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Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.
Yeong, JL, Loveman, E, Colquitt, JL, Royle, P, Waugh, N, Lois, N
The Cochrane database of systematic reviews. 2020;(12):CD013154
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Abstract
BACKGROUND Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.
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AGE-RELATED MACULAR DEGENERATION AND THE RISK OF ALL-CAUSE AND CARDIOVASCULAR MORTALITY: A Meta-Analysis of Cohort Studies.
Xin, X, Sun, Y, Li, S, Xu, H, Zhang, D
Retina (Philadelphia, Pa.). 2018;(3):497-507
Abstract
PURPOSE We evaluated the association between age-related macular degeneration (AMD) and the risk of all-cause and cardiovascular mortality by meta-analyses of data from prospective studies. METHODS A literature search was performed in PubMed, Web of Science, Embase, Cocharne Library, and China National Knowledge Infrastructure for relevant articles published up to December 2016. We estimated hazard ratios with 95% confidence intervals with fixed-effect models and conducted meta-regression to explore the potential sources of heterogeneity. Small-study effect was estimated by Egger's test and funnel plot. RESULTS We identified 13 population-based prospective cohort studies that examined the relationship between AMD and all-cause and cardiovascular mortality. Overall, the hazard ratios (95% confidence intervals) of all-cause mortality and cardiovascular mortality associated with any AMD were 1.15 (1.05-1.27) and 1.05 (95% confidence intervals: 0.87-1.26), respectively. The risk of all-cause mortality and cardiovascular mortality associated with early AMD were 1.08 (1.00-1.18) and 1.05 (0.89-1.24), and the associations with late AMD were 1.23 (1.11-1.36) and 1.28 (1.04-1.57), respectively. No evidence of small-study effect was found. CONCLUSION This meta-analysis indicated that AMD, especially late AMD, was associated with increased risk of all-cause mortality and cardiovascular mortality based on comparisons with people who did not have AMD and who were of similar age and sex.
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The Association between the Lipids Levels in Blood and Risk of Age-Related Macular Degeneration.
Wang, Y, Wang, M, Zhang, X, Zhang, Q, Nie, J, Zhang, M, Liu, X, Ma, L
Nutrients. 2016;(10)
Abstract
Lipid metabolism may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with blood lipids. We performed a meta-analysis including a total of 19 studies to evaluate associations between blood lipids and this disease. The result reported that the high level of high-density lipoprotein cholesterol (HDL-C) obtained with an increment of 1 mmol/L could result in a significantly increase in the AMD risk of approximately 18% (relative risk (RR), 1.18; 95% confidence interval (CI), 1.01 to 1.35; I² = 53.8%; p = 0.007). High levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were significantly associated with a decreased risk of AMD (RRs ranging from 0.92 to 0.95; all p < 0.05). The stratified analysis based on AMD subtypes showed that these blood lipids were only significantly associated with the risk of early AMD (all p < 0.05). The association between the blood lipids and AMD risk did not differ substantially based on the other characteristics of the participants. A high HDL-C level was associated with an increased AMD risk, whereas participants with high TC, LDL-C, and TG concentrations may show a decreased risk for this disease. Further well-designed large studies are warranted to confirm the conclusions.
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Age-related macular degeneration and the incidence of cardiovascular disease: a systematic review and meta-analysis.
