Dante J. Pieramici

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.

BACKGROUND The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56). CONCLUSIONS Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).

Baseline Predictors for One-Year Visual Outcomes with Ranibizumab or Bevacizumab for Neovascular Age-related Macular Degeneration

OBJECTIVE To determine the baseline predictors of visual acuity (VA) outcomes 1 year after treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD). DESIGN Cohort study within the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). PARTICIPANTS A total of 1105 participants with neovascular AMD, baseline VA 20/25 to 20/320, and VA measured at 1 year. METHODS Participants were randomly assigned to ranibizumab or bevacizumab on a monthly or as-needed schedule. Masked readers evaluated fundus morphology and features on optical coherence tomography (OCT). Visual acuity was measured using electronic VA testing. Independent predictors were identified using regression techniques. MAIN OUTCOME MEASURES The VA score, VA score change from baseline, and ≥3-line gain at 1 year. RESULTS At 1 year, the mean VA score was 68 letters, mean improvement from baseline was 7 letters, and 28% of participants gained ≥3 lines. Older age, larger area of choroidal neovascularization (CNV), and elevation of retinal pigment epithelium (RPE) were associated with worse VA (all P<0.005), less gain in VA (all P<0.02), and a lower proportion gaining ≥3 lines (all P<0.04). Better baseline VA was associated with better VA at 1 year, less gain in VA, and a lower proportion gaining ≥3 lines (all P<0.0001). Predominantly or minimally classic lesions were associated with worse VA than occult lesions (66 vs. 69 letters; P=0.0003). Retinal angiomatous proliferans (RAP) lesions were associated with more gain in VA (10 vs. 7 letters; P=0.03) and a higher proportion gaining ≥3 lines (odds ratio, 1.9; 95% confidence interval, 1.2-3.1). Geographic atrophy (GA) was associated with worse VA (64 vs. 68 letters; P=0.02). Eyes with total foveal thickness in the second quartile (325-425 μm) had the best VA (P=0.01) and were most likely to gain ≥3 lines (P=0.004). Predictors did not vary by treatment group. CONCLUSIONS For all treatment groups, older age, better baseline VA, larger CNV area, predominantly or minimally classic lesion, absence of RAP lesion, presence of GA, greater total fovea thickness, and RPE elevation on optical coherence tomography were independently associated with less improvement in VA at 1 year. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Patient selection for macular translocation surgery using the scanning laser ophthalmoscope

OBJECTIVES To evaluate the use of the scanning laser ophthalmoscope (SLO) as a predictor for potential visual improvement in eyes with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) undergoing limited macular translocation. DESIGN Retrospective noncomparative case series. PARTICIPANTS Consecutive series of 71 eyes of 70 patients with subfoveal CNV secondary to AMD that underwent effective and uncomplicated limited macular translocation at the Wilmer Ophthalmological Institute. METHODS Evaluation of the fundus microperimetry and fixation pattern was conducted on all patients using the Rodenstock scanning laser ophthalmoscope (G. Rodenstock Instrument GmbH, Munich, Germany) within 72 hours before surgery. MAIN OUTCOME MEASURES Sensitivity and specificity in addition to positive and negative predictive values of SLO findings for visual outcome after macular translocation. RESULTS Stable fixation presented the highest positive predictive value for visual acuity equal to or better than 20/100 (30 of 33 = 0.91), and predominantly eccentric fixation had the highest negative predictive value for visual acuity worse than 20/100 (7 of 9 = 0.78). Sensitivity was higher for the presence of predominantly central fixation (42 of 48 = 0.87), and specificity was higher for relatively unstable/unstable fixation (20 of 23 = 0.87). CONCLUSIONS Eyes with stable and central fixation (without dense central scotoma) good preoperative visual acuity, and short length of symptoms are those with the greatest chance to achieve good vision after macular translocation. The knowledge of the fixation and microperimetry pattern enables better understanding of the macular function in eyes with AMD and may be useful for evaluation of baseline retinal cell viability. Incorporation of these testing modalities may help to optimize patient selection for macular translocation or other future techniques aimed at rescuing photoreceptors.

Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD

Background Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. Methods Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. Results Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL. Conclusions There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. Trial registration number NCT02118831.

Limited inferior macular translocation for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration.

