Ivan J. Suñer

Twelve-Month Efficacy and Safety of 0.5 mg or 2.0 mg Ranibizumab in Patients with Subfoveal Neovascular Age-related Macular Degeneration

OBJECTIVE To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD). DESIGN A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. PARTICIPANTS Patients aged ≥ 50 years with subfoveal wet AMD. METHODS Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. MAIN OUTCOME MEASURES The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥ 15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data. RESULTS At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥ 15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was -172.0 μm, -161.2 μm, -163.3 μm, and -172.4 μm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. CONCLUSIONS At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Improved vision-related function after ranibizumab for macular edema after retinal vein occlusion: Results from the BRAVO and CRUISE trials

PURPOSE To examine the impact of intravitreal ranibizumab on patient-reported visual function using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) through 6 months in patients with macular edema (ME) secondary to branch or central retinal vein occlusion (RVO). DESIGN Two multicenter, double-masked trials, which enrolled participants with ME secondary to branch or central RVO: the RanibizumaB for the Treatment of Macular Edema following BRAnch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) trial or the Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety (CRUISE) trial. PARTICIPANTS Three hundred ninety-seven BRAVO and 392 CRUISE patients. METHODS Patients were randomized 1:1:1 to monthly sham, 0.3-mg, or 0.5-mg injections of ranibizumab for 6 months. MAIN OUTCOME MEASURES Although visual acuity was the main outcome measure for the trials, mean change from baseline in NEI VFQ-25 scores at month 6 was a secondary outcome measure. RESULTS In BRAVO, among the 132, 134, and 131 patients randomized, respectively, to sham, 0.3 mg ranibizumab, or 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 121 (91.7%), 118 (88.1%), and 125 (95.4%) patients and 123 (93.2%), 128 (95.5%), and 125 (95.4%), respectively, had a 6-month follow-up visit. In CRUISE, among the 130, 132, and 130 patients randomized, respectively, to sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 117 (90.0%), 123 (93.2%), and 120 (92.3%) patients and 115 (88.5%), 129 (97.7%), and 119 (91.5%), respectively, had a 6-month follow-up visit. In both trials, patients treated with ranibizumab reported greater mean improvements in visual function, with substantial differences observed as early as month 1, including the NEI VFQ-25 composite score and near and distance activities subscales, compared with sham patients. P values for comparisons with sham for the composite score and these 2 subscales were <0.05. CONCLUSIONS These results from the BRAVO and CRUISE trials indicate that patients with ME from RVOs treated with monthly ranibizumab report greater improvements in vision-related function compared with sham-treated patients through 6 months, even when a majority of patients present with RVOs in the worse-seeing eye.

Vision-Related Function after Ranibizumab Treatment by Better- or Worse-Seeing Eye: Clinical Trial Results from MARINA and ANCHOR

