Monthly Ranibizumab Research Articles

Macular Morphology and Visual Acuity in the Second Year of the Comparison of Age-Related Macular Degeneration Treatments Trials

To describe the association between morphologic features on fundus photography (FP), fluorescein angiography (FA), and optical coherence tomography (OCT) and visual acuity (VA) in the second year of the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Prospective cohort study within a randomized clinical trial. Participants in the CATT. Study eye eligibility required angiographic and OCT evidence of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) and VA between 20/25 and 20/320. Treatment was assigned randomly to ranibizumab or bevacizumab with 3 different dosing regimens over a 2-year period. Fluid type, location, and thickness; retina and subretinal tissue complex thickness on OCT; size and lesion composition on FP and FA; and VA. Among 1185 CATT participants, 993 (84%) had fluid on OCT at baseline and completed 2 years of follow-up. At 2 years, intraretinal fluid (IRF), subretinal fluid (SRF), sub-retinal pigment epithelium (RPE) fluid, and subretinal tissue complex thickness decreased in all treatment groups. Ranibizumab monthly was best able to resolve each type of fluid. Eyes with SRF in the foveal center on OCT had better mean VA than eyes with no SRF (72.8 vs. 66.6 letters; P = 0.006). Eyes with IRF in the foveal center had worse mean VA than eyes without IRF (59.9 vs. 70.9 letters; P < 0.0001). Eyes with retinal thickness <120 μm had worse VA compared with eyes with retinal thickness 120 to 212 and >212 μm (59.4 vs. 71.3 vs. 70.3 letters; P < 0.0001). At 2 years, the mean VA (letters) of eyes varied substantially by the type of subfoveal pathology on FP and FA: 70.6 for no pathology; 74.1 for fluid only; 73.3 for CNV or pigment epithelial (RPE) detachment; 68.4 for nongeographic atrophy; and 62.9 for geographic atrophy, hemorrhage, RPE tear, or scar (P < 0.0001). The associations between VA and morphologic features identified through year 1 were maintained or strengthened during year 2. Eyes with foveal IRF, abnormally thin retina, greater thickness of the subretinal tissue complex on OCT, and subfoveal geographic atrophy or scar on FP/FA had the worst VA. Subretinal fluid was associated with better VA.

Systemic Safety of Prolonged Monthly Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema: A Systematic Review and Meta-analysis.

Anti-vascular endothelial growth factor (VEGF) therapy is commonly used to treat numerous retinal conditions and appears safe, yet controversy remains regarding systemic safety. To evaluate the systemic safety of intravitreous anti-VEGF injections in high-risk patients with diabetic macular edema (DME) and to investigate separately the subgroup of these patients with the highest level of exposure to anti-VEGF monthly treatment for 2 years. A search of MEDLINE, Cochrane Central Register of Controlled Trials, clincaltrials.gov, and ophthalmology congress abstracts January 1, 1947, to May 19, 2015. Randomized clinical trials were selected that evaluated monthly anti-VEGF injections for DME for 2 years and reported the outcome measures of cerebrovascular accidents, myocardial infarctions, arteriothrombotic events, and mortality. Two reviewers collected data independently from each study for the meta-analysis. Data were pooled using a fixed-effects model and analyzed from November 6, 2014, to June 28, 2015. Peto odds ratios with 95% CIs were calculated. Primary end points included cerebrovascular accidents and all-cause mortality in the highest-dose arms. Secondary outcomes included myocardial infarctions, arteriothrombotic events, and vascular-related death. Of 1126 articles reviewed, 598 were removed as duplicate studies and 524, for lack of monthly treatment data for 2 years, leaving 4 studies for the meta-analysis that met the search criteria: 2 trials using monthly aflibercept and 2 using monthly ranibizumab, representing 1328 patients. The primary evaluation (1078 patients) combined the monthly aflibercept and the 0.5-mg ranibizumab arms and yielded an increased risk for death compared with sham and laser treatments (odds ratio [OR], 2.98; 95% CI, 1.44-6.14; P = .003). Analysis including monthly aflibercept and 0.5-mg ranibizumab yielded an increased risk for cerebrovascular accidents (OR, 2.33; 95% CI, 1.04-5.22; P = .04) and vascular death (OR, 2.51; 95% CI, 1.08-5.82; P = .03). No definitive increased risk for myocardial infarctions and arteriothrombotic events was seen with all dose combinations. In this meta-analysis of anti-VEGF agents for patients with DME, assessment of the highest-level exposure group (those high-risk patients with DME who received 2 years of monthly treatment) revealed a possible increased risk for death and potentially for cerebrovascular accidents. Consideration of total exposure to anti-VEGF agents when treating those at high risk for vascular disease may be important.

Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion

To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab. Secondary outcome measure in randomized double-masked controlled clinical trial. Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). Subjects were randomized to 0.5 or 2.0 mg ranibizumab every month for 6 months and then were re-randomized to pro re nata (PRN) groups receiving either ranibizumab plus scatter laser photocoagulation or ranibizumab alone for an additional 30 months. Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5 versus 2.0 mg ranibizumab, during monthly injections versus ranibizumab PRN, and in patients treated with ranibizumab PRN versus ranibizumab PRN plus laser. In RVO patients given monthly injections of 0.5 or 2.0 mg ranibizumab for 6 months, there was no significant difference in the percentage who showed reduction or increase in the area of RNP. However, regardless of dose, during the 6-month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared with subsequent periods of ranibizumab PRN treatment. After the 6-month period of monthly injections, BRVO patients, but not CRVO patients, randomized to ranibizumab PRN plus laser showed significantly less progression of RNP compared with patients treated with ranibizumab PRN. Regardless of dose (0.5 or 2.0 mg), monthly ranibizumab injections promote improvement and reduce progression of RNP compared with PRN injections. The addition of scatter photocoagulation to ranibizumab PRN may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO.

Outcomes with As-Needed Ranibizumab after Initial Monthly Therapy: Long-Term Outcomes of the Phase III RIDE and RISE Trials

To determine whether the efficacy and safety achieved with monthly ranibizumab as treatment for diabetic macular edema (DME) can be maintained with less-than-monthly treatment. Open-label extension (OLE) phase of randomized, sham-controlled phase III trials: RIDE (NCT00473382) and RISE (NCT00473330). Five hundred of 582 adults who completed the 36-month randomized core studies elected to enter the OLE. All patients participating in the OLE were eligible to receive 0.5 mg ranibizumab according to predefined re-treatment criteria: Treatment was administered when DME was identified by the investigator on optical coherence tomography or when best-corrected visual acuity (BCVA) worsened by ≥5 Early Treatment Diabetic Retinopathy Study letters versus month 36. Patients were observed at 30-, 60-, or 90-day intervals depending on the need for treatment. The incidence and severity of ocular and nonocular events, proportion of patients with ≥15-letter best-corrected visual acuity (BCVA) gain from baseline, mean BCVA change from month 36 (final core study visit), mean central foveal thickness (CFT), and mean CFT change from month 36. A mean of 4.5 injections were administered over a mean follow-up of 14.1 months. Approximately 25% of patients did not require further treatment based on protocol-defined re-treatment criteria. Mean BCVA was sustained or improved in these patients through the end of follow-up. Approximately 75% of patients received ≥1 criteria-based re-treatment; mean time to first re-treatment was approximately 3 months after the last masked-phase visit. Mean BCVA remained stable in re-treated patients; CFT was generally stable with a trend toward slight thickening in all patients when mandatory monthly therapy was relaxed. Vision gains achieved after 1 or 3 years of monthly ranibizumab therapy were maintained with a marked reduction in treatment frequency; some patients required no additional treatment. These observations are consistent with other studies evaluating induction followed by maintenance ranibizumab therapy for DME. Patients whose treatment was deferred by 2 years (randomized initially to sham) did not ultimately achieve the same BCVA gains as patients who received ranibizumab from baseline. Ranibizumab's safety profile in the OLE appeared similar to that observed in the controlled core studies and other studies.

Retinal Pigment Epithelial Atrophy in Neovascular Age-Related Macular Degeneration After Ranibizumab Treatment

To investigate the risk factors for development and progression of retinal pigment epithelial (RPE) atrophy during ranibizumab treatment for neovascular age-related macular degeneration (AMD) in Japanese patients. Retrospective interventional case series. This study included 195 eyes with treatment-naïve subfoveal neovascular AMD. All patients were treated with an as-needed regimen after 3 monthly ranibizumab treatments. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy diagnosis. Baseline characteristics and ARMS2 A69S and CFH I62V polymorphisms were analyzed for their association with development and progression of RPE atrophy. Ten of 195 eyes (5.1%) had RPE atrophy at baseline; 3 had typical AMD and 7 had polypoidal choroidal vasculopathy (PCV). Among 185 eyes without preexisting RPE atrophy at baseline, 7 (3.8%) developed RPE atrophy at 12 months and 10 (5.4%) during the mean follow-up of 26.7 months. The incidence of newly developed RPE atrophy was lower in PCV than in typical AMD (P = .036), while the progression of the RPE atrophy area was faster in typical AMD than in PCV (0.57 ± 0.35 and 0.31 ± 0.13 mm/year, respectively; P = .018). The ARMS2 A69S and CFH I62V polymorphisms were significantly associated with the baseline RPE atrophy (P = .014 and P = .009, respectively). The RPE atrophy developed in 5.4% of eyes with neovascular AMD during the 26.7 months of ranibizumab treatment. When compared with white individuals, RPE atrophy developed less frequently in Japanese patients, but the progression rate was similar. The subtype of AMD thus affects the development of RPE atrophy.

