33

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

earch Strategy

OLDMEDLINE® 1947 to February Week 1 2011 -- Date Searched 2011/02/15 - QUESTION 1

Search String N

Exp macular degeneration/ OR geographic atrophy/ OR macular edema/ OR wet macular degeneration/ OR macular degeneration.mp OR AMD.mp OR ((moderate OR intermediate) ADJ5 (macular degeneration OR AMD OR maculopath$ OR macular dystroph$)).mp OR (age ADJ4 maculopath$).mp OR (age ADJ4 macular).mp OR (retinal ADJ4 degeneration).mp OR macular dystrophy.mp OR Retinal drusen/ OR retinal druse$.mp OR Retinal neovascularization/ OR Retinal Pigment Epithelium/ OR retinal pigment epithelium hyperplasia.mp OR RPE.mp OR retinal pigment epithelium atroph$.mp OR retinal pigment epithelium depigmentation.mp OR geographic atrophy.mp OR Choroidal neovascularization/ OR Choroidal neovascularization.mp OR AREDS stage 1.mp OR AREDS stage 3.mp OR subjacent retinal pigmentation epithelium.mp OR choriocapillaris.mp OR lipofuscin.mp OR neovascular AMD.mp OR CNV.mp OR macular pigment optical density.mp OR MPOD.mp OR (age ADJ1 related ADJ1 eye ADJ1 disease ADJ1 study).mp OR Pigment epithelium of eye/ OR Macula Lutea/ OR fovea centralis/ OR Retinal detachment/

57,272

Dietary supplements/ OR (dietary ADJ1 supplement$).mp OR (nutritional ADJ1 supplement$).mp OR Vitamins/ OR Carotenoids/ OR carotenoid$.mp OR zeaxanthin.mp OR Lutein/ OR lutein.mp OR Beta carotene/ OR beta-carotene.mp OR beta carotene.mp OR Antioxidants/ OR antioxidant$.mp OR Zinc/ OR zinc.mp OR Vitamin E/ OR (vitamin ADJ1 E).mp OR Ascorbic acid/ OR (vitamin ADJ1 C).mp OR Fatty Acids, Omega-3/ OR omega 3 fatty acids.mp OR alpha-Linolenic Acid/ OR alpha linolenic acid.mp OR Docosahexaenoic Acids/ OR Docosahexaenoic acid.mp OR Eicosapentaenoic Acid/ OR Eicosapentaenoic acid.mp OR tocopherols.mp

268,101

(randomized controlled trial OR controlled clinical trial OR meta-analysis).pt OR randomized.ab OR placebo.ab OR drug therapy.fs OR randomly.ab OR trial.ab OR groups.ab OR (systematic ADJ1 review).mp 

2,611,405

1 AND 2 AND 3 523

11/03/17 - QUESTION 1

Search String N‘retina macula age related degeneration’/exp OR ‘retina macula degeneration’/exp OR ‘retina macula edema’/exp OR ‘drusen’/exp OR ‘retina neovascularization’/exp OR ‘pigment epithelium’/exp OR ‘subretinal neovascularization’/exp OR ‘retina macula lutea’/exp OR ‘retina fovea’/exp OR ‘retina detachment’/exp OR ‘macular degeneration’/de OR ‘macular degeneration’ OR ‘geographic atrophy’ OR ‘macular edema’/de OR ‘macular edema’ OR ‘wet macular degeneration’ OR ‘amd’/de OR amd OR (moderate OR intermediate) NEAR/5 (‘macular degeneration’ OR amd OR maculopat* OR ‘macular dystrophy’) OR age NEAR/4 maculopath* OR age NEAR/4 macular OR retinal NEAR/4 degenerat* OR ‘macular dystrophy’/de OR ‘macular dystrophy’ OR rpe OR ‘retinal pigment epithelium atrophy’ OR ‘retinal pigment epithelium depigmentation’ OR ‘areds stage 1’ OR ‘areds stage 3’ OR ‘subjacent retinal pigmentation epithelium’ OR ‘choriocapillaris’/de OR choriocapillaris OR ‘lipofuscin’/de OR lipofuscin OR ‘neovascular amd’ OR cnv OR ‘macular pigment optical density’ OR mpod AND [embase]/lim*search also required that the term be a major focus of the article

