A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8

When the 1063 participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities were excluded, the odds reduction estimate for antioxidants plus zinc was OR 0.66 (99% CI, 0.47-0.91).

“Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91;zinc: OR, 0.71; 99% CI, 0.52-0.99;antioxidants: OR, 0.76; 99% CI, 0.55-1.05).”

The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99).

“The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99).”

The 5-year estimated probability of progression to advanced AMD in either eye in Category 3 participants was 18%.

“The 5-year estimated probability of progression to advanced AMD in either eye in participants with extensive intermediate drusen, large drusen, or noncentral GA (Category 3) was 18%.”

When the 1063 participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities were excluded, the odds reduction estimate for antioxidants was OR 0.76 (99% CI, 0.55-1.05).

“Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91;zinc: OR, 0.71; 99% CI, 0.52-0.99;antioxidants: OR, 0.76; 99% CI, 0.55-1.05).”

No statistically significant serious adverse effect was associated with any of the formulations.

“No statistically significant serious adverse effect was associated with any of the formulations.”

Only 15 participants in Category 2 (3 in the placebo arm) developed an AMD event by 5 years of follow-up.

“Only 15 participants in Category 2 (3 in the placebo arm) developed an AMD event by 5 years of follow-up.”

Zinc alone produced an odds ratio of 0.75 (99% CI, 0.55-1.03) for development of advanced AMD compared with placebo.

“The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03)and 0.80 (99% CI, 0.59-1.09),respectively.”

Compared with placebo, antioxidants plus zinc produced a statistically significant odds reduction for the development of advanced AMD (OR, 0.72; 99% CI, 0.52-0.98).

“Comparison with placebo demonstrated a statistically significant odds reduction for the development of advanced AMD with antioxidants plus zinc (odds ratio [OR], 0.72; 99% confidence interval [CI], 0.52-0.98).”

Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD.

“Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD.”

In approximately 8% of identified cases of advanced AMD, based on central grading of color stereo photographs, the AMD lesions were not seen on subsequent yearly photographs.

“We found that in approximately 8% of the identified cases of advanced AMD, based on central grading of color stereo photographs, the AMD lesions were not seen on subsequent yearly photographs.”

Category 4 participants had a 43% expected probability of progression to advanced AMD in the fellow study eye at 5 years.

“Participants with advanced AMD in 1 eye or vision loss due to nonadvanced AMD in 1 eye (Category 4) had a 43% expected probability of progression to advanced AMD in the fellow study eye at 5 years.”

When the 1063 participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities were excluded, the odds reduction estimate for zinc was OR 0.71 (99% CI, 0.52-0.99).

“Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91;zinc: OR, 0.71; 99% CI, 0.52-0.99;antioxidants: OR, 0.76; 99% CI, 0.55-1.05).”

Antioxidants alone produced an odds ratio of 0.80 (99% CI, 0.59-1.09) for development of advanced AMD compared with placebo.

“The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03)and 0.80 (99% CI, 0.59-1.09),respectively.”

The antioxidants plus zinc arm showed a suggestive reduction compared with placebo in the risk of visual acuity loss of 15 letters or more among participants in Categories 2, 3, and 4 (OR, 0.79; 99% CI, 0.60-1.04).

“The antioxidants plus zinc arm (OR, 0.79; 99% CI, 0.60-1.04)showed a suggestive reduction compared with placebo in the risk of visual acuity loss of 15 letters or more, among participants in Categories 2, 3, and 4.”

When evaluating main effects, there was a nonsignificant effect on persons assigned to antioxidants (OR, 0.87; 99% CI, 0.70-1.09).

“and a nonsignificant effect on persons assigned to antioxidants (ie, combining those participants taking antioxidants alone with those taking antioxidants plus zinc; OR, 0.87; 99% CI, 0.70-1.09).”

• AssumptionThe authors state this as an assumption: There is no interaction between the antioxidant formulation and the zinc formulation.