Alternating Bi-Weekly Intravitreal Ranibizumab and Bevacizumab for Refractory Neovascular Age-Related Macular Degeneration with Pigment Epithelial Detachment

Objective: To describe visual and anatomical outcomes following bi-weekly intravitreal ranibizumab/bevacizumab injections in eyes with refractory neovascular age-related macular degeneration (AMD) and pigment epithelial detachment (PED). Design: Retrospective, consecutive, interventional case series. Participants: Eighteen patients diagnosed with neovascular AMD that were refractory to anti-VEGF therapy and received alternating biweekly ranibizumab/bevacizumab injections were included. Methods: Patients with neovascular AMD and PED that were refractory to at least 11 monthly ranibizumab or bevacizumab injections were included in this study at a large, single retina practice. Following inclusion, patients received four bi-weekly alternating ranibizumab/bevacizumab intravitreal injections. After completing a course of four bi-weekly injections, patients were treated with variable regimens of intravitreal anti-vascular endothelial growth factor (VEGF) therapy. The primary outcomes of the study included change in visual acuity (VA) and central foveal thickness (CFT) at eight weeks follow-up. Results: Study eyes had previously received a mean of 22 intravitreal anti-VEGF injections. At enrollment, mean VA was 20/95 and mean CFT was 455 µm. After four bi-weekly anti-VEGF injections, mean VA improved to 20/65 (p < 0.001), and mean CFT decreased to 387 µm (p = 0.029). In patients with PED, there was a mean 27.9% reduction in height (p = 0.046) at eight weeks’ follow-up. Conclusions: Four injections of bi-weekly alternating ranibizumab/bevacizumab improved visual acuity and reduced macular thickness in a number of patients with refractory neovascular AMD and PED.

Factors Associated with Recurrence of Age-Related Macular Degeneration after Anti-Vascular Endothelial Growth Factor Treatment: A Retrospective Cohort Study

To investigate the predictive factors associated with recurrence after anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). Retrospective cohort study. A total of 343 eyes of 326 patients with subfoveal neovascular AMD who were treated with an as-needed regimen after 3 monthly loading doses of intravitreal ranibizumab. Patients were followed up by an as-needed regimen for more than 1 year after the first injection. Baseline data and CFH I62V and ARMS2 A69S polymorphisms were analyzed for their association with recurrence after anti-VEGF treatment. Regression analysis was used to identify independent predictors of visual acuity (VA) prognosis. The primary end point was the presence or absence of recurrence. The secondary end point was VA improvement. In total, 236 eyes (68.8%) showed complete resolution of retinal exudative change after the 3 loading injections, and 81 eyes (34.3%) experienced no recurrence during the first year. Of the 236 eyes, 139 (58.9%) were followed for more than 2 years and 35 (25.2%) showed no recurrent retinal exudation during 24 months. Visual acuity improvement was significantly better in eyes without recurrence than in eyes with recurrence during the 2-year period. Baseline characteristics and genotypes had no influence on response to ranibizumab loading treatment. Stepwise analysis revealed that age (P<0.001), subtype of AMD (P=0.041), and VA at baseline (P<0.001) were associated with VA at 24 months. Older patients (P=0.006) and male patients (P=0.018) tended to require re-treatment for recurrence during the first year, yet the statistical significance disappeared when evaluated in 2 years. The subtypes of neovascular AMD were solely associated with the interval to the recurrence, which was shorter in eyes with polypoidal choroidal vasculopathy (PCV) than in eyes with typical AMD (P=0.015). Older age and male sex may predict recurrence after 3 monthly ranibizumab injections, and PCV may be associated with shorter interval to recurrence. Predicting the risk of recurrence would help us to choose the most appropriate follow-up treatment strategy for patients with AMD.

