STUDY SUBJECTS

Major inclusion criteria:

• Age 55-85 years
• Bilateral large drusen or large drusen in 1 eye and Advanced AMD in fellow eye
• Passed the 1 month run-in phase prior to trial: took at least 75% of supplements and agreed to stop other use of supplements
• No other concurrent ocular diseases that complicates assessment of outcomes measures

Major exclusion criteria:

• Prior intraocular surgeries (with exception of cataract surgery at least 3 months prior to enrollment)
• Concurrent systemic diseases or other diseases with a poor 5 year survival

RANDOMIZATION SCHEME AND INTERVENTIONS

Primary Randomization 1:1:1:1 to

(a) “Placebo” (ie. AREDS supplement only-within or outside the secondary randomization)—no true placebo

(b) Lutein (10 mg) + zeaxanthin (2 mg) + AREDS*

(c) DHA (350 mg) + EPA (690 mg) + AREDS*

(d) Lutein (10 mg) + zeaxanthin (2 mg) DHA (350 mg) + EPA (690 mg) + AREDS*

PLUS

* Secondary Randomization of type of AREDS supplement 1:1:1:1 to

(a) Original AREDS formula: (vitamin C [500 mg], vitamin E [400 IU], beta carotene [15 mg], zinc [80 mg, as zinc oxide], and copper [2 mg, as cupric oxide

(b) AREDS and no beta carotene

(c) AREDS with low dose zinc (25 mg)

(d) AREDS with no beta carotene and low dose zinc

Follow up study visits were performed annually, which included a comprehensive eye examination, best-corrected visual acuity, stereoscopic funds photographs of macula and optic nerve.

PRIMARY OUTCOMES

Development of Advanced AMD in study eye at 5 years- determined by fundus photography

• Definition of Progression: Development of Central GA or choroidal neovascularization features on photographs or history of treatment for advanced AMD after enrollment

SECONDARY OUTCOMES

Progression to moderate vision loss (> 3 lines) from either baseline or treatment for choroidal neovascularization

RESULTS

Study population

• 4203 participants for first randomization
  • Of these, 3036 (72.2%) agreed to second randomization of type of AREDS supplement. The remaining participants (1148 (98.4%)) chose to take the original AREDS formulation.

PRIMARY OUTCOME RESULTS: DEVELOPMENT OF ADVANCED AMD

• Primary Randomization group:
  • No statistical difference in reduction of advanced AMD between placebo (AREDS only) and addition of lutein + zeaxanthin, DHA + EPA, or combination of both (with or without stratification from the Secondary Randomization of AREDS)
• Secondary Randomization group
  • No statistical difference in AMD progression in the lower dose zinc or no beta carotene groups compared to the original AREDS formulation
• Notable Post Hoc Subgroup Analyses
  • Patients with the lowest quintiles of dietary lutein+zeaxanthin intake had a statistically significant lower rate of AMD progression when taking the AREDS with lutein and zeaxanthin compared to the original AREDS without lutein and zeaxanthin (HR of 0.74 (95% CI, 0.59-0.94; P = .01). In contrast, there was no statistical difference in AMD progression in the highest quintile of dietary lutein + zeaxanthin group when taking the AREDS formula with lutein and zeaxanthin.
  • AREDS formula with lutein and zeaxanthin and NO beta carotene had statistically lower rate of overall AMD progression (HR 0.82 (95% CI, 0.69–0.96; P = .02) and neovascular AMD (HR 0.78 (95% CI, 0.64-0.94; P = .01) compared to AREDS with beta carotene only.

SECONDARY OUTCOME: VISION

No difference in development of moderate or worse vision loss in any of the treatment groups (lutein + zeaxanthin, DHA + EPA or both; or no beta carotene, low zinc or both)

Adverse Events:

• No statistically significant differences in the primary or secondary randomization group in serious adverse events or mortality
• However, there was an increase in lung cancers in the beta carotene group compared to no beta carotene group (23 [2.0%] vs 11 [0.9%]) (nominal P = .04))—even after excluding participants that were current smokers. 91% (31) of all patients who developed lung cancer were former smokers.

CONCLUSION

• There was no statistical beneficial or harmful effect of adding lutein and zeaxanthin, DHA + EPA, or both to the original AREDS formula on progression to advanced AMD
• There was no statistical difference in AMD progression rates when using lower dose zinc and/or eliminating beta carotene compared to the original AREDS formulation.
• Lutein and Zeaxanthin with AREDS may be most beneficial in providing a protective effect for AMD progression in those with the lowest amount of dietary lutein and zeaxanthin intake
• AREDS + Lutein and Zeaxanthin may reduce AMD progression when given without beta carotene

OFFICIAL AREDS2 FORMULA:
Vitamin C (500 mg), Vitamin E (400 IU), Zinc (80 mg). Copper (2 mg), lutein (10 mg ), zeaxanthin (2 mg)