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Original Investigation |

Effect of Long-Chain ω-3 Fatty Acids and Lutein + Zeaxanthin Supplements on Cardiovascular Outcomes:  Results of the Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial

JAMA Intern Med. 2014;174(5):763-771. doi:10.1001/jamainternmed.2014.328.
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Importance  Dietary supplements have been proposed as a mechanism to improve health and prevent disease.

Objective  To determine if supplementing diet with long-chain ω-3 polyunsaturated fatty acids or with macular xanthophylls results in a reduced rate of cardiovascular disease (CVD).

Design, Setting, and Participants  The Cardiovascular Outcome Study (COS) was an ancillary study of the Age-Related Eye Disease Study 2 (AREDS2), a factorial-designed randomized clinical trial of 4203 participants recruited from 82 US academic and community ophthalmology clinics, who were followed up for a median of 4.8 years. Individuals were eligible to participate if they were between the ages of 50 and 85 years, had intermediate or advanced age-related macular degeneration in 1 eye, and were willing to be randomized. Participants with stable, existing CVD (>12 months since initial event) were eligible to participate. Participants, staff, and outcome assessors were masked to intervention.

Interventions  Daily supplementation with long-chain ω-3 polyunsaturated fatty acids (350-mg docosahexaenoic acid [DHA] + 650-mg eicosapentaenoic acid [EPA]), macular xanthophylls (10-mg lutein + 2-mg zeaxanthin), combination of the two, or matching placebos. These treatments were added to background therapy of the AREDS vitamin and mineral formulation for macular degeneration.

Main Outcomes and Measures  A composite outcome of myocardial infarction, stroke, and cardiovascular death with 4 prespecified secondary combinations of the primary outcome with hospitalized heart failure, revascularization, or unstable angina.

Results  Study participants were primarily white, married, and highly educated, with a median age at baseline of 74 years. A total of 602 cardiovascular events were adjudicated, and 459 were found to meet 1 of the study definitions for a CVD outcome. In intention-to-treat analysis, no reduction in the risk of CVD or secondary CVD outcomes was seen for the DHA + EPA (primary outcome: hazard ratio [HR], 0.95; 95% CI, 0.78-1.17) or lutein + zeaxanthin (primary outcome: HR, 0.94; 95% CI, 0.77-1.15) groups. No differences in adverse events or serious adverse event were seen by treatment group. The sample size was sufficient to detect a 25% reduction in CVD events with 80% power.

Conclusions and Relevance  Dietary supplementation of long-chain ω-3 polyunsaturated fatty acids or macular xanthophylls in addition to daily intake of minerals and vitamins did not reduce the risk of CVD in elderly participants with age-related macular degeneration.

Trial Registration  clinicaltrials.gov Identifier: NCT00345176

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Figure 1.
Age-Related Eye Disease Study 2 (AREDS2) CONSORT Diagram for Cardiovascular Outcome Study

Treatments were given at the following doses: 350-mg docosahexaenoic acid (DHA) + 650-mg eicosapentaenoic acid (EPA); 10-mg lutein + 2-mg zeaxanthin.aParticipants included to point when lost to follow-up.

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Figure 2.
Time to First Cardiovascular Disease (CVD) Mortality/Morbidity Event

A, Time to first CVD mortality/morbidity event by docosahexaenoic acid plus eicosapentaenoic acid (DHA + EPA) and no DHA + EPA (adjudicated events only). B, Time to first CVD mortality/morbidity event by lutein + zeaxanthin vs no lutein + zeaxanthin (adjudicated events only). Treatments were given at the following doses: 350-mg DHA + 650-mg EPA; 10-mg lutein + 2-mg zeaxanthin.

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Figure 3.
Comparison of the Main Effects

A, Comparison of the main effects of docosahexaenoic acid plus eicosapentaenoic acid (DHA + EPA) vs no DHA + EPA stratified by cardiovascular medical history and dietary intake of DHA + EPA. B, Comparison of the main effects of lutein + zeaxanthin (LUT + ZEA) vs no LUT + ZEA stratified by cardiovascular medical history and dietary intake of LUT + ZEA. CVD indicates cardiovascular disease. Treatments were given at the following doses: 350-mg DHA + 650-mg EPA; 10-mg LUT + 2-mg ZEA.

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