A comparison of methods to estimate the survivor average causal effect in the presence of missing data: a simulation study.

BACKGROUND: Attrition due to death and non-attendance are common sources of bias in studies of age-related diseases. A simulation study is presented to compare two methods for estimating the survivor average causal effect (SACE) of a binary exposure (sex-specific dietary iron intake) on a binary outcome (age-related macular degeneration, AMD) in this setting. METHODS: A dataset of 10,000 participants was simulated 1200 times under each scenario with outcome data missing dependent on measured and unmeasured covariates and survival. Scenarios differed by the magnitude and direction of effect of an unmeasured confounder on both survival and the outcome, and whether participants who died following a protective exposure would also die if they had not received the exposure (validity of the monotonicity assumption). The performance of a marginal structural model (MSM, weighting for exposure, survival and missing data) was compared to a sensitivity approach for estimating the SACE. As an illustrative example, the SACE of iron intake on AMD was estimated using data from 39,918 participants of the Melbourne Collaborative Cohort Study. RESULTS: The MSM approach tended to underestimate the true magnitude of effect when the unmeasured confounder had opposing directions of effect on survival and the outcome. Overestimation was observed when the unmeasured confounder had the same direction of effect on survival and the outcome. Violation of the monotonicity assumption did not increase bias. The estimates were similar between the MSM approach and the sensitivity approach assessed at the sensitivity parameter of 1 (assuming no survival bias). In the illustrative example, high iron intake was found to be protective of AMD (adjusted OR 0.57, 95% CI 0.40-0.82) using complete case analysis via traditional logistic regression. The adjusted SACE odds ratio did not differ substantially from the complete case estimate, ranging from 0.54 to 0.58 for each of the SACE methods. CONCLUSIONS: On average, MSMs with weighting for exposure, missing data and survival produced biased estimates of the SACE in the presence of an unmeasured survival-outcome confounder. The direction and magnitude of effect of unmeasured survival-outcome confounders should be considered when assessing exposure-outcome associations in the presence of attrition due to death.

Association of Mortality with Ocular Diseases and Visual Impairment in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13.

PURPOSE: To evaluate the association of mortality with visual acuity (VA) impairment, age-related macular degeneration (AMD), and cataract surgery. DESIGN: Cohort study. PARTICIPANTS: Participants with at least intermediate AMD enrolled in a randomized controlled clinical trial of lutein/zeaxanthin and/or omega-3 fatty acids, the Age-Related Eye Disease Study 2 (AREDS2), for treatment of AMD and cataract. METHODS: Baseline and annual eye examinations included best-corrected visual acuity (BCVA) assessments, slit-lamp examinations, and stereoscopic fundus photographs that were centrally graded for development of late AMD (central geographic atrophy or neovascular AMD) or pseudophakia. Cause-specific mortality was determined on the basis of the International Classification of Diseases 9th or 10th Revision codes. Risk of all-cause and cause-specific mortality was assessed with Cox proportional hazards models adjusted for age, sex, AMD severity, VA, history of cataract surgery, and assigned AREDS2 study treatment. Analyses included baseline covariates: race, education, smoking status, diabetes, and cardiovascular disease. RESULTS: During follow-up (median 5 years), 368 (9%) of the 4203 AREDS2 participants died. Participants with neovascular AMD in 1 eye at baseline had a statistically significant increased risk for mortality compared with participants with no or few drusen (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.21-2.01; P < 0.001). Poorer survival was associated with bilateral cataract surgery before enrollment compared with baseline bilateral phakia (HR, 1.63; 95% CI, 1.29-2.07; P < 0.001) and with BCVA of less than 20/40 compared with participants with 20/40 or better (HR, 1.56; 95% CI, 1.06-2.30; P = 0.024), adjusted for age, sex, and statistically significant covariates. Participants who received antivascular endothelial growth factor therapies for neovascular AMD had decreased mortality compared with those who did not (HR, 0.71; 95% CI, 0.57-0.88; P = 0.002). The association between all-cause mortality and AREDS2 treatment whether assessing the main or individual treatment effect was not significantly different (omega-3 fatty acids main effect HR, 1.18; 95% CI, 0.96-1.45; P = 0.12; lutein/zeaxanthin main effect HR, 1.04; 95% CI, 0.85-1.28; P = 0.71). CONCLUSIONS: In AREDS2, the presence of late AMD, bilateral cataract surgery, and VA less than 20/40 was associated with decreased survival. However, oral supplementation with omega-3 fatty acids, lutein plus zeaxanthin, zinc, or beta-carotene had no statistically significant impact on mortality.

Age-related macular degeneration and mortality in community-dwelling elders: the age, gene/environment susceptibility Reykjavik study.

