The Association of Dietary Lutein plus Zeaxanthin and B Vitamins with Cataracts in the Age-Related Eye Disease Study: AREDS Report No. 37.

PURPOSE: To evaluate whether dietary intake of luteiin/zeaxanthin and B vitamins is associated with cataract prevalence and incidence. DESIGN: Clinic-based, baseline cross-sectional and prospective cohort study designs. PARTICIPANTS: Three thousand one hundred fifteen patients (6129 eyes) enrolled in the Age-Related Eye Disease Study 55 to 80 years of age followed up for mean of 9.6 years. METHODS: Participants completed baseline food frequency questionnaires. Baseline and annual lens photographs were graded centrally. Multivariate models controlling for previously identified risk factors for cataracts tested for the association of cataracts with reported dietary intake, using the lowest quintile as reference. MAIN OUTCOME MEASURES: Cataract surgery, cataract status (type and severity) at baseline, and development of cataracts. RESULTS: At baseline, increased dietary riboflavin and B12 were associated inversely with nuclear and cortical lens opacities. In comparisons of persons with and without cataract, persons with the highest riboflavin intake versus those with the lowest intake had the following associations: mild nuclear cataract: odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63-0.97; moderate nuclear cataract: OR, 0.62; 95% CI, 0.43-0.90; and mild cortical cataract: OR, 0.80; 95% CI, 0.65-0.99. For B12, the results were: mild nuclear cataract: OR, 0.78; 95% CI, 0.63-0.96; moderate nuclear cataract: OR, 0.62; 95% CI, 0.43-0.88; and mild cortical cataract: OR, 0.77; 95% CI, 0.63-0.95. Highest dietary B6 intake was associated with a decreased risk of moderate nuclear lens opacity developing compared with the lowest quintile (OR, 0.67; 95% CI, 0.45-0.99). Highest dietary intake levels of niacin and B12 were associated with a decreased risk of development of mild nuclear or mild cortical cataracts in participants not taking Centrum (Pfizer, New York, NY) multivitamins. For participants taking multivitamins during the study, the highest intake of dietary folate was associated with an increased risk of mild posterior subcapsular lens opacity development. No statistically significant associations were found between lutein plus zeaxanthin intake and presence at baseline or development of nuclear or cortical lens opacity outcomes. CONCLUSIONS: These findings are consistent with earlier studies suggesting that dietary intake of B vitamins may affect the occurrence of age-related lens opacities. Further investigations are warranted.

Changes in lens opacities on the age-related eye disease study grading scale predict progression to cataract surgery and vision loss: age-related eye disease study report no. 34.

PURPOSE: To investigate whether the 2-year change in lens opacity severity on the Age-Related Eye Disease Study (AREDS) lens grading scale predicts progression to cataract surgery or loss of visual acuity by 5 years. DESIGN: Prospective cohort study within a randomized clinical trial of oral supplements. PARTICIPANTS: The AREDS participants whose eyes were phakic at baseline and free of late age-related macular degeneration throughout the study. METHODS: Baseline and annual lens photographs of AREDS participants (n = 3466/4757; 73%) were graded for severity of cataracts using the AREDS system for classifying cataracts from photographs. Clinical examinations conducted semiannually collected data on cataract surgery and visual acuity. Association of the change in lens opacities at 2 years with these outcomes at 5 years was analyzed with adjusted Cox proportional hazard models. MAIN OUTCOME MEASUREMENTS: Progression of lens opacities on stereoscopic lens photographs at 2 years, cataract surgery, and visual acuity loss of 2 lines or more at 5 years. RESULTS: The adjusted hazard ratios (HRs) for association of progression to cataract surgery at 5 years were: nuclear cataract increase of 1.0 unit or more compared with less than 1.0-unit change at 2 years, 2.77 (95% confidence interval [CI], 2.07-3.70; P < 0.001); cortical cataract increase of 5% or more in lens opacity in the central 5 mm of the lens compared with less than 5% increase at 2 years, 1.91 (95% CI, 1.27-2.87; P = 0.002); and posterior subcapsular cataract increase of 5% or more versus less than 5% in the central 5 mm of the lens, 8.25 (95% CI, 5.55-12.29; P < 0.001). Similarly, HRs of vision loss of 2 lines or more at 5 years for this degree of lens changes at 2 years were the following: nuclear, 1.83 (95% CI, 1.49-2.25; P < 0.001); cortical, 1.13 (95% CI, 0.78-1.65; P = 0.519); and posterior subcapsular cataract, 3.05 (95% CI, 1.79-5.19; P < 0.001). CONCLUSIONS: Two-year changes in severity of lens opacities on the AREDS lens grading scale are predictive of long-term clinically relevant outcomes, making them potential surrogate end points in follow-up studies.

