Dr. Danis is a practicing medical retina specialist, Professor of Ophthalmology and Visual Sciences at the University of Wisconsin-Madison and UW Fundus Photograph Reading Center (FPRC), Principle Investigator on more than a dozen industry and federally funded multicenter clinical trials, and Co-Founder and Chief Science Officer of EyeKor. Dr. Danis' preclinical research has employed a variety of animal models of intraocular angiogenesis, including laser-induced choroidal neovascularization, oxygen-induced retinopathy, and ischemia-induced retinal neovascularization. His preclinical investigations cover a variety of therapeutic efforts, including photodynamic therapy, and systemic, periocular, and intravitreal administration of compounds. He has co-authored more than 150 peer-reviewed publications and book chapters. He has been awarded the Honor Award and the Senior Achievement Award by the American Academy of Ophthalmology and is a Fellow of the Association for Research in Vision and Ophthalmology.
Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study.
Ophthalmol Retina. 2018 May;2(5):441-450
Authors: Gensler G, Clemons TE, Domalpally A, Danis RP, Blodi B, Wells J, Rauser M, Hoskins J, Hubbard GB, Elman MJ, Fish GE, Brucker A, Margherio A, Chew EY
Objective/Purpose: To evaluate efficacy and safety of monthly intravitreal injections of sirolimus, an immunosuppressive drug, for the treatment of age-related macular degeneration associated geographic atrophy (GA).
Design: Randomized, controlled, single-masked multi-center phase 2 clinical trial of intravitreal sirolimus vs. sham therapy in AREDS2 clinical centers.
Subjects: Participants with GA.
Methods: Participants eligible in one eye were randomly assigned to a monthly intravitreal injection of sirolimus (20 µL [440 µg]) or sham treatment while participants with two study eyes were assigned to a monthly intravitreal injection in a randomly-selected eye. Best-corrected visual acuities (BVCA), spectral domain optical coherence tomography (OCT), fundus color photography and fundus autofluorescence (FAF) images were obtained at baseline and every 6 months until visit month 24.
Main Outcome Measures: Rate of progression of GA (mm2/year) measured on color fundus photograph from baseline to 24 months. Secondary outcome measures include change in BVCA, worsening of vision by ≥3 lines, and changes in area of GA measured on FAF and OCT.
Results: 52 participants (mean age 79 years) were enrolled with 27 study eyes assigned to sirolimus from May 2012 to March 2014. The baseline median area of GA was 4.73 DA (12.01 mm2). The mean (standard deviation) growth rates of GA detected on color fundus photographs were 2.27 (2.17) mm2 and 1.91 (2.27) mm2 at month 12, and 4.94 (2.96) mm2 and 5.72 (3.97) mm2 at month 24, for the sirolimus and sham groups, respectively. There was no statistically significant difference in the GA growth rates between the two treatment groups (P=0.33). Median visual acuity changes and incidence of 15-letter loss from baseline were not different between the 2 treatment groups (p=0.19). The intervention was stopped early because of sterile endophthalmitis that occurred in 3 participants in the sirolimus group. Participants were followed for safety until the study was closed in May 2015 due to lack of efficacy.
Conclusion: Sirolimus did not result in different rates of GA growth in this phase 2 study. Immunosuppression may be important for some stages of the AMD process but may not necessarily be the main pathway for the development of GA.
PMID: 29806044 [PubMed]
Choroidal Changes After Suprachoroidal Injection of Triamcinolone in Eyes With Macular Edema Secondary to Retinal Vein Occlusion.
Am J Ophthalmol. 2018 Mar 22;:
Authors: Willoughby AS, Vuong VS, Cunefare D, Farsiu S, Noronha G, Danis RP, Yiu G
PMID: 29576184 [PubMed - as supplied by publisher]
Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3.
Ophthalmology. 2017 Nov 02;:
Authors: Sadda SR, Guymer R, Holz FG, Schmitz-Valckenberg S, Curcio CA, Bird AC, Blodi BA, Bottoni F, Chakravarthy U, Chew EY, Csaky K, Danis RP, Fleckenstein M, Freund KB, Grunwald J, Hoyng CB, Jaffe GJ, Liakopoulos S, Monés JM, Pauleikhoff D, Rosenfeld PJ, Sarraf D, Spaide RF, Tadayoni R, Tufail A, Wolf S, Staurenghi G
PURPOSE: To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD).
DESIGN: Consensus meeting.
PARTICIPANTS: Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers.
METHODS: As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy.
MAIN OUTCOME MEASURES: A consensus classification system for atrophy and OCT-based criteria to identify atrophy.
RESULTS: OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear.
CONCLUSIONS: A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.
PMID: 29103793 [PubMed - as supplied by publisher]
Incidence of Intermediate-Stage Age-Related Macular Degeneration in Patients with the Acquired Immunodeficiency Syndrome.
Am J Ophthalmol. 2017 May 09;:
Authors: Jabs DA, Van Natta ML, Pak JW, Danis RP, Hunt PW
PURPOSE: To evaluate the incidence of intermediate-stage age-related macular degeneration (AMD) in patients with the acquired immunodeficiency syndrome (AIDS).
DESIGN: Cohort study.
METHODS: Patients enrolled in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) underwent 5- and 10-year follow-up retinal photographs. Intermediate-stage AMD (AREDS stage 3) was determined from these photographs by graders at a centralized Reading Center, using the Age-Related Eye Disease Study-2 grading system. The incidence of AMD in LSOCA was compared to that in the Multi-Ethnic Study of Atherosclerosis (MESA), a Human Immunodeficiency Virus (HIV)-uninfected cohort, which used a similar photographic methodology.
RESULTS: The incidence of AMD in LSOCA was 0.65/100 person-years (PY). In a multivariate analysis the only significant risk factor for AMD in LSOCA was smoking; the relative risk vs never smokers was 3.4 for former smokers (95% confidence interval [CI] 1.3, 9.5; P=0.02) and 3.3 for current smokers (95% CI 1.1, 9.7; P=0.03). Compared to the MESA cohort, the race/ethnicity- and gender-adjusted risk of AMD in LSOCA was 1.75 (95% CI 1.16, 2.64; P=0.008), despite the fact that the mean age of the MESA cohort was 17 years greater than the LSOCA cohort (61 + 9 years vs 44 + 8 years).
CONCLUSIONS: Patients with AIDS have a 1.75-fold increased race- and gender-adjusted incidence of intermediate-stage AMD compared with that found in an HIV-uninfected cohort. This increased incidence is consistent with the increased incidence of other age-related diseases in antiretroviral-treated, immune-restored, HIV-infected persons when compared to HIV-uninfected persons.
PMID: 28499708 [PubMed - as supplied by publisher]
Evaluating the Validity of the Age-Related Eye Disease Study Grading Scale for Age-Related Macular Degeneration: AREDS2 Report 10.
JAMA Ophthalmol. 2016 Sep 1;134(9):1041-7
Authors: Vitale S, Clemons TE, Agrón E, Ferris FL, Domalpally A, Danis RP, Chew EY, Age-Related Eye Disease Study 2 (AREDS2) Research Group
IMPORTANCE: To test potential treatments for age-related macular degeneration (AMD), clinical trials need standardized outcome measures that are valid for predicting AMD progression in different study populations.