In participants in AMD Categories 3 and 4, zinc compared with placebo reduced the odds of progression to advanced AMD (OR, 0.71; 99% CI, 0.52-0.99).

“zinc: OR, 0.71; 99% CI, 0.52-0.99”

Skin and subcutaneous tissue conditions were more frequent in the antioxidant arms (2.2% vs 1.0%; P=.003).

“Skin and subcutaneous tissue conditions were more frequent in the antioxidant arms (2.2% vs 1.0%; P=.003); most participants with these conditions also self-reported yellow skin.”

In participants in AMD Categories 3 and 4, antioxidants plus zinc compared with placebo reduced the odds of progression to advanced AMD (OR, 0.66; 99% CI, 0.47-0.91).

“antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91”

In participants in AMD Categories 3 and 4, antioxidants compared with placebo reduced the odds of progression to advanced AMD (OR, 0.76; 99% CI, 0.55-1.05).

“antioxidants: OR, 0.76; 99% CI, 0.55-1.05”

For participants in Categories 3 and 4, the OR for advanced AMD coincident with a decrease in visual acuity of at least 15 letters was 0.63 (99% CI, 0.44-0.92) for antioxidants plus zinc vs placebo.

“An OR estimate of 0.63 (99% CI, 0.44-0.92)was obtained for the antioxidants plus zinc vs placebo contrast.”

The effect of Centrum on serum levels of antioxidants and zinc in this population was negligible.

“The effect of Centrum, which contains RDA doses of the study medications, on serum levels of antioxidants and zinc in this population was negligible.”

Twenty percent of participants in Categories 3 and 4 experienced a decrease in visual acuity to worse than 20/100 in at least 1 eye.

“Twenty percent of participants in Categories 3 and 4 experienced a decrease in visual acuity to worse than 20/100 in at least 1 eye.”

A statistically significant benefit of treatment with antioxidants plus zinc compared with placebo was observed for neovascular AMD outcomes in participants in Categories 3 and 4 (OR, .62; 99% CI, 0.43-0.90).

“A statistically significant benefit of treatment with antioxidants plus zinc compared with placebo was observed for neovascular AMD outcomes in participants in Categories 3 and 4 (OR, .62;99% CI, 0.43-0.90).”

The estimated 5-year probability of bilateral visual acuity worse than 20/100 in Category 3 participants was 11% for placebo and 10% for antioxidants plus zinc (OR, 0.86; 99% CI, 0.50-1.49).

“The 5-year probability estimate of bilateral visual acuity worse than 20/100 in Category 3 participants assigned to placebo was 11% and was 10% for antioxidants plus zinc (antioxidants plus zinc: OR, 0.86; 99% CI, 0.50-1.49).”

Participants assigned to medications containing zinc had about an 18% increase in median serum level of zinc from baseline to year 1, maintained during the 5-year period.

“Similarly, participants assigned to medications containing zinc had about an 18% increase in median serum level of zinc from baseline to year 1 and this was maintained during the 5-year period.”

Only one of the other serum levels measured had a statistically significant change during follow-up: alpha carotene increased about 43% in antioxidant arms from baseline to year 1.

“Only one of the other serum levels measured had a statistically significant change during follow-up.Participants assigned to receive medications containing antioxidants had a statistically significant increased median percent change in serum levels of alpha carotene from baseline to year 1 of about 43% compared with no change for participants tak-ing nonantioxidant medications.”

When evaluating main effects, there was a suggestive reduction in the risk of developing advanced AMD for persons assigned to zinc (OR, 0.82; 99% CI, 0.66-1.03).

“When evaluating main effects, there is a suggestive reduction in the risk of developing advanced AMD for persons assigned to zinc (ie, combining those participants taking zinc alone with those taking zinc plus antioxidants; OR, 0.82; 99% confidence interval [CI], 0.66-1.03)”

• AssumptionThe authors state this as an assumption: There is no interaction between the antioxidant formulation and the zinc formulation.