Ranibizumab 0.5 mg for Diabetic Macular Edema with Bimonthly Monitoring after a Phase of Initial Treatment: 18-Month, Multicenter, Phase IIIB RELIGHT Study

To evaluate ranibizumab 0.5 mg using bimonthly monitoring and individualized re-treatment after monthly follow-up for 6 months in patients with visual impairment due to diabetic macular edema (DME). A phase IIIb, 18-month, prospective, open-label, multicenter, single-arm study in the United Kingdom. Participants (N = 109) with visual impairment due to DME. Participants received 3 initial monthly ranibizumab 0.5 mg injections (day 0 to month 2), followed by individualized best-corrected visual acuity (BCVA) and optical coherence tomography-guided re-treatment with monthly (months 3-5) and subsequent bimonthly follow-up (months 6-18). Laser was allowed after month 6. Mean change in BCVA from baseline to month 12 (primary end point), mean change in BCVA and central retinal thickness (CRT) from baseline to month 18, gain of ≥10 and ≥15 letters, treatment exposure, and incidence of adverse events over 18 months. Of 109 participants, 100 (91.7%) and 99 (90.8%) completed the 12 and 18 months of the study, respectively. The mean age was 63.7 years, the mean duration of DME was 40 months, and 77.1% of the participants had received prior laser treatment (study eye). At baseline, mean BCVA was 62.9 letters, 20% of patients had a baseline BCVA of >73 letters, and mean baseline CRT was 418.1 μm, with 32% of patients having a baseline CRT <300 μm. The mean change in BCVA from baseline to month 6 was +6.6 letters (95% confidence interval [CI], 4.9-8.3), and after institution of bimonthly treatment the mean change in BCVA at month 12 was +4.8 letters (95% CI, 2.9-6.7; P < 0.001) and +6.5 letters (95% CI, 4.2-8.8) at month 18. The proportion of participants gaining ≥10 and ≥15 letters was 24.8% and 13.8% at month 12 and 34.9% and 19.3% at month 18, respectively. Participants received a mean of 6.8 and 8.5 injections over 12 and 18 months, respectively. No new ocular or nonocular safety findings were observed during the study. The BCVA gain achieved in the initial 6-month treatment period was maintained with an additional 12 months of bimonthly ranibizumab PRN treatment.

REFRACTORY INTRARETINAL OR SUBRETINAL FLUID IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TREATED WITH INTRAVITREAL RANIZUBIMAB: Functional and Structural Outcome.

To investigate the visual acuity results of eyes with neovascular age-related macular degeneration and refractory fluid despite monthly treatment with ranibizumab, and to investigate differences between refractory subretinal fluid and intraretinal cystic changes. Retrospective chart review of consecutive treatment-refractory neovascular age-related macular degeneration, defined as persistent intraretinal or subretinal fluid despite monthly ranibizumab injections during 12 months or more. Data were evaluated for baseline characteristics, type and location of the refractory fluid, mean visual acuity change, number of injections, and the time point of first complete disappearance of all fluid on spectral domain optical coherence tomography. Seventy-six eyes (74 patients, mean age, 76.8 years) were identified. The mean follow-up was 33.6 months (range, 12-73 months). The mean number of injections was 11.4 in the first year and 27.7 over follow-up. The refractory fluid was located subfoveally in 61.8%. In 27 eyes (35.5%), the fluid resolved after a mean of 21.8 months (range, 13-49 months). Mean visual acuity increased by 9.0, 7.9, and 7.9 letters by Month 12, Month 24, and Month 36, respectively. Subgroup analysis revealed a higher risk for fibrosis (odds ratio, 3.30) or atrophy (odds ratio, 3.34) in patients with refractory cysts as compared with refractory subretinal fluid. Furthermore, refractory cysts showed a higher risk for a 10-letter visual acuity loss (P = 0.018). Fluid refractory to monthly treatment with ranibizumab for neovascular age-related macular degeneration still allowed for well-maintained visual improvement, even in subfoveal location. Late fluid resolution may occur. However, refractory cysts were associated with poorer anatomical and functional outcome than subretinal fluid.

Changes of choroidal neovascularization in indocyanine green angiography after intravitreal ranibizumab injection.

To investigate vascular structural changes of choroidal neovascularization (CNV) followed by intravitreal ranibizumab injections using indocyanine green angiography. A total of 31 patients with exudative age-related macular degeneration and CNV whose structures were identifiable in indocyanine green angiography were included. Ranibizumab was injected into the vitreous cavity once a month for 3 months and then as needed for the next 3 months prospectively. Indocyanine green angiography was performed at baseline, 3, and 6 months. Early to midphase images of the indocyanine green angiography in the details of vascular structure of the CNV were discerned the best were used in the image analysis. Vascular structures of CNV were described as arteriovenular and capillary components, and structural changes were assessed. Arteriovenular components were observed in 29 eyes (94%). Regression of the capillary components was observed in most cases. Although regression of arteriovenular component was noted in 14 eyes (48%), complete resolution was not observed. The eyes were categorized into 3 groups according to CNV structural changes: the regressed (Group R, 10 eyes, 31%), the matured (Group M, 7 eyes, 23%), and the growing (Group G, 14 eyes, 45%). In Group R, there was no regrowth of CNV found at 6 months. In Group M, distinct vascular structures were observed at 3 months and persisted without apparent changes at 6 months. In Group G, growth or reperfusion of capillary components from the persisting arteriovenular components was noted at 6 months. Both capillary and arteriovenular components were regressed during monthly ranibizumab injections. However, CNV regrowth was observed in a group of patients during the as-needed treatment phase.