OBJECTIVE To examine the effects of ranibizumab on the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) scores in neovascular age-related macular degeneration (AMD) according to whether the study eye was the better- or worse-seeing eye at baseline. DESIGN Within 2 randomized, double-masked clinical trials (MARINA and ANCHOR), the NEI VFQ-25 was administered at 0, 1, 2, 3, 6, 9, 12, 18, and 24 months. PARTICIPANTS We included 646 MARINA and 379 ANCHOR patients. INTERVENTION Patients were randomized 1:1:1 to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or control (sham injections for MARINA; photodynamic therapy [PDT] with verteporfin for ANCHOR). MAIN OUTCOME MEASURES Mean change from baseline in NEI VFQ-25 scores at 12 and 24 months. RESULTS Across all treatment arms, 21% to 38% of enrolled eyes were the better-seeing eye. At the 24-month follow-up visit, mean change in composite scores with ranibizumab seemed to be better than control for both better-seeing eyes (8.4 [95% confidence interval (CI), 5.2-11.6], 7.5 [95% CI, 3.7-11.4], and -9.4 [95% CI, -12.5 to -6.3] for the 0.3-mg, 0.5-mg, and sham groups, respectively) and worse-seeing eyes (1.7 [95% CI, -1.1 to 4.4], 1.7 [95% CI, -0.7 to 4.1], and -5.4 [95% CI, -7.9 to -2.8] for the 0.3-mg, 0.5-mg, and sham groups, respectively) in MARINA, as well as the better-seeing eye in ANCHOR (11.3 [95% CI, 5.3-17.3], 13.3 [95% CI, 7.7-19.0], and -2.7 [95% CI, -9.0 to 3.7] for the 0.3-mg, 0.5-mg, and PDT groups, respectively). When the worse-seeing eye was treated in ANCHOR, such differences could not be detected at 24 months (1.3 [95% CI, -1.7 to 4.2], 2.6 [95% CI, -1.1 to 6.3], and 0.1 [95% CI, -3.5 to 3.7] for the 0.3-mg, 0.5-mg, and PDT groups, respectively). CONCLUSIONS Analysis of patient perception of vision-related function in phase III trials evaluating ranibizumab for neovascular AMD demonstrates improved patient-reported outcomes regardless of whether the treated eye is the better- or worse-seeing eye at onset of treatment, and supports treatment of such lesions with ranibizumab, even those in the worse-seeing eye. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Responsiveness of NEI VFQ-25 to Changes in Visual Acuity in Neovascular AMD: Validation Studies from Two Phase 3 Clinical Trials

PURPOSE To examine the responsiveness of the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) by using data from the MARINA and ANCHOR trials in neovascular age-related macular degeneration (AMD) and to establish the change in the NEI VFQ-25 associated with a 15-letter change in best corrected visual acuity (BCVA). METHODS In MARINA, 716 patients were randomized to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections. In ANCHOR, 423 patients were randomized to monthly ranibizumab (0.3 or 0.5 mg) with sham photodynamic therapy (PDT) or sham ocular injections with verteporfin PDT. Patients had follow-up interviews and BCVA measurements over 24 months. Data were analyzed separately for MARINA and ANCHOR, and treatment groups were pooled within each trial. The clinically relevant difference in NEI VFQ-25 was estimated based on regression models of change from baseline to month 12 in BCVA. RESULTS Subgroups categorized by BCVA change (>or=15 letters gained, <15 letters lost or gained, or >or=15 letters lost) differed substantially in mean change in NEI VFQ-25 composite scores and three pre-specified subscale scores (near activities, distance activities, and vision-specific dependency) over 12 months. According to the regression models, the difference associated with a 15-letter change was 4 to 6 points for the composite score and the three pre-specified subscales. CONCLUSIONS These data support the use of the NEI VFQ-25 as a responsive and sensitive measure of vision-related function in neovascular AMD populations. Based on MARINA and ANCHOR data, a 4- to 6-point change in NEI VFQ-25 scores represents a clinically meaningful change corresponding to a 15-letter change in BCVA.

Needle Elevation of the Scleral Flap for Failing Filtration Blebs After Trabeculectomy With Mitomycin C