In an analysis restricted to participants in Categories 3 and 4, the combination of antioxidants plus zinc statistically significantly reduced the odds of visual acuity loss (OR, 0.73; 99% CI, 0.54-0.99).

“In an analysis restricted to participants in Categories 3 and 4, whose vision loss was more likely to be associated with progression of AMD, the combination of antioxidants plus zinc statistically significantly reduced the odds of visual acuity loss (OR, 0.73; 99% CI, 0.54-0.99).”

Participants assigned to medications containing antioxidants had statistically significant increases in median serum levels from baseline to year 1: about 25% for vitamin C, 82% for vitamin E-cholesterol ratio, and 485% for beta carotene.

“Participants assigned to medications containing antioxidants had statistically significant increases in median serum levels from baseline to year 1: about 25% for vitamin C, 82% for vitamin E-cholesterol ratio, and 485% for beta carotene.”

Five hundred ninety-two participants developed neovascular disease.

“Five hundred ninetytwo participants developed neovascular disease.”

There was no evidence of significant clinic differences in treatment effect.

“There was no evidence of significant clinic differences in treatment effect.”

Participants in the antioxidant arms more frequently reported yellow skin (8.3% vs 6.0%; P=.008).

“Participants in the antioxidant arms more frequently reported yellow skin (8.3% vs 6.0%; P=.008).”

No statistically significant difference between treatment arms in use of lipid-lowering medications at 5 years after enrollment was observed.

“In addition, no statistically significant difference between treatment arms in use of lipid-lowering medications at 5 years after enrollment was observed (data not shown).”

Hospitalizations for mild/moderate symptoms were more frequent in participants randomized to zinc arms (9.7% vs 7.8%; P=.04).

“Hospitalizations for mild/ moderate symptoms were also more frequent in participants randomized to zinc arms (9.7% vs 7.8%; P=.04).”

There were 175 visual acuity events in participants in Category 2, but only 13 (7%) were thought by the examining ophthalmologist to be primarily related to macular degeneration.

“There were 175 visual acuity events in participants in Category 2. However, only 13 of these events (7%) were thought by the examining ophthalmologist to be primarily related to macular degeneration.”

• AssumptionRests on an assumption: The examining ophthalmologist's attribution of visual acuity events to macular degeneration is accurate.

During the study, 407 participants without GA at baseline developed at least moderate GA (>360 μm) not necessarily involving the center of the macula.

“During the study, 407 participants without GA at baseline developed at least moderate GA (Ͼ360 µm) not necessarily involving the center of the macula.”

Participants in the antioxidant arms less frequently reported chest pains (20.2% vs 23.1%; P=.03) when asked at a follow-up visit.

“Participants in the antioxidant arms less frequently reported chest pains (20.2% vs 23.1%; P=.03) when asked at a follow-up visit.”

Only 28 of the 1063 participants who began the study in Category 2 progressed to advanced AMD in at least 1 eye at the end of follow-up (15 by year 5).

“Only 28 participants of the 1063 who began the study in Category 2 progressed to advanced AMD in at least 1 eye at the end of follow-up (15 by year 5).”

An advanced AMD event simultaneously occurred with vision loss during at least 1 visit in only 15 of the Category 2 participants with visual acuity events (9%).

“In addition, an advanced AMD event simultaneously occurred with vision loss during at least 1 visit in only 15 of these participants (9%).”

Vitamin A, beta-cryptoxanthin, and lycopene showed no statistically significant differences in change from baseline by treatment assignment.

“Vitamin A, ␤-cryptoxanthin, and lycopene showed no statistically significant differences in change from baseline by treatment assignment.”

Comparison of zinc or zinc plus antioxidants with placebo was not significant (P≥.14).

“Comparison of zinc or zinc plus antioxidants with placebo was not significant (PՆ.14).”

There was an increase in yellowing of skin in persons assigned to receive antioxidants (P<.01).

