Barbara A. Blodi

Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial

IMPORTANCE Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C and E, beta carotene, and zinc) has been shown to reduce the risk of progression to advanced age-related macular degeneration (AMD). Observational data suggest that increased dietary intake of lutein + zeaxanthin (carotenoids), omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]), or both might further reduce this risk. OBJECTIVES To determine whether adding lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation. DESIGN, SETTING, AND PARTICIPANTS The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double-masked, placebo-controlled phase 3 study with a 2 × 2 factorial design, conducted in 2006-2012 and enrolling 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye. INTERVENTIONS Participants were randomized to receive lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), lutein + zeaxanthin and DHA + EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both. MAIN OUTCOMES AND MEASURES Development of advanced AMD. The unit of analyses used was by eye. RESULTS Median follow-up was 5 years, with 1940 study eyes (1608 participants) progressing to advanced AMD. Kaplan-Meier probabilities of progression to advanced AMD by 5 years were 31% (493 eyes [406 participants]) for placebo, 29% (468 eyes [399 participants]) for lutein + zeaxanthin, 31% (507 eyes [416 participants]) for DHA + EPA, and 30% (472 eyes [387 participants]) for lutein + zeaxanthin and DHA + EPA. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD (hazard ratio [HR], 0.90 [98.7% CI, 0.76-1.07]; P = .12 for lutein + zeaxanthin; 0.97 [98.7% CI, 0.82-1.16]; P = .70 for DHA + EPA; 0.89 [98.7% CI, 0.75-1.06]; P = .10 for lutein + zeaxanthin and DHA + EPA). There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs no beta carotene group (23 [2.0%] vs 11 [0.9%], nominal P = .04), mostly in former smokers. CONCLUSIONS AND RELEVANCE Addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00345176.

Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement

OBJECTIVE To investigate the efficacy and safety of treating thick submacular hemorrhages with intravitreous tissue plasminogen activator (tPA) and pneumatic displacement. DESIGN Retrospective, noncomparative case series. PARTICIPANTS From 5 participating centers, 15 eligible patients had acute (<3 weeks) thick subretinal hemorrhage involving the center of the macula in eyes with pre-existing good visual acuity. Hemorrhages were secondary to age-related macular degeneration in 13 eyes and macroaneurysm and trauma in 1 eye each. METHODS The authors reviewed the medical records of 15 consecutive patients who received intravitreous injection of commercial tPA solution (25-100 microg in 0.1-0.2 ml) and expansile gas (0.3-0.4 ml of perfluoropropane or sulfur hexafluoride) for thrombolysis and displacement of submacular hemorrhage. After surgery, patients maintained prone positioning for 1 to 5 days (typically, 24 hours). MAIN OUTCOME MEASURES Degree of blood displacement from under the fovea, best postoperative visual acuity, final postoperative visual acuity, and surgical complications. RESULTS In 15 (100%) of 15 eyes, the procedure resulted in complete displacement of thick submacular hemorrhage out of the foveal area. Best postprocedure visual acuity improved by 2 lines or greater in 14 (93%) of 15 eyes. After a mean follow-up of 10.5 months (range, 4-19 months), final visual acuity improved by 2 lines or greater in 10 (67%) of 15 eyes and measured 20/80 or better in 6 (40%) of 15 eyes. Complications included breakthrough vitreous hemorrhage in three eyes and endophthalmitis in one eye. Four eyes developed recurrent hemorrhage 1 to 3 months after treatment, three of which were retreated with the same procedure. CONCLUSIONS Intravitreous injection of tPA and gas followed by brief prone positioning is effective in displacing thick submacular blood and facilitating visual improvement in most patients. The rate of serious complications appears low. Final visual outcomes are limited by progression of the underlying macular disease in many patients.

Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials.