Parafoveal contributions to retinal function during ranibizumab therapy for age-related macular degeneration

ObjectiveThe standard measure for the assessment of functional vision in the central retina is best corrected visual acuity (VA). Our aim was to investigate whether it is an advantage to include tests for functional changes in the near retinal periphery to monitor treatment effects in patients receiving multiple injections of anti–vascular endothelial growth factor (anti-VEGF) agents for advanced exudative age-related macular degeneration (AMD). DesignProspective pilot study. ParticipantsOur cohort consisted of 24 patients with exudative AMD (mean age ± SD: 77.46 ± 7.82 years) treated at an ophthalmology clinic. MethodsWe compared data from standard functional measurements, VA-near, and contrast sensitivity (CS), with results from the macular mapping test (MMT) at 10% and 100% contrast. Measurements of retinal thickness by optical coherence tomography (OCT) were used to document the morphologic efficacy of the anti-VEGF agent. Tests were performed at baseline and 4 weeks after 3 monthly ranibizumab injections. ResultsAll 4 functional tests yielded successes (equal or better visual performance after treatment) in 79.2% to 83.3% of cases. Including test locations in the near periphery yielded the highest success rate in the MMT at 10% contrast. Values for VA-near and CS also improved in a majority of cases. OCT measurements of retinal thickness indicated that the agent was effective in the fovea and near periphery. ConclusionsOur findings indicate that using the MMT adds information about functional changes in the near periphery of the retina and allows more sensitive assessment of treatment effects or disease progression without the high expense of other techniques.

Effects of Vitreomacular Traction on Ranibizumab Treatment Response in Eyes with Neovascular Age-related Macular Degeneration.

PurposeTo investigate the effects of vitreomacular traction (VMT) on ranibizumab treatment response for neovascular age-related macular degeneration (AMD).MethodsA retrospective review of 85 eyes of 85 patients newly diagnosed with neovascular AMD was conducted. Patients were eligible if they had received more than three consecutive monthly ranibizumab (0.50 mg) treatments and ophthalmic evaluations. Patients were classified into a VMT (+) group or VMT (-) group according to optical coherence tomography imaging. Best corrected visual acuity and central retinal thickness (CRT) measurements were obtained at three and six months after initial injection.ResultsOne month after the third injection, mean visual acuity (VA) increases of 6.36 and 9.87 letters were observed in the VMT (+) and VMT (-) groups, respectively. The corresponding mean CRT values decreased by 70.29 µm and 121.68 µm, respectively. A total 41 eyes were identified as eligible for a subsequent fourth injection; 71.1% of patients (27 eyes) in the VMT (+) group but only 29.8% of patients in the VMT (-) group needed a subsequent fourth injection. Follow-up was extended to six months for 42 of the 85 enrolled patients (49.4%). The trends in VA and optical coherence tomography were found to be maintained at six-month follow-up.ConclusionsVA and CRT appeared to be more improved after ranibizumab treatment in the VMT (-) group compared to the VMT (+) group. VMT might antagonize the effect of ranibizumab treatment in a subpopulation of AMD patients.

Dexamethasone intravitreal implant as adjunct therapy for patients with wet age-related macular degeneration with incomplete response to ranibizumab

PurposeTo evaluate the visual and anatomical outcomes of dexamethasone intravitreal implant (DXI; 700 μg, Ozurdex; Allergan, Irvine, California, USA) as adjunctive therapy for patients with refractory wet age-related macular degeneration...

Refractory subretinal fluid in patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab: visual acuity outcome.

To investigate the functional outcome of eyes with neovascular AMD (nAMD) and subretinal fluid (SRF) refractory to treatment with ranibizumab. Retrospective chart review of consecutive treatment-refractory SRF in nAMD despite monthly ranibizumab injections during 12 months or more. Data were evaluated for baseline characteristics, location of the refractory SRF, mean visual acuity (VA) change, number of injections, and timepoint of first complete disappearance of SRF. Forty-five eyes in 44 patients (mean age of 76 years) were included. The mean follow-up was 32.4 months (range 12-73 months). The mean number of injections was 11.6 in the first year and 27.5 over follow-up. The refractory SRF was located subfoveally in 66.7 %. In 12 eyes (26.7 %), complete absorption of SRF was found after a mean of 22.6 months (range, 13-41 months). Mean VA increased by 10.4, 8.2, and 8.6 letters by month 12, 24, and 36, respectively. Neovascular AMD with SRF refractory to monthly retreatment with ranibizumab may still allow good and maintained visual improvement, even if the fluid is located subfoveally. SRF may progressively absorb under continuous monthly treatment. The necessity to treat refractory SRF with monthly injections could be questioned and would need future investigations.