46,770

‘diet supplementation’/exp OR ‘vitamin’/exp OR ‘carotenoid’/exp OR ‘xanthophyll’/exp OR ‘beta carotene’/exp OR ‘antioxidant’/exp OR ‘zinc’/exp OR ‘alpha tocopherol’/exp OR ‘ascorbic acid’/exp OR ‘omega 3 fatty acid’/exp OR ‘linolenic acid’/exp OR ‘docosahexaenoic acid’/exp OR ‘icosapentaenoic acid’/exp OR ‘tocopherol’/exp OR ‘zeaxanthin’/exp

538,080
34

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

 

‘randomized controlled trial’/exp OR ‘controlled clinical trial’/exp OR ‘meta analysis’/exp OR ‘systematic review’/exp *Also searched as keyword and major focus of article

380,031

1 AND 2 AND 3 146

abase of Systematic Reviews; Database of Abstracts of Reviews of Effects; Cochrane Central Register of Controlled Trials) 

QUESTION 1

Search String N

“macular degeneration” OR “geographic atroph*” OR “macular edema” OR AMD “macular dystroph*” OR “Retinal druse*” OR “Retinal neovascularization” OR “Retinal Pigment Epithelium” OR RPE OR “Choroidal neovascularization” OR AREDS OR choriocapillaris OR lipofuscin OR “neovascular AMD” OR CNV OR “macular pigment optical density” OR MPOD OR “Macula Lutea” OR “fovea centralis” OR “Retinal detachment” (Title, Abstracts, or Keywords search)

28

Supplement* OR vitamin* OR carotenoid* OR xanthophyll OR beta carotene* OR antioxidant* OR zinc OR tocopherol* OR “ascorbic acid” OR “omega 3 fatty acid*” OR linolenic OR docosahexaenoic OR icosapentaenoic OR zeaxanthin(Title, Abstracts, or Keywords search)

530

1 AND 2 3

11/03/28 - QUESTION 1

Search String Nmacular degeneration OR geographic atroph* OR macular edema OR AMD macular dystroph* OR Retinal druse* OR Retinal neovascularization OR Retinal Pigment Epithelium OR RPE OR choroidal neovascularization OR AREDS OR choriocapillaris OR lipofuscin OR neovascular AMD OR CNV OR macular pigment optical density OR MPOD OR Macula Lutea OR fovea centralis OR Retinal detachment (Title, Abstracts, or Keywords search)

73,074

Supplement* OR vitamin* OR carotenoid* OR xanthophyll OR beta carotene* OR antioxidant* OR zinc OR tocopherol* OR “ascorbic acid” OR “omega 3 fatty acid*” OR linolenic OR docosahexaenoic OR icosapentaenoic OR zeaxanthin

4,296

1 AND 2 73

ate Searched 2011/03/28 - QUESTION 1

Search String N

macular degeneration OR geographic atroph* OR macular edema OR AMD macular dystroph* OR Retinal druse* OR Retinal neovascularization OR Retinal Pigment Epithelium OR RPE OR choroidal neovascularization OR AREDS OR choriocapillaris OR lipofuscin OR neovascular AMD OR CNV OR macular pigment optical density OR MPOD OR Macula Lutea OR fovea centralis OR Retinal detachment (Keywords search)

3,832

Supplement* OR vitamin* OR carotenoid* OR xanthophyll OR beta carotene* OR antioxidant* OR zinc OR tocopherol* OR “ascorbic acid” OR “omega 3 fatty acid*” OR linolenic OR docosahexaenoic OR icosapentaenoic OR zeaxanthin (Keywords search)

22,207

1 AND 2 68
35

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

OLDMEDLINE® 1947 to February Week 4 2011 -- Date Searched 2011/02/15 - QUESTION 2 SEARCH

Search String NAging/ OR aging.mp. OR ageing.mp. OR Aged/ OR aged.mp. OR “Aged, 80 and over”/ OR frail elderly/ OR Middle aged/ OR middle aged.mp. OR elder$.mp. OR senior$.mp. OR geriatric$.mp OR age-related.mp. OR (age adj1 related).mp.