Wu, J, Uchino, M, Sastry, SM, Schaumberg, DA
PloS one. 2014;(3):e89600
Abstract
IMPORTANCE Research has indicated some shared pathogenic mechanisms between age-related macular degeneration (AMD) and cardiovascular disease (CVD). However, results from prior epidemiologic studies have been inconsistent as to whether AMD is predictive of future CVD risk. OBJECTIVE To systematically review population-based cohort studies of the association between AMD and risk of total CVD and CVD subtypes, coronary heart disease (CHD) and stroke. DATA SOURCES A systematic search of the PubMed and EMBASE databases and reference lists of key retrieved articles up to December 20, 2012 without language restriction. DATA EXTRACTION Two reviewers independently extracted data on baseline AMD status, risk estimates of CVD and methods used to assess AMD and CVD. We pooled relative risks using random or fixed effects models as appropriate. RESULTS Thirteen cohort studies (8 prospective and 5 retrospective studies) with a total of 1,593,390 participants with 155,500 CVD events (92,039 stroke and 62,737 CHD) were included in this meta-analysis. Among all studies, early AMD was associated with a 15% (95% CI, 1.08-1.22) increased risk of total CVD. The relative risk was similar but not significant for late AMD (RR, 1.17; 95% CI, 0.98-1.40). In analyses restricted to the subset of prospective studies, the risk associated with early AMD did not appreciably change; however, there was a marked 66% (95% CI, 1.31-2.10) increased risk of CVD among those with late AMD. CONCLUSION Whereas the results from all cohort studies suggest that both early and late AMD are predictive of a small increase in risk of future CVD, subgroup analyses limited to prospective studies demonstrate a markedly increased risk of CVD among people with late AMD. Retrospective studies using healthcare databases may have inherent methodological limitations that obscure such association. Additional prospective studies are needed to further elucidate the associations between AMD and specific CVD outcomes.
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Association between complement factor H Val62Ile polymorphism and age-related macular degeneration susceptibility: a meta-analysis.
Wang, X, Geng, P, Zhang, Y, Zhang, M
Gene. 2014;(2):306-12
Abstract
BACKGROUND An increasing body of studies has assessed the contribution of Val62Ile polymorphism to age-related macular degeneration (AMD) risk, but the exact association still remains uncertain. This meta-analysis was undertaken in order to further characterize the potential association between Val62Ile polymorphism and AMD risk in four different ethnic populations. METHODS A meta-analysis was performed using data available from 16 case-control studies evaluating correlation between the Val62Ile polymorphism and AMD in Caucasian, Chinese, Japanese and South Korean populations. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) of allele contrast and genotype contrast were estimated using the random-effects model. The Q-statistic test was used to identify heterogeneity, and the funnel plot was adopted to evaluate publication bias. RESULTS Sixteen studies involving a total of 11,400 subjects based on the search criteria were included in the meta-analysis. In overall populations, the Val62Ile polymorphism seemed to be associated with AMD (ORAA vs. GG=0.40, 95% CI=0.28-0.59; ORAA+GA vs. GG=0.72, 95% CI=0.64-0.80; ORAA vs. GC+GG=0.50, 95% CI=0.36-0.70; ORA vs. G=0.68, 95% CI=0.58-0.78; ORGA vs. GG=0.71, 95% CI=0.65-0.77). Similarly, subgroup analysis also revealed that this polymorphism was related to AMD in all ethnicities. CONCLUSIONS This meta-analysis suggested that Val62Ile polymorphism was associated with susceptibility to AMD.
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Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.
Holliday, EG, Smith, AV, Cornes, BK, Buitendijk, GH, Jensen, RA, Sim, X, Aspelund, T, Aung, T, Baird, PN, Boerwinkle, E, et al
PloS one. 2013;(1):e53830
Abstract
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
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Causes of vision loss worldwide, 1990-2010: a systematic analysis.