ANTI-VEGF TREATMENT IN NEOVASCULAR AGE–RELATED MACULAR DEGENERATION

To evaluate 2-year visual acuity outcome of a treat-and-extend protocol of anti-vascular endothelial growth factor treatment in age-related macular degeneration. In this prospective cohort study, 120 age-related macular degeneration patients with choroidal neovascularization received 3 initial monthly ranibizumab or bevacizumab injections; monthly injections were continued until there was no choroidal neovascularization activity (subretinal/intraretinal fluid, loss of >5 letters, or persistent/recurrent retinal hemorrhage). When there was no choroidal neovascularization activity, the interval to the next visit/injection was extended by 2 weeks to a maximum of 12 weeks. In the presence of choroidal neovascularization activity, this interval was shortened by 2 weeks. Main outcome measures included the percentage losing <15 letters and the mean visual acuity change after 12 months and 24 months. Mean baseline visual acuity was 51.2 ± 12.1 Early Treatment Diabetic Retinopathy Study scores. Mean visual acuity change from baseline was +9.5 ± 10.9 and +8.0 ± 12.9 letters after 12 months and 24 months, respectively, with, on average, 8.6 ± 1.1 visits/injections in the first year and 5.6 ± 2.0 in the second year. After 12 months and 24 months, 97.5% and 95.0% of patients, respectively, lost <15 letters. The "inject-and-extend" protocol-with fewer injections and visits-delivered outcomes comparable to those of the pivotal clinical trials of monthly ranibizumab.

Pharmacokinetics of Ranibizumab after Intravitreal Administration in Patients with Retinal Vein Occlusion or Diabetic Macular Edema

To describe the systemic pharmacokinetics of ranibizumab after intravitreal administration in patients with retinal vein occlusion (RVO) or diabetic macular edema (DME). A population approach of nonlinear mixed-effect pharmacokinetics modeling based on serum concentrations of ranibizumab measured at various times after intravitreal administration. Patients with RVO (n = 441) and DME (n = 435) from 4 large, randomized, phase 3 clinical trials of monthly ranibizumab intravitreal administration. A 1-compartment pharmacokinetics model with first-order absorption and elimination rate constants previously developed in patients with age-related macular degeneration (AMD) was fitted separately to RVO and DME data. Population pharmacokinetic parameters and interindividual variability were estimated for each model. Baseline covariates were evaluated for potential effects on systemic pharmacokinetics. Model performance was validated using general diagnostic plots and a visual predictive check. Ranibizumab disposition was determined in RVO and DME patients and compared with that previously seen in AMD patients. The AMD pharmacokinetics model correctly predicted the measured serum ranibizumab concentration data for RVO and DME patients. Most observed data points were within the simulated 90% confidence interval, indicating that systemic ranibizumab concentrations were comparable among AMD, RVO, and DME patients. No disease-related covariates were identified by the population pharmacokinetics analysis. The systemic pharmacokinetics of ranibizumab were similar among patients with AMD, RVO, or DME. Disease-related differences and patient demographics, measured in this study, did not lead to variability in ocular elimination or in systemic exposure of ranibizumab after intravitreal administration. In all disease processes tested, ranibizumab exits the eye slowly and then is eliminated rapidly from the circulation, thus minimizing systemic exposure.

Time to Clinically Significant Visual Acuity Gains after Ranibizumab Treatment for Retinal Vein Occlusion