3,562,146

zeaxanthin.mp OR Lutein/ OR lutein.mp OR Beta carotene/ OR beta-carotene.mp OR beta carotene.mp OR Zinc/ OR zinc.mp OR Vitamin E/ OR (vitamin ADJ1 E).mp OR tocopherols.mp OR Ascorbic acid/ OR (vitamin ADJ1 C).mp OR alphaLinolenic Acid/ OR alpha linolenic acid.mp OR Docosahexaenoic Acids/ OR Docosahexaenoic acid.mp OR Eicosapentaenoic Acid/ OR Eicosapentaenoic acid.mp 

160,101

 

(randomized controlled trial OR controlled clinical trial OR meta-analysis).pt OR randomized.ab OR placebo.ab OR drug therapy.fs OR randomly.ab OR trial.ab OR groups.ab OR (systematic ADJ1 review).mp 

2,656,105

unsafe.mp OR safety.mp OR harm.mp OR harms.mp OR complication$.mp OR poison$.mp OR risk$.mp OR AE.fs OR MO.fs OR PO.fs OR TO.fs OR CT.fs OR side-effect$.mp OR (undesirable ADJ1 effect$).mp OR (treatment ADJ1 emergent).mp OR tolerab$.mp OR toxic$.mp OR adrs.mp OR (adverse ADJ2 (effect or effects or reaction or reactions or event or events or outcome or outcomes)).mp

3,492,667

1 AND 2 AND 3 AND 4 3,514

1/03/17 - QUESTION 2 

Search String N

‘aged’/mj OR ‘frail elderly’/mj OR ‘elderly’/mj OR ‘very elderly’/mj OR ‘aged hospital patient’/mj OR ‘middle aged’/mj OR senior* OR geriatric* OR ‘age near/1 related’ AND [embase]/lim

154,441

‘diet supplementation’/mj OR ‘carotenoid’/mj OR ‘xanthophyll’/mj OR ‘beta carotene’/mj OR ‘antioxidant’/mj OR ‘zinc’/mj OR ‘alpha tocopherol’/mj OR ‘ascorbic acid’/mj OR ‘omega 3 fatty acid’/mj OR ‘linolenic acid’/mj OR ‘docosahexaenoic acid’/mj OR ‘icosapentaenoic acid’/mj OR ‘tocopherol’/mj OR ‘zeaxanthin’/mj AND [embase]/lim

98,250

 

‘randomized controlled trial’/mj OR ‘randomized controlled trial’/de OR ‘randomized controlled trial’ OR ‘controlled clinical trial’/mj OR ‘controlled clinical trial’/de OR ‘controlled clinical trial’ OR ‘meta analysis’/mj OR ‘meta analysis’/de OR ‘meta analysis’ OR ‘systematic review’/mj OR ‘systematic review’/de OR ‘systematic review’ AND [embase]/lim*also searched as keyword and main topic of article

380,031

‘adverse drug reaction’/mj OR ‘adverse drug reaction’ OR ‘drug induced disease’/mj OR ‘drug induced disease’ OR ‘complication’/mj OR ‘complication’ OR ‘intoxication’/mj OR ‘intoxication’ OR ‘toxicity’/mj OR ‘toxicity’ OR ‘drug hypersensitivity’/mj OR ‘drug hypersensitivity’ OR unsafe OR ‘safety’/mj OR safety OR harm OR harms OR complication* OR poison* OR risk* OR undesirable NEAR/1 effect OR treatment NEAR/1 emergent OR tolerab* OR toxic* OR adrs OR adverse NEAR/2 (effect OR effects OR reaction OR reactions OR event OR events OR outcome OR outcomes) AND [embase]/lim

3,965,190
36

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

1 AND 2 AND 3 AND 4 108

11/03/17 - QUESTION 2

Search String N

aged OR elderly OR “middle aged” OR senior* OR geriatric* OR “age related” in TITLE-ABS-KEY 3,178,852 zeaxanthin OR lutein OR “Beta carotene” OR zinc OR “Vitamin E” OR tocopherol* OR “Ascorbic acid” OR “vitamin C” OR alpha-linolenic OR docosahexaenoic OR eicosapentaenoic in TITLE-ABS-KEY-AUTH

