Michele Melia

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.).

Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt versus Deferred Laser Treatment

OBJECTIVE To report the 3-year follow-up results within a previously reported randomized trial evaluating prompt versus deferred (for ≥24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5 mg ranibizumab for diabetic macular edema (DME). DESIGN Multicenter, randomized clinical trial. PARTICIPANTS Three hundred sixty-one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. METHODS Ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and random assignment to prompt or deferred (≥24 weeks) focal/grid laser treatment. MAIN OUTCOME MEASURES Best-corrected visual acuity and safety at the 156-week (3-year) visit. RESULTS The estimated mean change in visual acuity letter score from baseline through the 3-year visit was 2.9 letters more (9.7 vs. 6.8 letters; mean difference, 2.9 letters; 95% confidence interval, 0.4-5.4 letters; P = 0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group and deferral group, respectively, the percentage of eyes with a ≥10-letter gain/loss was 42% and 56% (P = 0.02), whereas the respective percentage of eyes with a ≥10-letter gain/loss was 10% and 5% (P = 0.12). Up to the 3-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively (P = 0.007), including 1 and 2 injections, respectively, from the 2-year up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness of 250 μm or more on time-domain optical coherence tomography were 36% in both groups (P = 0.90). In the deferral group, 54% did not receive laser treatment during the trial. Systemic adverse events seemed to be similar in the 2 groups. CONCLUSIONS These 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through 5 years continues.

Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin

Endostatin is a cleavage product of collagen XVIII that inhibits tumor angiogenesis and growth. Interferon alpha2a blocks tumor angiogenesis and causes regression of hemangiomas, but has no effect on choroidal neovascularization (CNV). Therefore, inhibitors of tumor angiogenesis do not necessarily inhibit ocular neovascularization. In this study, we used an intravenous injection of adenoviral vectors containing a sig-mEndo transgene consisting of murine immunoglobulin kappa-chain leader sequence coupled to sequence coding for murine endostatin to investigate the effect of high serum levels of endostatin on CNV in mice. Mice injected with a construct in which sig-mEndo expression was driven by the Rous sarcoma virus promoter had moderately high serum levels of endostatin and significantly smaller CNV lesions at sites of laser-induced rupture of Bruchs membrane than mice injected with null vector. Mice injected with a construct in which sig-mEndo was driven by the simian cytomegalovirus promoter had approximately 10-fold higher endostatin serum levels and had nearly complete prevention of CNV. There was a strong inverse correlation between endostatin serum level and area of CNV. This study provides proof of principle that gene therapy to increase levels of endostatin can prevent the development of CNV and may provide a new treatment for the leading cause of severe loss of vision in patients with age-related macular degeneration.

Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial

IMPORTANCE 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). OBJECTIVE To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES 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. RESULTS 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. CONCLUSIONS AND RELEVANCE 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01489189.

Intraocular expression of endostatin reduces VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment.

Endostatin, a proteolytic fragment of collagen XVIII, is an endogenous inhibitor of tumor angiogenesis that also inhibits choroidal neovascularization. In this study, we assessed the effects of increased intraocular expression of endostatin on vascular endothelial growth factor (VEGF)‐induced changes in the retina. After subretinal injection of a pair of gutless adenoviral vectors (AGV) designed to provide tamoxifen‐inducible expression of endostatin, diffuse endostatin immunoreactivity was induced thoroughout the retina by administration of tamoxifen. Induction of endostatin in double transgenic mice with doxycycline‐induced expression of VEGF in the retina resulted in significant suppression of leakage of intravascular [3H]mannitol into the retina. The ability of endostatin to reduce VEGF‐induced retinal vascular permeability was confirmed by using [3H]mannitol leakage and two other parameters, fluorescein leakage and retinal thickness, after subretinal injection of a bovine immunodeficiency lentiviral vector coding for endostatin (BIV‐vectored endostatin, or BIVendostatin). Subretinal injection of BIVendostatin resulted in more discrete, less intense staining for endostatin in the retina than that seen with the inducible AGV system, which suggested lower levels and allowed visualization of sites where endostatin was concentrated. Endostatin staining outlined retinal blood vessels, which suggested endostatin binding to a component of vessel walls. More prolonged or higher level expression of VEGF in the retina resulted in neovascularization and retinal detachment, both of which were also significantly reduced by BIVendostatin. These data suggest that endostatin may be an endogenous inhibitor of vasopermeability as well as neovascularization. In patients with diabetic retinopathy, endostatin gene transfer may provide a way to decrease the risk of three causes of visual loss: macular edema, neovascularization, and retinal detachment.

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.

Different effects of angiopoietin-2 in different vascular beds: new vessels are most sensitive

In this study, we used double transgenic mice with inducible expression of angiopoietin‐2 (Ang2) to investigate the role of Ang2 in the retinal and choroidal circulations and in three models of ocular neovascularization (NV). Mice with induced expression of Ang2 ubiquitously, or specifically in the retina, survived and appeared grossly normal. They also had normal‐appearing retinal and choroidal circulations, demonstrating that high levels of Ang2 did not induce regression of mature retinal or choroidal vessels. When Ang2 expression was induced soon after birth, there was increased density of the deep capillary bed on postnatal day (P) 11 that returned to normal by P18, the time that retinal vascular development is usually completed. In mice with ischemic retinopathy, induction of Ang2 during the ischemic period resulted in a significant increase in retinal NV, but induction of Ang2 at a later time point when ischemia (and vascular endothelial growth factor [VEGF]) was less, hastened regression of NV. In triple transgenic mice that coexpressed VEGF and Ang2, the increased expression of Ang2 inhibited VEGF‐induced NV in the retina. Increased expression of Ang2 also resulted in regression of choroidal neovascularization. These data suggest that ocular neovascularization, but not mature retinal or choroidal vessels, is sensitive to Ang2; a high Ang2/VEGF ratio promotes regression, while high Ang2 in the setting of hypoxia and/or concomitantly high Ang2 and VEGF stimulate neovascularization.