OBJECTIVE: To investigate the association between age-related macular degeneration (AMD) and mortality in older persons. DESIGN: Population-based prospective cohort study. PARTICIPANTS: Participants 67 to 96 years of age (43.1% male) enrolled between 2002 and 2006 in the Age, Gene/Environment Susceptibility-Reykjavik Study. METHODS: Retinal photographs of the macula were acquired digitally and evaluated for the presence of AMD lesions using the Wisconsin Age-Related Maculopathy grading scheme. Mortality was assessed prospectively through 2013 with cause of death available through 2009. The association between AMD and death, resulting from any cause and specifically cardiovascular disease (CVD), was examined using Cox proportional hazards regression with age as the time scale, adjusted for significant risk factors and comorbid conditions. To address a violation in the proportional hazards assumption, analyses were stratified into 2 groups based on the mean age at death (83 years). MAIN OUTCOME MEASURES: Mortality resulting from all causes and CVD. RESULTS: Among 4910 participants, after a median follow-up of 8.6 years, 1742 died (35.5%), of whom 614 (35.2%) had signs of AMD at baseline. Cardiovascular disease was the cause of death for 357 people who died before the end of 2009, of whom 144 (40%) had AMD (101 with early disease and 43 with late disease). After considering covariates, including comorbid conditions, having early AMD at any age or having late AMD in individuals younger than 83 years (n = 4179) were not associated with all-cause or CVD mortality. In individuals 83 years of age and older (n = 731), late AMD was associated significantly with increased risk of all-cause mortality (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.20-2.57) and CVD-related mortality (HR, 2.37; 95% CI, 1.41-3.98). In addition to having AMD, older individuals who died were more likely to be male and to have low body mass index, impaired cognition, and microalbuminuria. CONCLUSIONS: Competing risk factors and concomitant conditions are important in determining mortality risk resulting from AMD. Individuals with early AMD are not more likely to die than peers of comparable age. Late AMD becomes a predictor of mortality by the mid-octogenarian years.

Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration.

BACKGROUND: Neovascular age-related macular degeneration (AMD) is the leading cause of legal blindness in elderly populations of industrialised countries. Bevacizumab (Avastin®) and ranibizumab (Lucentis®) are targeted biological drugs (a monoclonal antibody) that inhibit vascular endothelial growth factor, an angiogenic cytokine that promotes vascular leakage and growth, thereby preventing its pathological angiogenesis. Ranibizumab is approved for intravitreal use to treat neovascular AMD, while bevacizumab is approved for intravenous use as a cancer therapy. However, due to the biological similarity of the two drugs, bevacizumab is widely used off-label to treat neovascular AMD. OBJECTIVES: To assess the systemic safety of intravitreal bevacizumab (brand name Avastin®; Genentech/Roche) compared with intravitreal ranibizumab (brand name Lucentis®; Novartis/Genentech) in people with neovascular AMD. Primary outcomes were death and All serious systemic adverse events (All SSAEs), the latter as a composite outcome in accordance with the International Conference on Harmonisation Good Clinical Practice. Secondary outcomes examined specific SSAEs: fatal and non-fatal myocardial infarctions, strokes, arteriothrombotic events, serious infections, and events grouped in some Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOC). We assessed the safety at the longest available follow-up to a maximum of two years. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE and other online databases up to 27 March 2014. We also searched abstracts and clinical study presentations at meetings, trial registries, and contacted authors of included studies when we had questions. SELECTION CRITERIA: Randomised controlled trials (RCTs) directly comparing intravitreal bevacizumab (1.25 mg) and ranibizumab (0.5 mg) in people with neovascular AMD, regardless of publication status, drug dose, treatment regimen, or follow-up length, and whether the SSAEs of interest were reported in the trial report. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and assessed the risk of bias for each study. Three authors independently extracted data.We conducted random-effects meta-analyses for the primary and secondary outcomes. We planned a pre-specified analysis to explore deaths and All SSAEs at the one-year follow-up. MAIN RESULTS: We included data from nine studies (3665 participants), including six published (2745 participants) and three unpublished (920 participants) RCTs, none supported by industry. Three studies excluded participants at high cardiovascular risk, increasing clinical heterogeneity among studies. The studies were well designed, and we did not downgrade the quality of the evidence for any of the outcomes due to risk of bias. Although the estimated effects of bevacizumab and ranibizumab on our outcomes were similar, we downgraded the quality of the evidence due to imprecision.At the maximum follow-up (one or two years), the estimated risk ratio (RR) of death with bevacizumab compared with ranibizumab was 1.10 (95% confidence interval (CI) 0.78 to 1.57, P value = 0.59; eight studies, 3338 participants; moderate quality evidence). Based on the event rates in the studies, this gives a risk of death with ranibizumab of 3.4% and with bevacizumab of 3.7% (95% CI 2.7% to 5.3%).For All SSAEs, the estimated RR was 1.08 (95% CI 0.90 to 1.31, P value = 0.41; nine studies, 3665 participants; low quality evidence). Based on the event rates in the studies, this gives a risk of SSAEs of 22.2% with ranibizumab and with bevacizumab of 24% (95% CI 20% to 29.1%).For the secondary outcomes, we could not detect any difference between bevacizumab and ranibizumab, with the exception of gastrointestinal disorders MedDRA SOC where there was a higher risk with bevacizumab (RR 1.82; 95% CI 1.04 to 3.19, P value = 0.04; six studies, 3190 participants).Pre-specified analyses of deaths and All SSAEs at one-year follow-up did not substantially alter the findings of our review.Fixed-effect analysis for deaths did not substantially alter the findings of our review, but fixed-effect analysis of All SSAEs showed an increased risk for bevacizumab (RR 1.12; 95% CI 1.00 to 1.26, P value = 0.04; nine studies, 3665 participants): the meta-analysis was dominated by a single study (weight = 46.9%).The available evidence was sensitive to the exclusion of CATT or unpublished results. For All SSAEs, the exclusion of CATT moved the overall estimate towards no difference (RR 1.01; 95% CI 0.82 to 1.25, P value = 0.92), while the exclusion of LUCAS yielded a larger RR, with more SSAEs in the bevacizumab group, largely driven by CATT (RR 1.19; 95% CI 1.06 to 1.34, P value = 0.004). The exclusion of all unpublished studies produced a RR of 1.12 for death (95% CI 0.78 to 1.62, P value = 0.53) and a RR of 1.21 for SSAEs (95% CI 1.06 to 1.37, P value = 0.004), indicating a higher risk of SSAEs in those assigned to bevacizumab than ranibizumab. AUTHORS' CONCLUSIONS: This systematic review of non-industry sponsored RCTs could not determine a difference between intravitreal bevacizumab and ranibizumab for deaths, All SSAEs, or specific subsets of SSAEs in the first two years of treatment, with the exception of gastrointestinal disorders. The current evidence is imprecise and might vary across levels of patient risks, but overall suggests that if a difference exists, it is likely to be small. Health policies for the utilisation of ranibizumab instead of bevacizumab as a routine intervention for neovascular AMD for reasons of systemic safety are not sustained by evidence. The main results and quality of evidence should be verified once all trials are fully published.

