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Omega-3 Ethylester Concentrate

A Review of its Use in Secondary Prevention Post-Myocardial Infarction and the Treatment of Hypertriglyceridaemia

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Summary

Abstract

Oral omega-3 ethylester concentrate (omega-3 EEC) [Omacor®; Lovaza™] is indicated 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 1000 mg capsule of omega-3 EEC consists of 460 mg of ethyl eicosapentaenoic acid and 380 mg of ethyl docosahexaenoic acid.

The addition of omega-3 EEC 1000 mg/day to standard medical therapy in the GISSI-Prevenzione study provided secondary prevention benefits in post-MI adult patients. The benefits were attributable to reductions in death and cardiovascular death (including sudden death). Additional data examining the extent and mechanisms of the cardiovascular benefit conferred by omega-3 EEC in secondary prevention would be useful. As an adjunct to diet, monotherapy with omega-3 EEC 4000 mg/day significantly reduced triglyceride levels in patients with hypertriglyceridaemia, although limited data suggest it was less effective than gemfibrozil. In addition, omega-3 EEC 4000 mg/day plus simvastatin or atorvastatin reduced triglyceride, non-high-density lipoprotein cholesterol (non-HDL-C) and/or very-low-density lipoprotein cholesterol (VLDL-C) levels to a significantly greater extent than placebo plus simvastatin or atorvastatin. Omega-3 EEC was generally well tolerated both as secondary prevention post-MI and in the treatment of hypertriglyceridaemia. Thus, omega-3 EEC is a useful option both in secondary prevention post-MI and the treatment of hypertriglyceridaemia.

Pharmacological Properties

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 β-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 lipoprotein 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 autonomic 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.

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 anticoagulant dosage adjusted as necessary.

The effect of omega-3 EEC on the prevention of restenosis is equivocal; however, 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-α 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 patients 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 1000 mg/day, as an adjuvant therapy to standard treatment (e.g. ACE inhibitors, antiplatelet agents, β-adrenergic receptor antagonists, HMG-CoA reductase inhibitors), demonstrated a secondary preventive effect in patients with recent (<3 months) MI in the 42-month, randomized, nonblind (endpoints validated by a blinded assessment committee), multicentre GISSI-Prevenzione study. Omega-3 EEC-based therapy (omega-3 EEC 1000 mg/day and omega-3 EEC 1000 mg/day plus tocopherol groups) significantly reduced the risk of a primary composite efficacy endpoint (death plus nonfatal MI plus nonfatal stroke) and various secondary or other endpoints (including death, cardiovascular 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 tocopherol 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 secondary 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-MI relative to standard therapy in terms of cost per life-year or quality-adjusted life-year gained.

Oral omega-3 EEC 4000 mg/day, as monotherapy or in combination with simvastatin or atorvastatin, was generally effective as an adjunct to diet in the treatment of hypertriglyceridaemia in adult patients. For the most part, omega-3 EEC monotherapy demonstrated significantly greater reductions from baseline than placebo in triglyceride, total cholesterol and VLDL-C levels, and significantly greater elevations from baseline in HDL-C levels in a well designed study. In contrast, significant elevations in low-density lipoprotein cholesterol levels were observed in omega-3 EEC monotherapy versus placebo recipients. Limited data suggest oral gemfibrozil was associated with significantly greater reductions in serum triglyceride levels (primary endpoint) and significantly 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 simvastatin was an effective lipid-modifying therapy in patients with hypertriglyceridaemia, 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 indicated that omega-3 EEC plus atorvastatin was associated with significantly greater reductions from baseline in non-HDL-C (primary endpoint), total cholesterol, triglyceride and VLDL-C levels and significantly greater improvements from baseline in HDL-C levels, than placebo plus atorvastatin in patients with hypertriglyceridaemia.

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 gastrointestinal in nature and mild or minor in intensity. In the GISSI-Prevenzione study, treatment-emergent gastrointestinal disturbances and nausea were observed 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.

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Sheridan M. Hoy & Gillian M. Keating

  2. Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Sheridan M. Hoy & Gillian M. Keating

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  1. Sheridan M. Hoy
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  2. Gillian M. Keating
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Correspondence to Sheridan M. Hoy.

Additional information

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

Data Selection

Sources: Medical literature published in any language since 1980 on ‘omega-3 ethylester’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health ∣ Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘omega-3 ethylester concentrate’ or ‘omega-3 acid ethyl esters’ or ‘Omacor’. Searches were last updated 22 May 2009.

Selection: Studies in patients with hypertriglyceridaemia or those with (or at risk of) myocardial infarction who received omega-3 ethylester concentrate. Inclusion of studies was based mainly on the methods section of the studies. When available, large, well controlled studies with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Omega-3 ethylester concentrate, hypertriglyceridaemia, myocardial infarction, pharmacodynamics, pharmacoeconomics, pharmacokinetics, therapeutic use, tolerability.

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Hoy, S.M., Keating, G.M. Omega-3 Ethylester Concentrate. Drugs 69, 1077–1105 (2009). https://doi.org/10.2165/00003495-200969080-00008

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