K. A. Muldrew

Secondary outcomes in a clinical trial of carotenoids with coantioxidants versus placebo in early age-related macular degeneration.

PURPOSE To report the secondary outcomes in the Carotenoids with Coantioxidants in Age-Related Maculopathy trial. DESIGN Randomized double-masked placebo-controlled clinical trial (registered as ISRCTN 94557601). PARTICIPANTS Participants included 433 adults 55 years of age or older with early age-related macular degeneration (AMD) in 1 eye and late-stage disease in the fellow eye (group 1) or early AMD in both eyes (group 2). INTERVENTION An oral preparation containing lutein (L), zeaxanthin (Z), vitamin C, vitamin E, copper, and zinc or placebo. Best-corrected visual acuity (BCVA), contrast sensitivity (CS), Raman spectroscopy, stereoscopic colour fundus photography, and serum sampling were performed every 6 months with a minimum follow-up time of 12 months. MAIN OUTCOME MEASURES Secondary outcomes included differences in BCVA (at 24 and 36 months), CS, Raman counts, serum antioxidant levels, and progression along the AMD severity scale (at 12, 24, and 36 months). RESULTS The differential between active and placebo groups increased steadily, with average BCVA in the former being approximately 4.8 letters better than the latter for those who had 36 months of follow-up, and this difference was statistically significant (P = 0.04). In the longitudinal analysis, for a 1-log-unit increase in serum L, visual acuity was better by 1.4 letters (95% confidence interval, 0.3-2.5; P = 0.01), and a slower progression along a morphologic severity scale (P = 0.014) was observed. CONCLUSIONS Functional and morphologic benefits were observed in key secondary outcomes after supplementation with L, Z, and coantioxidants in persons with early AMD.

Further validation of the Daily Living Tasks Dependent on vision : identification of domains

Aim: To examine the Daily Living Tasks Dependent on Vision (DLTV), a visual function questionnaire for domain structure, and redundancy. Method: 235 subjects underwent full ophthalmic assessment and completed the DLTV questionnaire by interview. Principal component analysis with varimax rotation and item response theory (IRT) were used to assign the items to domains. The internal consistency of each domain was examined using Cronbach’s alpha. Redundancy was assessed by regressing each item in a domain against the remainder of items in that domain. Results: Four domains were identified. Domain 1 was formed by nine items, which after applying IRT were seen to be among the most difficult questions in the instrument. Domain 2 contained eight items, all of which fell in the easier half of the instrument on applying IRT. Domain 3 contained only three items, all of which were among the easier questions and appear to deal with peripheral vision function. Domain 4 consisted of two items dealing with adaptation to light and dark conditions. Cronbach’s alpha for each domain was 0.96, 0.93, 0.73, 0.66. Redundancy was found to be present in domain 1, which was therefore reduced by two items, with little effect on internal consistency. Conclusions: The authors believe using the domains identified in this report will optimise the information provided by patients on their ability to function on visually demanding tasks.

Visual outcome after antioxidant supplementation.

