 4;[46,65,85,86,97,98] supplementary data fromone post hoc analysis[92] of the GISSI-Prevenzione study[65] are also discussed.

Oral omega-3 EEC was generally well toleratedin secondary prevention post-MI patients and inthe treatment of patients with hypertriglycer-idaemia.[46,65,85,86,97] Where reported, treatment-

0

1.0

2.0

3.0

4.0

5.0

6.0

TG TC VLDL-C LDL-C HDL-C

Mea

n lip

id le

vels

(m

mol

/L)

*** ***

**

**

*

**

Originally randomized to omega-3 EEC + SIM (n = 25)Originally randomized to PL (n = 21)

Fig. 3. Efficacy of extended oral omega-3 ethylester concentrate(omega-3 EEC) plus simvastatin (SIM) therapy in adult patients withhypertriglyceridaemia. Mean serum triglyceride (TG), total choles-terol (TC), very-low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C) and high-density lipoproteincholesterol (HDL-C) levels after 24 weeks’ therapy with omega-3EEC 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.



emergent adverse events associated withomega-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% and1.4% of patients receiving omega-3 EEC 1000mg/day-based therapy and in 2.9% and 0.4% of pa-tients receiving tocopherol 300mg/day-basedtherapy in studies of secondary prevention post-MI in adult patients (see figure 2 for defini-tions).[65] In the same study, a few patientsreceiving omega-3 EEC monotherapy, omega-3EEC plus tocopherol therapy, tocopherol mono-therapyor no treatment developed cancer (2.2–2.7%),including non-fatal cancer (0.9–1.5%).[65] Amongomega-3 EEC and tocopherol recipients, 11.6%and 7.3% of patients discontinued therapy at12 months and 28.5% and 26.2% of patients dis-continued therapy at 42 months;[92] therapy wasstopped because of adverse events in 3.8% ofpatients receiving omega-3 EEC and 2.1% ofpatients receiving tocopherol.[65]

Monotherapy with omega-3 EEC4000mg/day was generally well tolerated inpatients with hypertriglyceridaemia.[46,85] In the16-week study, 18.2% and 15.0% of patients ran-domized to receive omega-3 EEC 4000mg/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 EEC4000mg/day group (n = 45) and three patients inthe oral gemfibrozil 1200mg/day treatmentgroup (n = 44), with all the events classified asmild.[46] No patient in either study permanentlydiscontinued therapy because of adverseevents[46,85] and no serious drug-related adverseevents were reported in the 16-week study.[85]

Combination therapy with omega-3 EEC2000mg twice daily[86] or 4000mg once daily[97]

plus simvastatin 10–40[86]or 40[97] mg/day wasgenerally well tolerated in patients with hyper-triglyceridaemia.[86,97] No significant difference inthe incidence of treatment-emergent adverseevents between those patients receiving omega-3EEC 4000mg/day (n= 122) or placebo (n= 132)

plus simvastatin 40mg/day was reported in the8-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% ofpatients (and occurring more frequently inomega-3 EEC 4000mg/day plus simvastatin40mg/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% vs2.3%), bronchitis (1.6% vs 1.5%), cystitis (1.6% vs0.8%) and gastroenteritis (1.6% vs 0%).[97] In the24-week study, treatment-emergent adverse eventswere observed in 73.3% of patients receivingomega-3 EEC 4000mg/day plus simvastatin10–40mg/day (n = 30) compared with 58.6% ofpatients receiving placebo plus simvastatin10–40mg/day (n = 29) [no statistical analysis re-ported], with the majority of events classified asminor.[86] Few patients in either treatment groupwithdrew because of adverse events (3.3% vs3.4%).[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-3EEC 4000mg/day plus simvastatin 40mg/dayand 0.8% of placebo plus simvastatin 40mg/dayrecipients.[97] There were no reports of myopathyor rhabdomyolysis in omega-3 EEC 4000mg/dayplus simvastatin 40mg/day and placebo plussimvastatin 40mg/day recipients in the 8-week,combination therapy study.[97] No seriousdrug-related adverse events were reported in the16-week, combination therapy study.[98]

In general, laboratory parameters (e.g. levelsof 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% ofomega-3 EEC 4000mg/day plus simvas-

1096 Hoy & Keating


tatin 40mg/day recipients and 0.8% of placeboplus simvastatin 40mg/day recipients, with sig-nificantly greater increases in ALT (+5.7 vs-0.7U/L; p< 0.001) and AST (+1.9 vs +0.2U/L;p< 0.032) levels occurring in omega-3 EEC plussimvastatin recipients than in placebo plus sim-vastatin recipients.[97] Fasting blood glucose le-vels also increased to a significantly greater extentwith omega-3 EEC plus simvastatin than withplacebo plus simvastatin (+5.5 vs -0.1mg/dL).[97]

6. Dosage and Administration

Oral omega-3 EEC is indicated in the majorityof 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 inpost-MI adult patients. It is also indicated for useas an adjunct to diet in the treatment of hyper-triglyceridaemia, either as monotherapy (type IVhypertriglyceridaemia) or in combination withstatins (type IIb/III hypertriglyceridaemia whentriglyceride control is insufficient), in adultpatients who have not responded to dietarymeasures.[7] In the US, omega-3 EEC is indi-cated as an adjunct to diet in the treatment ofhypertriglyceridaemia (serum triglyceride levels‡5.6mmol/L [‡500mg/dL]) in adult patients.[32]

Each 1000mg capsule of omega-3 EEC consistsof ethyl EPA 460mg and ethyl DHA 380mg.[7]

The recommended omega-3 EEC dosage regimenfor secondary prevention post-MI is 1000mg/day.In patients with hypertriglyceridaemia, the re-commended dosage regimen is 2000mg/day in theUK, increasing to 4000mg/day if an adequate re-sponse is not achieved,[7] and 4000mg/day in theUS.[32] The capsule(s) may be administered withfood to avoid gastrointestinal disturbances.[7]

The regular monitoring of hepatic function(ALT and AST levels) is necessary in patientswith hepatic impairment, particularly those re-ceiving omega-3 EEC 4000mg/day.[7] Patients athigh risk of haemorrhage (e.g. those undergoingsurgery or receiving anticoagulant therapy)require monitoring (see section 2.4). Local pre-scribing information should be consulted for de-tailed information, including contraindications,

drug interactions, precautions and use in specialpatient populations.