Bourne, RR, Stevens, GA, White, RA, Smith, JL, Flaxman, SR, Price, H, Jonas, JB, Keeffe, J, Leasher, J, Naidoo, K, et al
The Lancet. Global health. 2013;(6):e339-49
Abstract
BACKGROUND Data on causes of vision impairment and blindness are important for development of public health policies, but comprehensive analysis of change in prevalence over time is lacking. METHODS We did a systematic analysis of published and unpublished data on the causes of blindness (visual acuity in the better eye less than 3/60) and moderate and severe vision impairment ([MSVI] visual acuity in the better eye less than 6/18 but at least 3/60) from 1980 to 2012. We estimated the proportions of overall vision impairment attributable to cataract, glaucoma, macular degeneration, diabetic retinopathy, trachoma, and uncorrected refractive error in 1990-2010 by age, geographical region, and year. FINDINGS In 2010, 65% (95% uncertainty interval [UI] 61-68) of 32·4 million blind people and 76% (73-79) of 191 million people with MSVI worldwide had a preventable or treatable cause, compared with 68% (95% UI 65-70) of 31·8 million and 80% (78-83) of 172 million in 1990. Leading causes worldwide in 1990 and 2010 for blindness were cataract (39% and 33%, respectively), uncorrected refractive error (20% and 21%), and macular degeneration (5% and 7%), and for MSVI were uncorrected refractive error (51% and 53%), cataract (26% and 18%), and macular degeneration (2% and 3%). Causes of blindness varied substantially by region. Worldwide and in all regions more women than men were blind or had MSVI due to cataract and macular degeneration. INTERPRETATION The differences and temporal changes we found in causes of blindness and MSVI have implications for planning and resource allocation in eye care. FUNDING Bill & Melinda Gates Foundation, Fight for Sight, Fred Hollows Foundation, and Brien Holden Vision Institute.
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Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
Evans, JR, Lawrenson, JG
The Cochrane database of systematic reviews. 2012;:CD000254
Abstract
BACKGROUND It has been proposed that antioxidants may prevent cellular damage in the retina by reacting with free radicals that are produced in the process of light absorption. Higher dietary levels of antioxidant vitamins and minerals may reduce the risk of progression of age-related macular degeneration (AMD). OBJECTIVES The objective of this review was to assess the effects of antioxidant vitamin or mineral supplementation on the progression of AMD in people with AMD. SEARCH METHODS We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 8), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2012), EMBASE (January 1980 to August 2012), Allied and Complementary Medicine Database (AMED) (January 1985 to August 2012), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 20 August 2012. We searched the reference lists of identified reports and the Science Citation Index. We contacted investigators and experts in the field for details of unpublished studies. We also searched for systematic reviews of harms of vitamin supplements. SELECTION CRITERIA We included randomised trials comparing antioxidant vitamin or mineral supplementation (alone or in combination) to placebo or no intervention in people with AMD. DATA COLLECTION AND ANALYSIS Two authors assessed risk of bias and extracted data from the included trials. Where appropriate, we pooled data using a random-effects model unless three or fewer trials were available in which case we used a fixed-effect model. MAIN RESULTS Thirteen trials (6150 participants) were included in this review. Over half the participants (3640) were randomised in one trial (AREDS in the USA), which found a beneficial effect of antioxidant (beta-carotene, vitamin C and vitamin E) and zinc supplementation on progression to advanced AMD (adjusted odds ratio (OR) 0.68, 95% confidence interval (CI) 0.53 to 0.87) over an average of 6.3 years. People taking supplements were less likely to lose 15 or more letters of visual acuity (adjusted OR 0.77, 95% CI 0.62 to 0.96). The other trials, in general, had shorter follow-up (less than two years). No evidence for an effect of supplementation was seen in these smaller trials of shorter duration. Overall we considered the strength of the evidence to be moderate. We did not consider included trials, in general, to be at risk of bias, although we found it difficult to assess reporting biases. The main reason for downgrading the strength of the evidence was because, for several analyses, only one trial was included and therefore consistency of the findings could not be assessed. The included trials reported the following adverse effects: hospitalisation for genito-urinary problems was more common in people taking zinc and yellowing of skin was more common in people taking antioxidants. Systematic searching of the literature identified other potential harms of vitamin supplementation, in particular an increased risk of lung cancer in smokers associated with beta-carotene supplements, but we were unable to identify a good systematic review of the evidence for harms of nutritional supplementation. AUTHORS' CONCLUSIONS People with AMD may experience delay in progression of the disease with antioxidant vitamin and mineral supplementation. This finding is drawn from one large trial conducted in a relatively well-nourished American population. The generalisability of these findings to other populations is not known. Although generally regarded as safe, vitamin supplements may have harmful effects. A systematic review of the evidence on harms of vitamin supplements is needed.
