Dennis M. Marcus

Ranibizumab for Diabetic Macular Edema: Results from 2 Phase III Randomized Trials: RISE and RIDE

PURPOSE To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients. DESIGN Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies. PARTICIPANTS Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT). INTERVENTION Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria. MAIN OUTCOME MEASURES Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months. RESULTS In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P<0.0001; difference vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [CI], 13.8-34.8) and 39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% CI, 10.7-31.1). In RIDE (NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more ranibizumab-treated patients gained ≥15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients (P<0.0001; adjusted difference, 20.8%; 95% CI, 11.4-30.2) and 45.7% of 0.5-mg ranibizumab patients (P<0.0001; adjusted difference, 33.3%; 95% CI, 23.8-42.8). Significant improvements in macular edema were noted on OCT, and retinopathy was less likely to worsen and more likely to improve in ranibizumab-treated patients. Ranibizumab-treated patients underwent significantly fewer macular laser procedures (mean of 1.8 and 1.6 laser procedures over 24 months in the sham groups vs 0.3-0.8 in ranibizumab groups). Ocular safety was consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total incidence of deaths from vascular or unknown causes, nonfatal myocardial infarctions, and nonfatal cerebrovascular accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to 5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients. CONCLUSIONS Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm.

Long-term Outcomes of Ranibizumab Therapy for Diabetic Macular Edema: The 36-Month Results from Two Phase III Trials: RISE and RIDE

PURPOSE To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME). DESIGN Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years. PARTICIPANTS Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography. METHODS Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary. MAIN OUTCOME MEASURES The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24. RESULTS Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group. CONCLUSIONS The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Sleep disorders: a risk factor for normal-tension glaucoma?

PurposeTo determine the prevalence of sleep-related symptoms and sleep-related breathing disorders by polysomnography in patients with normal-tension glaucoma (NTG). Patients and MethodsThis comparative case series included 23 patients with NTG, 14 NTG suspects, and 30 comparison patients without NTG. A sleep history was obtained and determined to be positive or negative. Polysomnography was offered for patients with a positive sleep history. Prevalence of a positive sleep history and prevalence of sleep disorders were the main outcome measures. ResultsThe NTG, NTG suspect, and comparison groups did not differ with respect to age, body mass index, systemic disease, gender, or race. Thirteen (57%) of 23 patients with NTG, 6 (43%) of 14 NTG suspects, and 1 (3%) of 30 comparison patients had a positive sleep history (P = 0.001). Nine of 13 patients with NTG and four of six NTG suspects with a positive sleep history chose to undergo polysomnography. Seven (78%) of nine patients with NTG and all four NTG suspects undergoing polysomnography were diagnosed with a sleep disorder. Five patients with NTG had sleep apnea and two had sleep hypopnea. Two NTG suspects had sleep apnea; one had sleep hypopnea; and one had upper airway resistance syndrome. The one comparison patient with a positive sleep history had upper airway resistance syndrome by polysomnography. ConclusionsSleep-disturbed breathing may be a risk factor for NTG. Although we do not provide evidence for a cause-and-effect relationship, various physiologic factors produced by sleep-disturbed breathing may play a significant role in the pathogenesis of this optic neuropathy. We recommend obtaining a sleep history from patients with NTG and performing polysomnography in those patients with sleep disturbance symptoms.

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.