OBJECTIVE: To evaluate the validity of the Age-Related Eye Disease Study (AREDS) detailed and simple AMD severity scales by comparing rates of development of late AMD (neovascular AMD and/or central geographic atrophy) between AREDS and AREDS2 participants.
DESIGN, SETTING, AND PARTICIPANTS: Both AREDS (1992-2001) and AREDS2 (2006-2012) enrolled patients from academic and community-based retinal practices across the United States. In AREDS (n = 4519), participants with varying severity of AMD-from no AMD to late AMD in 1 eye-were enrolled. In AREDS2 (n = 4203), participants with bilateral large drusen or large drusen in the study eye and late AMD in the fellow eye were enrolled.
MAIN OUTCOMES AND MEASURES: Five-year incidence of late AMD, assessed by annual masked centralized fundus photograph grading.
RESULTS: In AREDS, the mean (SD) age of the patients was 69.3 (5.7) years, and 2519 (55.7%) were female. In AREDS2, the mean (SD) age of the patients was 73.1 (7.7) years, and 2388 (56.8%) were female. The 5-year rates of late AMD did not differ between AREDS2 and AREDS participants within nearly all baseline AMD detailed severity scale levels: levels 1 to 3: 2.4% vs 0.5% (difference, 1.9%; 95% CI, -0.2% to 4.0%; P < .001); level 4: 6.5% vs 4.9% (difference, 1.6%; 95% CI, -1.7% to 4.8%; P = .34); level 5: 8.0% vs 5.6% (difference, 2.4%; 95% CI, -1.2% to 5.9%; P = .22); level 6: 12.8% vs 13.7% (difference, -0.9%; 95% CI, -4.8% to 3.1%; P = .66); level 7: 26.2% vs 27.8% (difference, -1.5%; 95% CI, -6.6% to 3.5%; P = .54); and level 8: 46.4% vs 44.7% (difference, 1.7%; 95% CI, -7.5% to 10.9%; P = .72). Within simple scale levels, AREDS2 and AREDS 5-year rates did not differ significantly except for level 1 (9.4% vs 3.1%, P = .02; level 2: 12.8% vs 11.8%, P = .65; level 3: 26.3% vs 25.9%, P = .90; and level 4: 45.6% vs 47.3%, P = .57).
CONCLUSIONS AND RELEVANCE: The AREDS detailed and simple AMD severity scales were useful measures for assessing the risk of developing late AMD in the AREDS2 population; these data suggest that they should be useful tools for clinical trials of AMD treatments.
PMID: 27442263 [PubMed - in process]
Evaluation of Geographic Atrophy from Color Photographs and Fundus Autofluorescence Images: Age-Related Eye Disease Study 2 Report Number 11.
Ophthalmology. 2016 Jul 19;
Authors: Domalpally A, Danis R, Agrón E, Blodi B, Clemons T, Chew E, Age-Related Eye Disease Study 2 Research Group
PURPOSE: To compare measurements of area of geographic atrophy (GA) and change in GA area from color photographs and fundus autofluorescence (FAF) images.
DESIGN: The Age-Related Eye Disease Study 2 (AREDS2) was a prospective multicenter randomized clinical trial evaluating progression of dry age-related macular degeneration (AMD) using color photographs at annual visits over a 5-year study period. The FAF images were acquired in a subset of participants who joined the FAF ancillary study at any of the annual visits over the study period.
PARTICIPANTS: The AREDS2 FAF ancillary study included 8070 corresponding color and FAF visits of 2202 participants with variable follow-up.
METHODS: Corresponding color and FAF images were independently evaluated at a central reading center for GA area measurement, lesion growth, and involvement of the macula center.
MAIN OUTCOME MEASURES: Presence, area, growth rate of GA, and involvement of center of macula from color and FAF images.
RESULTS: Hypoautofluorescence was visible in 2048 visits (25.4%). Agreement for the presence of GA between the 2 modalities had a kappa of 0.79, with 23% of visits with hypoautofluorescence not presenting with GA on color photographs. Percentage agreement for GA presence ranged from 43% at baseline to 81% at year 5 with improving agreement over time. The mean difference in GA area between the 2 modalities was 0.5 mm(2), with larger areas on FAF. Growth rate of GA was 1.45 mm(2) from color photographs and 1.43 mm(2) from FAF images. The center of the macula was involved in 51% of color photographs and 56% with FAF images.
CONCLUSIONS: Geographic atrophy may be detected earlier by the use of FAF images, but over the course of the study, the 2 modalities become comparable. Progression of GA area is comparable between color photographs and FAF images, but evaluating involvement of the center of the macula may differ, probably because of macular pigmentation blocking autofluorescence.
PMID: 27448832 [PubMed - as supplied by publisher]
Quantitative Assessment of Optic Nerve Changes in Patients With Diabetic Macular Edema Treated With Fluocinolone Acetonide Vitreous Implants.
Ophthalmic Surg Lasers Imaging Retina. 2016 May 1;47(5):418-25
Authors: Parrish RK, Traverso CE, Green K, Danis RP, FAME Study Group
BACKGROUND AND OBJECTIVE: To evaluate glaucomatous changes in patients with diabetic macular edema (DME) treated with intravitreal implants releasing 0.2 µg/day or 0.5 µg/day fluocinolone acetonide (FAc) (Iluvien 0.2 µg/day; Alimera Sciences, Alpharetta, GA) or sham control.
PATIENTS AND METHODS: Fundus photographs were assessed to determine clinically significant changes in glaucomatous indicators.
RESULTS: The mean cup-to-disc ratio (CDR) change was similar with all three treatments. Compared with sham control, a significantly greater proportion of patients treated with 0.5 µg/day but not 0.2 µg/day FAc experienced a CDR increase of greater than 0.1. There was no significant increase in the proportion of patients experiencing a CDR increase of greater than 0.2 with either dose of implant versus sham control. Other indicators of glaucomatous change did not differ significantly with treatment. Subgroup analyses showed no differences in cupping based on ocular or baseline characteristics.
CONCLUSION: Treatment with FAc for 36 months was not associated with significant glaucomatous optic nerve head changes in patients with DME with or without increased intraocular pressure. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:418-425.].
PMID: 27183545 [PubMed - in process]
Relationship of retinal vascular calibre and diabetic retinopathy in Chinese patients with type 2 diabetes mellitus: the Desheng Diabetic Eye Study.
Br J Ophthalmol. 2016 Jan 28;
Authors: Yang X, Deng Y, Gu H, Ren X, Lim A, Snellingen T, Liu X, Wang N, Won Pak J, Liu N, Danis RP
AIMS: To describe the relationship of retinal arteriolar and venular calibre with diabetic retinopathy (DR) and related risk factors, including glucose levels and other biomarkers in a Chinese population with type 2 diabetes mellitus (T2DM).
METHODS: A cross-sectional study. Patients with T2DM were recruited from a local community in urban Beijing. Seven fields 30° colour fundus photographs were taken and examined for the presence and severity of DR using a standardised grading system. Retinal vascular calibres were measured and expressed as average central retinal arteriolar and venular equivalent using a computer-based program.