7. Place of Omega-3 EthylesterConcentrate in Secondary PreventionPost-Myocardial Infarction and theTreatment of Hypertriglyceridaemia

The interaction of multiple risk factors,such as physical inactivity, smoking and an un-healthy diet, contributes to the occurrence ofCVD.[101,102] Modifying these risk factors hasbeen shown to reduce CVD morbidity and mor-tality, particularly in high-risk patients; thus,effective risk management should target allmodifiable risk factors.[101]

The 2006 update of the American Collegeof Cardiology/American Heart Association(ACC/AHA) guidelines for the secondary pre-vention of coronary and other atheroscleroticvascular disease[103] and the Fourth Joint TaskForce guidelines on CVD prevention in clinicalpractice[101] provide a range of risk reductionrecommendations 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 achieveadequate BP and diabetes control, modify lipidlevels and provide cardioprotection.

The NCEP ATP III has identified elevatedLDL-C levels as a major risk factor for CHD andthe primary target for lipid-lowering therapy.[99]

Thus, a goal for patients with CHD or CHD riskequivalents is a reduction in LDL-C levels to<2.6mmol/L (<100mg/dL).[99,104] Elevated tri-glyceride levels have recently been identified as anindependent risk factor for CHD, suggesting thatsome triglyceride-rich lipoproteins are athero-genic.[99] Factors leading to hypertriglyceridaemiainclude obesity, physical inactivity, smoking,excess alcohol intake, high carbohydrate diet, dis-eases such as type 2 diabetes and chronic renalfailure, some drugs (e.g. corticosteroids) andcertain genetic disorders (e.g. familial hyper-triglyceridaemia).[99] Hypertriglyceridaemia isalso associated with the metabolic syndrome.[99]



The treatment strategy for hypertriglycer-idaemia is dependent upon the cause and severityof the triglyceride elevation.[99] The primary aimof therapy in patients with hypertriglyceridaemiais to achieve the target LDL-C level.[99] In pa-tients with triglyceride levels of 1.70–2.25mmol/L(150–199mg/dL), the emphasis is placed on weightmanagement and physical activity.[99] For pa-tients with triglyceride levels of 2.26–5.63mmol/L(200–499mg/dL), non-HDL-C becomes a sec-ondary therapy target.[99] Fibric acid derivativesand niacin can also be administered.[99,105]

The presence of a high level of CHD risk or thefailure of lifestyle modification to lower LDL-Clevels warrants the utilization of drug ther-apy;[105] the majority of patients with CHD willrequire drug therapy to lower LDL-C levels.[99]

Statins are generally the first-line treatment op-tion for lowering LDL-C levels, in conjunctionwith 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 factorsother than LDL-C levels may also be warranted,as some patients require combination lipid-lowering therapy to achieve the various treatmentgoals.[101] Non-lipid risk factors may also requiremodification.[99]

Epidemiological data have demonstrated aninverse relationship between fish consumptionand cardiovascular morbidity and mortality;[106]

the omega-3 fatty acids EPA and DHA aremainly derived from oily fish.[5] The pharmaco-dynamic and cardiovascular effects of omega-3fatty acids have also been widely studied; takentogether, these data indicate that omega-3 fattyacids have cardioprotective effects,[1,25,29,107]

with an inverse correlation observed between therisk of coronary artery disease events and thequantity of DHA in plasma and cellular phos-pholipids (which is closely linked to the DHAcontent of the myocardium).[108] Despite this, it isnot yet known whether DHA, EPA or the com-bination of both contributes to the cardiopro-tective effect observed with omega-3 fatty acidtherapy.[109]

The consumption of large quantities of fishhas prompted concern regarding the levels ofcontaminants, particular dioxins, mercury andpolychlorinated biphenyls, in certain fish spe-cies.[24,107] However, current evidence suggeststhat the benefits of moderate fish consumptionoutweigh the potential risks among adults.[107]

Oral omega-3 EEC is the only omega-3 fattyacid product approved in Europe and the US.Omega-3 EEC 1000mg/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 preventionin post-MI adult patients (section 4.1). In theGISSI-Prevenzione study, omega-3 EEC-basedtherapy significantly reduced the risk of the pri-mary composite endpoint of death plus nonfatalMI 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 ofcardiovascular death plus nonfatal MI plus non-fatal stroke (coprimary composite efficacy end-point) with omega-3 EEC- versus non-omega-3EEC-based therapy.

Individual component and post hoc time-course analyses suggest that the reductions in therisk of death and cardiovascular death follow-ing omega-3 EEC monotherapy contribute tothe significant reductions observed in the risk ofthe coprimary composite efficacy endpoints(section 4.1). However, the 45% reduction in therisk of sudden death (secondary endpoint) wasthe major component in the reduction in the riskof death. Another post hoc analysis has suggestedthat omega-3 EEC therapy may have benefits inthe subgroup of post-MI patients with LVSD(section 4.1); however, randomized studies arerequired to assess this further.

Differing results were observed in the OME-GA study, with no significant difference inthe incidence of sudden cardiac death (primaryendpoint) and the various secondary endpointsseen between the omega-3 EEC and placebotreatment groups (section 4.1). Of note, theobserved incidence of sudden cardiac deathin both the omega-3 EEC and placebo groups(1.5% vs 1.5%) was lower than anticipated,

1098 Hoy & Keating


with the OMEGA study design assuming a sud-den cardiac death rate of 1.9% in omega-3 EECrecipients and 3.5% in placebo recipients, thuspreventing robust conclusions from being drawn.The 12-month OMEGA study (n = 3851) in-cluded only those patients who had experienced aMI within the previous 3–14 days, while the 42-month GISSI-Prevenzione study (n = 11 324) in-cluded those who had experienced a MI withinthe previous 3 months. With only preliminarydata from the OMEGA study currently available,further findings are awaited with interest.

Oral omega-3 EEC, as monotherapy or incombination with simvastatin or atorvastatin,was generally effective as an adjunct to diet in thetreatment of hypertriglyceridaemia in adult pa-tients (section 4.2). Omega-3 EEC monotherapydemonstrated significantly greater reductionsfrom baseline than placebo in triglyceride, totalcholesterol and VLDL-C levels, and significantlygreater elevations from baseline in HDL-C levelsin a small study (section 4.2.1). In another study,oral gemfibrozil was associated with significantlygreater reductions in serum triglyceride levels(primary endpoint) and significantly greater in-creases in HDL-C levels than omega-3 EECmonotherapy (section 4.2.1). However, no sig-nificant differences in total cholesterol andVLDL-C levels were observed between the twotreatment groups. It should be noted that theresults from this study[46] are at variance withthose from Stalenhoef et al.[40] (section 2.2);however, Stalenhoef et al.[40] was not powered todetermine any between-treatment differences.Additional studies would be of interest.