PURPOSE To investigate the cause of visual acuity (VA) loss in patients with neovascular age-related macular degeneration (AMD) receiving monthly ranibizumab injections in the pivotal ranibizumab phase III trials. DESIGN Retrospective analysis. PARTICIPANTS The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the treatment of Neovascular AMD (MARINA) and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trials. METHODS Demographics and lesion characteristics at baseline and month 24 were compared in patients with ≥15 letters VA loss and patients with ≥15 letters VA gain from baseline to month 24. Additional evaluations of fundus photographs from these patients were performed to assess features of non-exudative AMD, such as geographic atrophy (GA) and retinal pigment epithelium (RPE) abnormalities. MAIN OUTCOME MEASURES Differences in lesion characteristics between patients who lost versus gained ≥15 letters of VA from baseline to month 24. RESULTS At month 24, 9% of ranibizumab-treated patients from MARINA and 10% of ranibizumab-treated patients from ANCHOR had lost ≥15 letters VA; 30% of ranibizumab-treated patients from MARINA and 38% of ranibizumab-treated patients from ANCHOR had gained ≥15 letters VA. Baseline characteristics associated with VA loss at month 24 included older age, better VA, and larger lesions. At month 24, an increased area of RPE abnormality was associated with VA loss in both the MARINA (P = 0.0008) and ANCHOR (P = 0.0046) trials. Increased total lesion area at month 24 was associated with VA loss in both trials. In MARINA, the increase in total lesion area was attributable to an increase in the angiographic designation of atrophic scar among VA losers (P = 0.0043), but in ANCHOR it was attributable to an increased area of choroidal neovascularization (CNV) (P = 0.039) but not an increased area of leakage (P = 0.17). Increased areas of GA, fibrosis, and hemorrhage were not associated with VA loss. CONCLUSIONS Vision loss after 2 years of monthly ranibizumab therapy was associated with lesion characteristics commonly associated with suppressed CNV, such as pigmentary abnormalities, atrophic scar, and the absence of leakage. Future VA improvements in patients receiving ranibizumab therapy may require preservation of photoreceptor and RPE function rather than strategies that target CNV.

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.

Associations Between Age-Related Nuclear Cataract and Lutein and Zeaxanthin in the Diet and Serum in the Carotenoids in the Age-Related Eye Disease Study (CAREDS), an Ancillary Study of the Women's Health Initiative

OBJECTIVE To evaluate associations between nuclear cataract (determined from slitlamp photographs between May 2001 and January 2004) and lutein and zeaxanthin in the diet and serum in patients between 1994 and 1998 and macula between 2001 and 2004. DESIGN A total of 1802 women aged 50 to 79 years in Iowa, Wisconsin, and Oregon with intakes of lutein and zeaxanthin above the 78th (high) and below the 28th (low) percentiles in the Womens Health Initiative Observational Study (1994-1998) were recruited 4 to 7 years later (2001-2004) into the Carotenoids in Age-Related Eye Disease Study. RESULTS Women in the group with high dietary levels of lutein and zeaxanthin had a 23% lower prevalence of nuclear cataract (age-adjusted odds ratio, 0.77; 95% confidence interval, 0.62-0.96) compared with those with low levels. Multivariable adjustment slightly attenuated the association (odds ratio, 0.81; 95% confidence interval, 0.65-1.01). Women in the highest quintile category of diet or serum levels of lutein and zeaxanthin as compared with those in the lowest quintile category were 32% less likely to have nuclear cataract (multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.48-0.97; P for trend = .04; and multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.47-0.98; P for trend = .01, respectively). Cross-sectional associations with macular pigment density were inverse but not statistically significant. CONCLUSIONS Diets rich in lutein and zeaxanthin are moderately associated with decreased prevalence of nuclear cataract in older women. However, other protective aspects of such diets may in part explain these relationships.

