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Administración de suplementos de vitaminas antioxidantes y minerales para la prevención de la degeneración macular asociada a la edad

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References

References to studies included in this review

ATBC 1998 {published data only}

Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK, et al. Effects of alpha‐tocopherol and beta‐carotene supplements on cancer incidence in the Alpha‐tocopherol beta‐carotene cancer prevention study. American Journal of Clinical Nutrition 1995;62(6):1427S‐30S. CENTRAL
Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, et al. Alpha‐tocopherol and beta‐carotene supplements and lung cancer incidence in the Alpha‐tocopherol, beta‐carotene cancer prevention study: effects of base‐line characteristics and study compliance. Journal of the National Cancer Institute 1996;88(21):1560‐70. CENTRAL
Albanes D, Virtamo J, Rautalahti M, Pikkarainen J, Taylor PR, Greenwald P, et al. Pilot study: The US‐Finland lung cancer prevention trial. Journal of Nutrition, Growth and Cancer 1986;3(3):207‐14. CENTRAL
Albanes D, Virtamo J, Taylor PR, Rautalahti M, Pietinen P, Heinonen OP. Effects of supplemental beta‐carotene, cigarette smoking, and alcohol consumption on serum carotenoids in the Alpha‐tocopherol, beta‐carotene cancer prevention study. American Journal of Clinical Nutrition 1997;66(2):366‐72. CENTRAL
Blumberg J, Block G. The Alpha‐tocopherol, beta‐carotene cancer prevention study in Finland. Nutrition Review 1994;52(7):242‐5. CENTRAL
Buring JE, Hebert P, Hennekens CH. The Alpha‐tocopherol, beta‐carotene lung cancer prevention trial of vitamin E and beta‐carotene: the beginning of the answers. Annals of Epidemiology 1994;4(1):75. CENTRAL
Glynn SA, Albanes D, Pietinen P, Brown CC, Rautalahti M, Tangrea JA, et al. Alcohol consumption and risk of colorectal cancer in a cohort of Finnish men. Cancer Causes and Control 1996;7(2):214‐23. CENTRAL
Hartman TJ, Albanes D, Pietinen P, Hartman AM, Rautalahti M, Tangrea JA, et al. The association between baseline vitamin E, selenium, and prostate cancer in the Alpha‐tocopherol, beta‐carotene cancer prevention study. Cancer Epidemiology, Biomarkers and Prevention 1998;7(4):335‐40. CENTRAL
Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, et al. Prostate cancer and supplementation with alpha‐tocopherol and beta‐carotene: incidence and mortality in a controlled trial. Journal of the National Cancer Institute 1998;90:440‐6. CENTRAL
Laurila AL, Anttila T, Laara E, Bloigu A, Virtamo J, Albanes D, et al. Serological evidence of an association between Chlamydia pneumoniae infection and lung cancer. International Journal of Cancer 1997;74(1):31‐4. CENTRAL
Liede K, Hietanen J, Saxen L, Haukka J, Timonen T, Hayrinen Immonen R, et al. Long‐term supplementation with alpha‐tocopherol and beta‐carotene and prevalence of oral mucosal lesions in smokers. Oral Diseases 1998;4(2):78‐83. CENTRAL
Liede KE, Alfthan G, Hietanen JH, Haukka JK, Saxen LM, Heinonen OP. Beta‐carotene concentration in buccal mucosal cells with and without dysplastic oral leukoplakia after long‐term beta‐carotene supplementation in male smokers. European Journal of Clinical Nutrition 1998;52:872‐6. CENTRAL
Liede KE, Haukka JK, Saxen LM, Heinonen OP. Increased tendency towards gingival bleeding caused by joint effect of alpha‐tocopherol supplementation and acetylsalicylic acid. Annals of Medicine 1998;30(6):542‐6. CENTRAL
Pietinen P, Rimm EB, Korhonen P, Hartman AM, Willett WC, Albanes D, et al. Intake of dietary fiber and risk of coronary heart disease in a cohort of Finnish men. The Alpha‐tocopherol, beta‐carotene cancer prevention study. Circulation 1996;94(11):2720‐7. CENTRAL
Rapola JM, Virtamo J, Haukka JK, Heinonen OP, Albanes D, Taylor PR, et al. Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double‐blind, controlled trial. JAMA 1996;275(9):693‐8. CENTRAL
Rapola JM, Virtamo J, Ripatti S, Haukka JK, Huttunen JK, Albanes D, et al. Effects of alpha tocopherol and beta carotene supplements on symptoms, progression, and prognosis of angina pectoris. Heart 1998;79(5):454‐8. CENTRAL
Rapola JM, Virtamo J, Ripatti S, Huttunen JK, Albanes D, Taylor PR, et al. Randomised trial of alpha‐tocopherol and beta‐carotene supplements on incidence of major coronary events in men with previous myocardial infraction. Lancet 1997;349(9067):1715‐20. CENTRAL
Teikari JM, Laatikainen L, Rapola JM, Virtamo J, Haukka J, Liesto K, et al. Retinal vascular changes following supplementation with alpha‐tocopherol or beta‐carotene. Acta Ophthalmologica Scandinavica 1998;76(1):68‐73. CENTRAL
Teikari JM, Laatikainen L, Virtamo J, Haukka J, Rautalahti M, Liesto K, et al. Six‐year supplementation with alpha‐tocopherol and beta‐carotene and age‐related maculopathy. Acta Ophthalmologica Scandinavica 1998;76(2):224‐9. CENTRAL
Teikari JM, Rautalahti M, Haukka J, Jarvinen P, Hartman AM, Virtamo J, et al. Incidence of cataract operations in Finnish male smokers unaffected by alpha tocopherol or beta carotene supplements. Journal of Epidemiology and Community Health 1998;52(7):468‐72. CENTRAL
Teikari JM, Virtamo J, Rautalahti M, Palmgren J, Liesto K, Heinonen OP. Long‐term supplementation with alpha‐tocopherol and beta‐carotene and age‐related cataract. Acta Ophthalmologica Scandinavica 1997;75(6):634‐40. CENTRAL
The ATBC Cancer Prevention Study Group. The Alpha‐tocopherol, beta‐carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Annals of Epidemiology 1994;4(1):1‐10. CENTRAL
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 cancers in male smokers. New England Journal of Medicine 1994;330(15):1029‐35. CENTRAL
Tornwall M, Virtamo J, Haukka JK, Aro A, Albanes D, Edwards BK, et al. Effect of alpha‐tocopherol (vitamin E) and beta‐carotene supplementation on the incidence of intermittent claudication in male smokers. Arteriosclerosis, Thrombosis and Vascular Biology 1997;17(12):3475‐80. CENTRAL
Varis K, Taylor PR, Sipponen P, Samloff IM, Heinonen OP, Albanes D, et al. Gastric cancer and premalignant lesions in atrophic gastritis: a controlled trial on the effect of supplementation with alpha‐tocopherol and beta‐carotene. The Helsinki gastritis study group. Scandinavian Journal of Gastroenterology 1998;33(3):294‐300. CENTRAL
Virtamo J, Rapola JM, Ripatti S, Heinonen OP, Taylor PR, Albanes D, et al. Effect of vitamin E and beta‐carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Archives of Internal Medicine 1998;158(6):668‐75. CENTRAL