447,672

“randomized controlled trial*” OR “controlled clinical trial*” OR “meta analysis” OR “systematic review*” TITLE-ABSKEY-AUTH 529,484

“adverse drug reaction*” OR “adverse reaction*” OR complication* OR toxic* OR poison* OR harm* OR unsafe OR tolerab* OR adverse outcome* OR adverse event* OR adverse effect* TITLE-ABS-KEY-AUTH

252,917

, 

1 AND 2 AND 3 AND 4 309

Database of Systematic Reviews; Database of Abstracts of Reviews of Effects; Cochrane Central Register of Controlled Trials) -- 

UESTION 2

Search String N

aged OR elderly OR “middle aged” OR senior* OR geriatric* OR “age related” (Title, Abstracts or Keywords search) 1,238

zeaxanthin OR lutein OR “Beta carotene” OR zinc OR “Vitamin E” OR tocopherol* OR “Ascorbic acid” OR “vitamin C” OR alpha-linolenic OR docosahexaenoic OR eicosapentaenoic (Title, Abstracts or Keywords search) 

79

reaction* OR complication* OR toxic* OR poison* OR harm* OR unsafe OR safety OR tolerab* OR adverse (Title, Abstracts or Keywords search) 

4,283

1 AND 2 AND 3 23

ate Searched 2011/03/25 - QUESTION 2

Search String N

aged OR elderly OR “middle aged” OR senior* OR geriatric* OR “age related” (Keyword search) 21,302
37

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

zeaxanthin OR lutein OR “Beta carotene” OR zinc OR “Vitamin E” OR tocopherol* OR “Ascorbic acid” OR “vitamin C” OR “omega 3 fatty acid*” OR alpha-linolenic OR docosahexaenoic OR eicosapentaenoic (Keyword search) 

9,376

reaction* OR complication* OR toxic* OR poison* OR harm* OR unsafe OR safety OR tolerab* OR adverse (Keyword search) 

98,395

1 AND 2 AND 3 1
38

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

APPENDIX B. Inclusion/Exclusion Criteria

1. Is the full text of the article in English? 

Yes......................................................................Proceed to #2

No...................................................................Code X1. STOP

2. Is the article a controlled clinical trial or a systematic review/meta-analysis of controlled trials 

comparing the effects of supplemental/non-dietary carotenoids, antioxidants, or omega-3 fatty 

acids (alone or in combination) with usual care or placebo?

Yes......................................................................Proceed to #3

No ..............................................................Code X2. Go to #6

3. Does the population include adults with age-related macular degeneration? 

Yes......................................................................Proceed to #4

No.......................................................................Proceed to #5

4. Does the study report outcomes that include vision loss, quality of life, functional status, or 

adverse effects of treatment?

Yes................................................................... Code I4. STOP

No...............................................................Code X4. Go to #6

5. Does the study report the adverse effects of treatment in a population of ≥100 adults without agerelated macular degeneration who were observed for >24 weeks?

Yes................................................................... Code I5. STOP

No.......................................................Code X5. Proceed to #6

6. Is the article potentially useful for background, discussion, or reference-mining?

Yes............................................................ Add Code B. STOP

No................................................................................... STOP

PICOTS

Patients: KQ1: Adults with age-related macular degeneration

KQ2: Adults, exclude patients with severe chronic illnesses such as end-stage liver 

disease, ESRD, severe COPD, metastatic cancer, ALS, severe heart failure

Interventions: Carotenoids – zeaxanthin, lutein, beta-carotene

Antioxidants – zinc, vitamin e, vitamin c

Omega-3 fatty acids – alpha linolenic acid (C18:3n-3), docosahexaenoic acid (DHA; 

C22:6n-3), eicosapentaenoic acid (EPA; C20:5n-3) 

Comparators: Placebo, usual care (usual diet)