SCORE Study Report 1: Baseline Associations between Central Retinal Thickness and Visual Acuity in Patients with Retinal Vein Occlusion

OBJECTIVE To investigate the relationship between baseline center point retinal thickness measured by optical coherence tomography (OCT) and best-corrected visual acuity in eyes with macular edema associated with retinal vein occlusion and to investigate other factors associated with baseline visual acuity letter score. DESIGN The Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study includes 2 multicenter, randomized clinical trials: one evaluating participants with central retinal vein occlusion (CRVO) and the other evaluating participants with branch retinal vein occlusion (BRVO). PARTICIPANTS After omitting 17 participants with missing or unreliable OCT measurements, analyses proceeded with 665 enrolled SCORE Study participants (665 eyes), including 262 with CRVO and 403 with BRVO. METHODS At baseline, center point thickness was measured by OCT (Stratus OCT 3 [n=663] and OCT2 [n=2]; Carl Zeiss Meditech, Dublin, CA), and visual acuity was measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) methodology. MAIN OUTCOME MEASURES Center point thickness and best-corrected E-ETDRS visual acuity letter score. RESULTS The correlation coefficient for the association between baseline OCT-measured center point thickness and best-corrected E-ETDRS visual acuity letter score is -0.27 (95% confidence limit: -0.38 to -0.16) for participants in the CRVO trial and -0.28 (95% confidence limit: -0.37 to -0.19) in the BRVO trial. Regression modeling estimated the following decrease in baseline visual acuity letter score for every 100-microm increase in OCT-measured center point thickness: 1.7 letters (P=0.0007) for CRVO and 1.9 letters (P<0.0001) for BRVO. On the basis of multivariate regression models, baseline factors significantly associated (P<0.05, after adjusting for multiple testing) with baseline visual acuity letter score include age and duration of macular edema for CRVO participants and center point thickness and presence of cystoid spaces for BRVO participants. CONCLUSIONS The correlation between OCT-measured center point thickness and visual acuity letter score is modest. OCT-measured center point thickness represents a useful tool for the detection and monitoring of macular edema in retinal vein occlusion, but it cannot reliably substitute for visual acuity measurements.

Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4.

IMPORTANCE Age-related cataract is a leading cause of visual impairment in the United States. The prevalence of age-related cataract is increasing, with an estimated 30.1 million Americans likely to be affected by 2020. OBJECTIVE To determine whether daily oral supplementation with lutein/zeaxanthin affects the risk for cataract surgery. DESIGN, SETTING, AND PATIENTS The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, double-masked clinical trial, enrolled 4203 participants, aged 50 to 85 years, at risk for progression to advanced age-related macular degeneration. INTERVENTIONS Participants were randomly assigned to daily placebo; lutein/zeaxanthin, 10mg/2mg; omega-3 long-chain polyunsaturated fatty acids, 1 g; or a combination to evaluate the effects on the primary outcome of progression to advanced age-related macular degeneration. MAIN OUTCOMES AND MEASURES Cataract surgery was documented at annual study examination with the presence of pseudophakia or aphakia, or reported during telephone calls at 6-month intervals between study visits. Annual best-corrected visual acuity testing was performed. A secondary outcome of AREDS2 was to evaluate the effects of lutein/zeaxanthin on the subsequent need for cataract surgery. RESULTS A total of 3159 AREDS2 participants were phakic in at least 1 eye and 1389 of 6027 study eyes underwent cataract surgery during the study, with median follow-up of 4.7 years. The 5-year probability of progression to cataract surgery in the no lutein/zeaxanthin group was 24%. For lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratios for progression to cataract surgery was 0.96 (95% CI, 0.84-1.10; P = .54). For participants in the lowest quintile of dietary intake of lutein/zeaxanthin, the hazard ratio comparing lutein/zeaxanthin vs no lutein/zeaxanthin for progression to cataract surgery was 0.68 (95% CI, 0.48-0.96; P = .03). The hazard ratio for 3 or more lines of vision loss was 1.03 (95% CI, 0.93-1.13; P = .61 for lutein/zeaxanthin vs no lutein/zeaxanthin). CONCLUSIONS AND RELEVANCE Daily supplementation with lutein/zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00345176.