PHS I 2007 {published data only}

Belanger C, Buring JE, Cook N, Eberlein K, Goldhaber SZ, Gordon D, et al. Final report on the aspirin component of the ongoing Physicians' health study. New England Journal of Medicine 1989;321(3):129‐35. CENTRAL
Berger K, Kase CS, Buring JE. Interobserver agreement in the classification of stroke in the Physicians' health study. Stroke 1996;27(2):238‐42. CENTRAL
Buring JE, Hebert P, Romero J, Kittross A, Cook N, Manson J, et al. Migraine and subsequent risk of stroke in the Physicians' health study. Archives of Neurology 1995;52(2):129‐34. CENTRAL
Buring JE, Hennekens CH. Cost and efficiency in clinical trials: The U.S. Physicians' health study. Statistics in Medicine 1990;9(1‐2):29‐33. CENTRAL
Cairns J, Cohen L, Colton T, DeMets DL, Deykin D, Friedman L, et al. Issues in the early termination of the aspirin component of the Physicians' health study. Annals of Epidemiology 1991;1(5):395‐405. CENTRAL
Camargo CA, Stampfer MJ, Glynn RJ, Gaziano JM, Manson JE, Goldhaber SZ, et al. Prospective study of moderate alcohol consumption and risk of peripheral arterial disease in US male physicians. Circulation 1997;95(3):577‐80. CENTRAL
Christen WG, Ajani UA, Glynn RJ, Manson JE, Schaumberg DA, Chew EC, et al. Prospective cohort study of antioxidant vitamin supplement use and the risk of age‐related maculopathy. American Journal of Epidemiology 1999;149(5):476‐84. CENTRAL
Christen WG, Glynn RJ, Manson JE, Agani UA, Buring JE. A prospective study of cigarette smoking and risk of age‐related macular degeneration in men. JAMA 1996;276(14):1147‐51. CENTRAL
Christen WG, Manson JE, Glynn RJ, Ajani UA, Schaumberg DA, Sperduto RD, et al. Low‐dose aspirin and risk of cataract and subtypes in a randomized trial of U.S. physicians. Ophthalmic Epidemiology 1998;5(3):133‐42. CENTRAL
Christen WG, Manson JE, Glynn RJ, Gaziano JM, Chew EY, Buring JE, et al. Beta carotene supplementation and age‐related maculopathy in a randomized trial of US physicians. Archives of Ophthalmology 2007;125(3):333‐9. CENTRAL
Christen WG, Manson JE, Seddon JM, Glynn RJ, Buring JE, Rosner B, et al. A prospective study of cigarette smoking and risk of cataract in men. JAMA 1992;268(8):989‐93. CENTRAL
Fotouhi N, Meydani M, Santos MS, Meydani SN, Hennekens CH, Gaziano JM. Carotenoid and tocopherol concentrations in plasma, peripheral blood mononuclear cells, and red blood cells after long‐term beta‐carotene supplementation in men. American Journal of Clinical Nutrition 1996;63(4):553‐8. CENTRAL
Gann PH, Manson JE, Glynn RJ, Buring JE, Hennekens CH. Low‐dose aspirin and incidence of colorectal tumors in a randomized trial. Journal of the National Cancer Institute 1993;85(15):1220‐4. CENTRAL
Glynn RJ, Christen WG, Manson JE, Bernheimer J, Hennekens CH. Body mass index. An independent predictor of cataract. Archives of Ophthalmology 1995;113(9):1131‐7. CENTRAL
Guallar E, Hennekens CH, Sacks FM, Willett WC, Stampfer MJ. A prospective study of plasma fish oil levels and incidence of myocardial infarction in U.S. male physicians. Journal of the American College of Cardiology 1995;25(2):387‐94. CENTRAL
Hebert PR, Rich Edwards JW, Manson JE, Ridker PM, Cook NR, O'Connor GT, et al. Height and incidence of cardiovascular disease in male physicians. Circulation 1993;88(4 (Pt 1)):1437‐43. CENTRAL
Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, et al. Lack of effect of long‐term supplementation with beta‐carotene on the incidence of malignant neoplasms and cardiovascular disease. New England Journal of Medicine 1996;334(18):1145‐9. CENTRAL
Hennekens CH, Eberlein K. A randomized trial of aspirin and beta‐carotene among U.S. physicians. Preventive Medicine 1985;14(2):165‐8. CENTRAL
Lang JM, Buring JE, Rosner B, Cook N, Hennekens CH. Estimating the effect of the run‐in on the power of the Physicians' health study. Statistics in Medicine 1991;10(10):1585‐93. CENTRAL
Lee IM, Hennekens CH, Berger K, Buring JE, Manson JE. Exercise and risk of stroke in male physicians. Stroke 1999;30(1):1‐6. CENTRAL
Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Research 1997;57(6):1098‐102. CENTRAL
Manson JE, Buring JE, Satterfield S, Hennekens CH. Baseline characteristics of participants in the Physicians' health study: a randomized trial of aspirin and beta‐carotene in U.S. physicians. American Journal of Preventive Medicine 1991;7(3):150‐4. CENTRAL
Manson JE, Christen WG, Seddon JM, Glynn RJ, Hennekens CH. A prospective study of alcohol consumption and risk of cataract. American Journal of Preventive Medicine 1994;10(3):156‐61. CENTRAL
Morris MC, Manson JE, Rosner B, Buring JE, Willett WC, Hennekens CH. Fish consumption and cardiovascular disease in the Physicians' health study: a prospective study. American Journal of Epidemiology 1995;142(2):166‐75. CENTRAL
O'Donnell CJ, Ridker PM, Glynn RJ, Berger K, Ajani U, Manson JE, et al. Hypertension and borderline isolated systolic hypertension increase risks of cardiovascular disease and mortality in male physicians. Circulation 1997;95(5):1132‐7. CENTRAL
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C‐reactive protein and risk of developing peripheral vascular disease. Circulation 1998;97(5):425‐8. CENTRAL
Ridker PM, Hennekens CH, Roitman Johnson B, Stampfer MJ, Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998;351(9004):88‐92. CENTRAL
Ridker PM, Manson JE, Gaziano JM, Buring JE, Hennekens CH. Low‐dose aspirin therapy for chronic stable angina. A randomized, placebo‐controlled clinical trial. Annals of Internal Medicine 1991;114(10):835‐9. CENTRAL
Robbins AS, Manson JE, Lee IM, Satterfield S, Hennekens CH. Cigarette smoking and stroke in a cohort of U.S. male physicians. Annals of Internal Medicine 1994;120(6):458‐62. CENTRAL
Salvini S, Stampfer MJ, Barbieri RL, Hennekens CH. Effects of age, smoking and vitamins on plasma DHEAS levels: a cross‐sectional study in men. Journal of Clinical Endocrinology and Metabolism 1992;74(1):139‐43. CENTRAL
Santos MS, Gaziano JM, Leka LS, Beharka AA, Hennekens CH, Meydani SN. Beta‐carotene‐induced enhancement of natural killer cell activity in elderly men: an investigation of the role of cytokines. American Journal of Clinical Nutrition 1998;68(1):164‐70. CENTRAL
Santos MS, Leka LS, Ribaya Mercado JD, Russell RM, Meydani M, Hennekens CH, et al. Short‐ and long‐term beta‐carotene supplementation do not influence T cell‐mediated immunity in healthy elderly persons. American Journal of Clinical Nutrition 1997;66(5):917‐24. CENTRAL
Santos MS, Meydani SN, Leka L, Wu D, Fotouhi N, Meydani M, et al. Natural killer cell activity in elderly men is enhanced by beta‐carotene supplementation. American Journal of Clinical Nutrition 1996;64:772‐7. CENTRAL
Satterfield S, Greco PJ, Goldhaber SZ, Stampfer MJ, Swartz SL, Stein EA, et al. Biochemical markers of compliance in the Physicians' health study. American Journal of Preventive Medicine 1990;6(5):290‐4. CENTRAL
Schaumberg DA, Hennekens CH. Effect of 12 years of beta‐carotene supplementation on malignant non‐melanoma skin cancer: results from the Physicians' health study. American Journal of Epidemiology 1996;143:S9. CENTRAL
Seddon JM, Christen WG, Manson JE, LaMotte FS, Glynn RJ, Buring JE, et al. The use of vitamin supplements and the risk of cataract among US male physicians. American Journal of Public Health 1994;84(5):788‐92. CENTRAL
Stampfer MJ, Buring JE, Willett W, Rosner B, Eberlein K, Hennekens CH. The 2 x 2 factorial design: its application to a randomized trial of aspirin and carotene in U.S. physicians. Statistics in Medicine 1985;4(2):111‐6. CENTRAL
Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994;25(10):1924‐30. CENTRAL
Zee RY, Ridker PM, Stampfer MJ, Hennekens CH, Lindpaintner K. Prospective evaluation of the angiotensin‐converting enzyme insertion/deletion polymorphism and the risk of stroke. Circulation 1999;99(3):340‐3. CENTRAL

PHS II 2012 {published data only}

Christen WG, Gaziano JM, Hennekens CH. Design of Physicians' health study II ‐ a randomized trial of beta‐carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease and review of results of completed trials. Annals of Epidemiology 2000;10(2):125‐34. CENTRAL
Christen WG, Glynn RJ, Sesso HD, Kurth T, Macfadyen J, Bubes V, et al. Vitamins E and C and medical record‐confirmed age‐related macular degeneration in a randomized trial of male physicians. Ophthalmology 2012;119(8):1642‐9. CENTRAL

VECAT 2002 {published data only}

Garrett SKM, McNeil JJ, Silagy C, Sinclair M, Thomas AP, Robman LD, et al. Methodology of the VECAT study: vitamin E intervention in cataract and age‐related maculopathy. Ophthalmic Epidemiology 1999;6:195‐208. CENTRAL
Robman LD, Tikellis G, Garrett SKM, Harper CA, McNeil JJ, Taylor HR, et al. Baseline ophthalmic findings in the vitamin E, cataract and age‐related maculopathy (VECAT) study. Australian and New Zealand Journal of Ophthalmology 1999;27:410‐6. CENTRAL
Taylor H, Tikellis G, Robman L, McCarty C, McNeil J. Vitamin E supplementation and macular degeneration: randomised controlled trial. BMJ 2002;325:325‐11. CENTRAL
Taylor HR, Tikellis G, Robman LD, McCarty CA, McNeil. Vitamin E supplementation and age‐related maculopathy. Investigative Ophthalmology and Visual Science 2001;42:S311. CENTRAL

WHS 2010 {published data only}

Buring JE, Hennekens CH. Randomized trials of primary prevention of cardiovascular disease in women. An investigator's view. Annals of Epidemiology 1994;4(2):111‐4. CENTRAL
Christen WG, Glynn RJ, Chew EY, Buring JE. Vitamin E and age‐related macular degeneration in a randomized trial of women. Ophthalmology 2010;117(6):1163‐8. CENTRAL
Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. Low‐dose aspirin in the primary prevention of cancer: the Women's health study: a randomized controlled trial. JAMA 2005;294(1):47‐55. CENTRAL
Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's health study: a randomized controlled trial. JAMA 2005;294(1):56‐65. CENTRAL
Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low‐dose aspirin in the primary prevention of cardiovascular disease in women. New England Journal of Medicine 2005;352(13):1293‐304. CENTRAL

References to studies excluded from this review

ADSC 1997 {published data only}

Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha‐tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. New England Journal of Medicine 1997;336(17):1216‐22. CENTRAL

Andrews 1969 {published data only}

Andrews J, Letcher M, Brook M. Vitamin C supplementation in the elderly: a 17‐month trial in an old persons' home. British Medical Journal 1969;2(5654):416‐8. CENTRAL

AREDS 2001 {published data only}

Age‐related Eye Disease Study Research Group. 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;119(10):1417‐36. CENTRAL