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Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis.
Chakravarthy, U, Wong, TY, Fletcher, A, Piault, E, Evans, C, Zlateva, G, Buggage, R, Pleil, A, Mitchell, P
BMC ophthalmology. 2010;:31
Abstract
BACKGROUND Age-related macular degeneration (AMD) is the leading cause of blindness in Western countries. Numerous risk factors have been reported but the evidence and strength of association is variable. We aimed to identify those risk factors with strong levels of evidence which could be easily assessed by physicians or ophthalmologists to implement preventive interventions or address current behaviours. METHODS A systematic review identified 18 prospective and cross-sectional studies and 6 case control studies involving 113,780 persons with 17,236 cases of late AMD that included an estimate of the association between late AMD and at least one of 16 pre-selected risk factors. Fixed-effects meta-analyses were conducted for each factor to combine odds ratio (OR) and/or relative risk (RR) outcomes across studies by study design. Overall raw point estimates of each risk factor and associated 95% confidence intervals (CI) were calculated. RESULTS Increasing age, current cigarette smoking, previous cataract surgery, and a family history of AMD showed strong and consistent associations with late AMD. Risk factors with moderate and consistent associations were higher body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen. Risk factors with weaker and inconsistent associations were gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease, and serum total and HDL cholesterol and triglyceride levels. CONCLUSIONS Smoking, previous cataract surgery and a family history of AMD are consistent risk factors for AMD. Cardiovascular risk factors are also associated with AMD. Knowledge of these risk factors that may be easily assessed by physicians and general ophthalmologists may assist in identification and appropriate referral of persons at risk of AMD.
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Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
Evans, JR
The Cochrane database of systematic reviews. 2006;(2):CD000254
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Abstract
BACKGROUND It has been proposed that antioxidants may prevent cellular damage in the retina by reacting with free radicals that are produced in the process of light absorption. OBJECTIVES The objective of this review was to assess the effects of antioxidant vitamin or mineral supplementation, or both, on the progression of age-related macular degeneration (AMD). SEARCH STRATEGY We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2005, Issue 4); MEDLINE (1966 to January 2006); SIGLE (1980 to March 2005); EMBASE (1980 to January 2005); NRR (2005, Issue 4); AMED (1985 to January 2006); and PubMed (24 January 2006 covering last 60 days), reference lists of identified reports and the Science Citation Index. We contacted investigators and experts in the field for details of unpublished studies. SELECTION CRITERIA We included randomised trials comparing antioxidant vitamin or mineral supplemention (alone or in combination) to a control intervention in people with AMD. DATA COLLECTION AND ANALYSIS The author extracted data and assessed trial quality. Where appropriate, data were pooled using a random-effects model unless three or fewer trials were available in which case a fixed-effects model was used. MAIN RESULTS Eight trials were included in this review. The majority of people were randomised in one trial (AREDS in the USA) that found a beneficial effect of antioxidant (beta-carotene, vitamin C and vitamin E) and zinc supplementation on progression to advanced AMD (adjusted odds ratio 0.68, 99% confidence interval 0.49 to 0.93). People taking supplements were less likely to lose 15 or more letters of visual acuity (adjusted odds ratio 0.77, 99% confidence interval 0.58 to 1.03). Hospitalisation for genito-urinary problems was more common in people taking zinc and yellowing of skin was more common in people taking antioxidants. The other trials were, in general, small and the results were inconsistent. AUTHORS' CONCLUSIONS The evidence as to the effectiveness of antioxidant vitamin and mineral supplementation in halting the progression of AMD comes mainly from one large trial in the USA. The generalisability of these findings to other populations with different nutritional status is not known. Further large, well-conducted randomised controlled trials in other populations are required. Long-term harm from supplementation cannot be ruled out. Beta-carotene has been found to increase the risk of lung cancer in smokers; vitamin E has been associated with an increased risk of heart failure in people with vascular disease or diabetes.