PURPOSE To report the incidence of failing filtration blebs after trabeculectomy with mitomycin C and to report the outcome of needling procedures for failing filtration blebs in these eyes. METHODS We conducted a retrospective analysis of 537 eyes of 434 patients who had trabeculectomy with mitomycin C and reviewed the clinical course of 441 eyes of 338 patients with a minimum of three months of follow-up. RESULTS In 441 eyes of 338 patients followed up for three months or more after trabeculectomy with mitomycin C, 88 (20.0%) eyes from 85 patients underwent needle elevation of the scleral flap. Forty-nine (22.4%) of 219 eyes required needle revision after trabeculectomy alone, and 39 (17.6%) of 222 eyes after trabeculectomy combined with cataract extraction and intraocular lens implantation. Mean intraocular pressure (IOP) after needle revision (17.9 +/- 11.6 mm Hg) was significantly less than the mean preneedling IOP (27.1 +/- 10.4 mm Hg, P < .00001, paired Students t test). Sixty-three eyes of 60 patients had a minimum of three months of postneedling follow-up. Successful pressure control, defined as an IOP of 22 mm Hg or less with or without topical glaucoma control medications, was achieved in 46 (73.0%) of 63 eyes. Unsuccessful outcomes correlated significantly with higher preneedling IOP (R = 0.28, P = .03, df = 61) and prior surgery involving conjunctival incisions (R = 0.53, P < .00001, df = 61). CONCLUSIONS Needle elevation of the scleral flap may provide significantly long-lasting pressure reduction in eyes with failing mitomycin C blebs. Higher success rates are achieved in eyes with fewer prior conjunctival incisions, eyes requiring a single needle revision, and eyes with lower preneedling IOP.

Long-Term Outcomes in Eyes Receiving Fixed-Interval Dosing of Anti–Vascular Endothelial Growth Factor Agents for Wet Age-Related Macular Degeneration

PURPOSE To report on long-term visual outcomes in patients receiving continuous fixed-interval dosing of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD). DESIGN Single-practice retrospective chart review. PARTICIPANTS One hundred nine eyes with exudative AMD receiving continuous fixed-interval dosing (every 4-8 weeks) of anti-VEGF therapy (ranibizumab, bevacizumab, or aflibercept) for at least 5 years. Eyes were excluded if they averaged fewer than 6.5 injections per year. METHODS Snellen visual acuity was recorded at baseline and all subsequent injections. Changes from baseline were calculated at yearly intervals. MAIN OUTCOME MEASURES The primary outcome measure was mean change in letter score at 5, 6, and 7 years; secondary outcomes included the percentage of patients with 20/40 vision or better at 7 years and the mean change in letter score at each yearly time point based on baseline visual grouping (20/40 or better, 20/50-20/100, 20/200 or worse). RESULTS Forty-four, 75, and 109 patients with 7, 6, and 5 years, respectively, of continuous treatment were identified. Mean change in letter score at year 5 was +14.0 letters (P = 3.9 × 10(-9)), +12.2 letters at 6 years (P = 1.5 × 10(-7)), and +12.1 letters at 7 years (P = 3.8 × 10(-5)). Driving vision (20/40 or better) was achieved in 43.2% of treated eyes. Subanalysis revealed that the greatest visual gains at 5 and 7 years were seen in those patients with baseline visual acuity worse than 20/200 (+24.5 and +25.5 letters), followed by those with 20/50 to 20/100 vision (+6.7 and +6.9 letters), and finally those with 20/20 to 20/40 (+3.7 and +3.4 letters). Patients received an average of 10.5 injections per year. CONCLUSIONS Continuous fixed-interval dosing of anti-VEGF therapy in patients with exudative AMD results in favorable long-term preservation out to 7 years, with vision stabilizing or improving in 93.2% of eyes. Additionally, 43.2% of patients maintained driving vision in the treatment eye at 7 years compared with 10.1% at baseline. Our data suggest better outcomes with continuous therapy over published results with sporadic, as-needed therapy.