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.

Bilateral intravitreal injection of antivascular endothelial growth factor therapy.

PURPOSE: The purpose of this study was to review adverse events and patient preference after bilateral intravitreal injection of antibodies to vascular endothelial growth factor. METHODS: A retrospective case-control study. Patients with exudative age-related macular degeneration who received intravitreal antivascular endothelial growth factor agent injections in both eyes (bilateral group) on the same day over a 23-month period were compared with patients who received injections in only 1 eye. The occurrence of endophthalmitis, cerebrovascular accident, myocardial infarction, death, patient discomfort, and patient preference was compared between the two groups. RESULTS: One hundred and two patients received an average of 4.43 bilateral injections (range 1-13). A case-control group of 102 patients received an average of 10.2 unilateral injections, (range 2-28). Bevacizumab was injected 45.5%, ranibizumab 45.5%, and a combination of bevacizumab and ranibizumab 9% of the time for bilateral injections. Bevacizumab was used 50.3% and ranubizumab 49.7% of the time in unilateral injections. The follow-up of both groups averaged 18.4 months (range 4.7-36.5 months). There were no cases of endophthalmitis or cerebrovascular accident in either group. There was a single case of myocardial infarction in each group. There were two deaths in the bilateral group and three deaths in the unilateral group. More than 90% strongly preferred bilateral injections to unilateral injections. CONCLUSION: Bilateral injections of antivascular endothelial growth factor agents on the same day did not increase the rate of adverse events and was preferred by the majority of patients.

Age-related macular degeneration, anti-vascular endothelial growth factor agents, and short-term mortality: a postmarketing medication safety and surveillance study.