Long-term effects of vitamins C and E, ß-carotene, and zinc on age-related macular degeneration: AREDS report no. 35.

OBJECTIVE: To describe the long-term effects (10 years) of the Age-Related Eye Disease Study (AREDS) formulation of high-dose antioxidants and zinc supplement on progression of age-related macular degeneration (AMD). DESIGN: Multicenter, randomized, controlled, clinical trial followed by an epidemiologic follow-up study. PARTICIPANTS: We enrolled 4757 participants with varying severity of AMD in the clinical trial; 3549 surviving participants consented to the follow-up study. METHODS: Participants were randomly assigned to antioxidants C, E, and ß-carotene and/or zinc versus placebo during the clinical trial. For participants with intermediate or advanced AMD in 1 eye, the AREDS formulation delayed the progression to advanced AMD. Participants were then enrolled in a follow-up study. Eye examinations were conducted with annual fundus photographs and best-corrected visual acuity assessments. Medical histories and mortality were obtained for safety monitoring. Repeated measures logistic regression was used in the primary analyses. MAIN OUTCOME MEASURES: Photographic assessment of progression to, or history of treatment for, advanced AMD (neovascular [NV] or central geographic atrophy [CGA]), and moderate visual acuity loss from baseline (≥15 letters). RESULTS: Comparison of the participants originally assigned to placebo in AREDS categories 3 and 4 at baseline with those originally assigned to AREDS formulation at 10 years demonstrated a significant (P<0.001) odds reduction in the risk of developing advanced AMD or the development of NV AMD (odds ratio [OR], 0.66, 95% confidence interval [CI], 0.53-0.83 and OR, 0.60; 95% CI, 0.47-0. 78, respectively). No significant reduction (P = 0.93) was seen for the CGA (OR, 1.02; 95% CI, 0.71-1.45). A significant reduction (P = 0.002) for the development of moderate vision loss was seen (OR 0.71; 95% CI, 0.57-0.88). No adverse effects were associated with the AREDS formulation. Mortality was reduced in participants assigned to zinc, especially death from circulatory diseases. CONCLUSIONS: Five years after the clinical trial ended, the beneficial effects of the AREDS formulation persisted for development of NV AMD but not for CGA. These results are consistent with the original recommendations that persons with intermediate or advanced AMD in 1 eye should consider taking the AREDS formulation. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Risk factors associated with incident cataracts and cataract surgery in the Age-related Eye Disease Study (AREDS): AREDS report number 32.