RESULTS: A total of 1340 patients with T2DM were included for analysis. Of these, 472 (35.22%) had DR. Wider retinal venular calibre, but not arteriolar calibre, was associated with increasing glucose and glycosylated haemoglobin A1c levels (p<0.006) and dyslipidaemia (p for trend <0.05). After adjusting for possible covariates, the higher quartile of retinal venular calibre was associated with higher prevalence of any DR (OR 2, 95% CI 1.36 to 2.95). Venular calibre increased from 224.33 μm in those without retinopathy to 231.21 μm in those with mild, 241.01 μm in those with moderate and 235.65 μm in those with severe retinopathy (p for trend <0.001). Arteriolar calibre was not associated with DR.
CONCLUSIONS: In the current study, wider venular calibre, but not arteriolar calibre, was shown to be associated with development and increased severity of DR independently from other risk factors in a Chinese diabetic population.
PMID: 26823397 [PubMed - as supplied by publisher]
RELATIONSHIP BETWEEN RETINAL THICKNESS AND VISUAL ACUITY IN EYES WITH RETINAL VEIN OCCLUSION TREATED WITH DEXAMETHASONE IMPLANT.
Retina. 2015 Dec 11;
Authors: Danis RP, Sadda S, Jiao J, Li XY, Whitcup SM
PURPOSE: To evaluate the relationship between changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in eyes from two clinical trials of dexamethasone intravitreal implant 0.7 mg for macular edema after branch or central retinal vein occlusion.
METHODS: Patients with vision loss as a result of macular edema (≥6-week duration) after branch retinal vein occlusion or central retinal vein occlusion were treated with a single dexamethasone intravitreal implant or sham. Prospectively defined outcomes included BCVA and CRT (as assessed by optical coherence tomography).
RESULTS: There was a modest but statistically significant negative linear correlation between changes in CRT and changes in BCVA in both treatment groups at Days 90 and 180 (correlation coefficient: -0.23 to -0.34; P < 0.001). Improvements in BCVA at Day 180 were significantly greater (P < 0.001) in eyes that achieved and maintained CRT ≤250 μm from Day 90 to 180 (mean BCVA improvement: 14 letters; 49% of eyes with ≥15-letter gain) than in eyes that never achieved CRT ≤250 μm (mean BCVA improvement: 2 letters; 13% of eyes with ≥15-letter gain).
CONCLUSION: The greatest improvements in BCVA were seen in eyes that achieved and maintained the greatest improvements in CRT.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
PMID: 26655606 [PubMed - as supplied by publisher]
Natural History of Geographic Atrophy Progression Secondary to Age-Related Macular Degeneration (Geographic Atrophy Progression Study).
Ophthalmology. 2015 Nov 3;
Authors: Schmitz-Valckenberg S, Sahel JA, Danis R, Fleckenstein M, Jaffe GJ, Wolf S, Pruente C, Holz FG
PURPOSE: The Geographic Atrophy Progression (GAP) study was designed to assess the rate of geographic atrophy (GA) progression and to identify prognostic factors by measuring the enlargement of the atrophic lesions using fundus autofluorescence (FAF) and color fundus photography (CFP).
DESIGN: Prospective, multicenter, noninterventional natural history study.
PARTICIPANTS: A total of 603 participants were enrolled in the study; 413 of those had gradable lesion data from FAF or CFP, and 321 had gradable lesion data from both FAF and CFP.
METHODS: Atrophic lesion areas were measured by FAF and CFP to assess lesion progression over time. Lesion size assessments and best-corrected visual acuity (BCVA) were conducted at screening/baseline (day 0) and at 3 follow-up visits: month 6, month 12, and month 18 (or early exit).
MAIN OUTCOME MEASURES: The GA lesion progression rate in disease subgroups and mean change from baseline visual acuity.
RESULTS: Mean (standard error) lesion size changes from baseline, determined by FAF and CFP, respectively, were 0.88 (0.1) and 0.78 (0.1) mm(2) at 6 months, 1.85 (0.1) and 1.57 (0.1) mm(2) at 12 months, and 3.14 (0.4) and 3.17 (0.5) mm(2) at 18 months. The mean change in lesion size from baseline to month 12 was significantly greater in participants who had eyes with multifocal atrophic spots compared with those with unifocal spots (P < 0.001) and those with extrafoveal lesions compared with those with foveal lesions (P = 0.001). The mean (standard deviation) decrease in visual acuity was 6.2 ± 15.6 letters for patients with image data available. Atrophic lesions with a diffuse (mean 0.95 mm(2)) or banded (mean 1.01 mm(2)) FAF pattern grew more rapidly by month 6 compared with those with the "none" (mean, 0.13 mm(2)) and focal (mean, 0.36 mm(2)) FAF patterns.
CONCLUSIONS: Although differences were observed in mean lesion size measurements using FAF imaging compared with CFP, the measurements were highly correlated with one another. Significant differences were found in lesion progression rates in participants stratified by hyperfluorescence pattern subtype. This large GA natural history study provides a strong foundation for future clinical trials.
PMID: 26545317 [PubMed - as supplied by publisher]
Prevalence of intermediate-stage age-related macular degeneration in patients with acquired immunodeficiency syndrome.
Am J Ophthalmol. 2015 Jun;159(6):1115-1122.e1
Authors: Jabs DA, Van Natta ML, Sezgin E, Pak JW, Danis R, Studies of the Ocular Complications of AIDS Research Group
PURPOSE: To evaluate the prevalence of intermediate-stage age-related macular degeneration (AMD) in patients with acquired immunodeficiency syndrome (AIDS).
DESIGN: Cross-sectional study of patients with AIDS enrolled in the Longitudinal Study of the Ocular Complications of AIDS.
METHODS: Intermediate-stage AMD was determined from enrollment retinal photographs by graders at a centralized Reading Center, using the Age-Related Eye Disease Study grading system. Graders were masked as to clinical data.
RESULTS: Of 1825 participants with AIDS and no ocular opportunistic infections, 9.9% had intermediate-stage AMD. Risk factors included age, with an odds ratio (OR) of 1.9 (95% confidence interval [CI] 1.6, 2.3, P < .001) for every decade of age; the prevalence of AMD ranged from 4.0% for participants 30-39 years old to 24.3% for participants ≥60 years old. Other risk factors included the human immunodeficiency virus (HIV) risk groups of injection drug use (OR = 2.4, 95% CI 1.5, 3.9, P < .001) or heterosexual contact (OR = 1.9, 95% CI 1.3, 2.8, P = .001). Compared with the HIV-uninfected population in the Beaver Dam Offspring Study, there was an approximate 4-fold increased age-adjusted prevalence of intermediate-stage AMD.
CONCLUSIONS: Patients with AIDS have an increased age-adjusted prevalence of intermediate-stage AMD compared with that found in a non-HIV-infected cohort evaluated with similar methods. This increased prevalence is consistent with the increased prevalence of other age-related diseases in antiretroviral-treated, immune-restored, HIV-infected persons when compared to non-HIV-infected persons.