In general, omega-3 EEC plus simvastatin wasan effective lipid-modifying therapy in patientswith hypertriglyceridaemia, inducing signifi-cantly greater reductions from baseline in trigly-ceride and VLDL-C levels than placebo plussimvastatin in two clinical studies (section 4.2.2).For the most part, improvements in the lipidprofiles of patients with hypertriglyceridaemiaobserved in the 24-week, double-blind phase ofone study were sustained with continued omega-3EEC plus simvastatin therapy in the 24-week,noncomparative extension phase (section 4.2.2).Preliminary data indicate that omega-3 EEC plus

atorvastatin is associated with significantlygreater reductions from baseline in non-HDL-C(primary endpoint), total cholesterol, triglycerideand VLDL-C levels and significantly greaterimprovements from baseline in HDL-C levelsthan placebo plus atorvastatin in patients withhypertriglyceridaemia.

The precise mechanisms of action of omega-3EEC, in terms of both its triglyceride-loweringeffect and its secondary preventive effect inpatients with recent MI, are not yet fully under-stood (section 2.1). It has been suggested thatthe early protection against sudden cardiacdeath conferred by omega-3 EEC in the GISSI-Prevenzione study[65] (section 4.1) was due to anantiarrhythmic effect.[91] Indeed, evidence for anantiarrhythmic effect of omega-3 fatty acidscomes 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 possibleexplanations for the disparity in results, includingdifferences in background diet, the source andamount of omega-3 fatty acids administeredand the patient population.[30] For example,patients in the GISSI-Prevenzione study[65]

had experienced recent MI and were mostlikely experiencing ischaemic VF,[16] unlikepatients in ICD studies (which showed mixed re-sults; section 2.3). Thus, it has been suggestedthat the antiarrhythmic effects of omega-3 fattyacids may be greatest in the setting of acuteischaemia and VF, and that the mechanism ofbenefit may not involve suppression of re-entrantVF or VT.[16,110]

Other factors purported to contribute to thecardioprotective effects of omega-3 fatty acidsinclude antithrombotic, antiatherogenic andanti-inflammatory effects. Improvements in re-levant parameters have been reported in somestudies, although the effects are inconsistent(sections 2.4 and 2.5). Thus, it seems that inpatients with CHD, the most important con-tributor to the reduction in sudden cardiac deathis likely to be the effect of omega-3 fatty acids onthe physiology of the cardiac and/or autonomicnervous systems.[69]



Currently, the efficacy of omega-3 EEC1000mg/day is being assessed in cardiovasculardisease 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 GlargineIntervention]).[111] In addition, two recentlypublished, randomized, double-blind, placebo-controlled, clinical studies[112,113] have evaluatedthe efficacy of omega-3 EEC 1000[113] and2000[112] mg/day in cardiovascular disease pre-vention in patients with type 2 diabetes who werenot 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 chronicheart failure (GISSI-HF [GISSI-Heart Fail-ure]).[113] GISSI-HF observed a beneficial effectwith 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 HR0.92; 99% CI 0.849, 0.999) in patients withheart failure, suggesting an effect by omega-3EEC on the mechanisms leading to heart failureprogression.[113]

Pharmacoeconomic analyses of omega-3EEC in the treatment of patients with hyper-triglyceridaemia are currently lacking; however, alimited number of pharmacoeconomic analysesin secondary prevention post-MI are available(section 4.1.1). Data predict that omega-3 EECplus standard therapy is cost effective in second-ary prevention post-MI relative to standardtherapy. However, further long-term, robustpharmacoeconomic studies are required tofully establish the cost effectiveness of omega-3EEC.

Oral omega-3 EEC was generally well toler-ated in secondary prevention post-MI and thetreatment of hypertriglyceridaemia (section 5).Treatment-emergent adverse events associatedwith 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,

there is a concern that omega-3 EEC therapymay elevate the risk of bleeding (section 2.4).However, current clinical evidence indicatesa negligible risk of bleeding with omega-3EEC therapy.[24,26] Regardless, monitoring(with possible adjustments in the anticoagulantdosage) following the concurrent administrationof omega-3 EEC and anticoagulant therapy isrecommended, particularly with the utilization ofhigh (4000mg/day) oral omega-3 EEC dosages(sections 2.4 and 6).[7]

Oral omega-3 EEC is indicated in the majorityof 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-MIadult patients. It is also indicated for use asan adjunct to diet in the treatment of hyper-triglyceridaemia, either as monotherapy (type IVhypertriglyceridaemia) or in combination withstatins (type IIb/III hypertriglyceridaemia whentriglyceride control is insufficient), in adultpatients who have not responded to dietarymeasures.[7] In the US, omega-3 EEC is indi-cated as an adjunct to diet in the treatment ofhypertriglyceridaemia (serum triglyceride levels‡5.6mmol/L [‡500mg/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 theconsumption of omega-3 fatty acids, in the formof fish or omega-3 EEC capsules (1000mg/day)for secondary prevention post-MI, with higherdoses indicated for the treatment of hyper-triglyceridaemia.[103] Current literature, includingthe GISSI-Prevenzione study,[65] has served as thefoundation for the recommendation of omega-3fatty acid therapy in the treatment guidelines.[115]

However, a previous Cochrane review[116] andrecent meta-analysis[117] on the use of omega-3fatty acids for the prevention and treatment ofCVD concluded that it was unclear whether diet-ary or supplemental omega-3 fatty acids alteredthe rates of total death, combined cardiovascularevents or cancer in patients with, or at high riskof, CVDor in the general population and that fur-ther study was required. The Cochrane review[116]

analysed 48 randomized controlled studies

1100 Hoy & Keating


(36 913 patients) and 41 cohort studies, andfound no strong evidence of a reduction in therisk of total mortality (RR 0.87; 95% CI 0.73,1.03) or combined cardiovascular events (RR0.95; 95% CI 0.82, 1.12) in omega-3 fatty acidrecipients.[116,117] Following publication of theCochrane review, however, debate has ensuedregarding the inclusion of the DART (Diet andReinfarction Trial) II in the analysis;[115,118,119]

upon excluding DART II from the Cochraneanalysis, the RR of total death was 0.83 (95% CI0.75, 0.91).[116] Exclusion of DART II did not,however, result in a significant reduction in therisk of cardiovascular events following omega-3fatty acid therapy.[116]

