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
Archives of Ophthalmology, 2001 · paper · Clinical trials
A randomized, placebo-controlled trial of 3640 people aged 55–80 testing high-dose antioxidants, zinc, or both for age-related macular degeneration. Antioxidants plus zinc significantly reduced the odds of advanced disease (OR 0.72) and of moderate vision loss; no serious adverse effects were significant.
3 findings
Reference or label Reference 20 (Goldberg et al., NHANES I) is cited as "Am J Ophthalmol 1988;128:700–710". The volume does not fit that journal in 1988, and the journal is probably Am J Epidemiol.
- p. 21 Reference 20
Examination Survey. Am J Ophthalmol 1988;128:700–710.
- p. 21 Reference 20
Am J Ophthalmol 1988;128:700–710.
- p. 21 Reference 20
Am J Ophthalmol 1988;128:700–710
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: that Goldberg et al. 1988 appeared in Am J Epidemiol vol 128. Internal evidence supports it: the same list gives Am J Ophthalmol 2001;131 (ref 8), so volume 128 in 1988 is implausible for that journal, while Am J Epidemiol is 1998;148 (ref 21), which makes volume 128 in 1988 consistent. The page 21 image confirms the printed text.
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Reference or label Reference 15 gives the volume as "Age Ageing 1991;112:60–69"; the 1991 volume of Age Ageing is 20.
- p. 21 Reference 15
Age Ageing 1991;112:60–69.
- p. 21 Reference 15
Age Ageing 1991;112:60–69
- p. 21
Gerster H. Review: antioxidant protection of the ageing macula. Age Ageing 1991;112:60–69.
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: that Age and Ageing was volume 20 in 1991 (Crossref doi:10.1093/ageing/20.1.60). The page 21 image confirms "1991;112". Volume 112 matches the nearby Arch Ophthalmol 1994;112 entries, which suggests a transcription slip.
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Wording Category 1 is defined in the text as "total drusen area less than 5 small drusen (<63 μm)", but Table 1 gives the Category 1 drusen area as "<125 μm diameter circle (≈5–15 drusen) small".
- p. 13 Study Population, Category 1
with a total drusen area less than 5 small drusen (<63 μm)
- p. 33 Table 1, Category 1 drusen area
<125 μm diameter circle (≈5–15 drusen) small
- p. 13 Study Population
total drusen area less than 5 small drusen (<63 μm)
Only the authors can say what is right here.
Judge's note: The page 13 text and Table 1 (p33 upright) give different drusen-count equivalents for the Category 1 limit (fewer than 5 vs about 5–15). Only the authors can say which description is intended.
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19 minor (typos and the like; most checked by the judge only)
Wording "Two other trials assessed supplementation for patients with AMD" (citing refs 27 and 47) omits ref 29 (Stur et al, "Oral zinc and the second eye in age-related macular degeneration"), which the Introduction cites among the "small randomized clinical trials27–29".
- p. 10 Comment
Two other trials assessed supplementation for patients with AMD.
- p. 2 Introduction
small randomized clinical trials27–29
- p. 22 Reference 29
Oral zinc and the second eye in age-related macular degeneration
Only the authors can say what is right here.
Judge's note: The Introduction (p2) groups refs 27–29 as small randomized trials. Ref 29 (p22) is a zinc trial in AMD by its title. The Comment (p10) counts only two trials. Only the authors can say whether ref 29 was left out on purpose.
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Wording "The results of AREDS to date demonstrate no benefit of the study formulations for persons in Categories 1 or 2" is worded as a demonstrated null, whereas elsewhere the paper says the effect could not be assessed ("we cannot assess the effects of antioxidants in this group"; "Too few advanced AMD events occurred in Category 2 participants to assess ...").
- p. 12 Comment
The results of AREDS to date demonstrate no benefit of the study formulations for persons in Categories 1 or 2.
- p. 9 Comment
Too few advanced AMD events occurred in Category 2 participants to assess whether any treatment tested in this study could slow the progression
- p. 2 Results, Enrollment
we cannot assess the effects of antioxidants in this group on this outcome
Only the authors can say what is right here.
Judge's note: p2 (Category 1: 5 events, cannot assess), p9 (Category 2: too few events) and the same p12 paragraph ('the study has very low power') all describe the evidence as inconclusive rather than as a demonstrated absence of benefit.