OBJECTIVE: To investigate potential risk factors associated with incident nuclear, cortical, and posterior subcapsular (PSC) cataracts and cataract surgery in participants in the Age-Related Eye Disease Study (AREDS). DESIGN: Clinic-based prospective cohort study. PARTICIPANTS: Persons (n = 4425) 55 to 80 years of age enrolled in a controlled clinical trial of antioxidant vitamins and minerals, AREDS, for age-related macular degeneration and cataract. METHODS: Lens photographs were graded centrally for nuclear, cortical, and PSC opacities using the AREDS system for classifying cataracts. Type-specific incident cataracts were defined as an increase in cataract grade from none or mild at baseline to a grade of moderate at follow-up, also with a grade of at least moderate at the final visit, or cataract surgery. Cox regression analyses were used to assess baseline risk factors associated with type-specific opacities and cataract surgery. MAIN OUTCOME MEASURES: Moderate cataract was defined as a grade of 4.0 or more for nuclear opacity, 10% or more involvement within the full visible lens for cortical opacity, and 5% or more involvement of the central 5-mm circle of the lens for PSC opacity. These were graded on baseline and annual lens photographs. RESULTS: A clinic-based cohort of 4425 persons 55 to 80 years of age at baseline was followed up for an average of 9.8±2.4 years. The following associations were found: increasing age with increased risk of all types of cataract and cataract surgery; males with increased risk of PSC and decreased risk of cortical cataracts; nonwhite persons with increased risk of cortical cataract; hyperopia with decreased risk of PSC, nuclear cataract, and cataract surgery; Centrum (Wyeth Consumer Healthcare, Madison, NJ) use with decreased risk of nuclear cataract; diabetes with increased risk of cortical, PSC cataract, and cataract surgery; higher educational level with decreased risk of cortical cataract; and smoking with increased risk of cortical cataract and cataract surgery. Estrogen replacement therapy in female participants increased the risk of cataract surgery. CONCLUSIONS: These findings largely are consistent with the results of previous studies, providing further evidence for possible modifiable risk factors for age-related cataract. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Evaluation of the age-related eye disease study clinical lens grading system AREDS report No. 31.

PURPOSE: To examine the grading (interrater) reliability of the Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System (ARLNS). DESIGN: Evaluation of diagnostic test or technology. PARTICIPANTS: One hundred fifty volunteers (284 eyes). METHODS: Participants with lens opacities of varying severity were independently graded at the slit lamp for cataract severity by 2 examiners (retinal or anterior segment specialists) using the ARLNS, which employs 3 standard photographs of increasing severity for classifying each of the 3 major types of opacity. Lens photographs were taken and graded at a reading center using the more detailed AREDS System for Classifying Cataracts from photographs. MAIN OUTCOME MEASURES: The Pearson correlation, weighted-kappa, and limits-of-agreement statistics were used to assess the interrater agreement of the gradings. RESULTS: Examinations were performed on 284 lenses (150 participants). Tests of interrater reliability between pairs of clinicians showed substantial agreement between clinicians for cortical and posterior subcapsular opacities and moderate agreement for nuclear opacities. A similar pattern and strength of agreement was present when comparing scores of retinal versus anterior segment specialists. Interrater agreement between clinical and reading center gradings was not as great as inter-clinician agreement. CONCLUSIONS: Interrater agreements were in the moderate to substantial range for the clinical assessment of lens opacities. Inherent differences in cataract classification systems that rely on slit lamp vs photographic assessments of lens opacities may explain some of the disagreement noted between slit lamp and photographic gradings. Given the interrater reliability statistics for clinicians and the simplicity of the grading procedure, ARLNS is presented for use in studies requiring a simple, inexpensive method for detecting the presence and severity of the major types of lens opacities. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Risk of advanced age-related macular degeneration after cataract surgery in the Age-Related Eye Disease Study: AREDS report 25.

PURPOSE: To assess the risk of advanced age-related macular degeneration (AMD) developing after cataract surgery. DESIGN: Cohort study. PARTICIPANTS: Four thousand five hundred seventy-seven participants (8050 eyes) from a multicenter, controlled, randomized clinical trial, the Age-Related Eye Disease Study (AREDS). METHODS: Development of advanced AMD, either neovascular (NV) AMD or geographic atrophy (GA), was evaluated with annual fundus photographs, and history of cataract surgery was assessed every 6 months. Cox proportional hazard models with time-dependent covariates were conducted for NV AMD and GA separately. MAIN OUTCOME MEASURES: Neovascular AMD, GA, and central GA (CGA; involving the center of the macula). RESULTS: The Cox proportional hazards model of right eyes showed nonsignificant hazard ratios of 1.20 (95% confidence interval [CI], 0.82-1.75) for NV AMD, 0.80 (95% CI, 0.61-1.06) for GA, and 0.87 (95% CI, 0.64-1.18) for CGA. Similar results were obtained for left eyes: 1.07 (95% CI, 0.72-1.58) for NV AMD, 0.94 (95% CI, 0.71-1.25) for GA, and 0.86 (95% CI, 0.63-1.19) for CGA. For participants with advanced AMD in 1 eye (AREDS category 4), the hazard ratios for fellow eyes were 1.08 (95% CI, 0.65-1.72) for NV AMD and 0.98 (95% CI, 0.64-1.49) for CGA. CONCLUSIONS: The AREDS results showed no clear effect of cataract surgery on the risk of progression to advanced AMD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A randomized, double-masked, placebo-controlled clinical trial of multivitamin supplementation for age-related lens opacities. Clinical trial of nutritional supplements and age-related cataract report no. 3.