Of interest, a recent meta-analysis of 12 studiesinvolving >30 000 patients concluded that omega-3fatty acid therapy demonstrated no beneficialeffect on the coprimary (arrhythmic) endpoints ofimplantable cardiac defibrillation intervention(OR 0.90; 95% CI 0.55, 1.46) and sudden cardiacdeath (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 inthe secondary endpoint of mortality from cardiaccauses was seen (OR 0.80; 95% CI 0.69, 0.92).[120]

The potential mechanism behind this beneficialeffect remains to be elucidated.[120] Thus, while thebalance of evidence suggests that omega-3 fattyacids reduce cardiovascular risk,[119] further welldesigned studies would be of use in clarifyingthe extent to which omega-3 fatty acids reducecardiovascular morbidity and mortality and themechanisms behind this beneficial effect.[115,118]

In conclusion, the addition of omega-3 EEC1000mg/day to standard medical therapy in theGISSI-Prevenzione study provided secondaryprevention benefits in post-MI adult patients.The benefits were attributable to reductions indeath and cardiovascular death (including sud-den death). Additional data examining the extentand mechanisms of the cardiovascular benefitconferred by omega-3 EEC in secondary pre-vention would be useful. As an adjunct to diet,monotherapy with omega-3 EEC 4000mg/daysignificantly reduced triglyceride levels in patientswith hypertriglyceridaemia, although limiteddata suggest it was less effective than gemfibrozil.

In addition, omega-3 EEC 4000mg/day plussimvastatin 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 toleratedboth as secondary prevention post-MI and inthe treatment of hypertriglyceridaemia. Thus,omega-3 EEC is a useful option both in second-ary prevention post-MI and the treatment ofhypertriglyceridaemia.

Disclosure

The preparation of this review was not supported by anyexternal funding. During the peer review process, the manu-facturer of the agent under review was offered an opportunityto comment on this article. Changes resulting from commentsreceivedweremade on the basis of scientific and editorial merit.

References1. Psota TL, Gebauer SK, Kris-Etherton P. Dietary omega-3

fatty acid intake and cardiovascular risk. Am J Cardiol2006 Aug 21; 98 (4A): 3-18i

2. Kris-Etherton PM, Harris WS, Appel LJ. Fish consump-tion, fish oil, omega-3 fatty acids, and cardiovasculardisease. Circulation 2002 Nov 19; 106 (21): 2747-57

3. Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fattyacids and cardiovascular disease: new recommendationsfrom the American Heart Association. ArteriosclerThromb Vasc Biol 2003 Feb 1; 23 (2): 151-2

4. Bersot T, Haffner S, Harris WS, et al. Hypertriglycer-idemia: management of atherogenic dyslipidemia. J FamPract 2006 Jul; 55 (7): S1-8

5. Thompson GR.Management of dyslipidaemia. Heart 2004Aug; 90 (8): 949-55

6. Bays H. Rationale for prescription omega-3-acid ethyl estertherapy for hypertriglyceridemia: a primer for clinicians.Drugs Today (Barc) 2008 Mar; 44 (3): 205-46

7. Solvay Healthcare Limited. Omacor: summary of productcharacteristics [online]. Available from URL: http://emc.medicines.org.uk/medicine/10312/SPC/omacor/[Accessed 2008 Apr 17]

8. Balk E, Chung M, Lichtenstein A, et al. Effects of omega-3fatty acids on cardiovascular risk factors and intermediatemarkers of cardiovascular disease: evidence re-port/technology assessment no. 93 [AHRQ publicationno. 04-E010-2]. Rockville (MD): Agency for HealthcareResearch and Quality, 2004 Mar

9. Russo C, Olivieri O, Girelli D, et al. Omega-3 poly-unsaturated fatty acid supplements and ambulatory bloodpressure monitoring parameters in patients with mildessential hypertension. J Hypertens 1995 Dec; 13 (12 Pt 2):1823-6

10. Di Stasi D, Bernasconi R, Marchioli R, et al. Early modifica-tions of fatty acid composition in plasma phospholipids, plate-lets and mononucleates of healthy volunteers after low doses



of n-3 polyunsaturated fatty acids. Eur J Clin Pharmacol2004 May; 60 (3): 183-90

11. Hansen JB,Olsen JO,Wilsgard L, et al. Comparative effects ofprolonged intake of highly purified fish oils as ethyl ester ortriglyceride on lipids, haemostasis and platelet function innormolipaemicmen. Eur JClinNutr 1993 Jul; 47 (7): 497-507

12. Holm T, Andreassen AK, Aukrust P, et al. Omega-3 fattyacids improve blood pressure control and preserve renalfunction in hypertensive heart transplant recipients. EurHeart J 2001 Mar; 22 (5): 428-36

13. Brouwer IA, Zock PL, Camm AJ, et al. Effect of fish oil onventricular tachyarrhythmia and death in patients withimplantable cardioverter defibrillators: the Study on Ome-ga-3 Fatty Acids and Ventricular Arrhythmia (SOFA)randomized trial. JAMA 2006 Jun 14; 295 (22): 2613-9

14. Eritsland J, Arnesen H, Gronseth K, et al. Effect of dietarysupplementation with n-3 fatty acids on coronary arterybypass graft patency. Am J Cardiol 1996 Jan 1; 77 (1): 31-6

15. Leaf A, Albert CM, JosephsonM, et al. Prevention of fatalarrhythmias in high-risk subjects by fish oil n-3 fatty acidintake. Circulation 2005 Nov 1; 112 (18): 2762-8

16. Raitt MH, Connor WE, Morris C, et al. Fish oilsupplementation and risk of ventricular tachycardia andventricular fibrillation in patients with implantabledefibrillators. JAMA 2005 Jun 15; 293 (23): 2884-91

17. Cawood AL, Ding R, Napper FL, et al. Long chain omega-3 fatty acids enter advanced atherosclerotic plaques andare associated with decreased inflammation and decreasedinflammatory gene expression [abstract no. Tu-W20:3].Atherosclerosis 2006 Jun; 7 (3 Suppl.): 160-1