PURPOSE: To compare short-term (1 year) survival of subjects treated for exudative age-related macular degeneration (AMD) with those with AMD who received no treatment. METHODS: This was a case-control study. Beneficiaries of the Veterans Health Administration aged ≥55 years with a diagnosis of AMD in fiscal years 2007-2009 were included in this study. Veterans Health Administration clinical and pharmacy data sets were linked with a national Veterans Health Administration mortality registry. Anti-vascular endothelial growth factor exposure was identified through pharmacy records, coupled to procedure code for intravitreous injection and diagnosis code of exudative AMD. Control group consisted of patients with coded diagnosis of dry AMD and no pharmacy claims for case-defining medications. Cox proportional hazard model was adjusted for age, gender, number of injections, and ocular and medical comorbidities. The main outcome measure was hazard of death according to medication exposure. RESULTS: A total of 3,210 patients received intravitreous injections for exudative AMD. There were 117,364 nonexposed patients with dry AMD. Twelve-month all-cause mortality in the exposed and control groups were 3.9% and 4.5%, respectively. When adjusted for age, gender, and ocular and medical comorbidities, the death hazard was 0.89 (95% confidence interval, 0.74-1.06). The risk of all-cause mortality was similar for patients receiving bevacizumab and ranibizumab. CONCLUSION: Twelve-month all-cause mortality in a population of predominately men with exudative AMD and a high prevalence of medical comorbidities was unaffected by exposure to therapeutic levels of vitreous bevacizumab and ranibizumab. Commonly used anti-vascular endothelial growth factor agents for exudative AMD do not adversely impact short-term survival in men.

Association of Drusen Phenotype in Age-Related Macular Degeneration from Human Eye-Bank Eyes to Disease Stage and Cause of Death.

PURPOSE: To stage maculopathy, assess and quantify drusen, determine drusen subtype frequency, and compare subtypes with age-related macular degeneration (AMD) stage and cause of death using an eye-bank model of AMD. DESIGN: Cross-sectional study. PARTICIPANTS: Two thousand ninety-two human eyes from 1067 eye-bank donors, selected from a population at risk for AMD. METHODS: We analyzed donor eye tissue images (2005-2020) using both the 4- and 9-step Minnesota Grading System (MGS), an AMD grading system for eye-bank eyes corresponding to the Age-Related Eye Disease Study classification. The 9-step MGS quantifies total drusen area, hyperpigmentation, and depigmentation. We analyzed reticular pseudodrusen (RPD), basal laminar drusen (BLD), and calcified drusen (CaD) frequency within this population and explored associations with AMD stage, donor age, gender, and cause of death. Statistical analyses were performed using Wilcoxon rank-sum and chi-square tests. Testing encompassed staging eye-bank eyes using MGS analysis. MAIN OUTCOME MEASURES: Drusen subtype frequency associations with AMD stage and cause of death. RESULTS: We detected RPD in 228 (13%), BLD in 131 (7%), and CaD in 84 (5%) of the examined eyes (n = 1777). All subtypes were associated with advanced AMD (RPD: odds ratio [OR], 3.4 [95% confidence interval (CI), 2.5-4.5; P < 0.0001]; BLD: OR, 2.2 [95% CI, 1.5-3.2; P < 0.0001]; and CaD: OR, 39.1 [95% CI, 16.8-91.0; P < 0.0001]). Only the RPD subtype was associated statistically with cardiovascular death when compared with those without cardiovascular death (48% vs. 32%; OR, 2.0 [95% CI, 1.4-2.9]; P = 0.0002). CONCLUSIONS: In a large group of eye-bank eyes selected from a population at risk for AMD and graded using the 4-step and 9-step MGS, RPD, BLD, and especially CaD were associated strongly with advanced AMD. The RPD subtype was associated with a cardiovascular cause of death and may represent an ophthalmologic biomarker for cardiovascular disease.

Insights From Survival Analyses During 12 Years of Anti-Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration.