AREDS2 2008 {published data only}

Hubbard LD, Danis RP, Neider MW, Thayer DW, Wabers HD, White JK, et al. Brightness, contrast, and color balance of digital versus film retinal images in the age‐related eye disease study 2. Investigative Ophthalmology and Visual Science 2008;49(8):3269‐82. CENTRAL

Benner 1994 {published data only}

Benner SE, Lippman SM, Hong WK. Retinoid chemoprevention of second primary tumors. Seminars in Hematolology 1994;31(4 Suppl 5):26‐30. CENTRAL

Benton 1995 {published data only}

Benton D, Fordy J, Haller J. The impact of long‐term vitamin supplementation on cognitive functioning. Psychopharmacology 1995;117(3):298‐305. CENTRAL

Berrow 2016 {published data only}

Berrow EJ, Bartlett HE, Eperjesi F. The effect of nutritional supplementation on the multifocal electroretinogram in healthy eyes. Documenta Ophthalmologica 2016;132(2):123‐35. CENTRAL

Blok 1997 {published data only}

Blok WL, Deslypere JP, Demacker PN, Van der Ven Jongekrijg J, Hectors MP, Van der Meer JW, et al. Pro‐ and anti‐inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year. European Journal of Clinical Investigation 1997;27(12):1003‐8. CENTRAL

Bogden 1990 {published data only}

Bogden JD, Oleske JM, Lavenhar MA, Munves EM, Kemp FW, Bruening KS, et al. Effects of one year of supplementation with zinc and other micronutrients on cellular immunity in the elderly. Journal of the American College of Nutrition 1990;9(3):214‐25. CENTRAL

Bone 2010 {published data only}

Bone RA, Landrum JT. Dose‐dependent response of serum lutein and macular pigment optical density to supplementation with lutein esters. Archives of Biochemistry and Biophysics 2010;504(1):50‐5. CENTRAL

Brewer 1997 {published data only}

Brewer GJ, Johnson V, Kaplan J. Treatment of Wilson's disease with zinc: XIV. Studies of the effect of zinc on lymphocyte function. Journal of Laboratory and Clinical Medicine 1997;129(6):649‐52. CENTRAL

Brown 1998 {published data only}

Brown BG, Zhao XQ, Chait A, Frohlich J, Cheung M, Heise N, et al. Lipid altering or antioxidant vitamins for patients with coronary disease and very low HDL cholesterol? The HDL‐atherosclerosis treatment study design. Canadian Journal of Cardiology 1998;14 Suppl A:6A‐13A. CENTRAL

Bussey 1982 {published data only}

Bussey HJ, DeCosse JJ, Deschner EE, Eyers AA, Lesser ML, Morson BC, et al. A randomized trial of ascorbic acid in polyposis coli. Cancer 1982;50(7):1434‐9. CENTRAL

Caligiuri 1997 {published data only}

Caligiuri MP, Lohr JB, Rotrosen J, Adler L, Lavori P, Edson R, et al. Reliability of an instrumental assessment of tardive dyskinesia: results from VA cooperative study 394. Psychopharmacology 1997;132(1):61‐6. CENTRAL

CARET 1996 {published data only}

Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta‐carotene and vitamin A on lung cancer and cardiovascular disease. New England Journal of Medicine 1996;334(18):1150‐5. CENTRAL

CARMIS 2011 {published data only}

Piermarocchi S, Saviano S, Parisi V, Tedeschi M, Panozzo G, Scarpa G, et al. Carotenoids in age‐related maculopathy Italian study (CARMIS): two‐year results of a randomized study. European Journal of Ophthalmology 2011;22(2):216‐25. CENTRAL

CCSG 1993 {published data only}

Roncucci L, Di Donato P, Carati L, Ferrari A, Perini M, Bertoni G, et al. Antioxidant vitamins or lactulose for the prevention of the recurrence of colorectal adenomas. Colorectal Cancer Study Group of the University of Modena and the Health Care District 16. Diseases of the Colon and Rectum 1993;36(3):227‐34. CENTRAL

Chandra 1992 {published data only}

Chandra RK. Effect of vitamin and trace‐element supplementation on immune responses and infection in elderly subjects. Lancet 1992;340(8828):1124‐7. CENTRAL

CHAOS 1996 {published data only}

Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge heart antioxidant study (CHAOS). Lancet 1996;347(9004):781‐6. CENTRAL

Clausen 1989 {published data only}

Clausen J, Nielsen SA, Kristensen M. Biochemical and clinical effects of an antioxidative supplementation of geriatric patients. A double blind study. Biological Trace Element Research 1989;20(1‐2):135‐51. CENTRAL

Constans 1996 {published data only}

Constans J, Delmas Beauvieux MC, Sergeant C, Peuchant E, Pellegrin JL, Pellegrin I, et al. One‐year antioxidant supplementation with beta‐carotene or selenium for patients infected with human immunodeficiency virus: a pilot study. Clinical Infectious Diseases 1996;23(3):654‐6. CENTRAL

Constantino 1988 {published data only}

Costantino JP, Kuller LH, Begg L, Redmond CK, Bates MW. Serum level changes after administration of a pharmacologic dose of beta‐carotene. American Journal of Clinical Nutrition 1988;48(5):1277‐83. CENTRAL

Cucinotta 1994 {published data only}

Cucinotta D, Senin U, Girardello R, Crepaldi G. Posatirelin effect on patients with senile dementia of Alzheimer type (SDAT): a double blind multicentre trial versus ascorbic acid and citicoline. Journal of Neurology 1994;241:S129. CENTRAL

DATATOP 1989 {published data only}

Shoulson I, Fahn S, Oakes D, Lang A, Langston JW, LeWitt P, et al. DATATOP: A multicenter controlled clinical trial in early Parkinson's disease. Archives of Neurology 1989;46(10):1052‐60. CENTRAL

DeCosse 1989 {published data only}

DeCosse JJ, Miller HH, Lesser ML. Effect of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. Journal of the National Cancer Institute 1989;81(17):1290‐7. CENTRAL

De Klerk 1998 {published data only}

De Klerk NH, Musk AW, Ambrosini GL, Eccles JL, Hansen J, Olsen N, et al. Vitamin A and cancer prevention II: comparison of the effects of retinol and beta‐carotene. International Journal of Cancer 1998;75:362‐7. CENTRAL

Dobson 1984 {published data only}

Dobson HM, Muir MM, Hume R. The effect of ascorbic acid on the seasonal variations in serum cholesterol levels. Scottish Medical Journal 1984;29(3):176‐82. CENTRAL

ECP‐IM 1995 {published data only}

Reed PI, Johnston BJ. Primary prevention of gastric cancer ‐ The ECP‐IM intervention study. Acta Endoscopica 1995;25:45‐54. CENTRAL

EUROSCAN 1994 {published data only}

Cianfriglia F, Iofrida RV, Calpicchio A, Manieri A. The chemoprevention of oral carcinoma with vitamin A and/or N‐acetylcysteine. Minerva Stomatologica 1994;43(6):255‐61. CENTRAL

Fairley 1996 {published data only}

Fairley CK, Tabrizi SN, Chen S, Baghurst P, Young H, Quinn M, et al. A randomized clinical trial of beta carotene vs placebo for the treatment of cervical HPV infection. International Journal of Gynecological Cancer 1996;6(3):225‐30. CENTRAL

Falsani 2010 {published data only}

Falsini B, Piccardi M, Minnella A, Savastano C, Capoluongo E, Fadda A, et al. Influence of saffron supplementation on retinal flicker sensitivity in early age‐related macular degeneration. Investigative Ophthalmology and Visual Science 2010;51(12):6118‐24. CENTRAL

Fontham 1995 {published data only}

Fontham ET, Malcom GT, Singh VN, Ruiz B, Schmidt B, Correa P. Effect of beta‐carotene supplementation on serum alpha‐tocopherol concentration. Cancer Epidemiology, Biomarkers and Prevention 1995;4(7):801‐3. CENTRAL

Galan 1997 {published data only}

Galan P, Preziosi P, Monget AL, Richard MJ, Arnaud J, Lesourd B, et al. Effects of trace element and/or vitamin supplementation on vitamin and mineral status, free radical metabolism and immunological markers in elderly long term‐hospitalized subjects. Geriatric Network MIN. VIT. AOX. International Journal for Vitamin and Nutrition Research 1997;67(6):450‐60. CENTRAL

Garawal 1995 {published data only}

Garewal H, Meyskens F, Katz RV, Friedman S, Morse DE, Alberts D, et al. Beta‐carotene produces sustained remissions in oral leukoplakia: results of a 1 year randomized, controlled trial. Proceedings of the Annual Meeting of the American Society of Clinical Oncology. 1995; Vol. 14:ABS. A1623. CENTRAL

GISSI 1993 {published data only}

Marchioli R, Di Pasquale A. The biochemical, pharmacological and epidemiological reference picture of the GISSI‐Prevention. The Gruppo Italiano per lo studio della Streptochinasi nell'Infarto miocardico [Il quadro di riferimento biochimico, farmacologico, epidemiologico del GISSI‐Prevenzione]. Giornale Italiano di Cardiologia 1993;23(9):933‐64. CENTRAL

HOPE 1996 {published data only}

Gerstein HC, Bosch J, Pogue J, Taylor DW, Zinman B, Yusuf S. Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high‐risk patients with diabetes. The MICRO‐HOPE Study. Microalbuminuria, cardiovascular, and renal outcomes. Heart outcomes prevention evaluation. Diabetes Care 1996;19(11):1225‐8. CENTRAL

Johnson 1997 {published data only}

Johnson MA, Porter KH. Micronutrient supplementation and infection in institutionalized elders. Nutrition Review 1997;55(11):400‐4. CENTRAL

