To develop a clinical classification system for age-related macular degeneration (AMD).
Evidence-based investigation, using a modified Delphi process.
Twenty-six AMD experts, 1 neuro-ophthalmologist, ...2 committee chairmen, and 1 methodologist.
Each committee member completed an online assessment of statements summarizing current AMD classification criteria, indicating agreement or disagreement with each statement on a 9-step scale. The group met, reviewed the survey results, discussed the important components of a clinical classification system, and defined new data analyses needed to refine a classification system. After the meeting, additional data analyses from large studies were provided to the committee to provide risk estimates related to the presence of various AMD lesions.
Delphi review of the 9-item set of statements resulting from the meeting.
Consensus was achieved in generating a basic clinical classification system based on fundus lesions assessed within 2 disc diameters of the fovea in persons older than 55 years. The committee agreed that a single term, age-related macular degeneration, should be used for the disease. Persons with no visible drusen or pigmentary abnormalities should be considered to have no signs of AMD. Persons with small drusen (<63 μm), also termed drupelets, should be considered to have normal aging changes with no clinically relevant increased risk of late AMD developing. Persons with medium drusen (≥ 63-<125 μm), but without pigmentary abnormalities thought to be related to AMD, should be considered to have early AMD. Persons with large drusen or with pigmentary abnormalities associated with at least medium drusen should be considered to have intermediate AMD. Persons with lesions associated with neovascular AMD or geographic atrophy should be considered to have late AMD. Five-year risks of progressing to late AMD are estimated to increase approximately 100 fold, ranging from a 0.5% 5-year risk for normal aging changes to a 50% risk for the highest intermediate AMD risk group.
The proposed basic clinical classification scale seems to be of value in predicting the risk of late AMD. Incorporating consistent nomenclature into the practice patterns of all eye care providers may improve communication and patient care.
To describe outcomes 5 years after initiating treatment with bevacizumab or ranibizumab for neovascular age-related macular degeneration (AMD).
Cohort study.
Patients enrolled in the Comparison of ...AMD Treatments Trials.
Patients were assigned randomly to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After 2 years, patients were released from the clinical trial protocol. At 5 years, patients were recalled for examination.
Visual acuity (VA) and morphologic retinal features.
Visual acuity was obtained for 647 of 914 (71%) living patients with average follow-up of 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments was 15.4. Most patients (60%) were treated 1 time or more with a drug other than their assigned drug. At the 5-year visit, 50% of eyes had VA of 20/40 or better and 20% had VA of 20/200 or worse. Mean change in VA was -3 letters from baseline and -11 letters from 2 years. Among 467 eyes with fluorescein angiography, mean total lesion area was 12.9 mm(2), a mean of 4.8 mm(2) larger than at 2 years. Geographic atrophy was present in 213 of 515 (41%) gradable eyes and was subfoveal in 85 eyes (17%). Among 555 eyes with spectral-domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub-retinal pigment epithelium). Mean foveal total thickness was 278 μm, a decrease of 182 μm from baseline and 20 μm from 2 years. The retina was abnormally thin (<120 μm) in 36% of eyes. Between 2 and 5 years, the group originally assigned to ranibizumab for 2 years lost more VA than the bevacizumab group (-4 letters; P = 0.008). Otherwise, there were no statistically significant differences in VA or morphologic outcomes between drug or regimen groups.
Vision gains during the first 2 years were not maintained at 5 years. However, 50% of eyes had VA of 20/40 or better, confirming anti-vascular endothelial growth factor therapy as a major long-term therapeutic advance for neovascular AMD.
To report expanded 2-year follow-up of a previously reported randomized trial evaluating intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid ...laser alone for treatment of diabetic macular edema (DME).
Multicenter, randomized clinical trial.
A total of 854 study eyes of 691 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea.
Continuation of procedures previously reported for the randomized trial.
Best-corrected visual acuity and safety at the 2-year visit.
At the 2-year visit, compared with the sham + prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab + prompt laser group (95% confidence interval adjusted for multiple comparisons aCI, -0.4 to +7.7), 5.8 letters greater in the ranibizumab + deferred laser group (95% aCI, +1.9 to +9.8), and 1.5 letters worse in the triamcinolone + prompt laser group (95% aCI, -5.5 to +2.4). After the 1- to 2-year visit in the ranibizumab + prompt or deferred laser groups, the median numbers of injections were 2 and 3 (potential maximum of 13), respectively. At the 2-year visit, the percentages of eyes with central subfield thickness ≥250 μm were 59% in the sham + prompt laser group, 43% in the ranibizumab + prompt laser group, 42% in the ranibizumab + deferred laser group, and 52% in the triamcinolone + prompt laser group. No systemic events attributable to study treatment were apparent. Three eyes in 3 (0.8%) of 375 participants had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group.
The expanded 2-year results reported are similar to results published previously and reinforce the conclusions originally reported: Ranibizumab should be considered for patients with DME and characteristics similar to those of the cohort in this clinical trial, including vision impairment with DME involving the center of the macula.
Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
Multicenter, ...randomized clinical trial.