18. Maki KC, DavidsonMH, Bays HE, et al. Effects of omega-3-acid ethyl esters on LDL particle size in subjects withhypertriglyceridemia despite statin therapy [abstract no.231.2]. FASEB J 2007; 21: 231.2

19. Gapinski JP, VanRuiswyk JV, Heudebert GR, et al.Preventing restenosis with fish oils following coronaryangioplasty: a meta-analysis. Arch Intern Med 1993Jul 12; 153 (13): 1595-601

20. Geleijnse JM, Giltay EJ, Grobbee DE, et al. Blood pressureresponse to fish oil supplementation: metaregression analysisof randomized trials. J Hypertens 2002 Aug; 20 (8): 1493-9

21. Mozaffarian D, Geelen A, Brouwer IA, et al. Effect of fishoil on heart rate in humans: a meta-analysis of randomizedcontrolled trials. Circulation 2005 Sep 27; 112 (13): 1945-52

22. O’Connor GT, Malenka DJ, Olmstead EM, et al. A meta-analysis of randomized trials of fish oil in prevention ofrestenosis following coronary angioplasty. Am J PrevMed 1992 May-Jun 30; 8 (3): 186-92

23. Anand RG, Alkadri M, Lavie CJ. The role of fish oil inarrhythmia prevention. J Cardiopulm Rehabil Prev 2008Mar-Apr 30; 28 (2): 92-8

24. Bays HE. Safety considerations with omega-3 fatty acids.Am J Cardiol 2007 Mar 19; 99 (6A): 35-43C

25. Christensen JH. n-3 fatty acids and the risk of suddencardiac death: emphasis on heart rate variability. DanMed Bull 2003 Nov; 50 (4): 347-67

26. HarrisWS. Expert opinion: omega-3 fatty acids and bleeding –cause for concern?Am JCardiol 2007Mar 19; 99 (6A): 44-6C

27. Harrison N, Abhyankar B. The mechanism of action ofomega-3 fatty acids in secondary prevention post-myocardialinfarction. Curr Med Res Opin 2005 Jan; 21 (1): 95-100

28. Knapp HR. Dietary fatty acids in human thrombosis and he-mostasis. Am J Clin Nutr 1997 May; 65 (5 Suppl.): 1687-8S

29. Lee JH, O’Keefe JH, Lavie CJ, et al. Omega-3 fatty acids forcardioprotection. Mayo Clin Proc 2008 Mar; 83 (3): 324-32

30. Reiffel JA,McDonald A. Antiarrhythmic effects of omega-3 fatty acids. Am J Cardiol 2006 Aug 21; 98 (4A): 50-60i

31. Robinson JG, Stone NJ. Antiatherosclerotic and antith-rombotic effect of omega-3 fatty acids. Am J Cardiol 2006Aug 21; 98 (4 Suppl. 1): 39-49i

32. Reliant Pharmaceuticals. Lovaza prescribing information[online]. Available from URL: http://www.fda.gov/cder/foi/label/2008/021654s021lblR.pdf [Accessed 2009 Apr 2]

33. Bryhn M, Hansteen H, Schanche T, et al. The bioavail-ability and pharmacodynamics of different concentra-tions of omega-3 acid ethyl esters. Prostaglandins LeukotEssent Fatty Acids 2006 Jul; 75 (1): 19-24

34. Rustan AC, Nossen JO, Christiansen EN, et al. Eicosa-pentaenoic acid reduces hepatic synthesis and secretion oftriacylglycerol by decreasing the activity of acyl-coenzymeA:1,2-diacylglycerol acyltransferase. J Lipid Res 1988Nov; 29 (11): 1417-26

35. Jump DB. Fatty acid regulation of gene transcription. CritRev Clin Lab Sci 2004; 41 (1): 41-78

36. Lee SS, Chan WY, Lo CK, et al. Requirement of PPAR-alpha in maintaining phospholipid and triacylglycerolhomeostasis during energy deprivation. J Lipid Res 2004Nov; 45 (11): 2025-37

37. Sampath H, Ntambi JM. Polyunsaturated fatty acid regu-lation of gene expression. Nutr Rev 2004 Sep; 62 (9): 333-9

38. Davidson MH. Mechanisms for the hypotriglyceridemiceffect of marine omega-3 fatty acids. Am J Cardiol 2006Aug 21; 98 (4A): 27-33i

39. Bays HE, Tighe AP, Sadovsky R, et al. Prescriptionomega-3 fatty acids and their lipid effects: physiologicmechanisms of action and clinical implications. ExpertRev Cardiovasc Ther 2008 Mar; 6 (3): 391-409

40. Stalenhoef AF, de Graaf J, Wittekoek ME, et al. The effectof concentrated n-3 fatty acids versus gemfibrozil onplasma lipoproteins, low density lipoprotein hetero-geneity and oxidizability in patients with hypertriglycer-idemia. Atherosclerosis 2000 Nov; 153 (1): 129-38

41. Pownall HJ, Brauchi D, Kilinc C, et al. Correlation ofserum triglyceride and its reduction by omega-3 fattyacids with lipid transfer activity and the neutral lipidcompositions of high-density and low-density lipopro-teins. Atherosclerosis 1999 Apr; 143 (2): 285-97

42. Abe Y, El-Masri B, Kimball KT, et al. Soluble cell adhe-sion molecules in hypertriglyceridemia and potential sig-nificance on monocyte adhesion. Arterioscler ThrombVasc Biol 1998 May; 18 (5): 723-31

43. Mackness MI, Bhatnagar D, Durrington PN, et al. Effectsof a new fish oil concentrate on plasma lipids and lipo-proteins in patients with hypertriglyceridaemia. Eur J ClinNutr 1994 Dec; 48 (12): 859-65

44. Calabresi L, Donati D, Pazzucconi F, et al. Omacor infamilial combined hyperlipidemia: effects on lipids andlow density lipoprotein subclasses. Atherosclerosis 2000Feb; 148 (2): 387-96

45. Maki KC, McKenney JM, Reeves MS, et al. Effects ofadding prescription omega-3 acid ethyl esters to simvas-tatin (20mg/day) on lipids and lipoprotein particles inmen and women with mixed dyslipidemia. Am J Cardiol2008 Aug 15; 102 (4): 429-33