PURPOSE To review a series of patients with age-related macular degeneration undergoing limited macular translocation for the treatment of subfoveal choroidal neovascularization, to determine short-term visual acuity outcomes, to measure amounts of attainable retinal movement, and to identify prognostic factors. METHODS A retrospective review was conducted on a consecutive series of patients undergoing inferior limited macular translocation with scleral imbrication for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. The main outcome measures investigated were distance of macular translocation, visual acuity at 3 and 6 months after surgery, change in visual acuity from baseline, and the development of intraoperative and postoperative complications. Univariate and multivariate analyses of a number of potential prognostic factors were undertaken. RESULTS Macular translocation was achieved in all 102 eyes (101 patients) included in this study. The range of movement varied from 200 to 2,800 microm with a median movement of 1, 200 microm. Nearly 33% of the study group achieved a visual acuity better than 20/100 at 3 months, and 49% achieved this vision at 6 months. At 3 and 6 months, 37% and 48% of the study group, respectively, experienced 2 or more lines of improvement on visual acuity testing, and by 6 months 16% experienced greater than 6 lines of visual improvement. Good baseline vision, achieving the desired amount of macular translocation, a greater amount of macular translocation, and recurrent choroidal neovascularization at baseline were associated with better visual acuities at 3 and 6 months. Poor preoperative vision and the development of complications were associated with worse vision at 3 and 6 months. CONCLUSIONS Limited macular translocation is a technically feasible procedure that can lead to significant visual improvement and good visual acuity in some patients presenting with subfoveal choroidal neovascularization associated with age-related macular degeneration. A randomized prospective clinical trial of this surgical technique is warranted.

Ranibizumab for the Treatment of Macular Edema Associated with Perfused Central Retinal Vein Occlusions

PURPOSE Assessment of biological effect, visual acuity changes, and safety of intravitreal (IVT) ranibizumab in patients with macular edema associated with perfused central retinal vein occlusion (CRVO). DESIGN Ongoing, prospective, open-label, single-center, uncontrolled study. PARTICIPANTS Ten adult patients with macular edema associated with perfused CRVO. METHODS Patients were randomly assigned to receive 3 monthly IVT injections of either 0.3 or 0.5 mg ranibizumab (n = 5 at each dose). Additional injections were administered quarterly as needed over the ensuing 21 months at the physicians discretion for recurrent or persistent macular edema. MAIN OUTCOME MEASURES The predetermined primary endpoint was the percentage of patients gaining >or=15 letters of best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity (BCVA). The secondary endpoints include the mean change in BCVA and central retinal thickness (CRT) measured by optical coherence tomography, the rate of progression to ischemic CRVO, extent of intraocular hemorrhage, retinal vein diameter, optic nerve head swelling, and the incidence and severity of ocular and nonocular adverse events. RESULTS After 3, 6, and 9 months of follow-up, 40%, 10%, and 30% of patients, respectively, gained >or=15 letters in BCVA; mean BCVA improved by 12+/-20 letters, 3+/-21 letters, and 1+/-24 letters, respectively, compared with baseline; CRT showed a mean decrease of 272+/-244 microm, 88+/-178 microm, and 119+/-153 microm, compared with baseline. No significant differences were observed between the 0.3- and 0.5-mg doses. Most patients experienced decreases in the extent of retinal hemorrhage, retinal vein diameter, and optic nerve head swelling at months 3 and 6 compared with baseline. No patients progressed to ischemic CRVO or experienced a severe adverse event that was attributed to ranibizumab. CONCLUSIONS Ranibizumab is generally well-tolerated and may improve BCVA and decrease CRT. The improvements in BCVA and CRT observed during the initial monthly injection period (0 to 3 months) were possibly lost to the recurrence of macular edema in between ranibizumab injection during the quarterly treatments (3 to 9 months). The extent of retinal hemorrhage, retinal vein diameter, and nerve swelling continued to normalize for most of the patients from baseline to 6 months. Follow-up is ongoing, and alternative dosing regimens are being evaluated.