Importance: Although multiple imputation models for missing data and the use of mixed-effects models generally provide better outcome estimates than using only observed data or last observation carried forward in clinical trials, such approaches usually cannot be applied to visual outcomes from retrospective analyses of clinical practice settings, also called real-world outcomes. Objective: To explore the potential usefulness of survival analysis techniques for retrospective clinical practice visual outcomes. Design, Setting, and Participants: This retrospective cohort study covered a 12-year observation period at a tertiary eye center. Of 10 744 eyes with neovascular age-related macular degeneration receiving anti-vascular endothelial growth factor (VEGF) therapy between October 28, 2008, and February 1, 2020, 7802 eyes met study criteria (treatment-naive, first-treated eyes starting anti-VEGF therapy). Eyes were excluded from the analysis if they received photodynamic therapy or macular laser, any previous anti-VEGF therapy, treatment with anti-VEGF agents other than ranibizumab or aflibercept, or had an unknown date or visual acuity (VA) value at first injection. Main Outcomes and Measures: Kaplan-Meier estimates and Cox proportional hazards modeling were used to consider VA reaching an Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 70 (Snellen equivalent, 20/40) or better, duration of VA sustained at or better than 70 (20/40), and VA declining to 35 (20/200) or worse. Results: A total of 7802 patients (mean [SD] age, 78.7 [8.8] years; 4776 women [61.2%]; and 4785 White [61.3%]) were included in the study. The median time to attaining a VA letter score greater than or equal to 70 (20/40) was 2.0 years (95% CI, 1.87-2.32) after the first anti-VEGF injection. Predictive features were baseline VA (hazard ratio [HR], 1.43 per 5 ETDRS letter score or 1 line; 95% CI, 1.40-1.46), baseline age (HR, 0.88 per 5 years; 95% CI, 0.86-0.90), and injection number (HR, 1.12; 95% CI, 1.10-1.15). Of the 4439 of 7802 patients (57%) attaining this outcome, median time sustained at an ETDRS letter score of 70 (20/40) or better was 1.1 years (95% CI, 1.1-1.2). Conclusions and Relevance: In this cohort study, patients with neovascular age-related macular degeneration beginning anti-VEGF therapy were more likely to experience positive visual outcomes within the first 2.0 years after treatment, typically maintaining this outcome for 1.1 years but then deteriorating to poor vision within 8.7 years. These findings demonstrate the potential usefulness of the proposed analyses. This data set, combined with the statistical approach for retrospective analyses, may provide long-term prognostic information for patients newly diagnosed with this condition.

Association of Age-Related Macular Degeneration With Risk of All-Cause and Specific-Cause Mortality in the National Health and Nutrition Examination Survey, 2005 to 2008.

Importance: Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment and blindness in the United States if subretinal neovascularization is left untreated. Knowledge of the association between AMD and survival is informative for underlying mechanisms of AMD. Objective: To examine the association between AMD and risk of all-cause and specific-cause mortality in a representative US sample. Design, Setting, and Participants: This population-based prospective cohort study included 5603 participants 40 years or older who responded to the National Health and Nutrition Examination Survey (NHANES) in the 2005-2008 phase. Retinal photographs were graded as early, late, or no AMD. All analyses accounted for the complex and stratified design of NHANES with weighted data. Risks of all-cause mortality were assessed with Cox proportional hazards regression models; risks of specific-cause mortality, with Fine and Gray competing risks regression models. Time to death was counted from baseline to date of death or December 31, 2011, whichever came first. Data analysis was conducted from April 1 through 30, 2018. Exposures: Age-related macular degeneration status as determined by digital fundus images. Main Outcomes and Measures: Mortality resulting from all causes and specific causes until December 31, 2011. Results: Among the 5603 participants (52.6% female [n = 2793] and 77.1% white [n = 3017]; mean [SE] age, 56.4 [0.4] years), weighted prevalence of any AMD was 6.6%, with 386 (5.8%) having early AMD and 55 (0.8%) having late AMD. After a median follow-up of 4.5 years (interquartile range, 3.6-5.6 years), 433 (5.3%) died of all causes, of whom 361 (83.1%) had no AMD, 54 (11.5%) had signs of early AMD, 18 (5.4%) had signs of late AMD, and 72 (16.9%) had any AMD at baseline. Overall, unadjusted all-cause and specific-cause mortality rates were higher for those participants who had early, late, or any AMD compared with no AMD. However, after adjusting confounding factors, only late AMD was associated with more than a doubling of all-cause mortality (hazard ratio [HR], 2.01; 95% CI, 1.00-4.03) and more than a 3-fold higher risk of mortality due to causes other than cardiovascular disease and cancer (HR, 3.42; 95% CI, 1.38-8.49). No association was identified between AMD presence or early AMD and all-cause or specific-cause mortality. Conclusions and Relevance: In this study's findings, only late AMD was independently associated with all-cause mortality and mortality due to causes other than cardiovascular disease and cancer, indicating that late AMD may be a marker of biological aging. Alternatively, this association may be due to unmeasured or inadequately assessed confounding factors for late AMD.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES OF TORPEDO MACULOPATHY.

BACKGROUND/PURPOSE: To investigate the retinal and choroidal vasculature in patients with torpedo maculopathy with optical coherence tomography-angiography (OCT-A). METHODS: Retrospective case series of four patients who were examined at the department of Ophthalmology at the University Hospital Bern. Main Outcome was the lesion size over time in OCT-A and fundus autofluorescence. RESULTS: Three patients had Type I and 1 patient had Type II torpedo maculopathy. Torpedo maculopathy lesion size remained stable in all patients over a mean period of observation of three years in OCT-A and fundus autofluorescence. The choriocapillaris network was attenuated focally within the lesion in OCT-A in all four cases. The lesion size in fundus autofluorescence was 2.77 mm and therefore comparable with the lesion size in OCT-A of 2.75 mm. CONCLUSION: OCT-A signal of the choriocapillaris was reduced within the cleft in both types of torpedo maculopathy. Whether the changes represent the primary site of malformation or whether these findings are the consequence of a defect in the retinal pigment epithelium remains speculative.