“The following 3 imbalances are notable (PϽ.01): an increase in hospitalization for genitourinary symptoms and an increase in self-reported anemia in persons assigned to receive zinc formulations; and an increase in yellowing of skin in persons assigned to receive antioxidants.”

About half of those supplementing were taking RDA doses rather than the 5- to about 15-fold higher doses of the AREDS ingredients.

“About half of those supplementing were taking RDA doses rather than the 5-to about 15-fold higher doses of the AREDS ingredients.”

Early imbalances in mortality were observed regardless of smoking status.

“Early imbalances in mortality were observed regardless of smoking status.”

The proportion of participants in the zinc arm with a visual acuity loss of at least 15 letters draws closer to the placebo arm by 7 years.

“The proportion of participants in the zinc arm with a visual acuity loss of at least 15 letters draws closer to the placebo arm by 7 years.”

The results of AREDS to date demonstrate no benefit of the study formulations for persons in Categories 1 or 2.

“The results of AREDS to date demonstrate no benefit of the study formulations for persons in Categories 1 or 2.”

There was no statistically significant evidence of a benefit in delaying the progression of Category 2 eyes to more severe drusen pathology.

“There was no statistically significant evidence of a benefit in delaying the progression of Category 2 eyes to more severe drusen pathology (eg, moving from Category 2 at baseline to Categories 3 or 4 during follow-up).”

Any increase in serum levels resulting from Centrum intake was negligible compared with serum increases from the use of the study supplements.

“Any increase in serum levels resulting from this intake was negligible compared with serum increases from the use of the study supplements.”

Data from AREDS suggest that the combination therapy confers a treatment benefit for AMD and visual acuity outcomes that is maintained through 7 years of follow-up in participants at risk for progression to advanced AMD.

“Data from AREDS suggest that the combination therapy confers a treatment benefit for AMD and visual acuity outcomes that is maintained through 7 years of follow-up in participants at risk for progression to advanced AMD.”

Approximately 67% of participants chose to take Centrum.

“Approximately 67% of participants chose to take Centrum”

The probability of developing advanced AMD by 5 years among placebo participants varied within Category 3 from about 27% for those with large drusen in both eyes or with GA not involving the center of the macula in at least 1 eye, to about 6% for the remaining participants in that category.

“The probability of developing advanced AMD by 5 years among participants assigned to receive placebo varied within Category 3 from about 27% for those with large drusen in both eyes or with GA not involving the center of the macula in at least 1 eye, to about 6% for the remaining participants in that category.”

For zinc alone, AREDS did not find a statistically significant reduction in the odds of a 15-letter visual acuity loss.

“For zinc alone, AREDS did not find a statistically significant reduction in the odds of a 15-letter visual acuity loss.”

Participants in Category 4 had the highest probability of progression, with an estimated probability of 43% at 5 years.

“Participants in Category 4 had the highest probability of progression, with an estimated probability of 43% at 5 years.”

The RR estimate for antioxidants on mortality remains in the direction of harm for participants who had never smoked.

“Results to date find no statistically significant deleterious effect of antioxidants on mortality, although the RR estimate remains in the direction of harm for participants who had never smoked.”

An analysis of zinc vs no zinc suggested a benefit on mortality (RR, 0.79; 99% CI, 0.61-1.02).

“An analysis of zinc vs no zinc suggested a benefit (RR, 0.79; 99% CI, 0.61-1.02).”

For the AMD clinical trial, none of the individual treatments, when compared with placebo, statistically significantly reduced or increased the risk of mortality (P>=.14 for all treatments).

“For the AMD clinical trial, none of the individual treatments, when compared with placebo, statistically significantly reduced or increased the risk of mortality (PՆ.14 for all treatments).”

Compared with the placebo group, participants in Categories 3 and 4 assigned to receive antioxidants plus zinc had the largest reduction of the risk of developing advanced AMD or visual acuity loss.