46. Van DamM, Stalenhoef AFH, Wittekoek J, et al. Efficacy ofconcentrated n-3 fatty acids in hypertriglyceridaemia: a com-

1102 Hoy & Keating


parison with gemfibrozil. Clin Drug Invest 2001;21 (3): 175-81

47. McKenney JM, Sica D. Role of prescription omega-3 fattyacids in the treatment of hypertriglyceridemia. Pharma-cotherapy 2007 May; 27 (5): 715-28

48. ChanDC,Watts GF, Barrett PH, et al. Regulatory effects ofHMG CoA reductase inhibitor and fish oils on apolipo-protein B-100 kinetics in insulin-resistant obese male sub-jects with dyslipidemia. Diabetes 2002 Aug; 51 (8): 2377-86

49. Toft I, Bonaa KH, Ingebretsen OC, et al. Effects of n-3polyunsaturated fatty acids on glucose homeostasis andblood pressure in essential hypertension: a randomized,controlled trial. Ann InternMed 1995Dec 15; 123 (12): 911-8

50. Bonaa KH, Bjerve KS, Straume B, et al. Effect of eicosa-pentaenoic and docosahexaenoic acids on blood pressure inhypertension: a population-based intervention trial from theTromso study. N Engl JMed 1990Mar 22; 322 (12): 795-801

51. Grundt H, Nilsen DW, Hetland O, et al. Improvement ofserum lipids and blood pressure during intervention withn-3 fatty acids was not associated with changes in insulinlevels in subjects with combined hyperlipidaemia. J InternMed 1995 Mar; 237 (3): 249-59

52. Nordoy A, Hansen JB, Brox J, et al. Effects of atorvastatinand omega-3 fatty acids on LDL subfractions and post-prandial hyperlipemia in patients with combined hyperli-pemia. Nutr Metab Cardiovasc Dis 2001 Feb; 11 (1): 7-16

53. Andreassen AK, Hartmann A, Offstad J, et al. Hypertensionprophylaxis with omega-3 fatty acids in heart transplantrecipients. J Am Coll Cardiol 1997 May; 29 (6): 1324-31

54. Hamaad A, Kaeng Lee W, Lip GY, et al. Oral omega n3-PUFA therapy (Omacor) has no impact on indices ofheart rate variability in stable post myocardial infarctionpatients. Cardiovasc Drugs Ther 2006 Oct; 20 (5): 359-64

55. Kang JX, Leaf A. Prevention of fatal cardiac arrhythmiasby polyunsaturated fatty acids. Am J Clin Nutr 2000 Jan;71 (1 Suppl.): 202-7S

56. McLennan PL, Abeywardena MY, Charnock JS. Dietaryfish oil prevents ventricular fibrillation following coro-nary artery occlusion and reperfusion. Am Heart J 1988Sep; 116 (3): 709-17

57. McLennan PL. Relative effects of dietary saturated, mono-unsaturated, and polyunsaturated fatty acids on cardiacarrhythmias in rats. Am J Clin Nutr 1993 Feb; 57 (2): 207-12

58. Billman GE, Kang JX, Leaf A. Prevention of sudden car-diac death by dietary pure omega-3 polyunsaturated fattyacids in dogs. Circulation 1999 May 11; 99 (18): 2452-7

59. Billman GE, Kang XL, Leaf A. Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturatedfatty acids in dogs. Lipids 1997 Nov; 32 (11): 1161-8

60. Fischer R, Dechend R, Qadri F, et al. Dietary n-3 poly-unsaturated fatty acids and direct renin inhibition im-prove electrical remodelling in a model of high humanrenin hypertension. Hypertension 2008 Feb; 51 (2): 540-6

61. Sellmayer A, Witzgall H, Lorenz RL. Effects of dietary fishoil on ventricular premature complexes. Am J Cardiol1995 Nov 1; 76 (12): 974-7

62. Pignier C, Revenaz C, Rauly-Lestienne I, et al. Directprotective effects of poly-unsaturated fatty acids, DHAand EPA, against activation of cardiac late sodium cur-rent: a mechanism for ischemia selectivity. Basic ResCardiol 2007 Nov; 102 (6): 553-64

63. Dujardin KS, Dumotier B, David M, et al. Ultrafast sodiumchannel block by dietary fish oil prevents dofetilide-induced

ventricular arrhythmias in rabbit hearts. Am J Physiol HeartCirc Physiol 2008 Oct; 295 (4): H1414-21

64. Xiao YF, Ma L, Wang SY, et al. Potent block of inactiva-tion-deficient Na+ channels by n-3 polyunsaturated fattyacids. Am J Physiol Cell Physiol 2006 Feb; 290 (2): C362-70

65. Dietary supplementation with n-3 polyunsaturated fattyacids and vitamin E after myocardial infarction: results ofthe GISSI-Prevenzione trial. Gruppo Italiano per lo Stu-dio della Sopravvivenza nell’Infarto miocardico. Lancet1999 Aug 7; 354 (9177): 447-55

66. Calo L, Bianconi L, Colivicchi F, et al. N-3 Fatty acids forthe prevention of atrial fibrillation after coronary arterybypass surgery: a randomized, controlled trial. J Am CollCardiol 2005 May 17; 45 (10): 1723-8

67. Christensen JH, Korup E, Aaroe J, et al. Fish consumption,n-3 fatty acids in cell membranes, and heart rate variabilityin survivors of myocardial infarction with left ventriculardysfunction. Am J Cardiol 1997 Jun 15; 79 (12): 1670-3

68. Christensen JH, Gustenhoff P, Korup P, et al. Effect of fishoil on heart rate variability in survivors of myocardialinfarction: a double blind randomised controlled trial.BMJ 1996 Mar 16; 312: 677-8

69. O’Keefe JH, Abuissa H, Sastre A, et al. Effects of omega-3fatty acids on resting heart rate, heart rate recovery afterexercise, and heart rate variability in men with healedmyocardial infarctions and depressed ejection fraction.Am J Cardiol 2006; 97 (8): 1127-30

70. Goodfellow J, Bellamy MF, Ramsey MW, et al. Dietarysupplementation with marine omega-3 fatty acids im-prove systemic large artery endothelial function in sub-jects with hypercholesterolemia. J Am Coll Cardiol 2000Feb; 35 (2): 265-70