Posterior Segment Complications after Vitrectomy for Macular Hole

PURPOSE The purpose of this study is to assess the rate of posterior segment complications after vitreous surgery for macular holes and to evaluate the effect of such complications on final visual outcome. METHODS The authors reviewed retrospectively all cases of vitreous surgery for macular holes performed between June 1990 and October 1993. Among 98 patients with a followup of 3 months or more, all patients with posterior segment complications during the postoperative course were identified. The rate of complications was compared with that seen after vitreous surgery for macular pucker performed by the same surgeons. RESULTS Posterior segment complications were noted in 23 (23%) of 98 patients. These included peripheral retinal breaks (3%), rhegmatogenous retinal detachment from a peripheral retinal break (14%), enlargement of the hole (2%), late reopening of the hole (2%), retinal pigment epithelium loss under the hole (1%), photic toxicity (1%), and endophthalmitis (1%). In 40% of these eyes, the final visual acuity was two lines or more below preoperative visual acuity. When compared with the macular pucker group, the rate of posterior segment complications, in particular the rate of peripheral retinal tears and detachments, was significantly higher (P < or = 0.05). CONCLUSIONS The authors conclude that visually significant posterior segment complications may occur after vitrectomy for macular hole, and the rate of these complications appears to be higher than expected.

Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies

PURPOSE To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME). DESIGN Two similarly designed, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement. METHODS Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. MAIN OUTCOME MEASURES The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. RESULTS Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters (P < 0.0001) in VISTA and 11.4, 9.4, and 0.7 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 100 was 38.3%, 33.1%, and 13.0% (P < 0.0001) in VISTA and 38.2%, 31.1%, and 12.1% (P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% (P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% (P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P < 0.0001) and VIVID (29.3% and 32.6% vs. 8.2%; P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control). CONCLUSIONS In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.

The 1-year Results of CLEAR-IT 2, a Phase 2 Study of Vascular Endothelial Growth Factor Trap-Eye Dosed As-needed After 12-week Fixed Dosing

OBJECTIVE To evaluate anatomic outcomes and vision, injection frequency, and safety during the as-needed (PRN) treatment phase of a study evaluating a 12-week fixed dosing period followed by PRN dosing to week 52 with vascular endothelial growth factor (VEGF) Trap-Eye for neovascular (wet) age-related macular degeneration (AMD). DESIGN Multicenter, randomized, double-masked trial. PARTICIPANTS We included 159 patients with subfoveal choroidal neovascularization (CNV) secondary to wet AMD. METHODS Patients were randomly assigned to 1 of 5 intravitreal VEGF Trap-Eye treatment groups: 0.5 mg or 2 mg every 4 weeks or 0.5, 2, or 4 mg every 12 weeks during the fixed-dosing period (weeks 1-12). From weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or 4 mg). MAIN OUTCOME MEASURES Change in central retinal/lesion thickness (CR/LT), change in total lesion and CNV size, mean change in best-corrected visual acuity (BCVA), proportion of patients with 15-letter loss or gain, time to first PRN injection, reinjection frequency, and safety at week 52. RESULTS The decrease in CR/LT at week 12 versus baseline remained significant at weeks 12 to 52 (-130 μm from baseline at week 52) and CNV size regressed from baseline by 2.21 mm(2) at 48 weeks. After achieving a significant improvement in BCVA during the 12-week, fixed-dosing phase for all groups combined, PRN dosing for 40 weeks maintained improvements in BCVA to 52 weeks (5.3-letter gain; P<0.0001). The most robust improvements and consistent maintenance of visual acuity generally occurred in patients initially dosed with 2 mg every 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks. Overall, a mean of 2 injections was administered after the 12-week fixed-dosing phase, and the mean time to first reinjection was 129 days; 19% of patients received no injections and 45% received 1 or 2 injections. Treatment with VEGF Trap-Eye was generally safe and well tolerated, with few ocular or systemic adverse events. CONCLUSIONS PRN dosing with VEGF Trap-Eye at weeks 16-52 maintained the significant anatomic and vision improvements established during the 12-week fixed-dosing phase with a low frequency of reinjections. Repeated dosing with VEGF Trap-Eye was well tolerated over 52 weeks of treatment. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

The effect of blood transfusion protocol on retinopathy of prematurity: A prospective, randomized study.