“The results are consistent in demonstrating that, compared with the placebo group, participants in Categories 3 and 4 assigned to receive antioxidants plus zinc had the largest reduction of the risk of developing advanced AMD or visual acuity loss.”

There was an increase in self-reported anemia in persons assigned to receive zinc formulations (P<.01).

“The following 3 imbalances are notable (PϽ.01): an increase in hospitalization for genitourinary symptoms and an increase in self-reported anemia in persons assigned to receive zinc formulations; and an increase in yellowing of skin in persons assigned to receive antioxidants.”

Fifty-seven percent of AREDS participants were using a multivitamin or at least 1 ingredient found in the AREDS formulation at the time of their AREDS screening examination.

“Fifty-seven percent of AREDS participants were using a multivitamin or at least 1 ingredient found in the AREDS formulation at the time of their AREDS screening examination.”

Results to date find no statistically significant deleterious effect of antioxidants on mortality.

“Results to date find no statistically significant deleterious effect of antioxidants on mortality, although the RR estimate remains in the direction of harm for participants who had never smoked.”

No statistically significant effect of zinc supplements on hematocrit or serum levels of lipids or copper was observed.

“Although there was an increase in self-reported anemia, no statistically significant effect of zinc supplements on hematocrit or serum levels of lipids or copper was observed.”

There was an increase in hospitalization for genitourinary symptoms in persons assigned to receive zinc formulations (P<.01).

“The following 3 imbalances are notable (PϽ.01): an increase in hospitalization for genitourinary symptoms and an increase in self-reported anemia in persons assigned to receive zinc formulations; and an increase in yellowing of skin in persons assigned to receive antioxidants.”

There was a nonstatistically significant trend for an increase in the risk of developing GA away from the center of the macula in the zinc and antioxidant plus zinc treatment groups compared with placebo.

“There was a nonstatistically significant trend for an increase in the risk of developing GA away from the center of the macula in the zinc and antioxidant plus zinc treatment groups compared with the placebo-treated group.”

Participants assigned to receive either zinc or antioxidants seem to have a lesser benefit from the study medication.

“Participants assigned to receive either zinc or antioxidants seem to have a lesser benefit from the study medication.”

The small number of deaths from lung cancer (29 [0.8%]) showed no statistically significant difference by treatment.

“The small number of deaths from lung cancer (29 [0.8%]) showed no statistically significant difference by treatment.”

Early in the trial, a nonstatistically significant increase in mortality was observed among participants assigned to the antioxidants-alone arm.

“Early in the trial, a nonstatistically significant increase in mortality was observed among participants assigned to the antioxidants-alone arm.”

A composite event of advanced AMD and loss of at least 15 letters in visual acuity observed concurrently resulted in estimates of odds reductions of about 25% for zinc and 37% for zinc plus antioxidants for participants in Categories 3 and 4 combined.

“This event definition resulted in estimates of odds reductions of about 25% for zinc and 37% for zinc plus antioxidants for participants in Categories 3 and 4 combined.”

In AREDS, persons in Categories 1 and 2 had low rates of progression to advanced AMD (1.3% in 5 years for Category 2 and <1% for Category 1).

“In AREDS, persons in these categories had low rates of progression to advanced AMD (1.3% in 5 years for Category 2 and Ͻ1% for Category 1)”

There is limited evidence from AREDS that supplements may delay further visual acuity loss in some more advanced eyes (Table 7).

“There is limited evidence from AREDS that supplements may delay further visual acuity loss in some of these more advanced eyes (Table 7)”

Analyses to date do not show that treatment is effective in slowing the progression of AMD from Category 2 to Categories 3 or 4.

“especially because analyses to date do not show that treatment is effective in slowing the progression of AMD from Category 2 to Categories 3 or 4.”

The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to antioxidants plus zinc.

“Although both zinc and antioxidants plus zinc significantly reduce the odds of developing advanced AMD for participants in Categories 3 and 4, the only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to antioxidants plus zinc.”