Dear Editor: In 2001, the National Eye Institute–funded Age-related Eye Disease Study (AREDS) published its findings. The AREDS was a double-masked, randomized, placebo-controlled trial of 4757 subjects over a period of 5 years that showed that supplementation with antioxidants vitamins C and E, -carotene, and zinc in combination resulted in a 25% relative reduction in the risk of progression from intermediate to advanced and visually consequential age-related macular degeneration (AMD). The AREDS supplement did not contain the macular pigment carotenoids lutein and zeaxanthin, compounds believed to confer protection against development and/or progression of AMD because of their antioxidant and/or optical (blue light-filtering) properties. There is an emerging body of opinion that deficiency of macular pigment might play an etiological role in the development of AMD. We report the results of the Carotenoids in Age-related Maculopathy study (ISRCTN number 94557601), a randomized, double-blind, placebo-controlled clinical trial of lutein and zeaxanthin with co-antioxidants versus placebo in persons at high risk of progression to late AMD. Participants were aged 55 years with features of early AMD in both eyes (group 1) or exhibiting late stage features of choroidal neovascularization or geographic atrophy in only 1 eye (group 2). Randomization was double masked and participants were assigned to receive an oral antioxidant preparation that consisted of a tablet taken twice a day to deliver a daily dose of 12 mg of lutein, 0.6 mg zeaxanthin, 15 mg d-tocopherol (vitamin E), 150 mg ascorbic acid (vitamin C), 20 mg zinc oxide, and 0.4 mg copper gluconate, or placebo. The levels of these components were lower than that used in AREDS owing to regulatory restrictions in the European Union. Of the 433 participants who entered the study, 216 participants were assigned to receive the active preparation and 217 placebo. Two hundred fifty-two of the participants belonged to group 1 contributing 2 study eyes to the analysis. The remaining 181 contributed a sole study eye. We originally chose the difference in photopic interferometric acuity between groups as the primary outcome measure at 12 months. However, this parameter was found to be unreliable and at the recommendation of the independent data and safety monitoring committee we changed it to best-corrected visual acuity (BCVA). Participants underwent a full, general physical examination, and collection of demographic information at baseline. These included measurement of height, weight, sitting blood pressure, and completion of a set of questionnaires that included information on diet and lifestyle. Ocular examinations were undertaken at all study visits, which occurred at baseline and at 6 monthly intervals, and included BCVA, photopic interferometry, contrast sensitivity, shape discrimination testing, fundus photography, and Raman spectroscopy. There were no imbalances in any of the measured baseline variables by treatment assignment. Eighty-eight participants (20%) exited the study before the 12-month visit and were equally distributed between the 2 arms. The mean change in BCVA was 0.1 (standard deviation [SD] 7.0) in the treatment group and 0.3 (SD 7.7) in the placebo group. This differential change was not significant. Although no difference in BCVA (which was the primary outcome measure) was found between the supplemented and placebo groups at 12 months, a number of secondary outcomes suggested functional benefits in the interventional arm and are consistent with emerging reports from other studies. These are the subject of a further detailed report.

Verteporfin Photodynamic Therapy Cohort Study: Report 1: Effectiveness and Factors Influencing Outcomes

PURPOSE To compare the visual outcomes after verteporfin photodynamic therapy (VPDT) administered in routine clinical practice with those observed in the Treatment of Age-related macular degeneration with Photodynamic therapy (TAP) trials and to quantify the effects of clinically important baseline covariates on outcome. DESIGN A prospective longitudinal study of patients treated with VPDT in 45 ophthalmology departments in the United Kingdom with expertise in the management of neovascular age-related macular degeneration (nAMD). PARTICIPANTS Patients with wholly or predominantly classic choroidal neovascularization (CNV) of any cause with a visual acuity >or=20/200 in the eye to be treated. METHODS Refracted best-corrected visual acuity (BCVA) and contrast sensitivity were measured in VPDT-treated eyes at baseline and subsequent visits. Eyes were retreated at 3 months if CNV was judged to be active. Baseline angiograms were graded to quantify the percentages of classic and occult CNV. Treated eyes were categorized as eligible or ineligible for TAP, or unclassifiable. MAIN OUTCOME MEASURES Best-corrected visual acuity and contrast sensitivity during 1 year of follow-up after initial treatment. RESULTS A total of 7748 treated patients were recruited. Data from 4043 patients with a diagnosis of nAMD were used in the present analysis. Reading center determination of lesion type showed that 87% were predominantly classic CNV. Eyes received 2.4 treatments in year 1 and 0.4 treatments in year 2. Deterioration of BCVA over 1 year was similar to that observed in the VPDT arms of the TAP trials and was not influenced by TAP eligibility classification. Best-corrected visual acuity deteriorated more quickly in current smokers; with increasing proportion of classic CNV, increasing age, and better baseline BCVA; and when the fellow eye was the better eye. CONCLUSIONS Patients in the cohort who would have been eligible for the TAP trials demonstrated deterioration in BCVA similar to VPDT-treated TAP participants but with fewer treatments. Clinical covariates with a significant impact on BCVA outcomes were identified.