Nitric oxide is proangiogenic in the retina and choroid.

Nitric oxide (NO) has been shown to have proangiogenic or antiangiogenic effects depending upon the setting. In this study, we used mice with targeted deletion of one of the three isoforms of nitric oxide synthase (NOS) to investigate the effects of NO in ocular neovascularization. In transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors, deficiency of any of the three isoforms caused a significant decrease in subretinal neovascularization, but no alteration of VEGF expression. In mice with laser‐induced rupture of Bruchs membrane, deficiency of inducible NOS (iNOS) or neuronal NOS (nNOS), but not endothelial NOS (eNOS), caused a significant decrease in choroidal neovascularization. In mice with oxygen‐induced ischemic retinopathy, deficiency of eNOS, but not iNOS or nNOS caused a significant decrease in retinal neovascularization and decreased expression of VEGF. These data suggest that NO contributes to both retinal and choroidal neovascularization and that different isoforms of NOS are involved in different settings and different disease processes. A broad spectrum NOS inhibitor may have therapeutic potential for treatment of both retinal and choroidal neovascularization. J. Cell. Physiol. 191: 116–124, 2002.

Complications associated with limited macular translocation

PURPOSE To report the ocular complications associated with the limited macular translocation procedure. METHODS Retrospective review of 153 consecutive eyes of 151 patients that had the limited macular translocation procedure for subfoveal choroidal neovascularization between April 1996 and February 1999. The major study variables investigated included the incidence of specific ocular complications and their impact on visual acuity at 3 months after the surgery. In addition, baseline patient characteristics and operative factors were evaluated to determine whether they were significant risk factors for the development of an ocular complication. The existence of a surgical procedure learning process was investigated. RESULTS One hundred forty-one (92.15%) of 153 eyes achieved at least 3-month follow-up. At least one complication occurred in 53 of 153 eyes (34.6%) and in 51 of these 53 eyes (96. 22%) the complications occurred before 3 months of postoperative follow-up. The intraoperative and postoperative complications included retinal detachment (17.4%), retinal breaks (13.4%), macular holes (7.8%), macular fold (4.6%), and intraocular hemorrhage (vitreous, subretinal, or choroidal; 9.2%). Eyes that developed retinal detachment, subretinal hemorrhage, and macular fold had significantly more loss of visual acuity than eyes without each of these complications (P =.0001, P =.038, and P =.027, respectively). The presence of predominantly classic choroidal neovascularization, the occurrence of an intraoperative retinal break, any intraocular hemorrhage, or macular fold formation were significantly associated with retinal detachment (P =.021, P =.025, P =.013, and P =.014, respectively). The incidence of any complication, retinal detachment, and hemorrhage significantly decreased during the study period, suggesting a learning process (P =.03, P =.006, P =.027, respectively). CONCLUSIONS A variety of ocular complications can occur during or after limited macular translocation, and some are associated with reduced postoperative visual acuity. Improved surgical techniques and experience may significantly reduce the incidence of these complications.

Increased expression of VEGF in retinal pigmented epithelial cells is not sufficient to cause choroidal neovascularization.

Increased expression of vascular endothelial cell growth factor (VEGF) in the retina is sufficient to stimulate sprouting of neovascularization from the deep capillary bed of the retina, but not the superficial retinal capillaries or the choriocapillaris. Coexpression of VEGF and angiopoietin 2 (Ang2) results in sprouting of neovascularization from superficial and deep retinal capillaries, but not the choriocapillaris. However, retina‐derived VEGF and Ang2 may not reach the choriocapillaris, because of tight junctions between retinal pigmented epithelial (RPE) cells. To eliminate this possible confounding factor, we used the human vitelliform macular dystrophy 2 (VMD2) promoter, an RPE‐specific promoter, combined with the tetracycline‐inducible promoter system, to generate double transgenic mice with inducible expression of VEGF in RPE cells. Adult mice with increased expression of VEGF in RPE cells had normal retinas and choroids with no choroidal neovascularization (CNV), but when increased expression of VEGF in RPE cells was combined with subretinal injection of a gutless adenoviral vector containing an expression construct for Ang2 (AGVAng2), CNV consistently occurred. In contrast, triple transgenic mice with induced expression of Ang2 and VEGF in RPE cells, did not develop CNV. These data suggest that increased expression of VEGF and/or Ang2 in RPE cells is not sufficient to cause CNV unless it is combined with a subretinal injection of a gutless adenoviral vector, which is likely to perturb RPE cells. These data also suggest that the effects of angiogenic proteins may vary among vascular beds, even those that are closely related, and, therefore, generalizations should be avoided.