Carotenoids in Age-related Maculopathy Italian Study (CARMIS): two-year results of a randomized study. Multicenter ophthalmic and nutritional age-related macular degeneration study--part 2: antioxidant intervention and conclusions. Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease: a randomized controlled trial. Methodology of the VECAT study: vitamin E intervention in cataract and age-related maculopathy. The Antioxidants in Prevention of Cataracts Study: effects of antioxidant supplements on cataract progression in South India. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Six-year supplementation with alpha-tocopherol and beta-carotene and age-related maculopathy. A randomized, prospective, placebo-controlled clinical trial of a novel zinc-monocysteine compound in age-related macular degeneration.
The high concentration of carotenoids in the macula, plus evidence linking oxidative stress to age-related macular degeneration (AMD) and carotenoids to antioxidation, generated the hypothesis that higher antioxidant intakes can prevent AMD. The aim of this study was to determine whether nutritional supplementation with a targeted nutritional supplement improves visual acuity and visual function in AMD.
                In this multicenter, prospective open-label randomized study, 145 patients were randomly assigned to 2 different treatment groups. Interventions were lutein (10 mg), zeaxanthin (1 mg), astaxanthin (4 mg; AZYR SIFI, Catania, Italy), and antioxidants/vitamins supplementation formula or no dietary supplementation for 2 years. Primary outcome was mean changes in visual acuity (VA) at 12 and 24 months. Other measures included contrast sensitivity (CS) and National Eye Institute visual function questionnaire (NEI VFQ-25) scores at 12 and 24 months.
                Patients in the treated group showed stabilization of VA with significantly (p=0.003) better VA scores (81.4 ± 7.2) compared to the nontreated group (76.8 ± 8.9) at 24-month follow-up. An improvement in CS (p=0.001) and final mean NEI VFQ-25 composite scores at 12 and 24 months higher in treated group compared to nontreated group were also shown (p<0.001).
                Patients treated with lutein/zeaxanthin and astaxanthin together with other nutrients were more likely to report clinically meaningful stabilization/improvements in VA, CS, and visual function through 24 months compared with nontreated subjects. Further studies are needed with more patients and for longer periods of time. The experimental design, subjects, procedures and baseline data for the prospective double blind dry ARMD-antioxidant intervention study have been described in Part 1.
                At eight DVA medical centers, 32 patients (group one) were assigned a placebo and 39 patients (group two) a "broad spectrum" antioxidant capsule. Data was collected in five areas: demographic; ophthalmic; dietary analysis of daily food intake; serum analysis; and adverse gastrointestinal symptoms. Data was serially acquired at baseline, 6 months, 12 months and 18 months, and was analyzed by univariate repeated factors ANOVA, p = 0.05.
                Group two (antioxidant po BID) maintained their distance LogMAR visual acuity (p = 0.03), while there was a trend toward both stabilized near M print (p = 0.07) and 6 cycle/degree contrast sensitivity (p approximately 0.10), in left eyes. However, group two (antioxidant) also had increased cortical opacification of the right lens (p = 0.04), compared to group one (placebo). Self perceived stabilization of vision was reported by subjects in group two and supported the objective data (Pearson chi square; p = 0.05).
                A specific 14 component antioxidant capsule taken twice daily stabilized but did not improve dry ARMD over the study period of 1.5 years. The ARMD stabilized eyes had less advanced disease functionally but not by fundus appearance. Decreased intake of cardioprotective nutrients (vitamin E, zinc, magnesium, B6 and folate) in ARMD patients remained constant over the course of the trial. The aim of the study is to determine the effect of lutein combined with vitamin and mineral supplementation on contrast sensitivity in people with age-related macular disease (ARMD).
                A prospective, 9-month, double-masked randomized controlled trial.
                Aston University, Birmingham, UK and a UK optometric clinical practice.
                Age-related maculopathy (ARM) and atrophic age-related macular degeneration (AMD) participants were randomized (using a random number generator) to either placebo (n=10) or active (n=15) groups. Three of the placebo group and two of the active group dropped out.
                The active group supplemented daily with 6 mg lutein combined with vitamins and minerals. The outcome measure was contrast sensitivity (CS) measured using the Pelli-Robson chart, for which the study had 80% power at the 5% significance level to detect a change of 0.3 log units.