To assess time to first achievement of clinically significant visual acuity (VA) gains from baseline in patients with retinal vein occlusion (RVO) receiving ranibizumab versus sham treatment.Post hoc analyses of 2 phase 3 clinical trials assessing efficacy and safety of ranibizumab in patients with branch RVO (Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety [BRAVO] study; NCT00061594) and central RVO (Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety [CRUISE]; NCT00056836) over 12 months.Seven hundred eighty-nine patients (BRAVO, n = 397; CRUISE, n = 392).Randomization to monthly intraocular ranibizumab injections (0.3 mg/0.5 mg) or sham. After 6 monthly injections (treatment period), patients meeting prespecified criteria received as-needed (pro re nata [PRN]) ranibizumab at their assigned dose (sham patients, ranibizumab 0.5 mg) through month 12 (observation period). BRAVO patients meeting specific eligibility criteria could receive rescue laser treatment once during the treatment and once during the observation periods.Time to first gain of 15 letters or more from baseline, analyzed using Kaplan-Meier methods. To evaluate the effect of delaying ranibizumab treatment, sham patients' VA data also were analyzed, with month 6 considered as baseline to assess vision gains during the 6 months of receiving ranibizumab PRN.Median time to first 15-letter or more gain from baseline was 12.0 (sham), 4.8 (ranibizumab 0.3 mg), and 4.0 months (ranibizumab 0.5 mg) in BRAVO and 12.2, 5.9, and 5.2 months, respectively, in CRUISE. The cumulative proportion of patients who had ever gained 15 letters or more from baseline by month 12 was 50% (sham), 68% (ranibizumab 0.3 mg), and 71% (ranibizumab 0.5 mg) in BRAVO and 42%, 61%, and 66%, respectively, in CRUISE. After 6 months of ranibizumab PRN treatment, a cumulative 10.8% (BRAVO) and 26.2% (CRUISE) of initially sham-treated patients ever gained 15 letters or more.This retrospective analysis shows that more than 50% of patients treated with monthly ranibizumab achieved clinically significant vision gains during the initial 6 months of treatment, which largely were maintained using PRN treatment to 12 months. In comparison, less than 50% of patients initially randomized to sham (and later receiving ranibizumab 0.5 mg PRN treatment) ever achieved clinically significant vision gains. These results suggest that initiating treatment immediately after diagnosis may provide the greatest vision gains. The potential benefits of early treatment should be evaluated further in prospective clinical studies.

SYSTEMIC SAFETY OF RANIBIZUMAB FOR DIABETIC MACULAR EDEMA

To evaluate systemic safety of ranibizumab for diabetic macular edema. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were systematically reviewed. Eligible studies were randomized trials on ranibizumab for diabetic macular edema with observation at least 6 months and ≥80% completion rate that reported systemic adverse events of cerebrovascular accident, myocardial infarction, vascular death, and overall mortality. The numbers of adverse events were compared between patients treated with ranibizumab and those without. Furthermore, dose-dependent effect of ranibizumab was estimated for overall mortality through Poisson meta-regression. Six trials with 2,459 patients were included. All trials had exclusion criteria on systemic vascular conditions for enrollment. Risk ratio for cerebrovascular accident, myocardial infarction, vascular death, and overall mortality were 0.80 (95% confidence interval, 0.37-1.73; P = 0.57), 0.91 (95% confidence interval, 0.46-1.80; P = 0.78), 1.29 (95% confidence interval, 0.58-2.86; P = 0.53), and 1.92 (95% confidence interval, 0.78-4.73; P = 0.16), respectively. Poisson regression model showed a significant dose-dependent increase in overall mortality in the largest randomized trial using monthly ranibizumab (P = 0.04). However, the significance disappeared (P = 0.133) when pooled with other studies using ranibizumab on pro re nata basis. Ranibizumab for diabetic macular edema is considered safe when the patients are carefully selected based on systemic vascular conditions and it is used on pro re nata basis. Further evaluation is necessary on more intensive use or on high-risk patients.

Ranibizumab for age-related macular degeneration: a meta-analysis of dose effects and comparison with no anti-VEGF treatment and bevacizumab

Ranibizumab is used monthly or as-needed (PRN) for the treatment of age-related macular degeneration. However, which treatment regimen is more effective remains unknown. The objectives of this study are to: (i) compare the efficacy of monthly versus as-needed quarterly treatment; and (ii) compare the efficacy of ranibizumab 0·5 mg treatment with: (a) no anti-vascular endothelial growth factor (VEGF); (b) ranibizumab 0·3 mg; and (c) bevacizumab. This is a systematic meta-analytic review of randomized-controlled clinical trials of ranibizumab in neovascular AMD. Weighted multiple regression analyses were used to compare the monthly vs. PRN/quarterly treatment. Eight randomized controlled trials met our inclusion criteria. Patients on the monthly ranibizumab treatment had higher visual acuity letter gains (β = 0·441, P < 0·05) compared with patients on as-needed/quarterly treatment. More patients on the monthly treatment gained ≥15 letters than as-needed/quarterly treatment (β = 0·582, P < 0·05). Ranibizumab produced significantly higher improvement in visual acuity (d = 1·20, z = 7·14, P < 0·05) and led to a higher proportion of patients gaining ≥15 letters (OR: 6·67; 95% CI 3·16-14·06; P < 0·05) when compared with non-anti-VEGF. Ranibizumab did not show any advantage in visual acuity compared with bevacizumab. No significant differences were found between ranibizumab 0·3 mg and 0·5 mg. This is the first meta-analysis to systematically evaluate the efficacy of different treatment regimens for anti-VEGF therapy. Ranibizumab 0·3 or 0·5 mg monthly treatment was more effective for neovascular AMD than non-anti-VEGF treatments but is no better than bevacizumab.