OBJECTIVE: To evaluate the effect of a multivitamin/mineral supplement on development or progression of age-related lens opacities. DESIGN: Randomized, double-masked, single center, placebo-controlled clinical trial. PARTICIPANTS: One thousand twenty participants, 55 to 75 years old and with early or no cataract, were randomly assigned to a daily tablet of a multivitamin/mineral formulation or a placebo. METHODS: Baseline and annual lens photographs were graded for severity of lens opacities according to a modification of the Age-Related Eye Disease Study system for classifying cataracts. MAIN OUTCOME MEASURES: The primary outcome was a prespecified increase from baseline in nuclear, cortical, or posterior subcapsular cataract (PSC) opacity grades or cataract surgery. Secondary outcomes included an increase in type-specific opacity grades, cataract surgery, and visual acuity (VA) loss from baseline > or =15 letters. RESULTS: Participants were observed for an average of 9.0+/-2.4 years. There was a decrease in total lens events in participants assigned to the multivitamin/mineral formulation compared with those assigned to the placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.68-0.98; P = 0.03). Nuclear events were significantly less common (HR, 0.66; 95% CI, 0.50-0.88; P = 0.004) and PSC events significantly more common (HR, 2.00; 95% CI, 1.35-2.98; P<0.001) in participants taking the multivitamin/mineral formulation than in those assigned to the placebo. No statistically significant treatment effects were seen for cortical opacities, moderate VA loss, or cataract surgery. CONCLUSIONS: Lens events were less common in participants who took the multivitamin/mineral formulation, but treatment had opposite effects on the development or progression of nuclear and PSC opacities, the 2 most visually important opacity subtypes.

Cataract classification using serial examinations in the age-related eye disease study: age-related eye disease study report no. 24.

PURPOSE: To describe use of serial lens examinations to assign cataract phenotype in the Age-Related Eye Disease Study (AREDS). DESIGN: Cohort study. METHODS: Lens photographs were graded annually using the AREDS system for classifying cataracts. Nuclear grades (0.9 to 6.1) were assigned using standard photographs. Percentage of pupillary involvement was used to assign cortical and posterior subcapsular grades. Cutpoints were established for the presence or absence of each type of opacity (absent<4.0 for nuclear, <10% for cortical, and <5% of central 5 mm for posterior subcapsular). An algorithm weighted for grades at the last three examinations was used to assign cataract phenotype. Separately, cataract phenotype was assigned as grade predicted at final visit by linear regression of serial grades. Results from the two approaches were compared and final person phenotypes were established. These person cataract phenotype assignments were compared with phenotype assignments based on the last serial grade alone. RESULTS: Four thousand six hundred and twenty-eight AREDS participants aged 55 to 80 years at baseline had median follow-up of 10.6 years. Person phenotype assignments agreed for the two approaches in 4,557 (98.5%) participants after some algorithmic adjudication. Phenotypes were no cataract (n=1,418), nuclear (n=1,287), cortical (n=1,396), posterior subcapsular (n=541), cataract surgery and no specific opacity type (n=335), and questionable (n=426). Phenotype assignments based on serial grades and on last examination alone were in good agreement. CONCLUSIONS: Serial lens photographs obtained over a 10-year period were used to provide a robust assignment of cataract phenotype. Well-characterized cataract phenotypes are of importance as genetic studies of the AREDS cohort are considered.

The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22.