71. Kim DN, Eastman A, Baker JE, et al. Fish oil, atherogen-esis, and thrombogenesis. Ann N Y Acad Sci 1995 Jan 17;748: 474-80

72. Agren JJ, Vaisanen S, Hanninen O, et al. Hemostatic factorsand platelet aggregation after a fish-enriched diet or fish oilor docosahexaenoic acid supplementation. ProstaglandinsLeukot Essent Fatty Acids 1997 Oct; 57 (4-5): 419-21

73. Mori TA, Beilin LJ, Burke V, et al. Interaction betwendietary fat, fish, fish oils and their effects on plateletfunction in men at risk of cardiovascular disease. Arter-ioscler Thromb Vasc Biol 1997 Feb; 17 (2): 279-86

74. Lee KW, Blann AD, Lip GY. Effects of omega-3 poly-unsaturated fatty acids on plasma indices of thrombo-genesis and inflammation in patients post-myocardialinfarction. Thromb Res 2006; 118 (3): 305-12

75. Nordoy A, Bonaa KH, Sandset PM, et al. Effect of omega-3 fatty acids and simvastatin on hemostatic risk factorsand postprandial hyperlipemia in patients with combinedhyperlipemia. Arterioscler Thromb Vasc Biol 2000 Jan;20 (1): 259-65

76. Nilsen DW, Dalaker K, Nordoy A, et al. Influence of a con-centrated ethylester compound of n-3 fatty acids on lipids,platelets and coagulation in patients undergoing coronarybypass surgery. ThrombHaemost 1991Aug 1; 66 (2): 195-201

77. Hansen JB, Lyngmo V, Svensson B, et al. Inhibition ofexercise-induced shortening of bleeding time by fish oil infamilial hypercholesterolemia (type IIa). ArteriosclerThromb 1993 Jan; 13 (1): 98-104

78. Johansen O, Brekke M, Seljeflot I, et al. N-3 fatty acids donot prevent restenosis after coronary angioplasty: resultsfrom the CART study. Coronary Angioplasty RestenosisTrial. J Am Coll Cardiol 1999 May; 33 (6): 1619-26



79. Thies F, Garry J, Yaqoob P, et al. Association of n-3polyunsaturated fatty acids with stability of athero-sclerotic plaques: a randomised controlled trial. Lancet2003 Feb 8; 361 (9356): 477-85

80. Kaminski WE, Jendraschak E, Kiefl R, et al. Dietaryomega-3 fatty acids lower levels of platelet-derived growthfactor mRNA in human mononuclear cells. Blood 1993Apr 1; 81 (7): 1871-9

81. Mehra MR, Lavie CJ, Ventura HO, et al. Fish oils produceanti-inflammatory effects and improve body weight in severeheart failure. J Heart Lung Transplant 2006 Jul; 25 (7): 834-8

82. Chan DC, Watts GF, Barrett PH, et al. Effect of atorvas-tatin and fish oil on plasma high-sensitivity C-reactiveprotein concentrations in individuals with visceral obe-sity. Clin Chem 2002 Jun; 48 (6 Pt 1): 877-83

83. Nordoy A, Barstad L, ConnorWE, et al. Absorption of then-3 eicosapentaenoic and docosahexaenoic acids as ethylesters and triglycerides by humans. Am J Clin Nutr 1991May; 53 (5): 1185-90

84. Luley C,WielandH,Grunwald J. Bioavailability of omega-3fatty acids: ethylester preparations are as suitable as trigly-ceride preparations. Aktuel Ernahrungsmed 1990; 15: 123-5

85. Harris WS, Ginsberg HN, Arunakul N, et al. Safety andefficacy of Omacor in severe hypertriglyceridemia. J Car-diovasc Risk 1997 Oct-Dec 31; 4 (5-6): 385-91

86. Durrington PN, Bhatnagar D, Mackness MI, et al. Anomega-3 polyunsaturated fatty acid concentrate adminis-tered for one year decreased triglycerides in simvastatintreated patients with coronary heart disease and persistinghypertriglyceridaemia. Heart 2001 May; 85 (5): 544-8

87. Di Spirito M, Morelli G, Doyle RT, et al. Effect of omega-3-acid ethyl esters on steady-state plasma pharmacoki-netics of atorvastatin in healthy adults. Expert OpinPharmacother 2008 Dec; 9 (17): 2939-45

88. Gosai P, Liu J, Doyle RT, et al. Effect of omega-3-acidethyl esters on the steady-state plasma pharmacokineticsof rosuvastatin in healthy adults. Expert Opin Pharmac-other 2008 Dec; 9 (17): 2947-53

89. McKenney M, Swearingen D, Di Spirito M, et al. Study ofthe pharmacokinetic interaction between simvastatin andprescription omega-3-acid ethyl esters. J Clin Pharmacol2006 Jul; 46 (7): 785-91

90. Senges J, Schiele R, Schneider S, et al. Randomized trial ofomega-3 fatty acids on top of modern therapy after acutemyocardial infarction: the OMEGA trial [oral presenta-tion]. 58th Annual Scientific Session of the AmericanCollege of Cardiology; 2009 Mar 29-31; Orlando (FL)

91. Marchioli R, Barzi F, Bomba E, et al. Early protectionagainst sudden death by n-3 polyunsaturated fattyacids after myocardial infarction: time-course analysisof the results of the Gruppo Italiano per lo Studiodella Sopravvivenza nell’Infarto miocardico (GISSI)-Prevenzione. Circulation 2002 Apr 23; 105 (16): 1897-903

92. Verboom CN. Highly purified omega-3 polyunsaturated fattyacids are effective as adjunct therapy for secondary preventionof myocardial infarction. Herz 2006 Dec; 31 Suppl. 3: 49-59

93. Macchia A, Levantesi G, Franzosi MG, et al. Left ventricularsystolic dysfunction, total mortality, and sudden death in pa-tients with myocardial infarction treated with n-3 poly-unsaturated fatty acids. Eur JHeart Fail 2005Aug; 7 (5): 904-9

94. RauchB, SchieleR, Schneider S, et al. Highly purified omega-3fatty acids for secondary prevention of sudden cardiac deathafter myocardial infarction: aims and methods of the OME-GA-study. Cardiovasc Drugs Ther 2006 Oct; 20 (5): 365-75

95. Lamotte M, Annemans L, Kawalec P, et al. A multi-countryhealth economic evaluation of highly concentrated N-3 poly-unsaturated fatty acids in secondary prevention after myo-cardial infarction. Pharmacoeconomics 2006; 24 (8): 783-95