This Issue At A Glance

In the largest study of the issue to date, Bertelsen et al (p. 637) evaluated the mortality rate of patients with central retinal vein occlusion (CRVO). They found that CRVO was associated with an overall increase in mortality and that the increase could be attributed to cardiovascular and cerebrovascular disease. For this registry-based study, Danish researchers evaluated 439 patients with CRVO and 2195 age- and gender-matched controls. Over a mean follow-up period of 5.1 years for the CRVO patients and 5.7 years for the controls, the overall mortality rate was 5.9 deaths/100 person years for the CRVO patients and 4.3 deaths/100 person years for the controls. In addition, CRVO patients were at increased risk of developing peripheral artery disease, congestive heart failure, ischemic heart disease and myocardial infarction, and cerebrovascular disease. Given this association, the researchers recommended that CRVO patients be treated for such conditions as hypertension and diabetes and, if needed, be referred to a primary care physician. What are the risk factors for scar formation in eyes treated with monthly or as-needed ranibizumab or bevacizumab for wet age-related macular degeneration (AMD)? Daniel et al (p. 656) found that eyes with classic choroidal neovascularization, blocked fluorescence on fluorescein angiography, increased retinal thickness, and more fluid or material under the foveal center of the retina were more likely to develop a scar. For this prospective cohort study within the larger Comparison of AMD Treatments Trial (CATT), the investigators found that scar developed in 480 (45.3%) of 1059 eyes by the 2-year mark, with 339 of the 480 eyes developing a scar during the first year of treatment. Fibrotic scars developed in 262 eyes (24.7%) and nonfibrotic scars developed in 218 eyes (20.6%). Baseline risk factors for scar types were similar, except that eyes with larger lesion size or visual acuity below 20/40 were more likely to develop fibrotic scars. Drug choice, dosing regimen, and genotyping had no impact on scar risk. Yehoshua et al (p. 693) evaluated the effect of eculizumab, a systemic inhibitor of complement component 5 (C5), on the growth of geographic atrophy (GA) in eyes with dry age-related macular degeneration (AMD). They found that the drug failed to reduce the growth rate of GA. For this prospective, double-masked trial, the investigators evaluated 30 eyes of 30 patients, with 18 fellow eyes analyzed as a secondary endpoint. All eyes had a total GA area of 1.25-18 mm2 and visual acuity of 20/63 or better. The patients were randomized to receive low-dose eculizumab, high-dose eculizumab, or placebo. After the treatment period ended at the 26-week mark, patients were followed without treatment every 3 months for an additional 6 months. Although the drug was well tolerated, GA enlarged at 26 weeks in the eculizumab and placebo groups by 0.19 mm and 0.18 mm, respectively, and by 0.37 mm in both groups at 52 weeks. None of the eyes converted to wet AMD. Okada et al (p. 763) evaluated the effect of the centration and circularity of manually created capsulorrhexes on refractive outcomes. They found no correlation between the degree of capsulorrhexis circularity, diameter, decentration, and rim-to-optic overlap and postoperative refractions at 1 month or 1 year of follow-up. However, decentration >0.4 mm was associated with a 0.25 D postoperative change in spherical equivalent, and incomplete capsulorrhexis-optic overlap was associated with a 0.50 D change in spectacle cylinder from 1 month to 1 year. For this prospective, observational study, the researchers evaluated 113 eyes from 108 patients undergoing cataract surgery with manual continuous curvilinear capsulorrhexis (CCC). At 1 month, the mean circularity index was 0.83±0.01 and the mean decentration from pupillary center was 0.30±0.14 mm. At 1 year, the capsulorrhexes were more circular (mean circularity index, 0.87±0.03), more centered (0.23±0.12 mm), and smaller (4.18±0.68 mm). Levy-Clarke et al (p. 785) conducted a systematic review of published studies on anti-tumor necrosis factor alpha (TNF-α) biologic agents in patients with ocular inflammatory diseases. They recommended the following strategies: (1) Infliximab and adalimumab should be considered first-line agents for the treatment of ocular manifestations of Behçet's disease, and (2) the 2 drugs should be used as second-line agents for treating uveitis associated with juvenile arthritis. Methotrexate may, if tolerated, be combined with infliximab therapy. Moreover, (3) infliximab and adalimumab should be second-line therapy in patients with chronic uveitis from seronegative spondyloarthropathy, and (4) may be considered for other forms of ocular inflammation in patients with vision-threatening, corticosteroid-dependent disease who have failed first-line treatments. Additional recommendations are as follows: (5) Adalimumab appears to show similar efficacy to infliximab, although more comparative data are needed. Adalimumab may be efficacious in patients who have become intolerant to or have developed reduced response to infliximab. (6) Infliximab or adalimumab should be considered before etanercept.