Digital indocyanine green videoangiography and choroidal neovascularization. 1992.

This report describes a new system for digital indocyanine green videoangiography (ICGV) that provides enhanced imaging of the choroidal circulation. This newly assembled system was used to study a consecutive series of 129 patients with exudative age-related macular degeneration (AMD), and ill-defined or occult choroidal neovascularization (CNV). Overall, 39% of the patients in this study with occult CNV could be reclassified as having well-delineated or so-called classic CNV by virtue of the additional findings provided by ICGV. In this series, ICGV was particularly useful in identifying occult CNV in eyes with a large, serous pigment epithelial detachment (PED) and in eyes with recurrent CNV after previous laser photocoagulation treatment. Some of these patients were selected for laser photocoagulation of the abnormal choroidal vessels in order to evaluate the feasibility of this form of treatment on the basis of combined clinical, fluorescein angiographic, and ICGV findings. The results of this study suggest that ICGV is an important adjunct in the evaluation, classification, and laser treatment of patients with occult CNV secondary to AMD.

Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease.

Aptamers are oligonucleotide ligands that are selected for high-affinity binding to molecular targets. Pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer) is an RNA aptamer directed against vascular endothelial growth factor (VEGF)-165, the VEGF isoform primarily responsible for pathological ocular neovascularization and vascular permeability. After nearly a decade of preclinical development to optimize and characterize its biological effects, pegaptanib was shown in clinical trials to be effective in treating choroidal neovascularization associated with age-related macular degeneration. Pegaptanib therefore has the notable distinction of being the first aptamer therapeutic approved for use in humans, paving the way for future aptamer applications.

Pegaptanib for neovascular age-related macular degeneration.

BACKGROUND: Pegaptanib, an anti-vascular endothelial growth factor therapy, was evaluated in the treatment of neovascular age-related macular degeneration. METHODS: We conducted two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials using broad entry criteria. Intravitreous injection into one eye per patient of pegaptanib (at a dose of 0.3 mg, 1.0 mg, or 3.0 mg) or sham injections were administered every 6 weeks over a period of 48 weeks. The primary end point was the proportion of patients who had lost fewer than 15 letters of visual acuity at 54 weeks. RESULTS: In the combined analysis of the primary end point (for a total of 1186 patients), efficacy was demonstrated, without a dose-response relationship, for all three doses of pegaptanib (P<0.001 for the comparison of 0.3 mg with sham injection; P<0.001 for the comparison of 1.0 mg with sham injection; and P=0.03 for the comparison of 3.0 mg with sham injection). In the group given pegaptanib at 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity, as compared with 55 percent among the controls (P<0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their visual acuity or gained acuity (33 percent vs. 23 percent; P=0.003). As early as six weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). Among the adverse events that occurred, endophthalmitis (in 1.3 percent of patients), traumatic injury to the lens (in 0.7 percent), and retinal detachment (in 0.6 percent) were the most serious and required vigilance. These events were associated with a severe loss of visual acuity in 0.1 percent of patients. CONCLUSIONS: Pegaptanib appears to be an effective therapy for neovascular age-related macular degeneration. Its long-term safety is not known.

Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.

OBJECTIVE: To study effects of intravitreal pegaptanib (Macugen) on retinal neovascularization. DESIGN: Retrospective analysis of a randomized clinical trial. PARTICIPANTS, INTERVENTION, AND MAIN OUTCOME MEASURES: Individuals with retinal neovascularization identified from a multicenter, randomized, controlled trial evaluating pegaptanib for treatment of diabetic macular edema, with a best-corrected visual acuity letter score between 68 and 25 (approximate Snellen equivalent between 20/50 and 20/320) and receiving a sham injection or intravitreal pegaptanib (0.3 mg, 1 mg, 3 mg) administered at study entry, week 6, and week 12, with additional injections and/or focal photocoagulation as needed during the ensuing 18 weeks, up to a maximum of 6 pegaptanib/sham therapies, were evaluated. Scatter panretinal photocoagulation before study enrollment was permitted, but not within 6 months of randomization and study entry. Changes in retinal neovascularization were assessed on fundus photographs and fluorescein angiograms graded at a reading center in a masked fashion. RESULTS: Of 172 participants, 19 had retinal neovascularization in the study eye at baseline. Excluding 1 who had scatter photocoagulation 13 days before randomization and 2 with no follow-up photographs, 1 of the remaining 16 subjects had panretinal photocoagulation during study follow-up. Of these 16 subjects, 8 of 13 (62%) in a pegaptanib treatment group (including the one receiving panretinal photocoagulation), 0 of 3 in the sham group, and 0 of 4 fellow (nonstudy) eyes showed either regression of neovascularization on fundus photographs or regression or absence of fluorescein leakage from neovascularization (or both) at 36 weeks. In 3 of 8 with regression, neovascularization progressed at week 52 after cessation of pegaptanib at week 30. CONCLUSIONS: Most subjects with retinal neovascularization at baseline assigned to pegaptanib showed regression of neovascularization by week 36. These findings suggest a direct effect of pegaptanib upon retinal neovascularization in patients with diabetes mellitus.