Association of Age-related Macular Degeneration With Mortality in Patients With Acquired Immunodeficiency Syndrome; Role of Systemic Inflammation.

PURPOSE: To evaluate the relationships among age-related macular degeneration (AMD), mortality, and biomarkers of systemic inflammation in patients with acquired immunodeficiency syndrome (AIDS). DESIGN: Case-control study. METHODS: In participants with intermediate-stage AMD at enrollment in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) and 2:1 controls matched for age and sex, cryopreserved baseline plasma specimens were assayed for biomarkers of inflammation, including high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, interferon-γ inducible protein (IP)-10, soluble CD14 (sCD14), soluble CD163 (sCD163), kynurenine/tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP). Main outcome measure was mortality. RESULTS: The study included 189 patients with AMD and 385 controls. In the unadjusted analysis, AMD was associated with mortality (hazard ratio [HR] 1.48; 95% confidence interval [CI] 1.02, 2.15; P = .04). In an adjusted analysis, CRP (HR 1.36; 95% CI 1.08, 1.71; P = .009), IL-6 (HR 1.45; 95% CI 1.11, 1.90; P = .006), and IP-10 (HR 1.41; 95% CI 1.08, 1.84; P = .01) were associated with mortality. In a Cox regression analysis adjusted for human immunodeficiency virus load, blood CD4+ T cell level, CRP, IL-6, and IP-10, the association of AMD with mortality was attenuated (HR 1.08; 95% CI 0.73, 1.59; P = .70), primarily by the addition of the inflammatory biomarkers. CONCLUSIONS: These data suggest that the increased mortality observed in patients with AIDS with AMD is, at least in part, a result of systemic inflammation.

Age-related macular degeneration and mortality: the Beijing eye study.

PURPOSE: To assess the association between age-related macular degeneration (AMD) and mortality in a population-based setting. PROCEDURES: At baseline in 2001, the Beijing Eye Study examined 4,378 subjects for AMD with a detected frequency of 110/4,378 (2.5%) subjects for early AMD and of 12/4,378 (0.3%) subjects for late AMD. In 2006, all study participants were re-invited for a follow-up examination. RESULTS: Out of the 4,378 subjects, 3,218 (73.5%) returned for a follow-up examination while 138 (3.2%) were dead and 1,022 (23.3%) did not agree to be re-examined or had moved away. Early AMD and late AMD were not significantly associated with mortality (p = 0.40 and 0.33, respectively), neither in univariate analysis nor in multivariate analysis. CONCLUSIONS: AMD may not be associated with an increased mortality in adult Chinese.

Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study.

PURPOSE: To describe the 15-year cumulative incidence of signs of early and late age-related macular degeneration (AMD). DESIGN: Population-based cohort study. PARTICIPANTS: We included 3917 persons, 43 to 86 years of age at the time of a baseline examination in 1988 through 1990 and with information collected in follow-up in 1993 through 1995, and/or 1998 through 2000, and/or 2003 through 2005. METHODS: Grading of stereoscopic fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. MAIN OUTCOME MEASURES: Cumulative incidence of drusen type and size, pigmentary abnormalities, geographic atrophy, and exudative AMD accounting for competing risk of death. RESULTS: The 15-year cumulative incidence was 14.3% for early AMD (the presence of either soft indistinct drusen or the presence of pigmentary abnormalities together with any type of drusen) and 3.1% for late AMD (presence of exudative AMD or geographic atrophy). There was an increased incidence of AMD lesions with age (P<0.05). Individuals > or = 75 years of age at baseline had significantly (P<0.01) higher 15-year incidences of the following characteristics than people 43 to 54 years of age: larger drusen (125 mum in diameter, 24.1% vs 10.6%), soft indistinct drusen (18.7% vs 6.5%), retinal pigmentary abnormalities (20.2% vs 3.7%), exudative macular degeneration (4.4% vs 0.4%), and pure geographic atrophy (3.2% vs 0%). Controlling for age, compared with those with small numbers of only small hard drusen (1-2), those with large numbers of only hard drusen (> or =8) had an increased 15-year age-adjusted incidence of both soft indistinct drusen (16.3% vs 4.7%) and pigmentary abnormalities (10.6% vs 2.7%). Eyes with soft indistinct drusen or pigmentary abnormalities at baseline were more likely to develop late AMD at follow-up than eyes without these lesions (17.8% vs 1.2% and 12.9% vs 1.7%, respectively). CONCLUSIONS: We document the long-term incidence of signs of AMD and a continuum from small hard drusen to late AMD in older persons in the population. The 15-year cumulative incidence of late AMD in people > or = 75 years of age (8%) indicates a public health problem of significant proportions because the United States population this age is expected to increase by 54% between 2005 and 2025.