Airbags and Eye Injuries: Epidemiology, Spectrum of Injury, and Analysis of Risk Factors

Although airbags measurably reduce the overall risk of injury to adults (including eye injury), and death from motor vehicle accidents, injuries attributed to airbag deployment have been reported. To identify reported cases of ocular trauma related to airbag deployment, a MEDLINE search from 1991 to 2000 was performed. A total of 263 injuries in 101 patients were identified. Patient demographics, details of the accident, specific ocular structures injured, and visual outcomes when available where tabulated and analyzed. The most common of these affect the eyes. Damage to the orbit and virtually every ocular and adnexal structure has been seen. Although most injuries are self-limited and do not significantly compromise vision, some result in severe, permanent visual loss. Most common is damage to anterior structures due to either blunt, contusive forces and/or chemical injury. Posterior segment trauma is less common but generally more visually devastating because of the involvement of the retina or optic nerve. Data are not available to determine whether the wearing of eyeglasses or previous intraocular surgery affects the nature, severity, or outcome of these injuries. Awareness of the spectrum of airbag-associated ocular trauma will help physicians recognize these problems early and optimize their management. Data derived from analyses of these injuries will be critical to the development of safer, more effective devices.

The prognostic significance of a system for classifying mechanical injuries of the eye (globe) in open-globe injuries.

PURPOSE The aim of this study was to determine the prognostic significance of a previously published system for classifying mechanical injuries of the eye (globe) in open-globe injuries. METHODS The medical records of 150 patients with open-globe injuries identified from an established institutional database were retrospectively reviewed to classify all injuries at presentation by the four specific variables of the classification system: type of injury, defined by the mechanism of injury; grade of injury, defined by visual acuity in the injured eye at initial examination; pupil, defined as the presence or absence of a relative afferent pupillary defect in the injured eye; and zone of injury, defined by the location of the eye-wall opening. Final visual outcomes for these injuries were also recorded. Logistic regression models were used to analyze the data and to determine whether relationships existed between the specific classification variables and final visual acuity in the injured eyes. RESULTS All four classification variables were significant predictors of visual outcome. When adjusted for the other variables, grade and pupil were the most significant predictors of final visual acuity. CONCLUSION This system for classifying mechanical injuries of the eye appears to be prognostic for visual outcomes in open-globe injuries. In particular, the measurement of visual acuity and testing for a relative afferent pupillary defect at the initial examination should be performed in all injured eyes because of their relative prognostic significance.

Computed tomography in the diagnosis and prognosis of open-globe injuries

OBJECTIVE Determine sensitivity, specificity, and prognostic signs of orbital and ocular computed tomography (CT) in diagnosing patients with open globe injury. DESIGN Randomized masked review of computed tomograms and retrospective clinical correlation of patients with ocular trauma. PARTICIPANTS Two hundred patients who underwent CT evaluation for ocular trauma between 1989 and 1993. METHODS CTs were read by three masked observers; findings were tabulated and compared for variability among observers; sensitivity and specificity were calculated and CT findings were grouped according to visual outcome retrieved from record review. RESULTS In the absence of clinical information, sensitivity and specificity were 75% and 93%, respectively. The positive predictive value ranged from 88% to 97%, with a calculated overall positive predictive value of 95%. Patients who had a poor visual outcome (visual acuity <2/200) or who underwent enucleation had significantly more CT findings than patients with a good visual outcome. Vitreous hemorrhage, absence of lens, and severe distortion of vitreous space are among the most common CT findings associated with poor visual outcome. CONCLUSIONS CT is not sensitive enough to be solely relied upon for diagnosis of all open globe injuries. CT findings only complement clinical findings, increasing the clinicians overall ability to make an accurate diagnosis of open globe injury, and may provide useful prognostic information regarding visual outcome.

Open globe injuries in children: a retrospective analysis.

PURPOSE To study the outcome of open globe injuries in patients aged <14 years and compare the results between patients who presented approximately 30 years ago and a recent series. METHODS Between January 1970 and January 1993, 180 eyes of children who presented with an open globe injury were retrospectively analyzed. Patients were divided into two groups. One group of children underwent treatment of an open globe injury between January 1970 and December 1981 (group A) and another between December 1985 and January 1993 (group B). Main outcome measures studied were final visual acuity and enucleation rates. Risk factors studied included age, race, sex, visual acuity, type of trauma, and various injury characteristics at presentation. RESULTS The factors associated with visual outcomes included: age, type of injury, wound size, initial visual acuity, and retinal detachment. Final visual outcome and enucleation rates were not significantly different between the older series (group A) and the recent series (group B). Lenticular damage, location, posterior extent of the injury, and presence of an intraocular foreign body had been significant prognostic factors in the older series, but were not statistically associated with the prognosis in the recent series. CONCLUSION The nature of the injury and the patients age are the main determining factors in the outcome of open globe injuries in children.