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Wording "72 participants (2.0% of all participants and 18% of smokers)" (also "the 18% of current smokers who withdrew"). The smoker denominator behind 18% is not stated, and it does not match the 8% current smokers among the 3609 participants in Table 3.
- p. 18 Change in Treatment
72 participants (2.0% of all participants and 18% of smokers)
- p. 3 Data Quality
the 18% of current smokers who withdrew from study medication
- p. 36 Table 3, Currently smoking
Currently smoking
Only the authors can say what is right here.
Judge's note: The other percentages in this passage fit the AMD-trial population: 72/3609 gives 2.0%, 15/894 gives 1.7% (placebo arm), and 84/3609 gives 2.3%. Table 3 and the text on page 3 give 8% current smokers, about 289 people. 72/289 is about 25%, and even an upper rounding of 8.5% gives about 23%. An 18% share would need about 400 smokers. The 18% may use another denominator (for example all 4757 AREDS participants, or current plus former smokers offered the change), but the paper does not say which. Only the authors can clarify.
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Wording "on almost 719 participants (88% of those alive at 5 years)": 'almost' before an exact count is unclear. In Table 9, 719 is the largest n among the serum specimens (n ranges 675–719).
- p. 7 Serum Levels
on almost 719 participants (88% of those alive at 5 years)
Judge's note: In Table 9 (p42), n is 719 for total cholesterol and triglycerides and lower for the other specimens. 'Up to 719' appears to be meant.
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Wording Discussion says "increase in the risk of developing GA away from the center of the macula", but Results define the outcome as "at least moderate GA (>360 μm) not necessarily involving the center of the macula".
- p. 9 Comment
increase in the risk of developing GA away from the center of the macula
- p. 7 Results
at least moderate GA (>360 μm) not necessarily involving the center of the macula
Only the authors can say what is right here.
Judge's note: Results (p7) define an outcome that does not exclude central GA. The Comment (p9) describes it as noncentral GA and sets it against central GA. The two descriptions of the same secondary outcome differ.
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Wording Discussion: "Possible differences between treatment groups and the placebo group were assessed for approximately 100 adverse events". Results and Table 10 report these as "comparisons of zinc vs no zinc and antioxidants vs no antioxidants".
- p. 11 Comment, safety paragraph
Possible differences between treatment groups and the placebo group were assessed for approximately 100 adverse events
- p. 8 Results, Safety Outcomes
comparisons of zinc vs no zinc and antioxidants vs no antioxidants
Judge's note: Results (p8) and the Table 10 layout (No Antioxidants vs Antioxidants; No Zinc vs Zinc) show factorial main-effect comparisons, not each treatment group vs placebo. The Comment (p11) describes the comparison differently.
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Wording "serum levels of each of the vitamins or minerals in the assigned study formulations ... were elevated throughout the study", yet the formulations contained copper (2 mg as cupric oxide), and Table 9 shows no rise in copper (zinc arms: −2/−1% at year 1, −3/+2% at year 5).
- p. 11 Comment, adherence paragraph
serum levels of each of the vitamins or minerals in the assigned study formulations
- p. 42 Table 9, Copper row
−2
Judge's note: Copper is a formulation ingredient (p1 and Methods), although it was added to prevent anemia rather than tested. Table 9 (p42) copper row and the Results text ('no differential effect ... on copper levels') show copper was not elevated. The sentence probably refers only to the tested nutrients, but as written it says 'each'.
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Wording "The following 3 imbalances are notable (P<.01)" lists genitourinary hospitalization, anemia and yellowing of skin, but Table 10 also marks with ‡ (P<.01) mild/moderate-symptom hospitalizations and skin/subcutaneous adverse experiences in the antioxidant comparison.
- p. 11 Comment, safety paragraph
The following 3 imbalances are notable (P<.01)
- p. 43 Table 10, ‡ entries
Skin, subcutaneous tissue‡
Judge's note: Table 10 (p43) carries ‡ on mild/moderate symptoms (181 vs 135, antioxidants), skin/subcutaneous tissue (18 vs 41), change in skin color, genitourinary (and males), and anemia. 'Notable' may be a deliberate selection, but read as a list of the P<.01 imbalances the sentence is incomplete.
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Typo Corresponding-author footnote ends with a doubled period: "(e-mail: aredspub@emmes.com).."
- p. 1 Corresponding author footnote
aredspub@emmes.com)..