PMID: 25769246 [PubMed - in process]
Darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in diabetic macular edema: a 3-month placebo-controlled study.
Ophthalmology. 2015 May;122(5):990-6
Authors: Staurenghi G, Ye L, Magee MH, Danis RP, Wurzelmann J, Adamson P, McLaughlin MM, Darapladib DME Study Group
PURPOSE: To investigate the potential of lipoprotein-associated phospholipase A2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME).
DESIGN: Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study.
PARTICIPANTS: Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18).
METHODS: Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months.
MAIN OUTCOME MEASURES: Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography.
RESULTS: Five patients in the study received intravitreal anti-vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3-5.8) and of 57 μm in central subfield thickness (95% CI, -84 to -30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, -1.0 to 4.4) and a decrease in center subfield thickness of 34 μm (95% CI, -75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups.
CONCLUSIONS: Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A2 inhibitory mechanism for the treatment of DME.
PMID: 25749297 [PubMed - in process]
Long-term Outcomes of Cytomegalovirus Retinitis in the Era of Modern Antiretroviral Therapy: Results from a United States Cohort.
Ophthalmology. 2015 Apr 16;
Authors: Jabs DA, Ahuja A, Van Natta ML, Lyon AT, Yeh S, Danis R, Studies of the Ocular Complications of AIDS Research Group
PURPOSE: To describe the long-term outcomes of patients with cytomegalovirus (CMV) retinitis and AIDS in the modern era of combination antiretroviral therapy.
DESIGN: Prospective, observational cohort study.
PARTICIPANTS: Patients with AIDS and CMV retinitis.
METHODS: Immune recovery, defined as a CD4+ T-cell count >100 cells/μl for ≥3 months.
MAIN OUTCOME MEASURES: Mortality, visual impairment (visual acuity <20/40), and blindness (visual acuity ≤20/200) on logarithmic visual acuity charts and loss of visual field on quantitative Goldmann perimetry.
RESULTS: Patients without immune recovery had a mortality of 44.4/100 person-years (PYs) and a median survival of 13.5 months after the diagnosis of CMV retinitis, whereas those with immune recovery had a mortality of 2.7/100 PYs (P < 0.001) and an estimated median survival of 27.0 years after the diagnosis of CMV retinitis. The rates of bilateral visual impairment and blindness were 0.9 and 0.4/100 PYs, respectively, and were similar between those with and without immune recovery. Among those with immune recovery, the rate of visual field loss was approximately 1% of the normal field per year, whereas among those without immune recovery it was approximately 7% of the normal field per year.
CONCLUSIONS: Among persons with CMV retinitis and AIDS, if there is immune recovery, long-term survival is likely, whereas if there is no immune recovery, the mortality rate is substantial. Although higher than the rates in the population not infected by human immunodeficiency virus, the rates of bilateral visual impairment and blindness are low, especially when compared with rates in the era before modern antiretroviral therapy.
PMID: 25892019 [PubMed - as supplied by publisher]
Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration.
Ophthalmology. 2015 Mar;122(3):579-88
Authors: Csaky KG, Dugel PU, Pierce AJ, Fries MA, Kelly DS, Danis RP, Wurzelmann JI, Xu CF, Hossain M, Trivedi T
PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops.
PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections.
METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed.
MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24.
RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported.
CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.
PMID: 25432081 [PubMed - in process]
Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
PLoS One. 2015;10(11):e0141286
Authors: Lorenzi GM, Braffett BH, Arends VL, Danis RP, Diminick L, Klumpp KA, Morrison AD, Soliman EZ, Steffes MW, Cleary PA, DCCT/EDIC Research Group
Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.
PMID: 26529311 [PubMed - in process]
The cross-sectional and longitudinal associations of diabetic retinopathy with cognitive function and brain MRI findings: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
Diabetes Care. 2014 Dec;37(12):3244-52
Authors: Hugenschmidt CE, Lovato JF, Ambrosius WT, Bryan RN, Gerstein HC, Horowitz KR, Launer LJ, Lazar RM, Murray AM, Chew EY, Danis RP, Williamson JD, Miller ME, Ding J
OBJECTIVE: Longitudinal evidence linking diabetic retinopathy with changes in brain structure and cognition is sparse. We used data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to determine whether diabetic retinopathy at baseline predicted changes in brain structure or cognition 40 months later.
RESEARCH DESIGN AND METHODS: Participants from the ACCORD-MIND and ACCORD-Eye substudies were included in analyses of cognition (n = 1,862) and MRI-derived brain variables (n = 432). Retinopathy was categorized as none, mild nonproliferative, or moderate/severe. Tests of cognition included the Mini-Mental State Examination (MMSE), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test, and Stroop test. Primary brain outcomes were gray matter and abnormal white matter volumes.
RESULTS: Baseline retinopathy was associated with lower gray matter volume (adjusted means of 470, 466, and 461 cm(3) for none, mild, and moderate/severe retinopathy, respectively; P = 0.03). Baseline retinopathy also predicted a greater change in MMSE and DSST scores at 40 months in each retinopathy category (MMSE: -0.20, -0.57, and -0.42, respectively [P = 0.04]; DSST: -1.30, -1.84, and -2.89, respectively [P = 0.01]).
CONCLUSIONS: Diabetic retinopathy is associated with future cognitive decline in people with type 2 diabetes. Although diabetic retinopathy is not a perfect proxy for diabetes-related brain and cognitive decline, patients with type 2 diabetes and retinopathy represent a subgroup at higher risk for future cognitive decline.
PMID: 25193529 [PubMed - in process]
Retinal vascular abnormalities in neovascular age-related macular degeneration.
Retina. 2014 Mar;34(3):568-75
Authors: Jackson TL, Danis RP, Goldbaum M, Slakter JS, Shusterman EM, OʼShaughnessy DJ, Moshfeghi DM
PURPOSE: To determine the prevalence of retinal vascular abnormalities (RVA) in neovascular age-related macular degeneration (AMD).
METHODS: A post hoc subanalysis of images acquired during a Phase III randomized controlled trial was undertaken, selecting images from participants with untreated, neovascular AMD in at least one eye. Protocol mandated fundus photographs and fluorescein angiograms were acquired at baseline and Year 2, from 107 sham-treated study eyes with neovascular AMD and 107 untreated fellow eyes. Images were reanalyzed by an independent reading center for the presence of RVA, defined as at least one of the following: microaneurysms, vessel staining or leakage, dilated or tortuous vessels, intraretinal hemorrhage, vessel sheathing or narrowing, capillary nonperfusion, or capillary infarcts.
RESULTS: The baseline prevalence of RVA in the sham-treated study eyes was 14.4% (15 of 104 gradable images) versus 8.3% (5 of 60) in the fellow eyes with dry AMD. The baseline prevalence of individual RVAs in study eyes was: microaneurysms (6.7%), vessel staining or leakage (6.7%), dilated or tortuous vessels (4.8%), intraretinal hemorrhage (4.8%), vessel sheathing or narrowing (2.9%), capillary nonperfusion (0%), and capillary infarcts (0%). Results were similar at 24 months.
CONCLUSION: Compared with several studies that relied solely on fundus photographs, this study included fluorescein angiography and found a higher prevalence of RVAs occurring in eyes with neovascular AMD.