Because some lesions that define the study outcome are apparently transient, a life-table technique such as Kaplan-Meier to estimate the probability of progression is problematic.

“Because some of the lesions that define the study outcome are apparently transient, a life-table technique such as Kaplan-Meier to estimate the probability of progression is problematic”

Assessment of treatment effect of the size seen in Categories 3 and 4 was not possible in Category 2.

“Therefore, assessment of treatment effect of the size seen in Categories 3 and 4 was not possible in this group.”

Oxidative damage to the retina may be involved in the pathogenesis of AMD.

“Oxidative damage to the retina may be involved in the pathogenesis of AMD.[14][15][16][17]”

• cites [14] 14. Fliesler SJ, Anderson RE. Chemistry and metabolism of lipids in the vertebrate retina. Prog Lipid Res. 1983;22:79-131. sourceNot checked — no full text of the source
• cites [15] 15. Gerster H. Review: antioxidant protection of the ageing macula. Age Ageing. 1991; 112:60-69.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [16] 16. Young RW. Solar radiation and age-related macular degeneration. Surv Oph- thalmol. 1988;32:252-269.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Results from the Cox proportional hazards model are consistent with observations from the repeated-measures analysis for progression to advanced AMD.

“Results from the Cox proportional hazards model (not shown) are consistent with observations from the repeatedmeasures analysis.”

Adjustment for age, sex, race, AMD category, and smoking status at enrollment did not materially alter the size or direction of the treatment estimates for progression to advanced AMD.

“An analysis adjusted for age, sex, race, AMD Category, and smoking status at enrollment did not materially alter the size or direction of these estimates.”

Data from epidemiological studies as well as small randomized clinical trials do not show consistent associations between intake of antioxidants or zinc and risk of AMD.

“However, data from epidemiological studies [18][19][20][21][22][23][24][25][26] as well as small randomized clinical trials [27][28][29] do not show consistent associations between intake of antioxidants or zinc and risk of AMD.”

• cites [18] 18. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E and advanced age-related macular degeneration. JAMA. 1994;272:1413- 1420.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [19] 19. Eye Disease Case-Control Study Group. Antioxidant status and neovascular age- related macular degeneration. Arch Ophthalmol. 1993;111:104-109.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [20] 20. Goldberg J, Flowerdew, Smith E, Brody JA, Tso MOM. Factors associated with age-related macular degeneration: an analysis of data from the First National Health and Nutrition Examination Survey. Am J Ophthalmol. 1988;128:700-710. sourceNot checked — no full text of the source

Losses to follow-up were balanced across treatment groups.

“Losses to follow-up were balanced across treatment groups.”

At present, there is no proven treatment that slows or prevents the development of advanced AMD.

“At present, there is no proven treatment that slows or prevents the development of advanced AMD.”

One small, randomized, 2-year, placebo-controlled clinical trial of zinc supplementation found a statistically significant reduction in visual acuity loss in the zinc-treated group.

“One small, randomized, 2-year, placebo-controlled clinical trial of zinc supplementation found a statistically significant reduction in visual acuity loss in the zinc-treated group and recommended a more definitive trial before a general recommendation could be made for zinc supplementation in those at risk of vision loss from advanced AMD. 27”

• cites [27] 27. Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular de- generation. Arch Ophthalmol. 1988;106:192-198. sourceNot checked — no full text of the source

Overall, adherence was estimated to be 75% or greater for 71% of the participants at 5 years.

“Overall, adherence was estimated to be 75% or greater (ie, participants took 75% or more of their study tablets) for 71% of the participants at 5 years.”

The study has only about 40% power to demonstrate a statistically significant OR of 0.75 for one of the treatment arms vs placebo for central GA.

“the study has only about 40% power to demonstrate a statistically significant OR of 0.75 for one of the treatment arms vs placebo.”

An analysis adjusted for age, sex, race, AMD category, and baseline smoking status did not materially alter the size or direction of the odds ratio estimates for visual acuity loss.