Outcomes: Vision loss 

Visual impairment in the best eye defined as: ≤ 20/60 by Snellen acuity; or ≤ 6/18 metric acuity; or 

doubling of the visual angle (e.g. 20/50 to 20/100); or ≥ three lines of loss; or ≥ 15 letters lost; or 

progression to advanced disease (either geographic atrophy or wet macular degeneration); quality of 

life; functional status.
39

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

ssessment of methodologic quality and risk of bias in randomized

trials of oral supplements for age-related macular degeneration

Allocation 

adequately 

concealed

Blinding of 

participants, 

personnel and 

outcome assessors

Incomplete outcome data 

adequately addressed

Absence of 

selective 

outcome 

reporting

Free of other 

sources of 

bias

Overall 

risk of 

bias

Funding source

Yes Yes; all meds and 

placebo were coded and concealed from subjects and examiners...codes were kept only in the coordinating center.

Yes; participants were dropped if not photographed or proper visual acuity measurements were not obtained...these dropped subjects were “evenly distributed across the groups”. Only 2.4% of subjects were lost to follow-up (missed at least 2 consecutive visits).

Yes; each stated outcome measure was reported in addition to adverse events.

Yes Low NIH; Bausch & Lomb Inc.

s; staff and 

bjects were 

asked.

Yes; all meds and placebos were masked from both subjects and investigators.

Yes; ITT analysis was done; 5/106 failed to complete study and details were reported of each.

Yes; outcomes were reported as indicated.

Yes Low Funding NR

Yes Yes Unclear Yes Yes Low Research Fund Department of 

Veterinary Science, Utah State University

s; study coor

nator provided 

pplements but did 

t complete data 

lection.

Yes; supplements identical in appearance.

Unclear; did not include data from subjects who dropped out or died.

Yes Yes Low Retinal Disease Research 

Foundation

Yes Yes Unclear: 12 of 71 rate of attrition, 

but no data provided for those patients, including treatment assignment.

Yes Yes; 17% 

loss to followup, unclear treatment assignment.

Low Twin Laboratories, Inc.; Eye 

Communications, Inc.; Stereo Optical, Inc; Illinois College of Optometry; Pacific University College of Optometry; Ezell Foundation, American Academy of Optometry

Yes Yes Yes Yes Yes Low DVA Medical Center, North 

Chicago; Kemin Foods, Vitacost.com; Nutraceutical Sciences Institute; Great Smokies Diagnostic Laboratory

Yes Yes Yes Yes Yes Low Austrian Foundation for the 

Propagation of Scientific Research
40

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

R REVIEW COMMENTS AND RESPONSES

Comment Response

ope, and methods for this review clearly described?

ods section that your literature focuses on patients with ARMD, 

round of the Executive Summary and the Introduction, it is noted that 

s suggest that people with dietary intakes higher in various nutritional 

ower risk of developing AMD”. Yet there is no mention of the data 

onal supplements may have a role in preventing ARMD. Since the data 

 of ARMD is not even addressed, perhaps a statement recognizing 

exists, but is outside the realm of this report would be beneficial.

The comment in the background was modified to clarify our purpose. The statement identifies the reason large supplementation trials were initiated to investigate the role of dietary supplements in AMD prevention. We note there is a large body of observational data suggesting dietary antioxidants, carotenoids and/or fish oils may be beneficial. This data is not reviewed here because of the risk of uncontrolled confounding and recall bias in observational cohort studies. 

tudy and methods are clearly described and are appropriate. Noted, thank you.

cellent review Noted, thank you.

n of bias in our synthesis of the evidence?

y stated at the very beginning of the report (It should also be stated 

page 3, the authors reject 298 of 335 (89 %) full-text scientific articles 

meeting the inclusion criteria of EBM; 2) Throughout the entire 

ctional” is used rather than the more precise term “Snellen Visual 

on 1: Limiting most all discussions of carotenoids to primarily a B 

xidants to 1 form of the 8 isomers of vitamin E (i.e. alpha tocopherol) 

n of nature and known science, (despite the fact that another 

NEI / NIH) made this decision to persist in using the same 1990s 

ts in the “new” AREDS II study). Given the relative lack of information

of xanthophylls, carotenoids and omega III fatty acids, future trials 

to assess the effects of these supplements in AMD patients”. The 

ould be replaced with “EBM” to be consistent. There are 1000’s of 

erning n3 fatty acids, and dozens concerning the salutary benefit 

 people worried about not getting it. I know of only a single negative 

y.