Hypotony Maculopathy after Filtering Surgery with Mitomycin C

PURPOSE Hypotony maculopathy after glaucoma filtering surgery with adjunctive mitomycin C has been reported to occur in 3% to 14% of cases. The authors evaluated its incidence when using a corneal safety-valve incisior intended to reduce its occurrence. The authors also evaluated a technique for reversing hypotony maculopathy by reoperation using two sets of stitches in the scleral flap, with one set tied tightly to temporarily raise the intraocular pressure, stretch the sclera, and flatten chorioretinal folds. METHODS The authors reviewed the results of 699 procedures performed between April 1991 and October 1994. All were performed or supervised by one surgeon (PFP). RESULTS Hypotony maculopathy developed in 9 (1.3%) of 699 eyes. There was a statistically significant higher incidence in primary filters (4%) as compared to secondary filters or combined procedures. After revision, eight (89%) of nine recovered visual acuity of greater than or equal to 20/30 and the mean intraocular pressure was 14.5 +/- 4 mmHg at a mean follow-up of 15 months. CONCLUSION The incidence of hypotony maculopathy after glaucoma filtering surgery with mitomycin C using a corneal safety-valve incision is less than that reported in the literature without this incision. There is an increased risk in myopes, young patients, and primary filters. Early intervention with the described scleral flap revision technique usually allows restoration of prefiltration visual acuity without compromise of bleb function.

Identification of Patients With Diabetic Macular Edema From Claims Data: A Validation Study

OBJECTIVE To assess the validity of an algorithm for identifying patients with diabetic macular edema (DME) using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes in administrative billing data from a convenience sample of physician offices. METHODS A convenience sample of 12 general ophthalmologists and 10 retina specialists applied prespecified algorithms based on ICD-9-CM diagnosis codes to the billing claims of their practices and selected the associated medical records. Four ophthalmologists abstracted data from the medical records, which were then compared with the coded diagnoses. Main outcome measures were sensitivity, specificity, and the kappa statistic for the DME algorithm (a combination of codes 250.xx and 362.53), treating medical record documentation of DME as the standard criterion. RESULTS The DME algorithm had a sensitivity of 0.88 and a specificity of 0.96 for identifying DME. Excellent agreement was noted between the algorithm and the medical records (kappa = 0.84). The algorithm performed less well in identifying patients with a diagnosis of clinically significant DME (sensitivity, 0.86; specificity, 0.84; kappa = 0.64). CONCLUSIONS The results of this pilot study suggest that patients with DME can be identified accurately in claims data using ICD-9-CM diagnosis codes. Application of this algorithm could improve investigations of disease prevalence and disease burden and provide an efficient means of assessing care and interventions.

Driving ability reported by neovascular age-related macular degeneration patients after treatment with ranibizumab

OBJECTIVES To determine the impact of ranibizumab on driving status, driving ability perception, and having 20/40 vision or better in patients with choroidal neovascularization resulting from age-related macular degeneration (AMD). DESIGN Phase III, multicenter, randomized clinical trials (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration [MARINA] and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration [ANCHOR]). PARTICIPANTS One thousand one hundred twenty-six patients with choroidal neovascularization resulting from AMD. METHODS Participants were assigned randomly to sham (n=238), 0.3-mg ranibizumab monthly injections (n=238), or 0.5-mg ranibizumab monthly injections (n=240) for 24 months (MARINA), or were randomized to verteporfin photodynamic therapy (PDT; n=143), 0.3-mg ranibizumab monthly injections (n=140), or 0.5-mg ranibizumab monthly injections (n=140) for 24 months (ANCHOR). MAIN OUTCOME MEASURES Self-reported driving status and driving ability perception were assessed as exploratory outcomes at baseline through 24 months after baseline using the 25-item National Eye Institute Visual Function Questionnaire. Best-corrected visual acuity in each eye was assessed monthly through 24 months. RESULTS At baseline, 68.6% of patients in the MARINA trial and 62.7% of patients in the ANCHOR trial reported driving. Among patients driving at baseline in the MARINA trial 2 years after randomization, 67.2% (95% confidence interval [CI], 59.2-75.2) of sham patients and 78.4% (95% CI, 71.8-85.0) of 0.5-mg patients reported that they were still driving. Among patients driving at baseline in the ANCHOR trial at 2 years after randomization, 71.6% (95% CI, 60.8-82.4) of PDT patients and 91.4% (95% CI, 85.3-97.5) of 0.5-mg patients were still driving. Also in the ANCHOR trial, ranibizumab-treated patients who were not driving at baseline seemed more likely to drive by months 12 and 24 than PDT patients. Perception of driving ability was correlated with improvement in visual acuity (VA) in the better-seeing eye at 12 and 24 months (R2=0.17 and R2=0.20 at 12 and 24 months, respectively [P<0.001], in the MARINA trial; R2=0.13 and R2=0.14, respectively [P<0.001], in the ANCHOR trial). Visual acuity in one or both eyes 2 years after randomization was more likely to be 20/40 or better in the ranibizumab-treated groups. CONCLUSIONS These results suggest that patients with neovascular AMD treated with ranibizumab are more likely to report driving ability and have vision of at least 20/40 than patients given sham treatment or PDT. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Effect of Ranibizumab on the Decision to Drive and Vision Function Relevant to Driving in Patients With Diabetic Macular Edema: Report From RESTORE, RIDE, and RISE Trials