“An analysis adjusted for age, sex, race, AMD category, and baseline smoking status did not materially alter the size or direction of these OR estimates.”

Baseline dietary intake of the study nutrients was balanced across treatment groups.

“Baseline dietary intake of the study nutrients was balanced across treatment groups.”

A projected sample size of 3600 would provide at least 80% power to detect treatment effects of 25% to 50% on progression to advanced AMD.

“After adjusting for noncompliance, for 2-sided ␣=.05, a projected sample size of 3600 would provide at least 80% power to detect treatment effects of 25% to 50% on progression to advanced AMD depending on possible interactions between zinc and antioxidants.”

These results indicate a definite serum response to each study ingredient.

“These results indicate a definite serum response to each study ingredient.”

• AssumptionRests on an assumption: Serum levels of antioxidants and zinc reflect adherence to study medication.

Data from AREDS demonstrate that treatment with zinc alone or in combination with antioxidants reduced the risk of progression to advanced AMD in participants in Categories 3 and 4.

“Data from AREDS demonstrate that treatment with zinc alone or in combination with antioxidants reduced the risk of progression to advanced AMD in participants in Categories 3 and 4.”

Other studies using similar doses of beta carotene in persons at high risk for lung cancer (cigarette smokers and asbestos workers) have demonstrated an increased incidence of cancer and mortality in persons assigned to beta carotene supplementation.

“Other studies using similar doses of beta carotene in persons at high risk for lung cancer (cigarette smokers and asbestos workers) have demonstrated an increased incidence of cancer and mortality in persons assigned to beta carotene supplementation.42,43”

• cites [42] 42. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150-1155. sourceNot checked — no full text of the source
• cites [43] 43. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other can- cers in male smokers. N Engl J Med. 1994;330:1029-1035.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The visual acuity benefit observed for the combination arm remains consistent for other, more severe, visual acuity outcomes, such as visual acuity worse than 20/100 or a decrease in visual acuity of 6 lines or more.

“The visual acuity benefit observed for the combination arm remains consistent for other, more severe, visual acuity outcomes, such as visual acuity worse than 20/100 or a decrease in visual acuity of 6 lines or more.”

Results from 2 other randomized clinical trials suggested increased risk of mortality among smokers supplementing with beta carotene.

“Results from 2 other randomized clinical trials suggested increased risk of mortality among smokers supplementing with beta carotene.”

• cites [42] 42. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150-1155. sourceNot checked — no full text of the source
• cites [43] 43. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other can- cers in male smokers. N Engl J Med. 1994;330:1029-1035.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

These levels of zinc and vitamins C and E generally can be obtained only by supplementation.

“These levels of zinc and vitamins C and E generally can be obtained only by supplementation.”

• AssumptionRests on an assumption: The 400-IU dose of vitamin E is about 13 times the RDA and the dose of zinc as zinc oxide is about 5 times the RDA.

For Americans older than age 70, approximately 80% fall in the low-risk groups (Categories 1 or 2).

“For Americans older than age 70, approximately 80% fall in these low-risk groups.37”

• cites [37] 37. Klein R, Klein BEK, Linton KLP. Prevalence of age-related maculopathy: The Bea- ver Dam Eye Study. Ophthalmology. 1992;99:933-943. sourceNot checked — no full text of the source

The study was not powered to assess whether there were differences between apparently effective treatments.

“The study was not powered to assess whether there were differences between apparently effective treatments.”

The apparent treatment benefit of antioxidants plus zinc and zinc alone was present for each of the events predefined in the study protocol to be signs of advanced AMD (development of signs of neovascular AMD, accounting for 70%-80% of events, and development of central GA).

“The apparent treatment benefit of antioxidants plus zinc and zinc alone was present for each of the events predefined in the study protocol to be signs of advanced AMD (development of signs of neovascular AMD, accounting for 70%-80% of events, and development of central GA).”

Serum levels of each vitamin or mineral in the assigned study formulations were elevated throughout the study in participants enrolled in the 3 AREDS clinics collecting specimens.