The inclusion and exclusion criteria were pre-specified before we undertook the review. The outcomes of interest and interventions of interest were determined based on discussion with a Technical Expert Panel. In the methods section, we defined functional vision loss in a variety of ways using both Snellen and non-Snellen methods. Given the problems inherent with observational data, we included only RCTs and only found one RCT of omega IIIs evaluating the outcomes of interest Noted, thank you.

of bias. English only studies were examined, but this is appropriate for 

egeneration as Caucasians are most frequently affected and relevant 

 Appropriate steps were taken to review appropriate studies in a 

accepted evaluation techniques. 

Noted, thank you.Noted, thank you.

ed or unpublished studies that we may have overlooked?

st the 298 rejected studies. Although we do not list excluded studies in our report, we can 

provide a list of excluded studies and reasons for exclusion separately upon request. 
41

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

Comment Response

e Rotterdam Study Reducing the Genetic Risk of AMD with Dietary 

 w3 fatty acids Arch Ophthalmol. 2011; 129 (6):758-66 (High dietary 

th antioxidant properties reduces the risk of early AMD in those at 

efore, clinicians should provide dietary advice to young susceptible 

ne or prevent the vision-disturbing consequences of AMD).

Thank you for suggesting this study. Our scope and inclusion criteria would exclude this study because the focus of the review is on supplemental rather than dietary intake of antioxidants. 

Women’s Health Study - Dietary w3 Fatty Acid and Fish Intake and 

en Arch Ophthalmol. 2011; 129 (7):921-9 (These prospective data 

 female health professionals without a diagnosis of AMD at baseline 

onsumption of DHAA and EPA and fish was associated with a 

d risk of incident AMD and may be of benefit in primary prevention of 

Our scope and inclusion criteria would exclude this study as well because the focus of the review is on supplemental rather than dietary intake of antioxidants. 

 Effects, Yellowing of the skin: it only notes that beta-carotene is 

wing of the skin. This effect is also noted with lutein. See ref: Regul 

06; 45: 289-298. 

We have added this suggested narrative review and references for the two trials it cites regarding lutein supplementation and carotenodermia. Noted, thank you.Noted, thank you.

al suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report.

nellen Visual Acuity throughout the report is used to define both 

 of disease”. However, foveal vision in humans is, more often than 

 until the patho-physiology of AMD has run its course. It is therefore 

describe both functional vision and the stage of disease in either dry 

 EBM model adopted within this report is in complete opposition 

tient-doctor encounter. It contradicts the results of both the LAST 

cently published ZVF study (FDA #78,973). In both studies patients 

2 visual acuity yet poor contrast sensitivity and glare recovery...i.e. 

ity. If we use an AREDS deterministic legal definition of 15 letter 

 your report is correct to assume that ours were negative studies by 

The outcomes of interest were determined after discussion with a group of technical experts who felt functional vision loss as we’ve defined it was the appropriate outcome to evaluate for the systematic review. Evaluation of these more proximal outcome metrics is outside the scope of our review. 
42

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

Comment Response

tated not once but twice that AMD changes occur slowly over time. 

e is younger than 85 – then the changes will occur very quickly. 

ed individuals are the fastest growing demographic in the United 

the number of patients with AMD between age 85 and 95 compared 

ot double). We are wasting time. 

We agree and have added the suggested text to the Discussion section.

k you for taking the time to develop this document. One suggestion 

eferences to the studies noted in the Executive Summary Table on 

We have added the study references to the summary table in the Conclusions of the main report, as suggested. We generally do not include citations in the Executive Summary. 

n, it is noted that only those studies with at least 24 weeks of follow

 100 were included, but some of the data is not consistent with that 

le, the Newsome, 2008 trial only contained 74 participants. 