                The CS score increased by 0.07+/-0.07 and decreased by 0.02+/-0.18 log units for the placebo and active groups, respectively. The difference between these values is not statistically significant (z=-0.903, P=0.376).
                The results suggest that 6 mg of lutein supplementation in combination with other antioxidants is not beneficial for this group. Further work is required to establish optimum dosage levels. Cataract is the leading cause of blindness in the world today, while age-related macular degeneration is responsible for the majority of new cases of visual impairment in the Western world. There is a growing body of evidence suggesting a role for antioxidant therapy to prevent the progression of these conditions. A 4-year prospective, randomised, controlled trial of an antioxidant versus placebo in a population of healthy volunteers aged 55-80 years at enrolment is described. This paper outlines the primary aims of the Vitamin E, Cataract and Age-related Macular Degeneration (VECAT) Study, the methodology, and the recruitment rates. Additional data on the toxicity and non-ocular effects of vitamin E will also be collected. Standardised clinical grading of macular and lens features, and comparison of serial macular photographs and digital lens photographs will form the basis for assessment of primary study outcomes. Information collected in this study will assist in the assessment of the potential value of antioxidants in preventing the enormous burden imposed on developed communities by age-related eye disease. In addition, important data on prevalence and progression rates of cataract and macular degeneration will be collected. To determine if antioxidant supplements (beta carotene and vitamins C and E) can decrease the progression of cataract in rural South India.
                The Antioxidants in Prevention of Cataracts (APC) Study was a 5 year, randomised, triple masked, placebo controlled, field based clinical trial to assess the ability of interventional antioxidant supplements to slow cataract progression. The primary outcome variable was change in nuclear opalescence over time. Secondary outcome variables were cortical and posterior subcapsular opacities and nuclear colour changes; best corrected visual acuity change; myopic shift; and failure of treatment. Annual examinations were performed for each subject by three examiners, in a masked fashion. Multivariate modelling using a general estimating equation was used for analysis of results, correcting for multiple measurements over time.
                Initial enrolment was 798 subjects. Treatment groups were comparable at baseline. There was high compliance with follow up and study medications. There was progression in cataracts. There was no significant difference between placebo and active treatment groups for either the primary or secondary outcome variables.
                Antioxidant supplementation with beta carotene, vitamins C and E did not affect cataract progression in a population with a high prevalence of cataract whose diet is generally deficient in antioxidants. Age-related macular degeneration (ARMD) is the leading cause of vision loss in aging Westem societies. The objective of the lutein antioxidant supplementation trial (LAST) is to determine whether nutritional supplementation with lutein or lutein together with antioxidants, vitamins, and minerals, improves visual function and symptoms in atrophic ARMD.
                The study was a prospective, 12-month, randomized, double-masked, placebo-controlled trial conducted at an urban midwestern Veterans Administration Hospital from August 1999 to May 2001. Ninety patients with atrophic ARMD were referred by ophthalmologists at two Chicago-area veterans medical facilities. Patients in Group 1 received lutein 10 mg (L); in Group 2, a lutein 10 mg/antioxidants/vitamins and minerals broad spectrum supplementation formula (L/A); and in Group 3, a maltodextrin placebo (P) over 12 months.
                In Groups 1 L and 2 L/A, mean eye macular pigment optical density increased approximately 0.09 log units from baseline, Snellen equivalent visual acuity improved 5.4 letters for Group 1 L and 3.5 letters for Group 2 L/A, and contrast sensitivity improved. There was a net subjective improvement in Amsler grid in Group 1 L. VFO-14 questionnaires conceming subjective glare recovery were nearly significant at 4 months for Group 2 L/A. Patients who received the placebo (Group 3) had no significant changes in any of the measured findings.
                In this study, visual function is improved with lutein alone or lutein together with other nutrients. Further studies are needed with more patients, of both genders, and for longer periods of time to assess long-term effects of lutein or lutein together with a broad spectrum of antioxidants, vitamins, and minerals in the treatment of atrophic age-related macular degeneration. Randomized trials have largely failed to support an effect of antioxidant vitamins on the risk of cardiovascular disease (CVD). Few trials have examined interactions among antioxidants, and, to our knowledge, no previous trial has examined the individual effect of ascorbic acid (vitamin C) on CVD.