Jyothirmayi 1996 {published data only}

Jyothirmayi R, Ramadas K, Varghese C, Jacob R, Nair MK, Sankaranarayanan R. Efficacy of vitamin A in the prevention of loco‐regional recurrence and second primaries in head and neck cancer. European Journal of Cancer Part B Oral Oncology 1996;32B(6):373‐6. CENTRAL

Kuklinski 1994 {published data only}

Kuklinski B, Weissenbacher E, Fahnrich A. Coenzyme Q10 and antioxidants in acute myocardial infarction. Molecular Aspects of Medicine 1994;Supplement:S143‐7. CENTRAL

Kvansakul 2006 {published data only}

Kvansakul J, Rodriguez‐Carmona M, Edgar DF, Barker FM, Kopcke W, Schalch W, et al. Supplementation with the carotenoids lutein or zeaxanthin improves human visual performance. Ophthalmic and Physiological Optics 2006;26(4):362‐71. CENTRAL

Leng 1997 {published data only}

Leng GC, Lee AJ, Fowkes FG, Horrobin D, Jepson RG, Lowe GD, et al. Randomized controlled trial of antioxidants in intermittent claudication. Vascular Medicine 1997;2(4):279‐85. CENTRAL

Li 1992 {published data only}

Li WG. Preliminary observations on effect of selenium yeast on high risk populations with primary liver cancer. Chung Hua Yu Fang I Hsueh Tsa Chih ‐ Chinese Journal of Preventive Medicine 1992;26(5):268‐71. CENTRAL

LINXIAN 1993 {published data only}

Li JY, Li B, Blot WJ, Taylor PR. Preliminary report on the results of nutrition prevention trials of cancer and other common diseases among residents in Linxian, China. Chung Hua Chung Liu Tsa Chih ‐ Chinese Journal of Oncology 1993;15(3):165‐81. CENTRAL
Sperduto RD, Hu TS, Milton RC, Zhao JL, Everett DF, Cheng QF, et al. The Linxian cataract studies. Two nutrition intervention trials. Archives of Ophthalmology 1993;111(9):1246‐53. CENTRAL

Mayne 1998 {published data only}

Mayne ST, Cartmel B, Silva F, Kim CS, Fallon BG, Briskin K, et al. Effect of supplemental beta‐carotene on plasma concentrations of carotenoids, retinol, and alpha‐tocopherol in humans. American Journal of Clinical Nutrition 1998;68(3):642‐7. CENTRAL

McKeown 1988 {published data only}

McKeown Eyssen G, Holloway C, Jazmaji V, Bright See E, Dion P, Bruce WR. A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. Cancer Research 1988;48(16):4701‐5. CENTRAL

Meyskens 1994 {published data only}

Meyskens FL, Liu PY, Tuthill RJ, Sondak VK, Fletcher WS, Jewell WR, et al. Randomized trial of vitamin A versus observation as adjuvant therapy in high‐risk primary malignant melanoma: a Southwest oncology group study. Journal of Clinical Oncology 1994;12(10):2060‐5. CENTRAL

Munoz 1987 {published data only}

Munoz N, Wahrendorf J, Bang LJ, Crespi M, Thurnham DI, Day NE, et al. No effect of riboflavine, retinol, and zinc on prevalence of precancerous lesions of oesophagus. Randomised double‐blind intervention study in high‐risk population of China. Lancet 1985;2(8447):111‐4. CENTRAL

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Munoz N, Vivas J, Buiatti E, Kato I, Oliver W. Chemoprevention trial on precancerous lesions of the stomach in Venezuela: summary of study design and baseline data. IARC Scientific Publications 1996;139:125‐33. CENTRAL

Nambour 1995 {published data only}

Ambler JS, Hirst LW, Clarke CV, Green AC. The Nambour study of ocular disease. I. Design, study population and methodology. Ophthalmic Epidemiology 1995;2(3):137‐44. CENTRAL

NCT00000161 (WAFACS) {published data only}

NCT00000161. Randomized trials of vitamin supplements and eye disease. clinicaltrials.gov/ct2/show/NCT00000161 (accessed 7 February 2008). CENTRAL

NCT00718653 {published data only}

NCT00718653. Effects of antioxidants on human macular pigments. clinicaltrials.gov/ct2/show/NCT00718653 (accessed 21 September 2010). CENTRAL

NCT00893724 {published data only}

NCT00893724. Supplemental adjuvants for intracellular nutrition and treatment (SAINTS). clinicaltrials.gov/ct2/show/NCT00893724 (accessed 20 March 2012). CENTRAL

NCT01208948 {published data only}

NCT01208948. Clinical trial on alpha lipoic acid in diabetic macular edema (RETIPON). clinicaltrials.gov/ct2/show/NCT01208948 (accessed 17 January 2012). CENTRAL

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Newsome DA. A randomized, prospective, placebo‐controlled clinical trial of a novel zinc‐monocysteine compound in age‐related macular degeneration. Current Eye Research 2008;33(7):591‐8. CENTRAL

NPCSG 1996 {published data only}

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Peng YM, Peng YS, Lin Y, Moon T, Baier M. Micronutrient concentrations in paired skin and plasma of patients with actinic keratoses: effect of prolonged retinol supplementation. Cancer Epidemiology, Biomarkers and Prevention 1993;2(2):145‐50. CENTRAL

PPP 1996 {published data only}

Primary prevention project (PPP) in the Mario Negri Institute in Milan. Ricerca E Pratica 1996;12:175‐218. CENTRAL

PPSG 1994 {published data only}

Greenberg ER, Baron JA, Tosteson TD, Freeman DH, Beck GJ, Bond JH, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. New England Journal of Medicine 1994;331(3):141‐7. CENTRAL

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Prasad MP, Mukundan MA, Krishnaswamy K. Micronuclei and carcinogen DNA adducts as intermediate end points in nutrient intervention trial of precancerous lesions in the oral cavity. European Journal of Cancer Part B Oral Oncology 1995;31B(3):155‐9. CENTRAL

REACT 1995 {published data only}

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Steiner M, Glantz M, Lekos A. Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. American Journal of Clinical Nutrition 1995;62(6 Suppl):1381S‐4S. CENTRAL

SUVIMAX 1997 {published data only}

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SWSCPSG 1997 {published data only}

Levine N, Moon TE, Cartmel B, Bangert JL, Rodney S, Dong Q, et al. Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double‐blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiology, Biomarkers and Prevention 1997;6(11):957‐61. CENTRAL

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Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML. Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids 1995;30(12):1179‐83. CENTRAL

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Tsubono Y, Okubo S, Hayashi M, Kakizoe T, Tsugane S. A randomized controlled trial for chemoprevention of gastric cancer in high‐risk Japanese population; study design, feasibility and protocol modification. Japanese Journal of Cancer Research 1997;88(4):344‐9. CENTRAL

Wahlqvist 1994 {published data only}

Wahlqvist ML, Wattanapenpaiboon N, Macrae FA, Lambert JR, MacLennan R, Hsu Hage BH. Changes in serum carotenoids in subjects with colorectal adenomas after 24 mo of beta‐carotene supplementation. Australian Polyp Prevention Project Investigators. American Journal of Clinical Nutrition 1994;60(6):936‐43. CENTRAL

Wong 2010 {published data only}

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Wright 1985 {published data only}

Wright JP, Mee AS, Parfitt A, Marks IN, Burns DG, Sherman M, et al. Vitamin A therapy in patients with Crohn's disease. Gastroenterology 1985;88(2):512‐4. CENTRAL

Yu 1991 {published data only}

Yu SY, Zhu YJ, Li WG, Huang QS, Huang CZ, Zhang QN, et al. A preliminary report on the intervention trials of primary liver cancer in high‐risk populations with nutritional supplementation of selenium in China. Biological Trace Element Research 1991;29(3):289‐94. CENTRAL

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Yu SY, Mao BL, Xiao P, Yu WP, Wang YL, Huang CZ, et al. Intervention trial with selenium for the prevention of lung cancer among tin miners in Yunnan, China. A pilot study. Biological Trace Element Research 1990;24(2):105‐8. CENTRAL

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Zaridze D, Evstifeeva T, Boyle P. Chemoprevention of oral leukoplakia and chronic esophagitis in an area of high incidence of oral and esophageal cancer. Annals of Epidemiology 1993;3(3):225‐34. CENTRAL

NCT01269697 (LIMPIA) {published data only}

NCT01269697. Lutein influence on macula of persons issued from AMD parents (LIMPIA). clinicaltrials.gov/ct2/show/NCT01269697 (accessed 6 April 2012). CENTRAL

SELECT {published data only}

Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E cancer prevention trial (SELECT). JAMA 2009;301(1):39‐51. CENTRAL

WACS {unpublished data only}

Manson JE, Gaziano JM, Spelsberg A, Ridker PM, Cook NR, Buring JE, et al. A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women. Rationale, design, and methods. The WACS Research Group. Annals of Epidemiology 1995;5(4):261‐9. CENTRAL

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ATBC 1994

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

ATBC 1998

Methods

Method of allocation: random. Sponsor provided coded capsules.

Masking: participant: yes; provider: yes; outcome: yes

Exclusions after randomisation: no

Losses to follow‐up: 31%. Random sample for maculopathy study: 9%.
2 x 2 factorial design. Maculopathy add‐on random sample in 2 regions.

Participants

Country: Finland

Number of participants randomised: 29,133. Random sample of 1035 selected for maculopathy study.

Age: 50 to 69 years in 1984. Maculopathy study 1992‐3 in people aged 65 plus.

