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Macrovascular Residual Risk Studies

1 June 2013
N-3 fatty acids in primary prevention of cardiovascular disease
In a primary prevention population with multiple cardiovascular risk factors, treatment with n-3 fatty acids, as a component of preventive strategies, did not reduce cardiovascular morbidity or mortality.
The Risk and Prevention Study Collaborative Group. N-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med 2013;368:1800-8.
Objective: To evaluate the efficacy of low-dose n-3 fatty acids supplementation in patients at high cardiovascular (CV) risk without previous myocardial infarction (MI) in a community-based primary prevention setting.
Study design: This was an event-driven, double-blind, placebo-controlled trial
Study population:

12,513 patients with at least one of the following criteria were enrolled: multiple (at least 4) CV risk factors (i.e. age ³65 years, male gender, hypertension, hypercholesterolemia, current smoker, obesity or family history of premature CVD); patients with diabetes had at least one of these criteria; clinical evidence of atherosclerotic vascular disease; or any other condition placing the individual at high CV risk in the opinion of the primary care practitioner. Overall, 12,505 patients (mean age 64.0 years, 61.5% men, 60% with diabetes and 71% with hypercholesterolemia) were included in the intention-to-treat (ITT) population: 6,239 received n-3 fatty acids and 6,296 received placebo.

Primary variables:
  • The planned primary end point was the cumulative rate of death, nonfatal myocardial infarction (MI) and nonfatal stroke. However, as the event rate for this end point at 1 year in the placebo group was lower than expected (1.4% per year rather than 2.0% per year as expected), this was subsequently redefined as the time to death from CV causes or first hospital admission for CV causes. With this revised end point, it was assumed that the 5-year event rate in the placebo group would reach 15%.

Eligible patients were randomised to n-3 fatty acids (1 g/day, containing polyunsaturated fatty acid ethyl esters with eicosapentaenoic acid and docosahexaenoic acid not <85%) using a central telephone randomisation procedure. Information on demographics, risk factors and concomitant therapy and conditions was collected at baseline and at scheduled yearly follow-up visits.  Clinicians also considered strategies aimed at lowering CV risk, based on current guidelines. At each yearly follow-up, any new diagnosis of CVD and the occurrence of study end points were recorded.

A Cox proportional hazards model was used to analyse the effect of treatment on the primary endpoint. Kaplan-Meier estimates of survival curves were based on the results of the log-rank test.

Main results:

After a median duration of 5 years follow-up, there was no significant difference in the primary endpoint between the two groups (Table 1).

Table 1. Primary end point analysis

Outcome, n (%)

n-3 fatty acids


Hazard ratio              (95% CI)


Primary end point

733 (11.7)

745 (11.9)

0.98 (0.88-1.08)


CVD death

142 (2.3)

137 (2.2)

1.03 (0.82-1.30)


Hospitalisation for CV causes

620 (9.9)

630 (10.1)

0.98 (0.87-1.09)


Subgroup analyses showed a significantly (p=0.04) lower event rate in women (hazard ratio 0.82, 95% CI 0.67-0.99) than men (hazard ratio 1.04, 95% CI 0.92-1.17). Age, the presence of atherosclerotic CVD, diabetes plus another CV risk factor, or ³4 CV risk factors, had no significant effect in subgroup analyses.

Authors’ conclusion:

In a large, general practice cohort of patients with multiple CV risk factors, daily treatment with n-3 fatty acids did not reduce CV mortality and morbidity.


N-3 fatty acids lower triglycerides-rich lipoproteins associated with atherogenic dyslipidemia. However, there are conflicting data whether treatment with n-3 fatty acids translates to clinical benefits. The GISSI studies (GISSI-Prevenzione and GISSI Heart Failure) showed improved clinical outcomes in patients with a previous MI or heart failure,1,2 although subsequent evaluation suggested that the underlying mechanism may be due to beneficial effects on cardiac arrhythmias, rather than on lipids or blood pressure.3 Subsequently, the Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS), showed that the addition of omega-3 fatty acids (1 g/day and 1.8 g/day) in high-risk hypercholesterolemic patients treated with a statin, significantly reduced major coronary events compared with statin alone (hazard ratio 0.81, 95% CI 0.69-0.95, p=0.011).4 In addition, subgroup analyses indicated benefit in patients with the metabolic syndrome and therefore likely to present with atherogenic dyslipidemia, the combination of high triglycerides and low high-density lipoprotein cholesterol (HDL-C).4 Despite this, the ORIGIN (Outcome Reduction With Initial Glargine Intervention) study showed that treatment with n-3 fatty acids (1 g/day) did not reduce the rate of CV events in dysglycemic patients at high risk for CV events.5

The GISSI and JELIS data provided a rationale for the current landmark trial in a population at high CV risk but without previous MI. Treatment with n-3 fatty acids in this study reduced triglycerides (by 19% versus 13% on placebo, p<0.0001) and marginally raised HDL-C (by 0.5% versus a decrease of 0.6% on placebo, p=0.04); there were no significant effects on other CV risk factors. Thus, the lack of benefit observed in the study may relate to limited impact on atherogenic dyslipidemia at this dose of n-3 fatty acids, which was considerably less than that recommended in clinical guidelines to reduce hypertriglyceridemia.6  In line with this, a previous meta-analysis of 20 studies involving nearly 70,000 patients (median dose of 1 g/day, range 0.5-1.8 g/day) also showed no significant effect on clinical outcomes.7  Alternatively, the findings may reinforce the view that the clinical benefits observed with low-dose n-3 fatty acid treatment relate to anti-arrhythmic effects, especially in populations at risk of arrhythmia, rather than effects on cholesterol or blood pressure in the study populations.  

Thus, to truly test the hypothesis whether n-3 fatty acids reduce CV risk, a dose that significantly impacts atherogenic dyslipidemia should be used. This is the focus of the ongoing REDUCE-IT trial,8 which is testing a new formulation of n-3 fatty acids (AMR101, 4 g/day) in statin-treated patients with elevated triglycerides (>1.7 mmol/L or 150 mg/dL) and at least one additional CV risk factor. This study will be a true test whether targeting atherogenic dyslipidemia reduces residual CV risk in statin-treated patients.


1. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardicoDietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447-455[Erratum, Lancet 2001;357:642, 2007;369:106].
2. GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1223-1230.
3. Leaf A. Omega-3 fatty acids and prevention of arrhythmias. Curr Opin Lipidol 2007; 18: 31-4.
4. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-109.
5. The ORIGIN Trial Investigators. n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-318
6. Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, Stalenhoef AF; Endocrine society. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012 Sep;97(9):2969-89.
7. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012;308:1024-33
8. REDUCE-IT trial. Available at Accessed 15 May 2013.

Key words

: n-3 fatty acids; cardiovascular risk; primary prevention; triglycerides