PMID: 24045343 [PubMed - indexed for MEDLINE]
Randomized trial of the ForeseeHome monitoring device for early detection of neovascular age-related macular degeneration. The HOme Monitoring of the Eye (HOME) study design - HOME Study report number 1.
Contemp Clin Trials. 2014 Mar;37(2):294-300
Authors: Chew EY, Clemons TE, Bressler SB, Elman MJ, Danis RP, Domalpally A, Heier JS, Kim JE, Garfinkel RA, Appendix 1 for AREDS2-HOME Study Research Group
OBJECTIVE: To evaluate the effects of a home-monitoring device with tele-monitoring compared with standard care in detection of progression to choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD), the leading cause of blindness in the US.
PATIENTS AND METHODS: Participants, aged 55 to 90 years, at high risk of developing CNV associated with AMD were recruited to the HOme Monitoring of Eye (HOME) Study, an unmasked, multi-center, randomized trial of the ForeseeHome (FH) device plus standard care vs. standard care alone. The FH device utilizes preferential hyperacuity perimetry and tele-monitoring to detect changes in vision function associated with development of CNV, potentially prior to symptom and visual acuity loss. After establishing baseline measurements, subsequent changes on follow-up are detected by the device, causing the monitoring center to alert the clinical center to recall participants for an exam. Standard care consists of instructions for self-monitoring visual changes with subsequent self-report to the clinical center. The primary objective of this study is to determine whether home monitoring plus standard care in comparison with standard care alone, results in earlier detection of incident CNV with better present visual acuity. The primary outcome is the decline in visual acuity at CNV diagnosis from baseline. Detection of CNV prior to substantial vision loss is critical as vision outcome following anti-angiogenic therapy is dependent on the visual acuity at initiation of treatment.
DISCUSSION: HOME Study is the first large scale study to test the use of home tele-monitoring system in the management of AMD patients.
PMID: 24530651 [PubMed - indexed for MEDLINE]
Pazopanib eye drops: a randomised trial in neovascular age-related macular degeneration.
Br J Ophthalmol. 2014 Feb;98(2):172-8
Authors: Danis R, McLaughlin MM, Tolentino M, Staurenghi G, Ye L, Xu CF, Kim RY, Johnson MW, Pazopanib Eye Drops Study Group
AIMS: To evaluate pazopanib eye drops in patients with subfoveal choroidal neovascularisation secondary to age-related macular degeneration.
METHODS: 70 patients with minimally classic or occult subfoveal choroidal neovascularisation were randomly assigned to 5 mg/mL TID, 2 mg/mL TID, and 5 mg/mL QD pazopanib eye drops for 28 days in a multicentre, double-masked trial with an optional safety extension for up to 5 additional months. The primary outcomes were central retinal thickness (CRT) and best-corrected visual acuity (BCVA) at Day 29.
RESULTS: No significant decrease from baseline in CRT was observed overall; however, an exploratory analysis showed improvement in CRT (mean decrease of 89 μm) in patients with the CFH TT genotype who received 5 mg/mL TID (p=0.01, n=5). Mean increases in BCVA were observed in the 5 mg/mL TID overall (4.32 letters (p=0.002, n=26)) and in those that with CFH Y402H TT (6.96 letters (p=0.02, n=5)) and CT (4.09 letters (p=0.05, n=9)) genotypes. No safety signals that precluded continued investigation were detected.
CONCLUSIONS: 5 mg/mL pazopanib eye drops resulted in mean improvement in BCVA at Day 29 and improvements in vision. However, improvement in macular oedema for age-related macular degeneration was found only in the subset of subjects with the CFH Y402H TT genotype, warranting further investigation.
PMID: 24227801 [PubMed - indexed for MEDLINE]
Application of random forests methods to diabetic retinopathy classification analyses.
PLoS One. 2014;9(6):e98587
Authors: Casanova R, Saldana S, Chew EY, Danis RP, Greven CM, Ambrosius WT
BACKGROUND: Diabetic retinopathy (DR) is one of the leading causes of blindness in the United States and world-wide. DR is a silent disease that may go unnoticed until it is too late for effective treatment. Therefore, early detection could improve the chances of therapeutic interventions that would alleviate its effects.
METHODOLOGY: Graded fundus photography and systemic data from 3443 ACCORD-Eye Study participants were used to estimate Random Forest (RF) and logistic regression classifiers. We studied the impact of sample size on classifier performance and the possibility of using RF generated class conditional probabilities as metrics describing DR risk. RF measures of variable importance are used to detect factors that affect classification performance.
PRINCIPAL FINDINGS: Both types of data were informative when discriminating participants with or without DR. RF based models produced much higher classification accuracy than those based on logistic regression. Combining both types of data did not increase accuracy but did increase statistical discrimination of healthy participants who subsequently did or did not have DR events during four years of follow-up. RF variable importance criteria revealed that microaneurysms counts in both eyes seemed to play the most important role in discrimination among the graded fundus variables, while the number of medicines and diabetes duration were the most relevant among the systemic variables.
CONCLUSIONS AND SIGNIFICANCE: We have introduced RF methods to DR classification analyses based on fundus photography data. In addition, we propose an approach to DR risk assessment based on metrics derived from graded fundus photography and systemic data. Our results suggest that RF methods could be a valuable tool to diagnose DR diagnosis and evaluate its progression.
PMID: 24940623 [PubMed - in process]
Circularity index as a risk factor for progression of geographic atrophy.
Ophthalmology. 2013 Dec;120(12):2666-71
Authors: Domalpally A, Danis RP, White J, Narkar A, Clemons T, Ferris F, Chew E
OBJECTIVE: To develop a parameter that can assess the relative rate of progression of geographic atrophy (GA) based on the hypothesis that noncircular configuration of the atrophic lesion may be a risk factor for enlargement.
DESIGN: Cohort study.
PARTICIPANTS: Digitized color photographs of 593 eyes with GA from the Age-Related Eye Disease Study (AREDS).
METHODS: A novel parameter called the "Geographic Atrophy Circularity Index" (GACI) was developed on the basis of area and perimeter measurements to categorize the irregularity of the shape of GA. The GACI ranges from 0.0 to 1.0 and is categorized into 3 groups: 0.25 (very irregular), 0.25 to <0.75 (partly irregular), and ≥ 0.75 (circular).
MAIN OUTCOME MEASURES: Growth rate of GA.
RESULTS: The mean growth rate in the 3 categories was 0.40 (± 0.18), 0.36 (± 0.30), and 0.21 (± 0.22) mm/year, respectively (P < 0.001). By adjusting for known confounders, baseline area, duration of GA, and configuration, GACI categories were significantly associated with increased growth rate of GA (P < 0.001).
CONCLUSIONS: The GACI was associated with the progression rate of GA and may be a useful measure for clinical trial eligibility. The association also suggests that enlargement of GA may be related to the extent of the junctional zone of damaged retinal pigment epithelium, which increases with noncircularity for a given GA area.
PMID: 24206616 [PubMed - indexed for MEDLINE]
Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4.