Sex: male

Inclusion criteria: 5 or more cigarettes daily

Exclusion criteria: history of cancer or serious disease limiting ability to participate; those taking supplements vitamin E, A, or beta‐carotene in excess of predefined doses; those treated with anticoagulants

Interventions

Intervention:

  • alpha‐tocopherol (50 mg/day) N = 237

  • beta‐carotene (20 mg/day) N = 234

  • alpha‐tocopherol (50 mg/day) and beta‐carotene (20 mg/day) N = 257

Comparator:

  • placebo N = 213

Duration: 5 to 8 years (median 6.1)

Outcomes

AMD: 4 grades:
Grade I: dry maculopathy with hard drusen, pigmentary changes, or both
Grade II: soft macular drusen
Grade III: disciform degeneration
Grade IV: geographic atrophy

Quote "A person was considered to have ARM if he had a class I or higher change in either
eye, and severity was classified according to the worst eye."

Notes

Compliance with treatment excellent; 4/5 active participants took more than 95% of scheduled capsules. Drop‐out rate and compliance similar between all 4 groups.

Funding source: Quote "This study was supported by the Juho Vainio Foundation, Helsinki, Finland. The ATBC study was supported by Public Health Service Contract N01‐CN‐45165 from the Division of Cancer Prevention and Control, National Cancer Institute of the United States."

Declarations of interest: NR

Date study conducted: Quote "The ophthalmological examination took place during their final follow‐up trial visit between December 1992 and March 1993"

Trial id: NCT00342992

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote "The participants were randomly assigned to one of four treatment groups: AT alone, AT and BC, BC alone, or placebo in a complete 2 x 2 factorial design" and "Randomization was performed in blocks of eight within each of the study areas."

Allocation concealment (selection bias)

Low risk

Quote "A coded reserve supply of capsule packs..."

Not clearly stated that allocation concealed, but the study was described as being "double‐blind"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement comment: placebo‐controlled study.

Blinding of outcome assessment (detection bias)
AMD

Low risk

Quote "The retinal specialist [...] examined six photographs (three per eye) of each participant without knowledge of the subject's treatment group"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote "A total of 941 persons participated (91%) and non‐participation rates were similar across the intervention groups."

Selective reporting (reporting bias)

Unclear risk

Visual acuity measured but not reported, but as the main results for AMD showed no difference between groups, it is not clear whether this was an example of selective reporting or whether, in fact, the investigators considered that visual acuity in this age group might be attributed to a variety of causes, and therefore, was not a relevant outcome.

PHS I 2007

Methods

Method of allocation: coded tablets

Masking: participant: yes; provider: yes; outcome: yes

99% follow‐up

2 x 2 factorial design.

Participants

Country: USA

Number randomised: originally 22,071 men were randomised:
21,142 participants were followed up for at least 7 years and provided information on diagnoses of AMD made during the first 7 years of the trial

Age: 40 to 84 years in 1982

Sex: male

Inclusion criteria: physician aged 40 to 84 years in 1982 with no history of cancer, myocardial infarction, stroke, or transient cerebral ischaemia

Exclusion criteria: personal history of cardiovascular disease or cancer; contraindications or current use of study medication;

Interventions

Intervention:

  • beta‐carotene (50 mg/alternate days) N = 11,036 randomised, 10,585 followed up

Comparator:

  • beta‐carotene placebo N = 11,035 randomised, 10,557 followed up

There was also an aspirin arm (2 x 2 factorial arm), which was terminated early (January 1988)

Mean duration 12 years range (range 11.6 to 14.2 years)

Outcomes

Self report of AMD followed by medical record review and questionnaire to relevant ophthalmologist

Primary endpoint: visually significant AMD, defined as a self‐report confirmed by medical record evidence of an initial diagnosis after randomisation, but before 31 December 1995, with a reduction in best‐corrected visual acuity to 20/30 or worse attributable to AMD

Secondary endpoints: AMD with or without vision loss, composed of all incident cases; Advanced AMD, encompassed of cases of visually significant AMD with pathological signs of disciform scar, RPE detachment, geographic atrophy, or subretinal neovascular membrane

Quote "Individuals, rather than eyes, were the unit of analysis because eyes were not examined independently, and participants were classified according to the status of the worse eye as defined by disease severity. When the worse eye was excluded because of visual acuity loss attributed to other ocular abnormalities the fellow eye was considered for classification."

Notes

Funding source: Quote "Supported by research grants HL 26490, HL 34595, CA 34944, CA 40360, and EY 06633 from the National Institutes of Health"

Declarations of interest: NR

Date study conducted: August 1985 (from clinicaltrials.gov) to December 1995

Trial id: NCT00000500

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote "The PHS I was a randomised, double‐masked, placebo controlled trial..."

"A total of 22,071 physicians were then randomised according to a two‐by‐two factorial design, with use of a computer‐generated list of random numbers..."

Allocation concealment (selection bias)

Low risk

Quote "The PHS I was a randomised, double‐masked, placebo controlled trial..."

Judgement Comment: Although this aspect of the trial was not well described, the placebo control was described (placebo and supplement identical appearance and packaging) and the study was described as double‐blind

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote "The PHS I was a randomised, double‐masked, placebo controlled trial..."

Judgement Comment: Although this aspect of the trial was not well described, the placebo control was described (placebo and supplement identical appearance and packaging) and the study was described as double‐blind

Blinding of outcome assessment (detection bias)
AMD

Low risk

Quote "The PHS I was a randomised, double‐masked, placebo controlled trial..."

Judgement Comment: Although this aspect of the trial was not well described, the placebo control was described and the study was described as double‐blind. Diagnosis of AMD by self‐report based on health questionnaire (confirmed by ophthalmologist or optometrist). Patients and researchers unaware of intervention.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote "At the end of 11 years of follow‐up (the last year completed for all participants), 99.2% were still providing information on morbidity, and the follow‐up for mortality was 99.9% complete. Eighty percent of participants in the beta‐carotene group and in the placebo group were still taking the study pills, with a mean compliance among pill takers of more than 97%. Therefore, even after 11 years, 78% of the study pills assigned in the beta‐carotene group were reported as still being taken. In the placebo group, 6% of participants reported taking supplemental beta carotene or vitamin A."

Selective reporting (reporting bias)

Low risk

Judgement comment: reported AMD outcomes as expected

PHS II 2012

Methods

Method of allocation: coded tablets

Masking: participant: yes; provider: yes; outcome: yes

95% follow‐up

2 x 2 x 2 x 2 factorial design.

Participants

Country: USA

Number randomised: 14,236 with no diagnosis of AMD at baseline according to vitamin C/E paper; 14,233 with no diagnosis of AMD at baseline according to multivitamin paper.

Average age: 64 years

Sex: male

Inclusion criteria: US male physicians; 50 years and older; participants in PHS I and new physician participants; willing to forego use of supplements for new trial; for new participants, do not report personal history of cancer (except non‐melanoma skin cancer). CVD, current liver disease, current renal disease, peptic ulcer or gout. Compliance with pill‐taking regimen in run‐in period.

Exclusion criteria:History of cirrhosis; active liver disease in past six months; participants reporting cataract or AMD at baseline.

Interventions

Intervention:

  • vitamin E (400 IU/alternate days) N = 7112

  • vitamin C (500 mg/day) N = 7149

  • multivitamin (Centrum silver: zinc 15 mg, vitamin E 45 IU, vitamin C 60 mg, beta‐carotene 5000 IU, vitamin A ‐ 20% as beta carotene, folic acid 2.5 mg, vitamin B6 50 mg, vitamin B12 1 mg/ day) N = 7111

Comparator:

  • separate placebos for each type of vitamin: vitamin E placebo N = 7124, vitamin C placebo N = 7087, multivitamin placebo N = 7122

Alternate day beta‐carotene (50 mg) component terminated in March 2003.

Lutein (added to Centrum Silver during course of study (250 µg) and doses of other nutrients changed

Follow‐up: the multivitamin component had a longer duration.

"An average of 8 years of treatment and follow‐up" for vitamin E and vitamin C

Median duration of treatment for multivitamin analyses 11.2 years, IQR 10.7 to 13.3

Outcomes

Age‐related macular degeneration: reported diagnosis followed up by contact with treating ophthalmologist/optometrist

Quote "We considered individuals, rather than eyes, as the unit of analysis and we classified individuals according to the status of the worse eye as defined by disease severity. When the worse eye was excluded because of visual acuity loss attributed to other ocular abnormalities, the fellow eye was considered for classification."

Notes

Funding source: Grants from National Eye Institute, National Institute on Ageing and the National Institutes of Health. BASF and DSM provided study agents and packaging.

Declarations of interest: "The authors have no proprietary or commercial interest in any of the materials discussed in this article."

Date study conducted: July 1997 to June 2011 (from clinicaltrials.gov)

Trial id: NCT00270647

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote "Randomisation to the other agents, using a computer generated list of random numbers, will be stratified according to age"

Allocation concealment (selection bias)

Low risk

Judgement comment: central randomisation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote "The Physicians’ Health Study (PHS II) was a randomised, double‐blind, placebo‐controlled, factorial trial evaluating a daily multivitamin (Centrum Silver), alternate day vitamin E (400 IU synthetic α‐tocopherol), and daily vitamin C (500 mg synthetic ascorbic acid) in the prevention of cancer and CVD among 14,641 male physicians aged 50 years and older."

Blinding of outcome assessment (detection bias)
AMD

Low risk

Quote "Random misclassification was reduced by the use of medical records to confirm the participant reports. Non‐random misclassification was unlikely since medical records were reviewed by an investigator (WGC) masked to treatment assignment, and study participants and treating ophthalmologists and optometrists were similarly unaware of treatment assignment."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote "Morbidity and mortality follow‐up were extremely high, at 95.3% and 97.9%, respectively."