Age-related macular degeneration and cancer mortality in the atherosclerosis risk in communities study.

OBJECTIVE: To examine the prospective association of early age-related macular degeneration (AMD) with cancer mortality. METHODS: A population-based cohort study of 10 029 persons aged 49 to 73 years free of cancer. The AMD signs were evaluated from retinal photographs taken in 1993 through 1995. Cancer mortality was determined from death records. RESULTS: There were 464 cases of early AMD. Over 10 years, there were 234 cancer deaths (71 lung cancer deaths). After controlling for age, sex, race, field center, education, smoking status, pack-years of smoking, body mass index (calculated as weight in kilograms divided by height in meters squared), and diabetes mellitus, early AMD was associated with cancer mortality (rate ratio [RR], 1.68; 95% confidence interval [CI], 1.03-2.73). This association was overall stronger in African American individuals (RR, 3.93; 95% CI, 1.67-9.22) than white individuals (RR, 1.28; 95% CI, 0.71-2.32) and for lung cancer deaths (RR, 2.14; 95% CI, 0.97-4.72) than non-lung cancer deaths (RR, 1.50; 95% CI, 0.81-2.78). In African American individuals, early AMD was associated with a 5-fold higher risk of lung cancer deaths (RR, 5.28; 95% CI, 1.52-18.40). CONCLUSIONS: Middle-aged African American individuals with early AMD may be at increased risk of dying of cancer, particularly lung cancer. This association was not present in white individuals and needs confirmation in other studies.

Visual impairment, age-related macular degeneration, cataract, and long-term mortality: the Blue Mountains Eye Study.

OBJECTIVE: To assess the association of visual impairment, age-related macular degeneration (ARMD), and cataract with long-term mortality. METHODS: At baseline, 3654 persons 49 years and older were examined in the Blue Mountains Eye Study (1992-1994). Standardized photographic grading was used to assess ARMD and cataract. Mortality and causes of death occurring between baseline and December 31, 2003, were obtained via data linkage with the Australian National Death Index. Age-standardized mortality rates were calculated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were assessed using Cox models. Result Age-standardized mortality was higher in persons with vs without visual impairment (54.0% vs 34.0%), ARMD (45.8% vs 33.7%), and cataract (39.2% vs 29.5%). After adjusting for factors that predict mortality, neither visual impairment (HR, 1.3; 95% CI, 0.98-1.7) nor ARMD (HR, 1.0; 95% CI, 0.8-1.3) was significantly associated with all-cause mortality in all ages. Among persons younger than 75 years, however, ARMD predicted higher all-cause mortality (HR, 1.6; 95% CI, 1.0-2.4). Any cataract (HR, 1.3; 95% CI, 1.0-1.5) and cortical (HR, 1.2; 95% CI, 0.97-1.4), nuclear (HR, 1.2; 95% CI, 0.98-1.5), and posterior subcapsular (HR, 1.3; 95% CI, 1.0-1.7) cataract were also associated with higher all-cause mortality. CONCLUSION: Cataract predicted increased mortality in persons 49 years and older, and ARMD predicted mortality in persons aged 49 to 74 years.

Age-Related Macular Degeneration and Mortality: A Systematic Review and Meta-Analysis.

PURPOSE: Age-related macular degeneration (AMD) is the leading cause of severe, irreversible vision loss in older adults. Evidence for an association between AMD and mortality remains inconclusive despite evidence for an association with cardiovascular and inflammatory diseases. We aim to compare all-cause, cardiovascular and cancer mortality between those with early or late AMD and control study participants. METHODS: A protocol was registered at PROSPERO (CRD42015020622). A systematic search of Medline (Ovid), PubMed, and Embase (Ovid) was conducted on 6 June 2015. Reference lists from identified studies and four clinical trial registries were searched for additional studies. Participants were required to be over the age of 40 years, and AMD status must have been objectively assessed. The Risk Of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) tool was used to assess the risk of bias. Random-effects meta-analyses were performed. RESULTS: A total of 12 reports from 10 studies were included in the meta-analysis. Late AMD was associated with elevated rates of all-cause (nine studies, hazard ratio (HR) 1.20, 95% confidence interval, CI, 1.02-1.41) and cardiovascular mortality (six studies, HR 1.46, 95% CI 1.13-1.98), but early AMD was not (all-cause mortality, 10 studies, HR 1.06, 95% CI 0.98-1.14; cardiovascular mortality, five studies, HR 1.12, 95% CI 0.96-1.31). There was no evidence of an association between early or late AMD and cancer mortality (early AMD, three studies, HR 1.17, 95% CI 0.78-1.75; late AMD, three studies, HR 1.01, 95% CI 0.77-1.33). CONCLUSION: Late AMD is associated with increased rates of all-cause and cardiovascular mortality, suggesting shared pathways between late AMD and systemic disease.