JAMA Ophthalmol. 2013 Jul;131(7):843-50
Authors: Age-Related Eye Disease Study 2 (AREDS2) Research Group, Chew EY, SanGiovanni JP, Ferris FL, Wong WT, Agron E, Clemons TE, Sperduto R, Danis R, Chandra SR, Blodi BA, Domalpally A, Elman MJ, Antoszyk AN, Ruby AJ, Orth D, Bressler SB, Fish GE, Hubbard GB, Klein ML, Friberg TR, Rosenfeld PJ, Toth CA, Bernstein P
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.
PMID: 23645227 [PubMed - indexed for MEDLINE]
Vascular changes in eyes treated with dexamethasone intravitreal implant for macular edema after retinal vein occlusion.
Ophthalmology. 2013 Jul;120(7):1423-31
Authors: Sadda S, Danis RP, Pappuru RR, Keane PA, Jiao J, Li XY, Whitcup SM
OBJECTIVE: To evaluate the angiographic findings in eyes from 2 clinical trials of the dexamethasone intravitreal implant (DEX implant) 0.7 mg in the treatment of macular edema (ME) after branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).
DESIGN: Post hoc analysis of pooled data from 2 identical phase 3 clinical trials.
PARTICIPANTS: Patients with vision loss as a result of ME (≥ 6 weeks' duration) after BRVO or CRVO for whom angiographic data were available (n = 329 eyes).
METHODS: Fluorescein angiography (FA) results assessed by masked, certified graders using standardized grading protocols.
MAIN OUTCOME MEASURES: The primary outcome measure in the parent studies was change from baseline in best-corrected visual acuity. Prospectively defined secondary outcomes included FA measurements (to assess macular capillary leakage, neovascularization, and nonperfusion) and optical coherence tomography results (to assess central retinal thickness [CRT]).
RESULTS: At baseline, 42% of eyes in the DEX implant group and 38% of eyes in the sham group had unreadable assessments because of hemorrhage. At day 180, significantly fewer DEX implant-treated eyes (2%) than sham-treated eyes (9%) had unreadable assessments because of hemorrhage (P = 0.029). Among eyes with gradable assessments, the incidence of nonperfusion remained fairly steady from baseline to day 180. The proportion of eyes with active neovascularization increased from baseline to day 180 in the sham group, but stayed relatively constant in the DEX implant group (P = 0.026 for DEX vs. sham). The mean area of overall nonperfusion and the mean area of macular capillary nonperfusion increased from baseline to day 180 in both treatment groups (no statistically significant between-group difference). There was a statistically significant positive correlation between changes in macular leakage and changes in CRT in both the DEX implant group (r = 0.22; 95% confidence interval, 0.03-0.40; P = 0.023) and the sham group (r = 0.29; 95% confidence interval, 0.10-0.46; P = 0.003).
CONCLUSIONS: This study demonstrated that the clinical improvements observed with the DEX implant were accompanied by significant improvements in vascular parameters and suggests that treatment with the DEX implant may be associated with some clinically significant improvements in angiographic findings, specifically active neovascularization.
PMID: 23499064 [PubMed - indexed for MEDLINE]
The effect of the oral PKC β inhibitor ruboxistaurin on vision loss in two phase 3 studies.
Invest Ophthalmol Vis Sci. 2013 Mar;54(3):1750-7
Authors: Sheetz MJ, Aiello LP, Davis MD, Danis R, Bek T, Cunha-Vaz J, Shahri N, Berg PH, MBDL and MBCU Study Groups
PURPOSE: To assess the effect of ruboxistaurin (RBX) on vision loss through a prospectively defined combined analysis of two phase 3 trials (MBDL and MBCU).
METHODS: Patients in both of these 3-year randomized, placebo-controlled, double-masked trials had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) ≥ 75 letters (∼20/32 Snellen), ETDRS retinopathy level 20 to 47D (MBDL) or 35B to 53E (MBCU), and no prior panretinal or focal photocoagulation in at least one eye at baseline. Patients received oral placebo (N = 508 total from both studies) or RBX 32 mg/d (N = 520 total). Best-corrected ETDRS VA was measured at 6-month intervals for 3 years (MBDL) or for 18 to 48 months (MBCU). Sustained moderate visual loss (SMVL) was defined as a 15-letter or more reduction from baseline in VA sustained for a patient's last 6 months of study participation.
RESULTS: In the combined studies (N = 1028 total), SMVL occurred in 4.4% of placebo- versus 2.3% of RBX-treated patients (P = 0.069). In patients with a minimum of 2 years of follow-up (N = 825 total), there was less SMVL in the RBX group (4.4% placebo versus 2.1% RBX, P = 0.045). Other VA-related measures (mean VA, contrast sensitivity, Visual Functioning Questionnaire 25 [VFQ-25]) either trended toward a benefit for RBX or were also statistically significant in favor of RBX. In contrast, diabetic macular edema (DME) morphology-related measures (occurrence of significant center of macula involvement, optical coherence tomography [OCT]-determined center of macula thickness, application of focal photocoagulation) did not show a consistent trend in favor of or against RBX.
CONCLUSIONS: SMVL data in a prospectively defined combined analysis from these two phase 3 trials suggest a magnitude of effect of RBX on vision loss similar to that seen in two prior studies (approximately 50% reduction above standard care). However, event rates were low and statistical significance was not achieved. (ClinicalTrials.gov numbers, NCT00133952, NCT00090519.).
PMID: 23404115 [PubMed - indexed for MEDLINE]
Correlates of hypertension in patients with AIDS in the era of highly active antiretroviral therapy.
J Int Assoc Provid AIDS Care. 2013 Sep-Oct;12(5):325-33
Authors: Krauskopf K, Van Natta ML, Danis RP, Gangaputra S, Ackatz L, Addessi A, Federman AD, Branch AD, Meinert CL, Jabs DA, Studies of the Ocular Complications of AIDS Research Group
BACKGROUND: It is unclear whether HIV-related factors modify risk of hypertension (HTN). In a cohort of patients with AIDS, the authors determined HTN incidence and prevalence and assessed associated traditional, HIV-specific, and retinal vasculature factors.
METHODS: Prospective observational cohort included 2390 patients with AIDS (1998-2011). Univariate analysis was used to assess the impact of traditional- and AIDS-related risk factors for HTN prevalence and incidence. Multivariate regression analyses were used to evaluate the adjusted impact of these factors.
RESULTS: Hypertension prevalence was 22%(95% confidence interval [CI] 21%-24%) and was associated with traditional HTN risk factors (age, black race, and higher weight) as well as diabetes, hyperlipidemia, time since AIDS diagnosis, and higher CD4 counts. Hypertension incidence was 64.1 per 1000 person-years (95% CI 58.7/1000-69.9/1000). Age, race, weight, and diabetes were associated with incident HTN but HIV-specific factors were not.
CONCLUSIONS: Hypertension, a prevalent cardiovascular risk factor in patients with AIDS, is associated with traditional and metabolic risk factors.
PMID: 23764503 [PubMed - indexed for MEDLINE]
The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1).