OBJECTIVE: To evaluate the relationship of dietary carotenoids, vitamin A, alpha-tocopherol, and vitamin C with prevalent age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Demographic, lifestyle, and medical characteristics were ascertained on 4519 AREDS participants aged 60 to 80 years at enrollment. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with < 15 small drusen). Nutrient intake was estimated from a self-administered semiquantitative food frequency questionnaire at enrollment. Intake values were energy adjusted and classified by quintiles. The relationship between diet and AMD status was assessed using logistic regression analyses. RESULTS: Dietary lutein/zeaxanthin intake was inversely associated with neovascular AMD (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.45-0.93), geographic atrophy (OR, 0.45; 95% CI, 0.24-0.86), and large or extensive intermediate drusen (OR, 0.73; 95% CI, 0.56-0.96), comparing the highest vs lowest quintiles of intake, after adjustment for total energy intake and nonnutrient-based covariates. Other nutrients were not independently related to AMD. CONCLUSION: Higher dietary intake of lutein/zeaxanthin was independently associated with decreased likelihood of having neovascular AMD, geographic atrophy, and large or extensive intermediate drusen.

The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20.

OBJECTIVE: To evaluate the association of lipid intake with baseline severity of age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Age-Related Eye Disease Study participants aged 60 to 80 years at enrollment (N = 4519) provided estimates of habitual nutrient intake through a self-administered semiquantitative food frequency questionnaire. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with <15 small drusen). RESULTS: Dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with neovascular (NV) AMD (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.41-0.90), as was docosahexaenoic acid, a retinal omega-3 LCPUFA (OR, 0.54; 95% CI, 0.36-0.80), comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR, 0.61; 95% CI, 0.37-1.00 and OR, 0.65; 95% CI, 0.45-0.93, respectively). Dietary arachidonic acid was directly associated with NV AMD prevalence (OR, 1.54; 95% CI, 1.04-2.29). No statistically significant relationships existed for the other lipids or AMD groups. CONCLUSION: Higher intake of omega-3 LCPUFAs and fish was associated with decreased likelihood of having NV AMD.

Centrum use and progression of age-related cataract in the Age-Related Eye Disease Study: a propensity score approach. AREDS report No. 21.

PURPOSE: To evaluate the effect of the multivitamin Centrum on the development and progression of age-related lens opacities. DESIGN: Clinic-based prospective cohort study. PARTICIPANTS: Four thousand five hundred ninety individuals with at least one natural lens and photographic follow-up (median, 6.3 years) were assessed for development or progression of lens opacities. MAIN OUTCOME MEASURES: Progression of "any" lens opacity or type-specific opacity was ascertained from lens photographs taken at baseline and at annual visits beginning at year 2. METHODS: The Age-Related Eye Disease Study (AREDS) showed no statistically significant effect of a high-dose antioxidant formulation on progression of lens opacities. Centrum also was provided to approximately two thirds of the study participants. Because Centrum use was elective, a logistic regression model of baseline characteristics was used to generate a propensity score for Centrum use. Repeated-measures logistic regression, adjusted for propensity score and other covariates, was used to evaluate associations of Centrum use and lens opacity. RESULTS: Centrum use, adjusted for propensity score and other covariates, was associated with a reduction in "any" lens opacity progression (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.72-0.98, P = 0.025). Results for individual lens opacity types suggested that Centrum use was protective for nuclear opacity events (OR = 0.75, 95% CI = 0.61-0.91, P = 0.004). CONCLUSION: Observational data from the AREDS and other studies suggest that use of a multivitamin may delay the progression of lens opacities. A National Eye Institute-sponsored clinical trial scheduled for completion in 2007 will provide additional data on Centrum use and cataract development.

Prevalence of visual impairment in the United States.

