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