Ophthalmology. 2012 Nov;119(11):2282-9
Authors: AREDS2 Research Group, Chew EY, Clemons T, SanGiovanni JP, Danis R, Domalpally A, McBee W, Sperduto R, Ferris FL
PURPOSE: The Age-Related Eye Disease Study (AREDS) demonstrated beneficial effects of oral supplementation with antioxidant vitamins and minerals on the development of advanced age-related macular degeneration (AMD) in persons with at least intermediate AMD (bilateral large drusen with or without pigment changes). Observational data suggest that other oral nutrient supplements might further reduce the risk of progression to advanced AMD. The primary purpose of the Age-Related Eye Disease Study 2 (AREDS2) is to evaluate the efficacy and safety of lutein plus zeaxanthin (L+Z) and/or ω-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation in reducing the risk of developing advanced AMD. The study also assesses the reduction in zinc and the omission of β-carotene from original AREDS formulation.
DESIGN: Multicenter, phase III, randomized, controlled clinical trial.
PARTICIPANTS: Persons aged 50 to 85 with bilateral intermediate AMD or advanced AMD in 1 eye.
METHODS: All participants were randomly assigned to placebo (n = 1012), L+Z (10 mg/2 mg; n = 1044), ω-3 LCPUFAs (eicosapentaenoic acid + docosahexaenoic acid [650 mg/350 mg]; n = 1069), or the combination of L+Z and ω-3 LCPUFAs (n = 1078). All participants were offered a secondary randomization to 1 of 4 variations of the original AREDS formulation keeping vitamins C (500 mg) and E (400 IU) and copper (2 mg) unchanged while varying zinc and β-carotene as follows: Zinc remains at the original level (80 mg), lower only zinc to 25 mg, omit β-carotene only, or lower zinc to 25 mg and omit β-carotene.
MAIN OUTCOME MEASURES: Progression to advanced AMD determined by centralized grading of annual fundus photographs.
RESULTS: We enrolled 4203 participants at 82 clinical centers located in the United States. Population characteristics at baseline were as follows: Mean age, 74 years; 57% female; 97% white; 7% current smokers; 19% with prior cardiovascular disease; and 44% and 50% taking statin-class cholesterol-lowering drugs and aspirin, respectively. Ocular characteristics include 59% with bilateral large drusen, 32% with advanced AMD in 1 eye and mean visual acuity of 20/32 in eyes without advanced AMD.
CONCLUSIONS: This report presents the AREDS2 study design and the participants' baseline demographic and ocular characteristics.
PMID: 22840421 [PubMed - indexed for MEDLINE]
Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy.
Am J Ophthalmol. 2012 Jun;153(6):1016-24.e5
Authors: Sugar EA, Jabs DA, Ahuja A, Thorne JE, Danis RP, Meinert CL, Studies of the Ocular Complications of AIDS Research Group
PURPOSE: To estimate the incidence of cytomegalovirus (CMV) retinitis in the era of highly active antiretroviral therapy (HAART) and to characterize the factors associated with increased risk of CMV retinitis.
DESIGN: Prospective cohort study.
METHODS: A total of 1600 participants with acquired immunodeficiency syndrome (AIDS) but without CMV retinitis at enrollment who completed at least 1 follow-up visit in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) were seen every 6 months to obtain disease and treatment history, ophthalmic examination, and laboratory testing. Incidence of CMV retinitis and risk factors for incident CMV retinitis were assessed.
RESULTS: The incidence rate of CMV retinitis in individuals with AIDS was 0.36/100 person-years (PY) based upon 29 incident cases during 8134 PY of follow-up. The rate was higher for those with a CD4+ T cell count at the immediately prior visit below 50 cells/μL (3.89/100 PY, P < .01), whereas only 1 individual with a CD4+ T cell count of 50 to 99 cells/μL and 2 individuals with a CD4+ T cell count >100 cells/μL developed CMV retinitis. Having a CD4+ T cell count below 50 cells/μL at the clinical visit prior to CMV retinitis evaluation was the single most important risk factor (HR: 136, 95% CI: 30 to 605, P < .0001) for developing retinitis.
CONCLUSIONS: Patients with AIDS, especially those with severely compromised immune systems, remain at risk for developing CMV retinitis in the HAART era, although the incidence rate is reduced from that observed in the pre-HAART era.
PMID: 22310076 [PubMed - indexed for MEDLINE]
Automated assessment of drusen using three-dimensional spectral-domain optical coherence tomography.
Invest Ophthalmol Vis Sci. 2012 Mar;53(3):1576-83
Authors: Iwama D, Hangai M, Ooto S, Sakamoto A, Nakanishi H, Fujimura T, Domalpally A, Danis RP, Yoshimura N
PURPOSE: To compare automated assessment of macular drusen delineated by the authors' originally developed algorithm on three-dimensional (3D) spectral-domain optical coherence tomography (SD-OCT) with the assessment by certified graders on color fundus photographs in nonneovascular age-related macular degeneration (AMD).
METHODS: Automated assessment of macular drusen was performed using raster scan by 3D OCT scans in 18 eyes with nonneovascular AMD with at least one large druse (≥125 μm) and predominantly soft indistinct drusen. Drusen was defined as the regions that have the distance between the retinal pigment epithelium and calculated Bruch's membrane lines > predefined threshold distances. The agreement was assessed on maximum drusen size and drusen area within grid between 3D SD-OCT and color fundus photographs, and false-negative and false-positive drusen at each threshold distance.
RESULTS: There was agreement or agreement within one step in all eyes in maximum drusen size, and 15 (83.3%) of the eyes in the drusen area, except 6 pixels, regardless of threshold distances. However, the number of eyes with exact agreement in the drusen area increased when the threshold distances were smaller than 4 pixels. In the three cases with disagreement in the drusen area, false-negative drusen on 3D SD-OCT were characterized by being small in area and height.
CONCLUSIONS: Automated assessment of drusen parameters based on the authors' algorithm on 3D SD-OCT, which was limited by the poor detection ability of small drusen, showed good agreement with the assessment by certified graders on color fundus photography in these subjects.
PMID: 22297491 [PubMed - indexed for MEDLINE]
Pilot study of the delivery of microcollimated pars plana external beam radiation in porcine eyes: 270-day analysis.
J Ophthalmol. 2012;2012:615214
Authors: Singh RP, Shusterman EM, Moshfeghi D, Danis R, Gertner M
Objective. To determine the dose response and toxicity threshold of micro-collimated X-rays delivered to porcine maculae by a stereotactic radiosurgical system after 270 days. Methods. Twelve eyes of six Yucatan mini-swine were randomized to receive up to 90 Gy to the retina, using an office-based trans-pars plana delivery system. To determine the safety profile of this radiation delivery, ophthalmic examination, fundus photography, fluorescein angiography (FA), and spectral domain optical coherence tomography (SD-OCT) were obtained at multiple time points up to 270 days post treatment. Results. No abnormalities were noted on external examination. Cataracts were noted in 4 of 12 eyes. Dose and time-dependent changes were noted on fundus examination, FA, ICG and SD-OCT. No significant abnormalities were seen in the control, 16 Gy or 24 Gy groups using any modality. Histopathology revealed a dose response effect with no discernable lesions in the 16 Gy group. Conclusion. The X-ray delivery system precisely targets the porcine retina in vivo with little effect on surrounding structures. No ophthalmic or intracranial adverse effects were noted at clinically relevant doses at 270 days following radiation delivery.