96. Quilici S, Martin M, McGuire A, et al. A cost-effectivenessanalysis of n-3 PUFA (Omacor) treatment in post-MIpatients. Int J Clin Pract 2006 Aug; 60 (8): 922-32

97. Davidson MH, Stein EA, Bays HE, et al. Efficacy andtolerability of adding prescription omega-3 fatty acids4 g/d to simvastatin 40mg/d in hypertriglyceridemic pa-tients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther 2007 Jul; 29 (7): 1354-67

98. Bays HE, McKenney J, Doyle RT, et al. Effect of prescrip-tion omega-3 fatty acids coadministered with escalatingdoses of atorvastatin in patients with hypertriglyceridemia[abstract no. 5150]. Circulation 2008; 118: S_1152

99. National Institutes of Health. Third report of the NationalCholesterol Education Program (NCEP): expert panel on de-tection, evaluation, and treatment of high blood cholesterol inadults (Adult Treatment Panel III) executive summary. Be-thesda (MD): National Institutes of Health, National Heart,Lung and Blood Institutes. NIH publication no. 01-3670

100. Data on file. Pronova BioPharma Norge AS, 2008

101. Graham I, Atar D, Borch-Johnsen K, et al. European guide-lines on cardiovascular disease prevention in clinical practice:executive summary. Fourth Joint Task Force of the Eur-opean Society of Cardiology and other societies on cardio-vascular disease prevention in clinical practice (constituted byrepresentatives of nine societies and by invited experts). Eur JCardiovasc Prev Rehabil 2007 Sep; 14 Suppl. 2: E1-40

102. World Health Organization. Cardiovascular diseases [on-line]. Available from URL: http://www.who.int/media-centre/factsheets/fs317/en [Accessed 2008 Oct 20]

103. Smith Jr SC, Allen J, Blair SN, et al. AHA/ACC guidelinesfor secondary prevention for patients with coronary andother atherosclerotic vascular disease: 2006 update. Cir-culation 2006 May 16; 113 (19): 2363-72

104. Grundy SM, Cleeman JI, Merz CN, et al. Implications ofrecent clinical trials for the National Cholesterol Educa-tion Program Adult Treatment Panel III guidelines.Circulation 2004 Jul 13; 110 (2): 227-39

105. Safeer RS, Ugalat PS. Cholesterol treatment guidelinesupdate. Am Fam Physician 2002 Mar 1; 65 (5): 871-80

106. von Schacky C. A review of omega-3 ethyl esters for cardi-ovascular prevention and treatment of increased blood tri-glyceride levels. VascHealthRiskManag 2006; 2 (3): 251-62

107. Mozaffarian D, Rimm EB. Fish intake, contaminants, andhuman health: evaluating the risks and the benefits.JAMA 2006 Oct 18; 296 (15): 1885-99

108. Harris WS, Poston WC, Haddock CK. Tissue n-3 and n-6fatty acids and risk for coronary heart disease events.Atherosclerosis 2007 Jul; 193 (1): 1-10

109. Brunner E, Iso H. Fish oil and secondary prevention ofcardiovascular disease. BMJ 2008; 337: a2541

110. Leaf A, Kang JX, Xiao Y-F, et al. Clinical prevention ofsudden cardiac death by n-3 polyunsaturated fatty acidsand mechanism of prevention of arrhythmias by n-3 fishoils. Circulation 2003 Jun 3; 107: 2646-52

111. Gerstein H, Yusuf S, Riddle MC, et al. Rationale, design,and baseline characteristics for a large international trialof cardiovascular disease prevention in people with dys-glycemia: the ORIGINTrial (OutcomeReduction with anInitial Glargine Intervention). The ORIGIN Trial In-vestigators. Am Heart J 2008 Jan; 155 (1): 26-32

1104 Hoy & Keating


112. Holman RR, Paul S, Farmer A, et al. Atorvastatin inFactorial with Omega-3 EE90 Risk Reduction in Diabetes(AFORRD): a randomised controlled trial. Diabetologia2009 Jan; 52 (1): 50-9

113. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3polyunsaturated fatty acids in patients with chronic heartfailure (the GISSI-HF trial): a randomised, double-blind,placebo-controlled trial. Lancet 2008 Oct 4; 372 (9645):1223-30

114. National Institute of Health and Clinical Excellence. MI: sec-ondary prevention. London:National Institute ofHealth andClinical Excellence, 2007 May. NICE clinical guideline 48

115. von Schacky C, Harris WS. Cardiovascular benefits of ome-ga-3 fatty acids. Cardiovasc Res 2007 Jan 15; 73 (2): 310-5

116. Hooper L, Thompson RL, Harrison RA, et al. Omega 3fatty acids for prevention and treatment of cardiovasculardisease. Cochrane Database Syst Rev 2004; (4): CD003177

117. Hooper L, Thompson RL, Harrison RA, et al. Risks andbenefits of omega 3 fats for mortality, cardiovasculardisease, and cancer: systematic review. BMJ 2006 Apr 1;332 (7544): 752-60

118. Graham I, Atar D, Borch-Johnsen K, et al. Europeanguidelines on cardiovascular disease prevention in clinicalpractice: full text. Fourth Joint Task Force of theEuropean Society of Cardiology and other societies oncardiovascular disease prevention in clinical practice(constituted by representatives of nine societies and byinvited experts). Eur J Cardiovasc Prev Rehabil 2007 Sep;14 Suppl. 2: S1-113

119. von Schacky C, Harris WS,Mozaffarian D, et al. Responseto Hoopers et al. Cochrane review [online]. Availablefrom URL: http://www.issfal.org.uk/response-to-hoopers-et-al-cochrane-review.html [Accessed 2008 Nov 25]

120. Leon H, Shibata MC, Sivakumaran S, et al. Effect of fishoil on arrhythmias and mortality: systematic review. BMJ2008; 337: a2931

Correspondence: Sheridan M. Hoy, Wolters KluwerHealth | Adis, 41 Centorian Drive, Private Bag 65901,Mairangi Bay, North Shore 0754, Auckland, New Zealand.E-mail: [email protected]



Omega 3

Documents

addition of omega

place of omega

capsule of omega

summaryabstract oral

secondary prevention

secondary prevention

cardiovascular effects

postmi adult patients