The Association between Age-Related Macular Degeneration and the Risk of Mortality.

Studies have investigated the association between age-related macular degeneration (AMD) and subsequent risks of mortality, but results have been equivocal. We conducted a comprehensive analysis of prospective cohort studies to assess the association of AMD and the risk of mortality in the general population. We searched PubMed and EMBASE for trials published from 1980 to 2016. We included 11 cohort studies that reported relative risks with 95% confidence intervals for the association of AMD and mortality, involving 57,069 participants. In a random-effects model, the adjusted RR (95% confidence interval) associated with AMD was 1.09 (1.02-1.17) for all-cause mortality. Findings from this research provide support that persons with AMD had a higher subsequent risk of mortality than persons without AMD.

Survival Bias When Assessing Risk Factors for Age-Related Macular Degeneration: A Tutorial with Application to the Exposure of Smoking.

PURPOSE: We illustrate the effect of survival bias when investigating risk factors for eye disease in elderly populations for whom death is a competing risk. Our investigation focuses on the relationship between smoking and late age-related macular degeneration (AMD) in an observational study impacted by censoring due to death. METHODS: Statistical methodology to calculate the survivor average causal effect (SACE) as a sensitivity analysis is described, including example statistical computing code for Stata and R. To demonstrate this method, we examine the causal effect of smoking history at baseline (1990-1994) on the presence of late AMD at the third study wave (2003-2007) using data from the Melbourne Collaborative Cohort Study. RESULTS: Of the 40,506 participants eligible for inclusion, 38,092 (94%) survived until the start of the third study wave, 20,752 (51%) were graded for AMD (60% female, aged 47-85 years, mean 65 ± 8.7 years). Late AMD was detected in 122 participants. Logistic regression showed strong evidence of an increased risk of late AMD for current smokers compared to non-smokers (adjusted naïve odds ratio 2.99, 95% confidence interval, CI, 1.74-5.13). Among participants expected to be alive at the start of follow-up regardless of their smoking status, the estimated SACE odds ratio comparing current smokers to non-smokers was at least 3.42 (95% CI 1.57-5.15). CONCLUSIONS: Survival bias can attenuate associations between harmful exposures and diseases of aging. Estimation of the SACE using a sensitivity analysis approach should be considered when conducting epidemiological research within elderly populations.

Age-related macular degeneration and mortality: the Melbourne Collaborative Cohort Study.

AimsTo assess associations between features of age-related macular degeneration (AMD) and mortality.MethodsA total of 21 129 participants from the Melbourne Collaborative Cohort Study aged 47-85 years (60% female) were assessed for AMD (2003-2007). Mortality data to December 31, 2012 were obtained through linkage with the National Death Index. Associations were assessed using Cox regression, adjusting for age, sex, smoking, region of birth, education, physical activity, diet and alcohol.ResultsLate AMD was identified in 122 (0.6%) participants, including those with choroidal neovascularisation (n=55, 0.3%), geographic atrophy (n=87, 0.4%) and reticular pseudodrusen (n=87, 0.4%). After a median follow-up period of 8.1 years, 1669 (8%) participants had died, including those from cardiovascular diseases (386), tobacco-related cancers (179), and neurodegenerative disease (157). There was evidence of an increased rate of all-cause mortality for those with choroidal neovascularisation (Hazard Ratio (HR) 1.71 95% CI 1.06-2.76) and geographic atrophy (HR 1.46 95% CI 0.99-2.16). Choroidal neovascularisation was also associated with an increased rate of cardiovascular mortality (HR 3.16 95% CI 1.62-6.15) and geographic atrophy was associated with an increased rate of death from tobacco-related cancer (HR 2.86 95% CI 1.15-7.09). Weak evidence was also present for an association between choroidal neovascularisation and death from neurodegenerative disease (HR 2.49 95% CI 0.79-7.85). Neither reticular pseudodrusen nor the earlier stages of AMD were associated with mortality.ConclusionsLate AMD is associated with an increased rate of all-cause mortality. Choroidal neovascularisation and geographic atrophy were associated with death from cardiovascular disease and tobacco-related cancer, respectively.