REDUCE-IT: Reduction of Cardiovascular Events Outcome tria

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Macrovascular Residual Risk Studies

11 December 2012

A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT)

STUDY SUMMARY

Objective:

To evaluate the effectiveness of AMR101 as an add-on to statin treatment in reducing major cardiovascular (CV) events in high-risk patients

Study design:

Multicentre, randomized, double-blind placebo-controlled, parallel group study

Study population:

8,000 men and women (¬≥45 years) with residual elevated triglycerides (>150 mg/dL or 1.7 mmol/L) despite statin therapy for at least 4 weeks, with or at high risk of CV disease. Concomitant treatment with niacin >200 mg/day or fibrates; any omega-3 fatty acid medications; dietary supplements containing omega-3 fatty acids (e.g., flaxseed oil, fish oil, krill oil, or algal oil); or bile acid sequestrants was prohibited.

Primary outcome:

Major CV events, defined as a composite of CV death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina.

Secondary variables:

Individual component CV events of primary outcome; lipid and lipoprotein levels

Method:

Eligible patients will be randomized to treatment with optimized statin therapy plus AMR101 or statin therapy alone. The estimated duration of follow-up is 4-6 years. The first patient was enrolled in December 2011.

COMMENT

There is a growing body of evidence linking elevated triglycerides and risk for CV disease.(1) Indeed, the position statement from the R3i highlights that high triglycerides are commonly associated with low high-density lipoprotein (HDL) cholesterol, atherogenic dyslipidemia, which itself is associated with increased CV risk.(2) For example, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study, simvastatin-treated type 2 diabetes patients with atherogenic dyslipidemia (triglycerides ≥204 mg/dL and HDL cholesterol ≤34 mg/dL) at baseline had a 70% increased risk of CV events compared with those without this dyslipidemic profile, even with LDL-C at or near goal. (3)

There is evidence from the Japan EPA Lipid Intervention Study (JELIS) that targeting elevated triglycerides in high-risk statin-treated patients with omega-3 fatty acids significantly reduced major coronary events (Fig).4 However, the dose used in this trial was less than that recommended by guidelines.(5,6) Moreover, with the current prescription formulation, there is also a risk of increased low-density lipoprotein (LDL) cholesterol levels, which may be attributed to the docosahexaenoic acid component.(7)

Fig: In JELIS, Supplementation with omega-3 fatty acids (1.8 g/day EPA) significantly reduced major coronary events.(4)

AMR101 differs from the current prescription formulation of omega-3 fatty acids in that it solely contains the ethyl ester of EPA. In Phase II trials,(8) AMR101 (4 g/day) significantly reduced median triglycerides (by 21.5%) without any increase in LDL cholesterol levels. Moreover, the reduction in triglycerides was greater in patients receiving high-intensity statin regimens (median reductions 20.2% with atorvastatin 40-80 mg, rosuvastatin 20-40 mg or simvastatin 80 mg) versus less intensive regimens.

Together, these data provide a rationale for testing the hypothesis that targeting elevated triglycerides, a component of atherogenic dyslipidemia, may offer the potential to reduce the residual risk of CV events in high-risk patients treated with statin therapy. Results from REDUCE-IT are anticipated in 2017.

References

1. Nordestgaard BG, Benn M, Schnohr P, Tybj√¶rg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299‚Äì308.
2. Fruchart JC, Sacks F, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008 Nov 17;102(10 Suppl):1K-34K.
3. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
4. Yokoyama M, Origasa H, Matsuzaki M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis. Lancet 2007;369:1090-8.
5. Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, Stalenhoef AF. J Clin Endocrinol Metab 2012;97:2969-89.
6. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
7. Neff LM, Culiner J, Cunningham-Rundles S et al. Algal docosahexaenoic acid affects plasma lipoprotein particle size distribution in overweight and obese adults. J Nutr 2011;141:207-13.
8. Ballantyne CM, Bays HE, Kastelein JJ et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR Study). Am J Cardiol 2012; 110:984-92

Key words

atherogenic dyslipidemia, omega-3 fatty acids, residual cardiovascular risk, triglycerides