Genetic evidence for role of carotenoids in age-related macular degeneration in the carotenoids in age-related eye disease study (CAREDS)

PURPOSE We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS). METHODS Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid-related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC). RESULTS A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0-4.9). CONCLUSIONS Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD.

The prevalence of macular telangiectasia type 2 in the Beaver Dam eye study.

PURPOSE To examine the prevalence of macular telangiectasia type 2 and lesions characterizing it. DESIGN Population-based cohort study. METHODS setting: City and township of Beaver Dam, 1988-1990. study population: A total of 4790 people 43-86 years of age. observation procedure(s): Grading from stereoscopic fundus photographs to measure macular telangiectasia type 2. main outcome measure: Prevalent macular telangiectasia type 2. RESULTS Macular telangiectasia type 2 was present at baseline in 0.1% of the population (95% confidence interval [CI] 0.09, 0.1). The frequencies of loss of retinal transparency, crystals in the inner retinal layers, blunted retinal vessels, localized intraretinal pigment migration in the juxtafoveolar region, and presence of yellow deposits and lamellar holes in the foveal area in those without macular telangiectasia type 2 varied from 0.06% for retinal telangiectatic vessels to 1.2% for lamellar holes. Smoking was associated with pigment clumping (odds ratio [OR] per pack year 1.02; 95% CI 1.00, 1.03; P = .02), retinal pigment epithelial (RPE) depigmentation (OR 1.02 per pack year; 95%CI 1.00, 1.04; P = .02), loss of transparency (OR 1.02 per pack year; 95% CI 1.00, 1.03; P = .008), and the presence of a yellow spot in the fovea (OR 2.24 current vs past or never smoker; 95% CI 1.29, 3.89; P = .004), but not with presence of macular telangiectasia type 2 (OR 2.72; 95% CI 0.45, 16.28; P = .27). CONCLUSIONS The prevalence of macular telangiectasia type 2 (0.1%) is higher than previously thought. These data are useful in estimating the burden of this condition in the population. The role of smoking in the development of macular telangiectasia type 2 requires further study.

Genetic determinants of macular pigments in women the carotenoids in age-related eye disease study

PURPOSE To investigate genetic determinants of macular pigment optical density in women from the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Womens Health Initiative Observational Study. METHODS 1585 of 2005 CAREDS participants had macular pigment optical density (MPOD) measured noninvasively using customized heterochromatic flicker photometry and blood samples genotyped for 440 single nucleotide polymorphisms (SNPs) in 26 candidate genes related to absorption, transport, binding, and cleavage of carotenoids directly, or via lipid transport. SNPs were individually tested for associations with MPOD using least-squares linear regression. RESULTS Twenty-one SNPs from 11 genes were associated with MPOD (P ≤ 0.05) after adjusting for dietary intake of lutein and zeaxanthin. This includes variants in or near genes related to zeaxanthin binding in the macula (GSTP1), carotenoid cleavage (BCMO1), cholesterol transport or uptake (SCARB1, ABCA1, ABCG5, and LIPC), long-chain omega-3 fatty acid status (ELOVL2, FADS1, and FADS2), and various maculopathies (ALDH3A2 and RPE65). The strongest association was for rs11645428 near BCMO1 (βA = 0.029, P = 2.2 × 10(-4)). Conditional modeling within genes and further adjustment for other predictors of MPOD, including waist circumference, diabetes, and dietary intake of fiber, resulted in 13 SNPs from 10 genes maintaining independent association with MPOD. Variation in these single gene polymorphisms accounted for 5% of the variability in MPOD (P = 3.5 × 10(-11)). CONCLUSIONS Our results support that MPOD is a multi-factorial phenotype associated with variation in genes related to carotenoid transport, uptake, and metabolism, independent of known dietary and health influences on MPOD.