A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.

OBJECTIVE: To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME). DESIGN: Randomized, double-masked, multicenter, dose-ranging, controlled trial. PARTICIPANTS: Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks. INTERVENTION: Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. MAIN OUTCOME MEASURES: Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36. RESULTS: One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss. CONCLUSIONS: In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.

Optical coherence tomography findings in nicotinic acid maculopathy.

PURPOSE: To report optical coherence tomography findings in nicotinic acid maculopathy. DESIGN: Observational case report. METHOD: The patient was examined with ophthalmoscopy, fluorescein angiography, and optical coherence tomography. RESULTS: A 71-year-old man presented with bilateral decreased visual acuity with metamorphopsia. Optical coherence tomography demonstrated cystoid spaces in the outer plexiform layer and inner nuclear layer. Fluorescein angiography did not show leakage. Two weeks after stopping the nicotinic acid, the cystoid spaces resolved. CONCLUSIONS: Niacin maculopathy causes cystoid spaces in the inner nuclear and outer plexiform layers that resolve with discontinuation of the drug.

Treatment of idiopathic subfoveal choroidal neovascular lesions using photodynamic therapy with verteporfin.

PURPOSE: To report the effects of photodynamic therapy using verteporfin in the treatment of patients with subfoveal idiopathic choroidal vascularization (CNV). DESIGN: Interventional case series. METHODS: In a retrospective study, eight eyes of eight consecutive patients aged 55 years or younger with subfoveal idiopathic CNV treated with photodynamic therapy using verteporfin were evaluated. Visual acuity was considered to be improved if the visual angle was halved, while acuity was thought to be worse if the visual angle doubled. RESULTS: The eight patients included three men and five women with a mean (+/- SD) age of 34.6 (+/- 9.7) years (range 25-53 years). The mean follow-up time was 13.5 months. At the end of the follow-up period the visual acuity improved in five eyes (62.5%), remained unchanged in one (12.5%), and decreased in two (25%). The mean acuity improvement was 3.6 lines of Snellen acuity by the end of the follow-up period, a change that was statistically significant (P =.027, Wilcoxon signed-rank test). No patient had any complication from the treatment. CONCLUSIONS: There is no widely accepted method for treating subfoveal idiopathic CNV and all previously investigated methods have had a significant number of serious side effects. Although the follow-up time and the number of patients in this pilot study were limited, the encouraging results and lack of complications suggest that further study is indicated.

Verteporfin infusion-associated pain.

PURPOSE: To determine if oral hydration decreases the incidence of verteporfin infusion-associated pain and to find out if other factors play a role in predisposing to this undesired complication. METHODS: Nonrandomized clinical trial. We prospectively examined 250 consecutive patients who have been diagnosed with subfoveal choroidal neovascularization secondary to age-related macular degeneration and received photodynamic therapy using verteporfin. One hundred twenty-five patients were assigned to receive 500 ml of water orally administered 30 minutes before beginning the verteporfin infusion, and the remaining 125 consecutive patients were used as controls. Historical and clinical factors in these patients were evaluated for their association with the presence of verteporfin infusion-associated pain. RESULTS: Out of 125 patients receiving water before treatment 12 (9.6%) experienced verteporfin infusion-associated pain. Among the 125 patients who did not get hydration before therapy 12(9.6%) experienced verteporfin infusion-associated pain. There was no statistical difference between the incidence of pain in the two groups (P = 1.0). No statistically significant association was evidenced between the presence of pain and participant's baseline characteristics, except for pain on previous administration of verteporfin (P < .001). Out of 250 total patients 24 (9.6%) developed verteporfin infusion-associated pain. Back pain was the most common and occurred in 21 (8.4%) patients, but other sites included leg, groin, chest, buttock, arm, and shoulder pain concurrently or independently. All patients had resolution of their pain, including chest pain, on cessation of the infusion. CONCLUSIONS: Verteporfin infusion-associated pain may be more common than has been previously reported and is not limited to the back area. It appears to be an idiosyncratic reaction to the drug. It does not seem to be prevented by oral hydration before infusion of verteporfin, and no baseline characteristics, other than a history of pain on previous infusion, seem to be predictive of verteporfin infusion-associated pain.