Selective reporting (reporting bias)

Low risk

Judgement comment: reported AMD outcomes as expected

VECAT 2002

Methods

Method of allocation: coded bottles

Masking: participant: yes; provider: yes; outcome: yes

Losses to follow‐up: not known

Participants

Country: Australia

Number of participants randomised: 1204

Eyes: worse eye used as the study eye

Age: 55 to 80 years, mean 66

Sex: 56% female

Inclusion criteria: lens and retina of at least one eye available for documentation

Exclusion criteria: previous cataract surgery or advanced cataract in both eyes; steroid or anticoagulation use; serious disease; regular use or sensitivity to vitamin E

Interventions

Intervention:

  • vitamin E (500 IU/day) natural vitamin E in soybean oil medium N = 595 randomised, 587 followed up

Comparator:

  • placebo identical in sight, taste and smell N = 598 randomised, 592 followed up

Duration: 4 years

Outcomes

2 m logMAR visual acuity; clinical examination; colour stereoscopic fundus photographs graded using International Grading Scheme

Quote "Participants were categorised by their worse eye."

Notes

Funding source: Quote "The VECAT study was funded in part by grants from the National Health and Medical Research Council, the Jack Brockhoff Foundation, the Eirene Lucas Foundation, the Stoicesco Foundation, the Carleton Family Charitable Trust, JeHope Knell Trust Fund, Smith and Nephew, Australia, and Henkel Australia".

Declarations of interest: none declared

Date study conducted: January 1995 to April 1996

Trial id: NR

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote "This random allocation was performed by using a “permuted blocks” allocation scheme"

Allocation concealment (selection bias)

Low risk

Quote "Study numbers were allocated sequentially by the study coordinator as participants were enrolled in the study. Participants were then randomly allocated to treatment group. The allocation list was stored at a remote site."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote "Participants randomly received either 500 IU natural vitamin E (335 mg d­á tocopherol) in a soybean oil suspension encapsulated in gelatin or a matched placebo capsule containing only the soybean oil." [...] "Bulk medications were dispensed into labelled jars by a person not involved in the study. Vitamin E and placebo were dispensed on different days to avoid confusion. Identical containers were used. The jars were packed in numerical order and then dispensed by study personnel. Vitamin E and placebo capsules were of identical appearance and taste. Neither study staff nor examiners or participants were aware of the treatment allocation, although all knew that participants would be randomly assigned to receive either vitamin E or placebo."

Blinding of outcome assessment (detection bias)
AMD

Low risk

Quote "Neither study staff nor examiners or participants were aware of the treatment allocation, although all knew that participants would be randomly assigned to receive either vitamin E or placebo." "At the end of the study we reassessed the initial and final photographs for any change with a “side by side” comparison in a masked and randomised fashion".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote "From the 1906 people who were screened by telephone, 1289 (69%) were examined and 1204 (93%) of these were enrolled and randomised. We excluded 11 participants after randomisation as they were outside the required age range at enrolment."

"In the vitamin E group, eight people were excluded from final data analysis: six developed diabetic retinopathy, one had myopic degeneration, and one had missing data. Six people were excluded from the placebo group: two developed adult vitelliform macular degeneration and four had missing data."

Figure 3: 1204 randomised, 11 excluded after randomisation, 14 excluded from analysis: 8/595 vitamin E group and 6/598 placebo group.

Selective reporting (reporting bias)

Low risk

Judgement comment: AMD incidence and progression reported but no difference between groups; visual acuity not reported but "Analysis of best corrected visual acuity and visual function data showed no differences between the groups (data not shown)." Therefore, no evidence that outcomes with "better" results selectively reported.

WHS 2010

Methods

Method of allocation: random allocation of coded bottles

Masking: participant: yes; provider: yes; outcome: yes

Losses to follow‐up: not known

Participants

Country: USA

Number of participants randomised: 39,876 women health professionals

Age: 45+

Sex: female

Inclusion/exclusion criteria: (a) Female; (b) aged 45 years or older; (c) postmenopausal or with no intention of becoming pregnant; (d) no reported personal history of cardiovascular disease, cancer (other than non‐melanoma skin cancer), gout, peptic ulcer, chronic renal or liver disease, or other serious illness precluding participation; (e) no reported history of serious side effects to the study treatments; (f) not currently taking aspirin, aspirin containing medication, or nonsteroidal anti‐inflammatory drugs (NSAIDs) more than 1 day per week or, if so doing, willing to forego use of these medications; (g) not currently taking individual supplements of vitamin E or beta‐carotene more than 1 day per week; (h) not currently taking anticoagulants or corticosteroids

Interventions

Intervention:

  • vitamin E (600 IU on alternate days) N = 19,697

Comparator:

  • placebo N = 19,724

Outcomes

Self‐report and review of medical records

Quote "Individuals, rather than eyes, were the unit of analysis because eyes were not examined independently, and participants were classified according to the status of the worse eye as defined by disease severity. When the worse eye was excluded because of visual acuity loss attributed to other ocular abnormalities, the fellow eye was considered for classification."

Notes

Funding source: Quote "Supported by research grants CA 47988, HL 43851, and EY 06633 from the National Institutes of Health, Bethesda, Md. Pills and packaging were provided by Bayer Healthcare and the Natural Source Vitamin E Association. Bayer Healthcare and the Natural Source Vitamin E Association had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript."

Declarations of interest: Quote "The authors have no proprietary or commercial interest in any materials discussed in this article."

Date study conducted: August 1993 to March 2004

Trial id: NCT00000161

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote "The WHS was a randomised, double‐blind, placebo‐controlled, 2 x 2 factorial trial..." "Randomization used blocks of size 16 within 5‐year age strata and took place from April 30, 1993, through January 24, 1996."

Allocation concealment (selection bias)

Low risk

Quote "The WHS was a randomised, double‐blind, placebo‐controlled, 2 x 2 factorial trial..."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote "Study medications and end‐point ascertainment were continued in a blinded fashion through the scheduled end of the trial (March 31, 2004)." "Pill taking and end point ascertainment were continued in blinded fashion through the scheduled end of the trial on March 31, 2004. Morbidity and mortality follow‐up were 97.2% and 99.4% complete, respectively."

Blinding of outcome assessment (detection bias)
AMD

Low risk

Quote "Study medications and end‐point ascertainment were continued in a blinded fashion through the scheduled end of the trial (March 31, 2004)." "Pill taking and end point ascertainment were continued in blinded fashion through the scheduled end of the trial on March 31, 2004. Morbidity and mortality follow‐up were 97.2% and 99.4% complete, respectively."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote "Compliance (defined as taking at least two thirds of the study capsules) was 78.9% at 5 years and 71.6% at 10 years, and averaged 75.8% throughout the trial."

"Pill taking and end point ascertainment were continued in blinded fashion through the scheduled end of the trial on March 31, 2004. Morbidity and mortality follow‐up were 97.2% and 99.4% complete, respectively."

Follow‐up balanced across treatment groups. See figure 1.

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting. The outcome was limited to the study design ‐ medical record review. Primary and secondary outcomes were apparently defined a priori and were reported.

AMD: age‐related macular degeneration
ETDRS: Early Treatment Diabetic Retinopathy Study
IU: international units
RPE: retinal pigment epithelium

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

ADSC 1997

No published data on AMD. No response from author.

Andrews 1969

No published data on AMD. Unable to contact author.

AREDS 2001

Age‐related maculopathy outcomes for people without age‐related maculopathy at baseline were not reported

AREDS2 2008

Participants had AMD

Benner 1994

No published data on AMD. No response from author.

Benton 1995

No data on AMD collected

Berrow 2016

No data on AMD collected

Blok 1997

No data on AMD collected

Bogden 1990

No published data on AMD. No response from author.

Bone 2010

Biological availability study only

Brewer 1997

No published data on AMD. No response from author.

Brown 1998

No published data on AMD. No response from author.

Bussey 1982

No published data on AMD. No response from author.

Caligiuri 1997

No published data on AMD. No response from author.

CARET 1996

No data on AMD collected

CARMIS 2011

Study on people with AMD (non‐advanced AMD), therefore, not on prevention in healthy people

CCSG 1993

No published data on AMD. No response from author.

Chandra 1992

No published data on AMD. No response from author.

CHAOS 1996

No data on AMD collected

Clausen 1989

No published data on AMD. No response from author.

Constans 1996

No published data on AMD. No response from author.

Constantino 1988

No data on AMD collected

Cucinotta 1994

No published data on AMD. No response from author.

DATATOP 1989

No published data on AMD. Unable to contact author.

De Klerk 1998

No data on AMD collected

DeCosse 1989

No published data on AMD. No response from author

Dobson 1984

No data on AMD collected

ECP‐IM 1995

No published data on AMD. No response from author.

EUROSCAN 1994

No published data on AMD. No response from author.

Fairley 1996

No published data on AMD. No response from author.

Falsani 2010

Participants had early AMD

Fontham 1995

No data on AMD collected

Galan 1997

No published data on AMD. No response from author.

Garawal 1995

No published data on AMD. No response from author.

GISSI 1993

No published data on AMD. No response from author.

HOPE 1996

No data on AMD collected

Johnson 1997

No published data on AMD. No response from author.

Jyothirmayi 1996

No published data on AMD. No response from author.

Kuklinski 1994

No published data on AMD. No response from author.

Kvansakul 2006

No AMD outcomes

Leng 1997

No published data on AMD. Unable to contact author.

Li 1992

No published data on AMD. No response from author.

LINXIAN 1993

No published data on AMD. No response from author.