IMPORTANCE The potential effect of treatments for diabetic macular edema (DME) on driving should be of value to patients and clinicians, such as ophthalmologists and other physicians, who treat patients with diabetes mellitus. OBJECTIVE To determine the effect of ranibizumab on driving and patient-reported vision function relevant to driving among patients with DME. DESIGN, SETTING, AND PARTICIPANTS This exploratory post hoc analysis was conducted between October 1, 2011, and July 25, 2015, based on deidentified data from phase 3, multicenter, randomized clinical trials (RIDE, RISE, and RESTORE trials). Individuals assigned randomly to monthly sham, 0.3-mg ranibizumab, or 0.5-mg ranibizumab in RIDE and RISE or to macular laser, macular laser plus 0.5-mg ranibizumab (3-monthly doses, then as needed), or 0.5-mg (3-monthly doses, then as needed) in RESTORE. MAIN OUTCOMES AND MEASURES Driving items from the National Eye Institute (NEI) Visual Function Questionnaire-25 (VFQ-25) at baseline through 24 months in RIDE/RISE (pooled) and through 12 months in RESTORE. RESULTS A total of 71.2% of 753 patients in RIDE/RISE and 50.4% of 345 patients in RESTORE reported driving at baseline; at least 55% reported still driving at follow-up. Among those not driving at baseline in RIDE/RISE, at 12 months, 7.0% (95% CI, -5.0 to 19.0) more in the 0.3-mg group and 14.4% (95% CI, 1.1 to 27.7) more in the 0.5-mg group vs the sham group reported driving. Among those not driving at baseline in RESTORE, at 12 months, 4.2% (95% CI, -7.7 to 16.1) more in the laser plus 0.5-mg group and 0.9% (95% CI, -10.3 to 12.1) more in the 0.5-mg group vs the laser group reported driving. Although balanced at baseline across treatment groups for RESTORE and RIDE/RISE, the proportion of patients with best-corrected visual acuity typically required for an unrestricted license (20/40 or better in at least 1 eye) appeared greater at month 12 in the ranibizumab groups (77 of 80 [96.3%] for 0.5 mg + laser and 91 of 93 [97.8%] for 0.5 mg) vs laser (71 of 79 [89.9%]) in RESTORE, and at months 12 (112 of 123 [91.1%] and 136 of 137 [99.3%] in 0.3- and 0.5-mg groups, respectively) and 24 (113 of 123 [91.9%] and 135 of 137 [98.5%] in the 0.3- and 0.5-mg groups, respectively) vs sham (121 of 147 [82.3%] and 122 of 147 [83.0%]) in RIDE/RISE. CONCLUSIONS AND RELEVANCE These results suggest that 12 months after initiating ranibizumab for vision impairment from center-involved DME, patients not driving at initiation of treatment are more likely to report driving and have driving-eligible visual acuity of 20/40 or better in the better-seeing eye than those treated with sham or laser. TRIAL REGISTRATION clinicaltrials.gov Identifier: RESTORE: NCT00687804; RIDE: NCT00473382; and RISE: NCT00473330.