Genotype-phenotype associations in neovascular age-related macular degeneration.

Purpose: To examine associations between recognized genetic susceptibility loci and angiographic subphenotypes of the neovascular variant of age-related macular degeneration (nvAMD). Methods: Participants (247 nvAMD, 52 early age-related macular degeneration [AMD], and 103 controls) were genotyped (complement factor H and ARMS2/HTRA1). nvAMD participants were assigned to one of two subcategories: mainly classic or mainly occult (based on the proportions of classic and occult choroidal neovascularization). nvAMD and early AMD were reassigned to two groups based on the extent and severity of drusen (retinal pigment epithelium dysfunction or not). Univariate and multivariate analysis were used to examine for associations between participant characteristics and genetic loci after adjusting for age, smoking status, and history of cardiovascular disease. Results: Univariate analysis confirmed the known significant associations between AMD stage and age, hypertension, and a history of cardiovascular disease. Those with retinal pigment epithelium dysfunction (F = 5.46; P = 0.02) or a positive smoking history (F = 3.89; P = 0.05) were more likely to have been classified as having mainly an occult rather than a mainly classic lesion. Multivariate analysis showed that significant associations were noted with the number of ARMS2/HTRA1 risk alleles (P < 0.001), smoking (ever vs. never) (P = 0.03), and cardiovascular disease (P = 0.01). With early AMD as the reference category, the mainly classic group exhibited significant associations with the number of ARMS2/HTRA1 risk alleles present (P < 0.001) and cardiovascular disease (P = 0.02). When mainly classic was compared with mainly occult, the latter was associated with the ARMS2/HTRA1 locus (P = 0.02). Conclusion: ARMS2/HTRA1 risk genotype may play a role in determining neovascular subphenoptye, whereas genetics/demographics, smoking, and systemic health factors contribute to the development of advanced AMD in the presence of early AMD.

Prevalence of age-related macular degeneration associated genetic risk factors and 4-year progression data in the Irish population

Background/aims Age-related macular degeneration (AMD) is estimated to affect 196 million people >50 years old globally. Prevalence of AMD-associated genetic risk factors and rate of disease progression are unknown in Ireland. Methods Prevalence of AMD-associated genetic risk variants, complement factor H (CFH) rs1061170, age-related maculopathy susceptibility 2 (ARMS2) rs10490924, component 3 (C3) rs2230199, complement factor B (CFB) rs641153 and superkiller viralicidic activity 2-like (SKIV2L) rs429608 and 4-year progression data in a population-representative cohort (The Irish Longitudinal study on Ageing (TILDA)) were assessed. 4473 participants ≥50 years were assessed. 4173 had no disease n=1843; 44% male and n=2330; 56% female, mean age 60±9.0, 300 had AMD n=136; 45% male and n=164; 55% female, mean age 64±9.0. A 4-year follow-up was undertaken with 66% of AMD cases attending. Progression and regression from early to late AMD were measured. Genetic association as indicators of disease and as predictors of progression were assessed by multinomial logistic regression. Results Older age and the presence of CFH and ARMS2 risk alleles are two main risk factors associated with the prevalence of AMD in the TILDA cohort. 23% progressed to a higher grade of AMD. Carriers of CFH risk allele showed a strong association for disease progression. Heterozygosity for ARMS2 risk allele predicted progression to late AMD. 75% of those who progressed from early to late disease had soft drusen and hyperpigmentation at baseline. Conclusions The prevalence of risk-associated genes and 4-year progression rates of AMD in this Ireland cohort are comparable with other Caucasian populations. CFH Y402H is associated with disease progression, with soft drusen and hyperpigmentation as high-risk features.