“this is supported by data showing that serum levels of each of the vitamins or minerals in the assigned study formulations in participants enrolled in the 3 AREDS clinics collecting specimens were elevated throughout the study.”

Individual effects of each of the antioxidant components (beta carotene, vitamin E, and vitamin C) cannot be evaluated.

“Individual effects of each of these components cannot be evaluated.”

A small randomized trial, completed before AREDS began, suggested a benefit of large doses of zinc on visual acuity in persons with AMD.

“A small randomized trial, completed before AREDS began, suggested a benefit of large doses of zinc on visual acuity in persons with AMD.27”

• cites [27] 27. Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular de- generation. Arch Ophthalmol. 1988;106:192-198. sourceNot checked — no full text of the source

The risk reduction for those taking antioxidants plus zinc was 25%.

“The risk reduction for those taking antioxidants plus zinc was 25%.”

It is unlikely that differential treatment effects on lens opacity are affecting this visual acuity result.

“It is unlikely that differential treatment effects on lens opacity are affecting this visual acuity result.”

The observation of a reduction in mortality associated with zinc arms compared with nonzinc arms may be somewhat exaggerated by the apparent nonstatistically significant increase in mortality observed for the antioxidants-alone arm.

“The observation of a reduction in mortality associated with zinc arms compared with nonzinc arms may be somewhat exaggerated by the apparent nonstatistically significant increase in mortality observed for the antioxidants-alone arm.”

Findings of AREDS suggest that the estimated 27% odds reduction in the visual acuity outcome for the combination arm may be the combined benefit of the zinc component (odds reduction of 17%) and the antioxidant component (odds reduction of 15%).

“Findings of AREDS suggest that the estimated 27% odds reduction in the visual acuity outcome for the combination arm may be the combined benefit of the zinc component (odds reduction of 17%) and the antioxidant component (odds reduction of 15%).”

Another randomized trial reported that after 4 years of supplementation, 500 IU per day of vitamin E had little benefit in reducing the risk of development or progression of AMD in a population of 1193 volunteers.

“Results from another randomized trial reported that after 4 years of supplementation, 500 IU per day of vitamin E had little benefit in reducing the risk of development or progression of AMD in a population of 1193 volunteers.47”

• cites [47] 47. Taylor HR, Tikellis G, Robman LD, McCarty CA, McNeil JJ. Vitamin E supple- mentation and age-related maculopathy [ARVO abstract]. Invest Ophthalmol Vis Sci. 2001;42:S311. Abstract No. 1676.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Too few advanced AMD events occurred in Category 2 participants to assess whether any treatment tested could slow progression to advanced AMD for participants with milder drusen and retinal pigment epithelial abnormalities.

“Too few advanced AMD events occurred in Category 2 participants to assess whether any treatment tested in this study could slow the progression to advanced AMD for participants with milder drusen and retinal pigment epithelial abnormalities.”

This analysis suggests that the reduction in risk of visual acuity loss observed with the antioxidant plus zinc formulation may be a result of the reduction in risk of progression to advanced AMD.

“This analysis suggests that the reduction in risk of visual acuity loss observed with the antioxidant plus zinc formulation may be a result of the reduction in risk of progression to advanced AMD.”

The study has very low power to assess the effect of these treatments on the development of advanced AMD in persons in Categories 1 and 2.

“and therefore the study has very low power to assess the effect of these treatments on the development of advanced AMD.”

The effect of using zinc supplementation alone can be estimated from these data.

“The effect of using zinc supplementation alone can be estimated from these data but the effect of using only some of the antioxidants or substituting other antioxidants, such as lutein, cannot be determined.”

The effect of using only some of the antioxidants or substituting other antioxidants, such as lutein, cannot be determined from these data.

“The effect of using zinc supplementation alone can be estimated from these data but the effect of using only some of the antioxidants or substituting other antioxidants, such as lutein, cannot be determined.”