                The Women's Antioxidant Cardiovascular Study tested the effects of ascorbic acid (500 mg/d), vitamin E (600 IU every other day), and beta carotene (50 mg every other day) on the combined outcome of myocardial infarction, stroke, coronary revascularization, or CVD death among 8171 female health professionals at increased risk in a 2 x 2 x 2 factorial design. Participants were 40 years or older with a history of CVD or 3 or more CVD risk factors and were followed up for a mean duration of 9.4 years, from 1995-1996 to 2005.
                A total of 1450 women experienced 1 or more CVD outcomes. There was no overall effect of ascorbic acid (relative risk [RR], 1.02; 95% CI, 0.92-1.13 [P = .71]), vitamin E (RR, 0.94; 95% CI, 0.85-1.04 [P = .23]), or beta carotene (RR, 1.02; 95% CI, 0.92-1.13 [P = .71]) on the primary combined end point or on the individual secondary outcomes of myocardial infarction, stroke, coronary revascularization, or CVD death. A marginally significant reduction in the primary outcome with active vitamin E was observed among the prespecified subgroup of women with prior CVD (RR, 0.89; 95% CI, 0.79-1.00 [P = .04]; P value for interaction, .07). There were no significant interactions between agents for the primary end point, but those randomized to both active ascorbic acid and vitamin E experienced fewer strokes (P value for interaction, .03).
                There were no overall effects of ascorbic acid, vitamin E, or beta carotene on cardiovascular events among women at high risk for CVD. Animal research and observational studies in man suggest a protective effect of antioxidant vitamins in the development of age-related maculopathy (ARM).
                The ATBC study, a population-based, controlled clinical trial of alpha-tocopherol and beta carotene to prevent lung cancer, took place in Finland between 1984 and 1993. Over 29,000 smoking males aged 50 to 69 years were randomly assigned to alpha-tocopherol (AT; 50 mg/day), beta-carotene (BC; 20 mg/day), both of these, or placebo. We performed an end-of-trial ophthalmological examination on a random sample of 941 participants aged 65 years or more from two of the fourteen study areas, to discover if the five to eight-year intervention with alpha-tocopherol and/or beta-carotene had been associated with a difference in ARM prevalence. Age-related maculopathy was assessed using colour photographs of the macula.
                Altogether, 269 cases of ARM were found; there were more cases in the AT group (32%; 75/237), BC group (29%; 68/234), and combined antioxidant group (28%; 73/257) than in the placebo group (25%; 53/213). However, neither substance was significantly associated with the risk of ARM in a logistic regression analysis controlling for possible risk factors.
                No beneficial effect of long-term supplementation with alpha-tocopherol or beta-carotene on the occurrence of ARM was detected among smoking males. To test the hypothesis that daily use of zinc-monocysteine (ZMC) supplement will be well tolerated and result in improved macular function in persons with dry age-related macular degeneration (AMD).
                Eligible, consenting subjects were randomized to either ZMC 25 mg or placebo twice daily for 6 months. Both ZMC and placebo groups enrolled 40 participants, with best corrected visual acuity 20/25 to 20/70, macular drusen, and pigment changes. Masked personnel determined baseline, 3- and 6-month best-corrected visual acuity, contrast sensitivity, and light flash recovery time. Differences between ZMC and placebo were analyzed by a one-sided unpaired t-test of the paired differences between baseline and 3- and 6-month timepoints for right and left eyes separately.
                By 6 months the ZMC group showed improved visual acuity (p < 0.0001) and contrast sensitivity (p < 0.0001). Macular light flash recovery time shortened in the ZMC group at 3 months by 2.1 sec (left eye, p = 0.0001) to 3.6 sec (right eye, p < 0.0001), and at 6 months by 7.2 sec (left eye, p < 0.0001) to 7.4 sec (right eye, p < 0.0001). This variable had no improvement in the placebo group. ZMC had a gastrointestinal irritation rate of under 2%.
                ZMC 25 mg twice daily was well tolerated and was associated with improved macular function in comparison to a placebo in persons with dry AMD.
There is accumulating evidence that taking vitamin E or beta-carotene supplements will not prevent or delay the onset of AMD. There is no evidence with respect to other antioxidant supplements, such as vitamin C, lutein and zeaxanthin, or any of the commonly marketed multivitamin combinations. Although generally regarded as safe, vitamin supplements may have harmful effects and clear evidence of benefit is needed before they can be recommended. People with AMD should see the related Cochrane review 'Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration' written by the same review team.