Antiangiogenesis agents.

Although these preliminary results on the use of antiangiogenesis drugs for the treatment of neovascular AMD appear promising, double-masked, placebo-controlled, multicenter clinical trials are needed to demonstrate the therapeutic efficacy of such treatments. For example, the first antiangiogenesis drug tested in AMD, interferon alpha-2a, raised great enthusiasm. Indeed, interferon alpha-2a had been shown to be antiangiogenic in animal and in vitro models. It proved to be ineffective, however, in halting the progression of neovascular AMD in a double-masked, placebo-controlled clinical trial [28]. Another antivasogenesis drug tested in a phase 3 clinical trial is thalidomide [67]. Although the enrollment of patients is finished, the results are not yet known.

Pegaptanib sodium for macular edema secondary to central retinal vein occlusion.

OBJECTIVES: To assess the safety and efficacy of intravitreous pegaptanib sodium for the treatment of macular edema following central retinal vein occlusion (CRVO). DESIGN: This dose-ranging, double-masked, multicenter, phase 2 trial included subjects with CRVO for 6 months' or less duration randomly assigned (1:1:1) to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks (0.3 mg and 1 mg, n=33; sham, n=32). MAIN OUTCOME MEASURE: Visual acuity at week 30. RESULTS: In the primary analysis at week 30, 12 of 33 (36%) subjects treated with 0.3 mg of pegaptanib sodium and 13 of 33 (39%) treated with 1 mg gained 15 or more letters from baseline vs 9 of 32 (28%) sham-treated subjects (P= .48 for 0.3 mg and P= .35 for 1 mg of pegaptanib sodium vs sham). In secondary analyses, subjects treated with pegaptanib sodium were less likely to lose 15 or more letters (9% and 6%; 0.3-mg and 1-mg pegaptanib sodium groups, respectively) compared with sham-treated eyes (31%; P= .03 for 0.3 mg and P= .01 for 1 mg of pegaptanib sodium vs sham) and showed greater improvement in mean visual acuity (+7.1 and +9.9, respectively, vs -3.2 letters with sham; P= .09 for 0.3 mg and P= .02 for 1 mg of pegaptanib sodium vs sham). By week 1, the mean central retinal thickness decreased in the 0.3-mg and 1-mg pegaptanib sodium groups by 269 microm and 210 microm, respectively, vs 5 microm with sham (P< .001). CONCLUSIONS: Based on this 30-week study, intravitreous pegaptanib sodium appears to provide visual and anatomical benefits in the treatment of macular edema following CRVO. APPLICATION TO CLINICAL PRACTICE: Benefits accrued with intravitreous pegaptanib sodium treatment of macular edema following CRVO suggest a role for vascular endothelial growth factor in the pathogenesis of this condition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00088283.

Age-dependent variations in the drusen fluorescence on indocyanine green angiography.

PURPOSE: To examine the fluorescence patterns of macular drusen using indocyanine green (ICG) angiography in human subjects of different ages. METHODS: A total of 180 eyes in 100 consecutive patients aged 34-90 years with macula drusen were evaluated with ICG angiography using the Topcon 1024 ImageNet system. Eyes were divided into two groups depending on age. The older group (subjects over the age of 55 years) comprised 170 eyes. The younger group (subjects 55 years or younger) comprised 10 eyes. The fluorescence patterns of the drusen were graded as hyper-fluorescent (brighter than the background fluorescence), hypofluorescent (darker than the background fluorescence) or isofluorescent (unable to be distinguished from the background fluorescence). The ICG angiogram appearances were correlated with the clinical types of drusen in differing age groups. RESULTS: An age-dependent difference in the fluorescence pattern of drusen was observed. Drusen in the older group were hypofluorescent or isofluorescent (169/170 eyes). In contrast, drusen in the younger group (55 years or younger) were hyperfluorescent (10/10 eyes). CONCLUSIONS: This study defines the distinct age-dependent differences in the ICG fluorescence pattern of drusen. This heterogeneity might be due to differential binding of extravasated ICG to the constituents and histological site of the drusen deposits. Furthermore, ICG angiography is able to differentiate drusen types not possible by clinical and fluorescein angiographic evaluation.