Judge's note: The page 1 crop shows two periods after the closing parenthesis, so this is not an extraction artefact.
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Typo Text names the survey "Third National Health and Nutrition Survey", but the cited ref 44 gives "Third National Health and Nutrition Examination Survey".
- p. 3 Enrollment and participant characteristics
Third National Health and Nutrition Survey
- p. 22 Reference 44
Third National Health and Nutrition Examination Survey
Judge's note: Page 3 text leaves out 'Examination'. Ref 44 on page 22 gives the full name. This is an internal inconsistency in a proper name.
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Typo Category 3 definition prints "at least 1 large druse (125 μm)" without the ≥ sign. Table 1 gives "Or large (≥125 μm)".
- p. 13 Study Population, Category 3 definition
at least 1 large druse (125 μm)
- p. 33 Table 1, Category 3a
Or large (≥125 μm)
Judge's note: The page 13 crop shows no ≥ sign. Table 1 (p33 upright) shows ≥125 μm.
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Typo Exclusion criteria text has run-together words "excluded forillness" and "orhemachromatosis". "hemachromatosis" is also a nonstandard spelling of hemochromatosis.
- p. 14 Study Population, exclusion criteria
orhemachromatosis
- p. 14 Study Population, exclusions
excluded forillness or
Judge's note: The page 14 crop shows the missing spaces in the typeset text, so they are not extraction artefacts.
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Typo Words run together in the exclusion criteria: "excluded forillness or disorders" and "orhemachromatosis" (should read "for illness" and "or hemochromatosis").
- p. 14 Study Population, exclusion criteria
excluded forillness or
Judge's note: The page 14 image shows both run-together words exactly as printed. The spelling "hemachromatosis" is also nonstandard.
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Typo The Acknowledgments misspell the institute as "National Eye Institue, Bethesda" (should be "Institute").
- p. 20 Acknowledgments
National Eye Institue
- p. 20 Acknowledgments
National Eye Institue,
Judge's note: The page 20 image shows "National Eye Institue,". The two crops show the same single instance. The name is spelled correctly elsewhere on the same page.
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Typo The Acknowledgments heading reads "Data and Safety Monitoring Committee (DSMC) Officios:". "Officios" is not a word; "Members" or similar was probably intended, since "DSMC Ex-Officios:" follows separately.
- p. 20 Acknowledgments
Committee (DSMC) Officios:
Only the authors can say what is right here.
Judge's note: The page 20 image confirms the heading. What it should read is uncertain, so only the authors can say.
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Typo Reference 20 lists the coauthor as "Goldberg J, Flowerdew, Smith E" with no initials for Flowerdew.
- p. 21 Reference 20
Goldberg J, Flowerdew, Smith E
Judge's note: The page 21 image confirms that the initials are missing; every other author in the list has initials.
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Typo A stray character follows the Table 3 column header: "Antioxidants (n = 936)s".
- p. 35 Table 3 header
Antioxidants (n = 936)s
- p. 36 Table 3 continued header
Antioxidants (n = 936)s
Judge's note: The page 36 upright image shows the stray 's'. The text layer on page 35 shows the same header with the 's'.
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Typo The Table 9 footnote § reads "low-density lipotrotein (LDC-C), 0.02586". It should be "low-density lipoprotein cholesterol (LDL-C)", matching the table row "LDL-C, mg/dL".
- p. 42 Table 9 footnote §
low-density lipotrotein
- p. 42 Table 9 footnote §
low-density lipotrotein (LDC-C)
- p. 42 Table 9 footnote §
low-density lipoprotein (LDC-C)
- p. 42
low-density lipotrotein (LDC-C), 0.02586
Judge's note: The page 42 upright image shows both the misspelling "lipotrotein" and the abbreviation "LDC-C", while the row label reads LDL-C. The quote "lipoprotein (LDC-C)" was not found because the printed word is "lipotrotein".
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Typo The Table 9 footnote || has an unmatched closing parenthesis: "Value calculated as total cholesterol level – HDL-C) – (triglycerides/5)."
- p. 42 Table 9 footnote ||
Value calculated as total cholesterol level – HDL-C) – (triglycerides/5).
- p. 42 Table 9 footnote ||
total cholesterol level – HDL-C) – (triglycerides/5)
Judge's note: The page 42 upright image confirms that the opening parenthesis before "total cholesterol" is missing. The intended formula (Friedewald) is recoverable.
Second check: none (judge only)