CONTEXT: The prevalence of visual impairment in the US public has not been surveyed nationally in several decades. OBJECTIVE: To estimate the number of US individuals aged 12 years or older who have impaired distance vision due to uncorrected refractive error. DESIGN, SETTING, AND PARTICIPANTS: The National Health and Nutrition Examination Survey (NHANES), using a multistage probability sampling design, included a vision evaluation in a mobile examination center. Visual acuity data were obtained from 13,265 of 14,203 participants (93.4%) who visited the mobile examination center in 1999-2002. Visual impairment was defined as presenting distance visual acuity of 20/50 or worse in the better-seeing eye. Visual impairment due to uncorrected refractive error was defined as (presenting) visual impairment that improved, aided by automated refraction results, to 20/40 or better in the better-seeing eye. MAIN OUTCOME MEASURES: Presenting distance visual acuity (measured with usual corrective lenses, if any) and distance visual acuity after automated refraction. RESULTS: Overall, 1190 study participants had visual impairment (weighted prevalence, 6.4%; 95% confidence interval [CI], 6.0%-6.8%), and of these, 83.3% could achieve good visual acuity with correction (95% CI, 80.9%-85.8%). Extrapolating these findings to the general US population, approximately 14 million individuals aged 12 years or older have visual impairment (defined as distance visual acuity of 20/50 or worse), and of these, more than 11 million individuals could have their vision improved to 20/40 or better with refractive correction. CONCLUSIONS: Visual impairment due to uncorrected refractive error is a common condition in the United States. Providing appropriate refractive correction to those individuals whose vision can be improved is an important public health endeavor with implications for safety and quality of life.

Galactokinase gene mutations and age-related cataract. Lack of association in an Italian population.

PURPOSE: To investigate possible associations between sequence changes in the galactokinase gene (GALK1) and age-related cataract in a European population. METHODS: Persons without lens opacities and persons with clinically significant age-related cataract were selected from those participating in the Collaborative Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract or from those attending the Section of Ophthalmology of the University of Parma for cataract surgery. Type and severity of the opacities were assessed by slit-lamp and retro-illumination lens photographs. Mutations in GALK1 were identified by PCR amplification of individual exons and flanking sequences and sequencing using fluorescent terminator technology in an ABI 377 Prism or 3100 automated DNA sequencer. RESULTS: DNA samples were obtained from 115 individuals with clear lenses and from 185 individuals with cataract (106 with any nuclear, 88 with any cortical, and 25 with any posterior sub capsular cataract). 157 of the 185 patients with cataract (85%) were age-matched with a control within an age range of plus or minus 1 year. SNPs causing amino acid changes in the galactokinase protein were identified in exon 4; I184M, 1/115 control versus 0/185 cataractous individuals, p=0.38, exon 6; G274D, 0/115 control versus 1/185 cataractous individuals, p>0.99, and exon 7; V338A, 0/115 control versus 1/185 cataractous individuals, p>0.99. Thus, there were no significant differences in the distribution of sequence alterations resulting in amino acid changes between control and cataractous individuals. Eighty samples showed a C to T transition 43 bases into intron 7 (46 cataracts and 34 controls). Testing the distribution of the intron 7 findings showed Hardy-Weinberg equilibrium for both cases (p=0.73) and controls (p=0.51). There was no difference in C/T distribution between cases and controls (p=0.27). CONCLUSIONS: In this northern Italian population age-related cataract does not appear to be associated with GALK1 alleles. Since this is due to a lack of sequence changes in both affected and control individuals, this study cannot rule out the possibility of an association in other populations.

Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study: AREDS Report No. 13.

OBJECTIVE: To assess the association of ocular disorders and high doses of antioxidants or zinc with mortality in the Age-Related Eye Disease Study (AREDS). METHODS: Baseline fundus and lens photographs were used to grade the macular and lens status of AREDS participants. Participants were randomly assigned to receive oral supplements of high-dose antioxidants, zinc, antioxidants plus zinc, or placebo. Risk of all-cause and cause-specific mortality was assessed using adjusted Cox proportional hazards models. RESULTS: During median follow-up of 6.5 years, 534 (11%) of 4753 AREDS participants died. In fully adjusted models, participants with advanced age-related macular degeneration (AMD) compared with participants with few, if any, drusen had increased mortality (relative risk [RR], 1.41; 95% confidence interval [CI], 1.08-1.86). Advanced AMD was associated with cardiovascular deaths. Compared with participants having good acuity in both eyes, those with visual acuity worse than 20/40 in 1 eye had increased mortality (RR, 1.36; 95% CI, 1.12-1.65). Nuclear opacity (RR, 1.40; 95% CI, 1.12-1.75) and cataract surgery (RR, 1.55; 95% CI, 1.18-2.05) were associated with increased all-cause mortality and with cancer deaths. Participants randomly assigned to receive zinc had lower mortality than those not taking zinc (RR, 0.73; 95% CI, 0.61-0.89). CONCLUSIONS: The decreased survival of AREDS participants with AMD and cataract suggests that these conditions may reflect systemic rather than only local processes. The improved survival in individuals randomly assigned to receive zinc requires further study.