Mayne 1998

No data on AMD collected

McKeown 1988

No data on AMD collected

Meyskens 1994

No published data on AMD. No response from author.

Munoz 1987

No published data on AMD. No response from author.

Munoz 1996

No published data on AMD. No response from author.

Nambour 1995

No follow‐up data on AMD collected

NCT00000161 (WAFACS)

Reported on folic acid, pyridoxine and cyanocobalamin combination treatment

NCT00718653

Study of macular pigment only

NCT00893724

Study on people with AMD

NCT01208948

No AMD outcomes

Newsome, 2008

Study on people with AMD

NPCSG 1996

No published data on AMD. No response from author.

Pastorino 1991

No published data on AMD. No response from author.

Pemp 2010

Study of ocular blood flow and endothelial function only in model of oxidative stress in health volunteers

Peng 1993

No published data on AMD. No response from author.

PPP 1996

No published data on AMD. No response from author.

PPSG 1994

No data on AMD collected

Prasad 1995

No published data on AMD. No response from author.

REACT 1995

No published data on AMD. No response from author.

Recchia 1995

No published data on AMD. No response from author.

Rein 2007

Study not a randomised controlled trial

Ret Pig 1993

No published data on AMD. No response from author

Rodriguez‐Carmona 2006

No AMD outcomes

SCPS 1989

No data on AMD collected

SECURE 1996

No published data on AMD. No response from author.

Shandong 1998

No data on AMD collected

Sharma 1989

No published data on AMD. No response from author.

Steiner 1995

No published data on AMD. No response from author.

SUVIMAX 1997

No published data on AMD. No response from author.

SWSCPSG 1997

No data on AMD collected

Takamatsu 1995

No published data on AMD. No response from author.

Tomeo 1995

No published data on AMD. No response from author.

Tsubono 1997

No data on AMD collected

Wahlqvist 1994

No data on AMD collected

Wong 2010

Participants had geographic atrophy

Wright 1985

No published data on AMD. No response from author.

Yu 1991

No published data on AMD. No response from author.

YUNNAN 1990

No published data on AMD. No response from author.

Zaridze 1993

No published data on AMD. No response from author.

AMD: age‐related macular degeneration

Characteristics of ongoing studies [ordered by study ID]

NCT01269697 (LIMPIA)

Trial name or title

Lutein influence on macula of persons issued from AMD parents

Methods

Multicentre, double‐masked, randomised clinical trial of supplementation with 'Nutrof Total' (lutein and zeaxanthin) versus placebo

Participants

People at high genetic risk for AMD because their parents had AMD. Age 40 to 70 years.

Interventions

Nutrof Total or placebo

Outcomes

Primary outcome measure:

Macular pigment density at 6 months after supplementation 

Secondary outcome measures:

Best corrected visual acuity 12 months

Cognitive ability 12 months 

Plasma fatty acids 12 months

Macular pigment density during supplementation and after stopping supplementation

Starting date

Contact information

Jean‐Francois Korobelnik
jean‐francois.korobelnik@chu‐bordeaux.fr

Notes

clinicaltrials.gov/show/NCT01269697

The principal Investigator was contacted in March 2016 and confirmed that the study should be published in the next year.

SELECT

Trial name or title

Selenium and Vitamin E Cancer Prevention Trial (SELECT) for prostate cancer

Methods

This is a randomised, double‐masked, multi‐centre study. Participants are randomised to one of 4 prevention arms:

Arm I: participants receive 2 different oral placebos once daily

Arm II: participants receive oral selenium and oral placebo once daily

Arm III: participants receive oral vitamin E and oral placebo once daily

Arm IV: participants receive oral selenium and oral vitamin E once daily.

Treatment continues for 7 to 12 years in the absence of unacceptable toxicity or diagnosis of prostate cancer

Quality of life is assessed at baseline and then at 1, 3, 5, and 7 years

Participants are followed annually

Participants

Healthy male volunteers. A total of 32,400 participants (8100 per prevention arm) will be accrued for this study within 5 years

Interventions

Dietary supplement: selenium
Dietary supplement: vitamin E

Outcomes

Primary outcome measures:

Effect on the clinical incidence of cancer
Effect on cancer‐free survival, overall survival and serious cardiovascular events
Quality of life
Association of biological molecular markers with cancer risk
Relationship between effects on cancer risk and genetic factors
Effects in terms of intake of other nutrients, foods and dietary supplements
Effect of other dietary nutrients and dietary patterns on cancer risk
Effects on the reduction of Alzheimer's disease incidence
Reduction in the risk of AMD or cataract

Starting date

July 2001

Contact information

Notes

clinicaltrials.gov/show/NCT00006392

We contacted the principal investigator in March 2016; data collection and analysis of AMD outcomes is still ongoing.

WACS

Trial name or title

Women's Antioxidant Cardiovascular Study

Methods

Participants

8171 female health professionals aged 40+ with pre‐existing cardiovascular disease (CVD) or high risk for developing CVD

Interventions

2 x 2 x 2 x 2 factorial design:

Vitamin E (600 IU on alternate days)

Vitamin C (500 mg daily)

Beta‐carotene (5 mg on alternate days)

Combination of folate (800 mg daily), vitamin B6 (25 mg daily) and vitamin B12 (1 mg daily)

Outcomes

Self‐report and review of medical records

Starting date

1993

Contact information

Notes

clinicaltrials.gov/show/NCT00000541

We contacted the principal investigator in March 2016; no reply as yet.

AMD: age‐related macular degeneration

Data and analyses

Open in table viewer
Comparison 1. Vitamin E versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Any AMD Show forest plot

4

55614

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.90, 1.06]

Analysis 1.1

Comparison 1 Vitamin E versus placebo, Outcome 1 Any AMD.

Comparison 1 Vitamin E versus placebo, Outcome 1 Any AMD.

2 Late AMD (either neovascular AMD or geographic atrophy or both) Show forest plot

4

55614

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [0.89, 1.67]

Analysis 1.2

Comparison 1 Vitamin E versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).

Comparison 1 Vitamin E versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).

3 Neovascular AMD or geographic atrophy separately Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 1.3

Comparison 1 Vitamin E versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.

Comparison 1 Vitamin E versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.

3.1 Neovascular AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Geographic atrophy

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Open in table viewer
Comparison 2. Beta‐carotene versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Any AMD Show forest plot

2

22083

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.88, 1.14]

Analysis 2.1

Comparison 2 Beta‐carotene versus placebo, Outcome 1 Any AMD.

Comparison 2 Beta‐carotene versus placebo, Outcome 1 Any AMD.

2 Late AMD (either neovascular AMD or geographic atrophy or both) Show forest plot

2

22083

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.65, 1.24]

Analysis 2.2

Comparison 2 Beta‐carotene versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).

Comparison 2 Beta‐carotene versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).

3 Neovascular AMD or geographic atrophy separately Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 2.3

Comparison 2 Beta‐carotene versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.

Comparison 2 Beta‐carotene versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.

3.1 Neovascular AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Geographic atrophy

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Open in table viewer
Comparison 3. Vitamin C versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AMD Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 3.1

Comparison 3 Vitamin C versus placebo, Outcome 1 AMD.

Comparison 3 Vitamin C versus placebo, Outcome 1 AMD.

1.1 Any AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Late AMD (either neovascular AMD or geographic atrophy or both)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Open in table viewer
Comparison 4. Multivitamin versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AMD Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 4.1

Comparison 4 Multivitamin versus placebo, Outcome 1 AMD.

Comparison 4 Multivitamin versus placebo, Outcome 1 AMD.

1.1 Any AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Late AMD (either neovascular AMD or geographic atrophy or both)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Vitamin E versus placebo, Outcome 1 Any AMD.
Figures and Tables -
Analysis 1.1

Comparison 1 Vitamin E versus placebo, Outcome 1 Any AMD.

Comparison 1 Vitamin E versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).
Figures and Tables -
Analysis 1.2

Comparison 1 Vitamin E versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).

Comparison 1 Vitamin E versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.
Figures and Tables -
Analysis 1.3

Comparison 1 Vitamin E versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.

Comparison 2 Beta‐carotene versus placebo, Outcome 1 Any AMD.
Figures and Tables -
Analysis 2.1

Comparison 2 Beta‐carotene versus placebo, Outcome 1 Any AMD.

Comparison 2 Beta‐carotene versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).
Figures and Tables -
Analysis 2.2

Comparison 2 Beta‐carotene versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).

Comparison 2 Beta‐carotene versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.
Figures and Tables -
Analysis 2.3

Comparison 2 Beta‐carotene versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.

Comparison 3 Vitamin C versus placebo, Outcome 1 AMD.
Figures and Tables -
Analysis 3.1

Comparison 3 Vitamin C versus placebo, Outcome 1 AMD.

Comparison 4 Multivitamin versus placebo, Outcome 1 AMD.
Figures and Tables -
Analysis 4.1

Comparison 4 Multivitamin versus placebo, Outcome 1 AMD.