We have clarified the methods to specify that we did not limit the sample size or duration of treatment of RCTs to answer the question of efficacy. Sample size of 100 or more pertained to included studies of adverse effects. 

hout the document. It should be ETDRS for Early Treatment Diabetic 

Thank you for this correction. We have changed “EDTRS” to ETDRS” throughout the document. 

excellent job of identifying the categories of AMD and incorporating 

lity as part of their evaluation. For example, studies evaluating 

y 1 and 2 AMD are not likely to find a benefit to supplementation 

ure of the disease process as well as the lack of vision loss in these 

g is of crucial importance in determining which patients may benefit 

n that does carry some risk. 

Noted, thank you.

 page 4 that there are not effective therapies is out of sequence. 

orn out in the grade 3 and 4 AMD patients with the supplements. 

orrect; clinicians refer to the AREDS trial as an indication of the use 

e only valid trial. As you noted there is additional AREDS2 looking at 

 progress. Also, there is a “smokers” AREDS without the antioxidants 

isk of lung cancer? I think the part that remains difficult is the 

k. If there were even marginal benefit and no risk then the treatment 

k you have addressed this in as much detail as is currently available

We have deleted the first sentence to improve clarity. We added text to the Discussion section regarding the amendment to the AREDS study in which smokers were offered a chance to change their randomization of treatment supplements to either zinc alone (without the antioxidants) or placebo. 

: In the AREDS study- please specify AREDS 1 and list the formula 

Done.

e document: please define “former” smoker if that information is 

 studies.

We have added definitions for “former” smoker, as suggested. 

: “Higher doses of vit E have been associated with increased mortality 

failure among those with high baseline risk”. High baseline risk needs 

onstitutes high baseline risk? Also, “carotenoids such as beta-carotene 

 with an increased risk of lung cancer among smokers. The absolute 

ow low is low? please clarify here.

We have added the estimated magnitude of increased risk for each outcome in this paragraph. 
43

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

Comment Response

mmary table. In the Comment Column, it would be nice to have 

d to help understand what authors mean by High-dose vit E, beta

gh risk patients” needs to be clarified.

Thank you for this suggestion. We have added the dose range to the Summary Table to better characterize the high-dose and low-dose studies. We have also added a footnote in Table 1 to specify the definition of high vs low risk AMD used in Stur, 1996. 

1 line: The natural history of AMD has not been shown definitely to 

any treatment modality. The authors should specify that they are 

the nonexudative AMD. 

Thank you for this suggestion, however, we have decided to delete this sentence to improve clarity in response to another comment. 

ts: Adults with age-related macular degeneration - please specify 

ted macular degeneration is being studied here.

Done.

e nice to point out here that a 3-line change in visual acuity (i.e. +/-

TDRS chart is equivalent to a doubling or halving of the visual angle 

line visual acuity measurement.

We have added the suggested text to the list of outcomes in the Methods section.

outpatients with (NON-EXUDATIVE- please add) age-related macular 

Done.

ph: Please add a reference at the end of the sentence that talks about 

roup.

Citation added.

ph: “In analysis limited to only those with Category 3 or 4 AMD, 

nal visual loss was noted with either supplement alone or in 

be clarified by specifying how much improvement was detected with 

ombination.

Thank you for this suggestion. We have revised the paragraph accordingly. 

 baseline characteristic differences were noted between the Category 

” is confusing, since these categories of participants are inherently 

her. Not sure what the sentence is saying. Please clarify.

We have clarified this sentence to read: “No significant differences in demographics, socioeconomic status, smoking status, or comorbidities were noted between the Category 2, 3 or 4 participants.”

he 4th-6th columns list outcomes, however no P-values are listed 

bers listed. Please include P-values (from articles listed) wherever is 

Done.

, the treatment arms will evaluate the effects of eliminating beta

nal AREDS formulation...” should be FROM the original AREDS. Would 

 ingredients of the AREDS formulation here.

Thank you for this correction. We have specified the ingredients of the original AREDS formulation, as suggested.

Cancer: please define what was meant by “former smokers”. How 

tting tobacco?

We have added definitions for “former” smokers, as suggested.