Objective. Controversy exists regarding the potential influence of anemia and blood transfusions on the rate of retinopathy of prematurity (ROP) in premature infants. A prospective, randomized, masked trial was performed to determine the influence of red blood cell transfusion protocol on ROP incidence and severity in a population of high-risk infants. Methods. A total of 50 infants with birth weights <1251 g were divided randomly into two groups beginning on day of life 29. Group 1 (n = 24) received red cell transfusions during the 6-week study period, only if certain symptom-based guidelines were met. Group 2 (n = 26) received red cell transfusions to maintain the hematocrit level above 40% for the entire 6 weeks. Infants were monitored for ROP, growth, and associated morbidity. Serial measurements of serum glucose, lactate, ferritin, total iron-binding capacity, and iron were performed. Results. ROP occurred in 83% of infants in group 1, and 73% of infants in group 2. There were no statistically significant differences in ROP severity, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or any of the laboratory values except hemoglobin (10.8 vs 13.2 g/dL) and hematocrit (33.9% vs 41.8%) between the groups. Combining data from both groups, there was no association between hemoglobin or hematocrit ratios and ROP incidence or severity. Conclusions. A transfusion policy aimed at limiting the amount of blood given to premature infants (symptom-based) during the neonatal period does not impart a significantly different risk for ROP or other associated conditions, than does a policy in which transfusions are given more liberally for replacement purposes.

Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Macular Edema After Focal/grid Laser for Diabetic Macular Edema in Eyes Also Receiving Panretinal Photocoagulation

Purpose: To evaluate 14-week effects of intravitreal ranibizumab or triamcinolone in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation. Methods: Three hundred and forty-five eyes with a visual acuity of 20/320 or better, center-involved diabetic macular edema receiving focal/grid laser, and diabetic retinopathy receiving prompt panretinal photocoagulation were randomly assigned to sham (n = 123), 0.5-mg ranibizumab (n = 113) at baseline and 4 weeks, and 4-mg triamcinolone at baseline and sham at 4 weeks (n = 109). Treatment was at investigator discretion from 14 weeks to 56 weeks. Results: Mean changes (±SD) in visual acuity letter score from baseline were significantly better in the ranibizumab (+1 ± 11; P < 0.001) and triamcinolone (+2 ± 11; P < 0.001) groups compared with those in the sham group (−4 ± 14) at the 14-week visit, mirroring retinal thickening results. These differences were not maintained when study participants were followed for 56 weeks for safety outcomes. One eye (0.9%; 95% confidence interval, 0.02%-4.7%) developed endophthalmitis after receiving ranibizumab. Cerebrovascular/cardiovascular events occurred in 4%, 7%, and 3% of the sham, ranibizumab, and triamcinolone groups, respectively. Conclusion: The addition of 1 intravitreal triamcinolone injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study.

23-gauge vitrectomy in 100 eyes: short-term visual outcomes and complications.

Purpose: To report the short-term outcomes and complications of patients undergoing 23-gauge transconjunctival sutureless pars plana vitrectomy. Methods: Retrospective, consecutive, noncomparative case series in which 100 eyes of 100 patients underwent elective 23-gauge pars plana vitrectomy for a variety of surgical indications. All patients were examined on postoperative day 1 and then approximately 1 and 4 weeks later. Demographic and ophthalmic data were recorded. Results: Fifty-two men and 48 women (mean age = 65 years) were observed for a mean of 26 weeks. Mean preoperative visual acuity was 20/842 and mean final postoperative visual acuity was 20/429. Postoperative visual acuity improved in 68% of patients, worsened in 16%, and remained unchanged in 16%. Mean preoperative intraocular pressure was 15 mmHg and mean postoperative intraocular pressure at final visit was 14 mmHg. No sutures were required to close sclerotomies and no intraoperative complications were observed, though one eye required conversion to 20-gauge pars plana vitrectomy during silicone oil removal. Postoperative complications included retinal detachment, cataract progression, vitreous hemorrhage, persistent macular hole, new macular hole, phthisis, posterior capsular opacification, and severe chemosis. Conclusions: Twenty-three-gauge pars plana vitrectomy demonstrates short-term visual outcomes and complication rates that are comparable to those reported with 20- and 25-gauge systems.