Summary of findings for the main comparison. Vitamin E versus placebo

Vitamin E versus placebo

Patient or population: general population
Setting: community
Intervention: vitamin E*
Comparison: placebo

Outcomes

Anticipated absolute effects (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo**

Risk with vitamin E

Any AMD

150 per 1000

146 per 1000
(135 to 159)

RR 0.97
(0.90 to 1.06)

55,614
(4 RCTs)

⊕⊕⊕⊕
HIGH

Average duration of treatment and follow‐up ranged from 4 years to 10 years

Late AMD (either neovascular AMD or geographic atrophy or both)

5 per 1000

6 per 1000
(4 to 8)

RR 1.22
(0.89 to 1.67)

55,614
(4 RCTs)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up ranged from 4 years to 10 years

Neovascular AMD

3 per 1000

11 per 1000
(2 to 51)

RR 3.62
(0.77 to 16.95)

941
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2

Average duration of treatment and follow‐up was 6 years

Geographic atrophy

2 per 1000

6 per 1000
(1 to 57)

RR 2.71
(0.28 to 26.00)

941
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2

Average duration of treatment and follow‐up was 6 years

Quality of life

Not reported

Adverse effects (AE)

⊕⊕⊝⊝
LOW3

Two trials reported similar numbers of AEs in vitamin E and placebo group. Another trial reported excess of haemorrhagic strokes in vitamin E group (39 vs 23 events, hazard ratio 1.74, 95% CI 1.04 to 2.91).

Resource use and costs

Not reported

* Dose of vitamin E used in studies were: 50 mg/day, 400 IU/alternate days, 600 IU/alternate days, and 500 IU/day

**The risk in the placebo group is the median risk in the placebo groups in the included studies. The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for imprecision due to wide confidence intervals i.e. are below 0.8 or above 1.25.

2 Downgraded one level for indirectness (only one trial in male smokers) and downgraded two levels for imprecision as very few cases (10 neovascular AMD, 4 geographic atrophy)

3 Downgraded one level for imprecision due to wide confidence intervals and lower confidence near 1 and downgraded one level for inconsistency as effect only reported by one trial.

Figures and Tables -
Summary of findings for the main comparison. Vitamin E versus placebo
Summary of findings 2. Beta‐carotene versus placebo

Beta‐carotene versus placebo

Patient or population: general population
Setting: community
Intervention: beta‐carotene*
Comparison: placebo

Outcomes

Anticipated absolute effects (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo**

Risk with beta‐carotene

Any AMD

150 per 1000

150 per 1000
(132 to 171)

RR 1.00
(0.88 to 1.14)

22,083
(2 RCTs)

⊕⊕⊕⊕
HIGH

Average duration of treatment and follow‐up was 6 years in one study and 12 years in the other study

Late AMD (either neovascular AMD or geographic atrophy or both)

5 per 1000

5 per 1000
(3 to 6)

RR 0.90
(0.65 to 1.24)

22,083
(2 RCTs)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up was 6 years in one study and 12 years in the other study

Neovascular AMD

3 per 1000

2 per 1000
(1 to 6)

RR 0.61
(0.17 to 2.15)

941
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2

Average duration of treatment and follow‐up was 6 years

Geographic atrophy

2 per 1000

1 per 1000
(0 to 6)

RR 0.31
(0.03 to 2.93)

941
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2

Average duration of treatment and follow‐up was 6 years

Quality of life

Not reported

Adverse effects

⊕⊕⊕⊕
HIGH

Beta‐carotene associated with increased risk of lung cancer in people who smoke.

Resource use and costs

Not reported

* Dose of beta‐carotene used was 20 mg/day in one study and 50 mg/alternate days in the other study.

**The risk in the placebo group is the median risk in the control groups of the four included studies in summary of findings Table for the main comparison. The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for imprecision due to wide confidence intervals i.e. are below 0.8 or above 1.25.

2 Downgraded one level for indirectness (only one trial in male smokers) and downgraded two levels for imprecision as very few cases (10 neovascular AMD, 4 geographic atrophy)

Figures and Tables -
Summary of findings 2. Beta‐carotene versus placebo
Summary of findings 3. Vitamin C versus placebo

Vitamin C versus placebo

Patient or population: general population
Setting: community
Intervention: vitamin C*
Comparison: placebo

Outcomes

Anticipated absolute effects (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo**

Risk with vitamin C

Any AMD

150 per 1000

144 per 1000
(119 to 177)

RR 0.96
(0.79 to 1.18)

14,236
(1 RCT)

⊕⊕⊕⊕
HIGH

Average duration of treatment and follow‐up was 8 years

Late AMD (either neovascular AMD or geographic atrophy or both)

5 per 1000

5 per 1000
(3 to 7)

RR 0.94
(0.61 to 1.46)

14,236
(1 RCT)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up was 8 years

Neovascular AMD

Not reported

Geographic atrophy

Not reported

Quality of life

Not reported

Adverse effects

None reported

Resource use and costs

Not reported

* Dose of vitamin C used was 500 mg/day.

**The risk in the placebo group is the median risk in the control groups of the four included studies in summary of findings Table for the main comparison. The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for imprecision due to wide confidence intervals i.e. are below 0.8 or above 1.25.

Figures and Tables -
Summary of findings 3. Vitamin C versus placebo
Summary of findings 4. Multivitamin versus placebo

Multivitamin versus placebo for preventing AMD

Patient or population: general population
Setting: community
Intervention: multivitamin*
Comparison: placebo

Outcomes

Anticipated absolute effects (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo**

Risk with multivitamin

Any AMD

150 per 1000

182 per 1000
(153 to 215)

RR 1.21
(1.02 to 1.43)

14,233
(1 RCT)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up was 11 years

Late AMD

5 per 1000

6 per 1000
(4 to 8)

RR 1.22
(0.88 to 1.69)

14,233
(1 RCT)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up was 11 years

Neovascular AMD

Not reported

Geographic atrophy

Not reported

Quality of life

Not reported

Adverse effects

⊕⊕⊕⊝
MODERATE 1

"Those taking the active versus placebo multivitamin were more likely to have skin rashes (2111 and 1973 men in corresponding active and placebo multivitamin groups; HR 1.08, 95% CI 1.01 to 1.15; P = 0.016)". PHS II

Resource use and costs

Not reported

* Multivitamin used was Centrum Silver (zinc 15 mg, vitamin E 45 IU, vitamin C 60 mg, beta‐carotene 5000 IU vitamin A, 20% as beta carotene, folic acid 2.5 mg, vitamin B6 50 mg, vitamin B12 1 mg)

**The risk in the placebo group is the median risk in the control groups of the four included studies in summary of findings Table for the main comparison. The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for imprecision

Figures and Tables -
Summary of findings 4. Multivitamin versus placebo
Table 1. Mapping the definition of AMD used in included studies to the review outcomes

Definition of AMD used in this review

Study

ATBC 1998

PHS I 2007PHS II 2012; WHS 2010

VECAT 2002

No AMD

0 = no ARM

Did not self‐report or no signs listed below in medical records

Any AMD

I = dry maculopathy, with hard drusen, pigmentary changes, or both

II = soft macular drusen

III = disciform degeneration

IV = geographic atrophy.

Drusen, RPE hypo or hyperpigmentation, geographic atrophy, RPE detachment, subretinal neovascular membrane,
or disciform scar

Early AMD 1: Soft intermediate or soft distinct or soft indistinct or pigment changes (hyperpigmentation or hypopigmentation)

Early AMD 2: Soft intermediate or soft distinct or soft indistinct and pigment changes (hyperpigmentation or hypopigmentation)

Early AMD 3: Soft distinct or soft indistinct or pigment changes (hyperpigmentation or hypopigmentation)

Early AMD 4: Soft distinct or soft indistinct and pigment changes (hyperpigmentation or hypopigmentation)

Late AMD: Serous or haemorrhagic detachment of the RPE or sensory retina, characteristic haemorrhages, or subretinal fibrous scars, central areolar zone of retinal pigment epithelial atrophy with visible choroidal vessels, at least 175 µm in diameter

Late AMD

III = disciform degeneration

IV = geographic atrophy.

Geographic atrophy, RPE detachment, subretinal neovascular membrane, or disciform scar

Serous or haemorrhagic detachment of the RPE or sensory retina, characteristic haemorrhages, or subretinal fibrous scars, central areolar zone of retinal pigment epithelial atrophy with visible choroidal
vessels, at least 175 µm in diameter

Neovascular AMD

III = disciform degeneration

RPE detachment, subretinal neovascular membrane, or disciform scar

Serous or haemorrhagic detachment of the RPE or sensory retina, characteristic haemorrhages, or subretinal fibrous scars

Geographic atrophy

IV = geographic atrophy.

Geographic atrophy

Central areolar zone of retinal pigment epithelial atrophy with visible choroidal
vessels, at least 175 µm in diameter, in the absence of signs of neovascular AMD in the same eye

RPE: retinal pigment epithelial
Method of detection: Grading of fundus photographs (ATBC 1998; VECAT 2002), and medical record review after self‐report of AMD diagnosis (PHS I 2007; PHS II 2012; WHS 2010)

Figures and Tables -
Table 1. Mapping the definition of AMD used in included studies to the review outcomes
Comparison 1. Vitamin E versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Any AMD Show forest plot

4

55614

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.90, 1.06]

2 Late AMD (either neovascular AMD or geographic atrophy or both) Show forest plot

4

55614

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [0.89, 1.67]

3 Neovascular AMD or geographic atrophy separately Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Neovascular AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Geographic atrophy

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 1. Vitamin E versus placebo
Comparison 2. Beta‐carotene versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Any AMD Show forest plot

2

22083

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.88, 1.14]

2 Late AMD (either neovascular AMD or geographic atrophy or both) Show forest plot

2

22083

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.65, 1.24]

3 Neovascular AMD or geographic atrophy separately Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Neovascular AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Geographic atrophy

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 2. Beta‐carotene versus placebo
Comparison 3. Vitamin C versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AMD Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Any AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Late AMD (either neovascular AMD or geographic atrophy or both)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 3. Vitamin C versus placebo
Comparison 4. Multivitamin versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AMD Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Any AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Late AMD (either neovascular AMD or geographic atrophy or both)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 4. Multivitamin versus placebo