A randomized trial of beta carotene and age-related cataract in US physicians.

OBJECTIVE: To examine the development of age-related cataract in a trial of beta carotene supplementation in men. DESIGN: Randomized, double-masked, placebo-controlled trial. METHODS: Male US physicians aged 40 to 84 years (n = 22 071) were randomly assigned to receive either beta carotene (50 mg on alternate days) or placebo for 12 years. MAIN OUTCOME MEASURES: Age-related cataract and extraction of age-related cataract, defined as an incident, age-related lens opacity, responsible for a reduction in best-corrected visual acuity to 20/30 or worse, based on self-report confirmed by medical record review. RESULTS: There was no difference between the beta carotene and placebo groups in the overall incidence of cataract (998 cases vs 1017 cases; relative risk [RR], 1.00; 95% confidence interval [CI], 0.91-1.09) or cataract extraction (584 vs 593; RR, 1.00; 95% CI, 0.89-1.12). In subgroup analyses, the effect of beta carotene supplementation appeared to be modified by smoking status at baseline (P =.02). Among current smokers, there were 108 cases of cataract in the beta carotene group and 133 in the placebo group (RR, 0.74; 95% CI, 0.57-0.95). Among current nonsmokers, there was no significant difference in the number of cases in the 2 treatment groups (884 vs 881; RR, 1.03; 95% CI, 0.94-1.13). The results for cataract extraction appeared to be similarly modified by baseline smoking status (P =.05). CONCLUSIONS: Randomized trial data from a large population of healthy men indicate no overall benefit or harm of 12 years of beta carotene supplementation on cataract or cataract extraction. However, among current smokers at baseline, beta carotene appeared to attenuate their excess risk of cataract by about one fourth.

Ten-year follow-up of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36.

IMPORTANCE: Providing long-term follow-up of the natural history of age-related macular degeneration (AMD) and associated risk factors will facilitate future epidemiologic studies and clinical trials. OBJECTIVE: To describe 10-year progression rates to intermediate or advanced AMD. DESIGN, SETTING, AND PARTICIPANTS: We observed the Age-Related Eye Disease Study (AREDS) participants for an additional 5 years after a randomized clinical trial of antioxidant vitamins and minerals was completed. Observation occurred at 11 clinical sites of medical retinal practices from academic institutions and community medical centers. Participants aged 55 to 80 years with no AMD or AMD of varying severity (n = 4757) were followed up in the AREDS trial for a median duration of 6.5 years. When the trial ended, 3549 of the 4203 surviving participants were followed for 5 additional years. EXPOSURE: Treatment with antioxidant vitamins and minerals. MAIN OUTCOMES AND MEASURES: Development of varying stages of AMD and changes in visual acuity. The rates of progression to large drusen and advanced AMD (neovascular AMD or central geographic atrophy) were evaluated using annual fundus photographs assessed centrally. Best-corrected visual acuity was measured at annual study visits. RESULTS: The risk of progression to advanced AMD increased with increasing age (P = .01) and severity of drusen. Women (P = .005) and current smokers (P < .001) were at increased risk of neovascular AMD. In the oldest participants with the most severe AMD status at baseline, the risks of developing neovascular AMD and central geographic atrophy by 10 years were 48.1% and 26.0%, respectively. Similarly, rates of progression to large drusen increased with increasing severity of drusen at baseline, with 70.9% of participants with bilateral medium drusen progressing to large drusen and 13.8% to advanced AMD in 10 years. Median visual acuity at 10 years in eyes that had large drusen at baseline but never developed advanced AMD was 20/25; eyes that developed advanced AMD had a median visual acuity of 20/200. CONCLUSIONS AND RELEVANCE: The natural history of AMD demonstrates relentless loss of vision in persons who developed advanced AMD. These progression data and the risk factor analyses may be helpful to investigators conducting research in clinic populations.

Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3.

IMPORTANCE: The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. OBJECTIVE: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS: The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONS: In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURE: S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCE: The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00345176.

Ten-year incidence rates of age-related cataract in the Age-Related Eye Disease Study (AREDS): AREDS report no. 33.

PURPOSE: To investigate the long-term incidence of age-related cataract and cataract surgery in the Age-Related Eye Disease Study (AREDS) cohort. METHODS: Baseline and annual lens photographs of participants, aged 55-80 years, were graded centrally for nuclear, cortical, and posterior subcapsular (PSC) lens opacities using the AREDS System for Classifying Cataracts. Progression from a baseline status of no or mild lens opacity to at least moderate severity was analyzed and cumulative incidence estimated rates were calculated for each lens opacity type and cataract surgery stratified by age, sex, race, age-related macular degeneration category, multivitamin (Centrum) use and history of diabetes. RESULTS: The ten-year cumulative incidence was 43.6% for any cataract, 23.1% for nuclear cataract, 22.0% for cortical cataract, 13.1% for PSC cataract, and 26.8% for cataract surgery. The 5- and 10-year incidence rates of all cataract types and cataract surgery were significantly higher with increasing age. Females had a higher incidence of any, nuclear and cortical cataract and cataract surgery (p = 0.02-0.05). Incidence of cortical cataract was higher in non-white participants (p = 0.001). CONCLUSIONS: These results are largely consistent with the results of previous observational studies. Long-term incidence rates of type-specific cataract can be useful in designing clinical studies of age-related cataract.

A post-trial survey to assess the impact of dissemination of results and unmasking on participants in a 13-year randomised controlled trial on age-related cataract.

BACKGROUND: The Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract was designed to assess the impact of a multivitamin-mineral supplement on age-related cataract. Trial results showed evidence of a beneficial effect of the supplement on all types of cataract combined, opposite effects on two of the three types of cataract (beneficial for nuclear opacities and harmful for posterior sub-capsular opacities) and no statistically significant effect on cortical opacities. No treatment recommendations were made. A post-trial survey was conducted on 817 surviving elderly participants to assess their satisfaction, their understanding of treatment assignment to supplement or placebo and the success of masking. METHODS: Trial results were communicated by letter and the level of satisfaction and of understanding of the results was assessed by a questionnaire. Participants were offered the option of being unmasked: a second questionnaire was administered to this subset to assess their understanding of the randomisation process and the success of masking. RESULTS: 610 participants (74.7%) responded to the survey:94.6% thought the description of the results was "very clear" or "quite clear", 5.4% "not clear" or "do not know"; 89.8% considered the results "very interesting" or "quite interesting", 10.2% "not interesting" or "do not know"; 60.3% expressed "satisfaction", 17.2% "both satisfaction and concern", 2.6% "concern", 19.9% "indifference" or "do not know".480 participants (78.7%) accepted the offer to be unmasked to their treatment assignment: 395 (82.3%) recalled/understood the possibility of assignment to vitamins or placebo, 85 (17.7%) did not. 68 participants (17.2%) thought they had taken vitamins (79.4% were correct; p = 0.0006), 47 (11.9%) thought they had taken placebo (59.6% were correct; p = 0.46) and 280 (70.9%) declared they did not know. CONCLUSIONS: The results were made difficult to explain to study participants by the qualitatively different effect of treatment on the two most visually significant types of cataract. Although the study did not lead to a recommendation to use the dietary supplement, the vast majority of participants reported satisfaction after they received the results but almost 20% of the participants expressed some concern. Masking to treatment assignment was successful in the majority of participants.