PMID: 22848793 [PubMed]
Effect of ruboxistaurin (RBX) On visual acuity decline over a 6-year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2).
Retina. 2011 Jun;31(6):1053-9
Authors: Sheetz MJ, Aiello LP, Shahri N, Davis MD, Kles KA, Danis RP, Mbdv Study Group
PURPOSE: The PKC-DRS2 was a Phase 3, randomized, double-masked, placebo (PBO)-controlled, 3-year study of the effect of 32 mg/day of ruboxistaurin (RBX), an orally administered protein kinase C inhibitor, on vision loss in patients with moderate to severe nonproliferative diabetic retinopathy. Ruboxistaurin reduced the occurrence of sustained moderate visual loss (SMVL; ≥15-letter decline in visual acuity sustained for the last 6 months of study participation) from 9.1% in the PBO group (N = 340) to 5.5% in the RBX group (N = 345, P = 0.034). This study evaluates the primary end point of SMVL in a 2-year open-label extension (OLE) of the PKC-DRS2, which began a median of 466 days (range, 263-1,296 days) after the conclusion of PKC-DRS2.
METHODS: Visual acuity was measured by certified examiners using the Early Treatment Diabetic Retinopathy Study chart.
RESULTS: Of the 514 patients who completed PKC-DRS2, 366 did so in the 32 study centers participating in the OLE, and of these, 203 (55%) enrolled in the OLE for treatment with 32 mg/day of RBX for 2 years. Of the 203 enrolled in the OLE, 100 had previously been treated with PBO (prior PBO subgroup) and 103 had been treated with RBX (prior RBX subgroup). PKC-DRS2 baseline patient and ocular characteristics were well matched between these two subgroups and were similar to the PKC-DRS2 patient population as a whole. Using the PKC-DRS2 baseline as the starting point, SMVL occurred in 6% of the prior PBO subgroup during the PKC-DRS2, increasing to 26% by the end of the OLE. However, in the prior RBX subgroup, SMVL occurred in only 4% and 8% during the PKC-DRS2 and by the end of the OLE, respectively (P < 0.001 for difference at the end of the OLE). In the prior PBO subgroup, mean visual acuity declined from 79.6 letters at PKC-DRS2 baseline to 73.1 letters at OLE end point (-6.5 letters). In the prior RBX subgroup, this loss was 2.7 letters (79.8 to 77.1) over the same period (P = 0.02).
CONCLUSION: Over a 6-year study period incorporating 3 years of a rigorously placebo-controlled trial, approximately 1 year off treatment and 2-year OLE where all groups received therapy, those patients with greatest RBX exposure (∼5 years) experienced less SMVL compared with those in the original PBO group (∼2-year RBX exposure).
PMID: 21386766 [PubMed - indexed for MEDLINE]
Pilot study of the delivery of microcollimated pars plana external beam radiation in porcine eyes.
Arch Ophthalmol. 2011 May;129(5):628-32
Authors: Barakat MR, Shusterman M, Moshfeghi D, Danis R, Gertner M, Singh RP
OBJECTIVE: To investigate the effects of a novel stereotactic radiosurgical system for pars plana delivery of microcollimated x-rays to the retina and determine the retinal radiological dose response and toxicity threshold in a pig model.
METHODS: The x-rays were delivered through the pars plana to the maculae of Yucatan miniswine to verify the targeting and safety of a cornea-scleral, stabilized, office-based delivery system. Twelve eyes were randomized to receive 0, 16, 24, 42, 60, or 90 Gy in a single dose to the retina. Eye examinations, fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were obtained at days 7, 30, 60, and 90. Indocyanine green angiography was done at day 90.
RESULTS: Through day 90 interim analysis, no abnormalities of external structures were noted. A small cortical lens opacity was noted in the 60-Gy group. Fundus evaluation revealed no abnormalities at 16 or 24 Gy. Beginning at day 30, circular pale retinal lesions with sharp margins were noted in the maculae of the eyes that received 42, 60, and 90 Gy. Higher-dose lesions showed late staining on fluorescein angiography, choroidal hypoperfusion on indocyanine green angiography, and defined photoreceptor loss and retinal thinning on spectral-domain optical coherence tomography.
CONCLUSION: Transscleral stereotactic radiation dosing of porcine eyes demonstrates no apparent clinical abnormalities in doses less than 24 Gy. Doses of 42 Gy or higher led to focal choroidal and retinal damage within the target area.
CLINICAL RELEVANCE: Radiation can induce small-blood vessel closure and thereby has therapeutic potential in neovascular diseases such as age-related macular degeneration.
PMID: 21555617 [PubMed - indexed for MEDLINE]
Repeatability of retinal thickness measurements between spectral-domain and time-domain optical coherence tomography images in macular disease.
Ophthalmic Surg Lasers Imaging. 2010 Nov-Dec;41 Suppl:S34-41
Authors: Domalpally A, Gangaputra S, Peng Q, Danis RP
BACKGROUND AND OBJECTIVE: To evaluate and compare the intra-session repeatability of retinal thickness measurements from the Topcon 3D OCT 1000 (Topcon Medical Systems; Paramus, NJ), a spectral-domain optical coherence tomography (SD-OCT) system, with the Stratus (Carl Zeiss Meditec, Inc., Dublin, CA), a time-domain OCT (TD-OCT) system, in eyes with retinal diseases.
PATIENTS AND METHODS: Repeated scans with both SD-OCT and TD-OCT were taken. Thickness measurements from high-quality scans were used to assess repeatability and compare measurements between the two instruments.
RESULTS: Paired scans from 127 eyes were evaluated, of which 63 pairs were of high quality. Coefficients of repeatability and variation for the central subfield were 20.1 μm (2.6%) with SD-OCT and 27.4 μm (4%) with TD-OCT (P = .38). The mean difference in central subfield thickness between the two instruments was 24.5 μm (standard deviation = 20.9).
CONCLUSION: Repeatability of retinal thickness measurements with the Topcon 3D OCT 1000 is comparable to the Stratus. The measurements of the two machines differ significantly and cannot be used interchangeably.
PMID: 20415296 [PubMed - indexed for MEDLINE]
Quantitative analysis of the Stratus optical coherence tomography fast macular thickness map reports.
Indian J Ophthalmol. 2010 Mar-Apr;58(2):131-6
Authors: Domalpally A, Danis RP, Myers D, Kruse CN
The cross sectional optical coherence tomography images have an important role in evaluating retinal diseases. The reports generated by the Stratus fast macular thickness scan protocol are useful for both clinical and research purposes. The centerpoint thickness is an important outcome measure for many therapeutic trials related to macular disease. The data is susceptible to artifacts such as decentration and boundary line errors and could be potentially erroneous. An understanding of how the data is generated is essential before utilizing the data. This article describes the interpretation of the fast macular thickness map report, assessment of the quality of an optical coherence tomography image and identification of the artifacts that could influence the numeric data.
PMID: 20195036 [PubMed - indexed for MEDLINE]