A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.
Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
Best-corrected visual acuity and safety at 1 year.
The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.
To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.
...Multicenter, randomized clinical trial.
Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial.
At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.
Mean change in visual acuity.
Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval CI, -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF).
Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.
Age-related macular degeneration Coleman, Hanna R, MD; Chan, Chi-Chao, MD; Ferris, Frederick L, MD ...
The Lancet,
11/2008, Volume:
372, Issue:
9652
Journal Article
Peer reviewed
Open access
Summary Age-related macular degeneration is the leading cause of blindness in elderly populations of European descent. The most consistent risk factors associated with this ocular condition are ...increasing age and cigarette smoking. Genetic investigations have shown that complement factor H, a regulator of the alternative complement pathway, and LOC387715/HtrA1 are the most consistent genetic risk factors for age-related macular degeneration. Although the pathogenesis of this disease is unknown, oxidative stress might have an important role. Treatment with antioxidant vitamins and zinc can reduce the risk of developing advanced age-related macular degeneration by about a quarter in those at least at moderate risk. Intravitreal injections of ranibizumab, a monoclonal antibody that inhibits all forms of vascular endothelial growth factor, have been shown to stabilise loss of vision and, in some cases, improve vision in individuals with neovascular age-related macular degeneration. These findings, combined with assessments of possible environmental and genetic interactions and new approaches to modulate inflammatory pathways, will hopefully further expand our ability to understand and treat age-related macular degeneration.
To develop consensus regarding clinical disease severity classification systems for diabetic retinopathy and diabetic macular edema that can be used around the world, and to improve communication and ...coordination of care among physicians who care for patients with diabetes.
Report regarding the development of clinical diabetic retinopathy disease severity scales.
A group of 31 individuals from 16 countries, representing comprehensive ophthalmology, retina subspecialties, endocrinology, and epidemiology.
An initial clinical classification system, based on the Early Treatment Diabetic Retinopathy Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy publications, was circulated to the group in advance of a workshop. Each member reviewed this using e-mail, and a modified Delphi system was used to stratify responses. At a later workshop, separate systems for diabetic retinopathy and macular edema were developed. These were then reevaluated by group members, and the modified Delphi system was again used to measure degrees of agreement.
Consensus regarding specific classification systems was achieved.
A five-stage disease severity classification for diabetic retinopathy includes three stages of low risk, a fourth stage of severe nonproliferative retinopathy, and a fifth stage of proliferative retinopathy. Diabetic macular edema is classified as apparently present or apparently absent. If training and equipment allow the screener to make a valid decision, macular edema is further categorized as a function of its distance from the central macula.
There seems to be a genuine need for consistent international
clinical classification systems for diabetic retinopathy and diabetic macular edema that are supported with solid evidence. The proposed clinical classification systems provide a means of appropriately categorizing diabetic retinopathy and macular edema. It is hoped that these systems will be valuable in improving both screening of individuals with diabetes and communication and discussion among individuals caring for these patients.
Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision ...loss or worsening diabetic macular edema (DME).
To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy.
Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015.
Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME.
The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.
Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified.
Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy.
clinicaltrials.gov Identifier: NCT01489189.
Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed.
To evaluate efficacy and safety of 0.5-mg ...intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR.
Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018.
Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group.
Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety.
The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified.
Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR.
ClinicalTrials.gov Identifier: NCT01489189.
We investigate whether ocular and person-based characteristics were associated with dark adaptation (DA).
Cross-sectional, single-center, observational study.
One hundred sixteen participants older ...than 50 years of age with a range of age-related macular degeneration (AMD) severity.
Participants underwent best-corrected visual acuity (BCVA) testing, ophthalmoscopic examination, and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images and was confirmed with optical coherence tomography. Eyes also were graded for AMD features (drusen, pigmentary changes, late AMD) to generate person-based AMD severity groups. One eye was designated the study eye for DA testing. Nonparametric statistical testing was performed on all comparisons.
The primary outcome of this study was the rod intercept time (RIT), which is defined as the time for a participant's visual sensitivity to recover to a stimulus intensity of 5×10(-3) cd/m(2) (a decrease of 3 log units), or until a maximum test duration of 40 minutes was reached.
A total of 116 study eyes from 116 participants (mean age, 75.4±9.4 years; 58% female) were analyzed. Increased RIT was associated significantly with increasing AMD severity, increasing age (r = 0.34; P = 0.0002), decreasing BCVA (r = -0.54; P < 0.0001), pseudophakia (P = 0.03), and decreasing subfoveal choroidal thickness (r = -0.27; P = 0.003). Study eyes with RPD (15/116 13%) had a significantly greater mean RIT compared with eyes without RPD in any AMD severity group (P < 0.02 for all comparisons), with 80% reaching the DA test ceiling.
Impairments in DA increased with age, worse visual acuity, presence of RPD, AMD severity, and decreased subfoveal choroidal thickness. Analysis of covariance found the multivariate model that best fit the data included age, AMD group, and presence of RPD (R(2) = 0.56), with the presence of RPD conferring the largest parameter estimate.
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