Rishi P. Singh

Ranibizumab for Macular Edema following Central Retinal Vein Occlusion: Six-Month Primary End Point Results of a Phase III Study

PURPOSE To assess the efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after central retinal vein occlusion (CRVO). DESIGN Prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. PARTICIPANTS A total of 392 patients with macular edema after CRVO. METHODS Eligible patients were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. MAIN OUTCOME MEASURES The primary efficacy outcome measure was mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6. Secondary outcomes included other parameters of visual function and central foveal thickness (CFT). RESULTS Mean (95% confidence interval [CI]) change from baseline BCVA letter score at month 6 was 12.7 (9.9-15.4) and 14.9 (12.6-17.2) in the 0.3 mg and 0.5 mg ranibizumab groups, respectively, and 0.8 (-2.0 to 3.6) in the sham group (P<0.0001 for each ranibizumab group vs. sham). The percentage of patients who gained > or =15 letters in BCVA at month 6 was 46.2% (0.3 mg) and 47.7% (0.5 mg) in the ranibizumab groups and 16.9% in the sham group (P<0.0001 for each ranibizumab group vs. sham). At month 6, significantly more ranibizumab-treated patients (0.3 mg = 43.9%; 0.5 mg = 46.9%) had BCVA of > or = 20/40 compared with sham patients (20.8%; P<0.0001 for each ranibizumab group vs. sham), and CFT had decreased by a mean of 434 microm (0.3 mg) and 452 microm (0.5 mg) in the ranibizumab groups and 168 microm in the sham group (P<0.0001 for each ranibizumab group vs. sham). The median percent reduction in excess foveal thickness at month 6 was 94.0% and 97.3% in the 0.3 mg and 0.5 mg groups, respectively, and 23.9% in the sham group. The safety profile was consistent with previous phase III ranibizumab trials, and no new safety events were identified in patients with CRVO. CONCLUSIONS Intraocular injections of 0.3 mg or 0.5 mg ranibizumab provided rapid improvement in 6-month visual acuity and macular edema following CRVO, with low rates of ocular and nonocular safety events.

Ranibizumab for Macular Edema following Central Retinal Vein Occlusion

PURPOSE To assess efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema following branch retinal vein occlusion (BRVO). DESIGN Prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. PARTICIPANTS A total of 397 patients with macular edema following BRVO. METHODS Eligible patients were randomized 1:1:1 to receive monthly intraocular injections of 0.3 mg or 0.5 mg of ranibizumab or sham injections. MAIN OUTCOME MEASURES The primary efficacy outcome measure was mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6. Secondary outcomes included other parameters of visual function and central foveal thickness (CFT). RESULTS Mean (95% confidence interval [CI]) change from baseline BCVA letter score at month 6 was 16.6 (14.7-18.5) and 18.3 (16.0-20.6) in the 0.3 mg and 0.5 mg ranibizumab groups and 7.3 (5.1-9.5) in the sham group (P<0.0001 for each ranibizumab group vs sham). The percentage of patients who gained > or =15 letters in BCVA at month 6 was 55.2% (0.3 mg) and 61.1% (0.5 mg) in the ranibizumab groups and 28.8% in the sham group (P<0.0001 for each ranibizumab group vs sham). At month 6, significantly more ranibizumab-treated patients (0.3 mg, 67.9%; 0.5 mg, 64.9%) had BCVA of > or =20/40 compared with sham patients (41.7%; P<0.0001 for each ranibizumab group vs sham); and CFT had decreased by a mean of 337 microm (0.3 mg) and 345 microm (0.5 mg) in the ranibizumab groups and 158 microm in the sham group (P<0.0001 for each ranibizumab group vs sham). The median percent reduction in excess foveal thickness at month 6 was 97.0% and 97.6% in 0.3 mg and 0.5 mg groups and 27.9% in the sham group. More patients in the sham group (54.5%) received rescue grid laser compared with the 0.3 mg (18.7%) and 0.5 mg (19.8%) ranibizumab groups. The safety profile was consistent with previous phase III ranibizumab trials, and no new safety events were identified in patients with BRVO. CONCLUSIONS Intraocular injections of 0.3 mg or 0.5 mg ranibizumab provided rapid, effective treatment for macular edema following BRVO with low rates of ocular and nonocular safety events.

Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome

Objective To evaluate the anatomical and visual outcomes of patients treated with ocriplasmin for the treatment of symptomatic vitreomacular adhesion (sVMA), including vitreomacular traction syndrome and macular holes. Design Retrospective, interventional, single centre, case series. Participants Patients with sVMA. Intervention Patients were treated with a single intravitreal injection of 0.125 mg ocriplasmin (Jetrea, Thrombogenics Inc, USA, Alcon/Novartis EU) with the reconstitution technique recommended by the manufacturer. Main outcome measures The primary study endpoint was the resolution of sVMA by spectral domain optical coherence tomography (SDOCT) at day 28. Secondary outcome measures included time to vitreous release, visual acuity (VA), changes in the optical coherence tomography (OCT) thickness and structure and macular hole closure rate. Results 17 patients were included in the study and resolution of vitreomacular adhesion (VMA) was verified by SDOCT in eight patients by day 28 (overall response rate of 47.1%, 8/17 eyes) with most patients experiencing VMA release by 7 days (41.2%, 7/17 eyes). Those who did not have VMA resolution showed no statistically significant change in VMA diameter as measured by horizontal and vertical 5-line raster scans at final follow-up (p=0.82 and p=0.75, respectively). The mean baseline Snellen VA was 20/49 and at final follow-up was 20/46 (p=0.59). The average central subfield thickness was 371 microns prior to treatment and 324 microns at final follow-up (range 191–767 microns, p=0.25). Patients meeting three of four positive predictors criteria (eg, no epiretinal membrane (ERM) at baseline, VMA diameter ≤1500 µm and phakic lens status) showed a response rate of 50.0% (seven of 14 patients); those meeting all four criteria (eg, younger than 65, no ERM at baseline, VMA diameter ≤1500 µm and phakic lens status) showed a response rate of 75.0% (three of four eyes). Transient outer segment ellipsoid zone loss was documented in seven patients and subretinal fluid presence following injection was noted in five patients. Four of the five patients with macular holes at baseline experienced resolution of their macular hole after injection. Conclusions This is the first study to quantify the extent of outer retinal changes seen in patients receiving ocriplasmin. Our initial experience with ocriplasmin shows a significant anatomical effect and is accompanied by transient changes in the outer retinal structures visualised by SDOCT.

The Prospective Intraoperative and Perioperative Ophthalmic ImagiNg With Optical CoherEncE TomogRaphy (PIONEER) Study: 2-Year Results

PURPOSE To evaluate the feasibility, safety, and utility of intraoperative optical coherence tomography (OCT) for use during ophthalmic surgery. DESIGN Prospective, consecutive case series. METHODS A prospective, single-center, consecutive case series was initiated to assess intraoperative OCT in ophthalmic surgery. Intraoperative scanning was performed with a microscope-mounted spectral-domain OCT system. Disease-specific or procedure-specific imaging protocols (eg, scan type, pattern, size, orientation, density) were used for anterior and posterior segment applications. A surgeon feedback form was recorded as part of the study protocol to answer specific questions regarding intraoperative OCT utility immediately after the surgical procedure was completed. RESULTS During the first 24 months of the PIONEER study, 531 eyes were enrolled (275 anterior segment cases and 256 posterior segment surgical cases). Intraoperative OCT imaging was obtained in 518 of 531 eyes (98%). Surgeon feedback indicated that intraoperative OCT informed surgical decision making and altered surgeon understanding of underlying tissue configurations in 69 of 144 lamellar keratoplasty cases (48%) and 63 of 146 membrane peeling procedures (43%). The most common anterior segment surgical procedure was Descemet stripping automated endothelial keratoplasty (DSAEK, n = 135). Vitrectomy with membrane peeling was the most common procedure for posterior segment surgery (n = 154). The median time that surgery was paused to perform intraoperative OCT was 4.9 minutes per scan session. No adverse events were specifically attributed to intraoperative OCT scanning during the procedure. CONCLUSIONS Intraoperative OCT is feasible for numerous anterior and posterior segment ophthalmic surgical procedures. A microscope-mounted intraoperative OCT system provided efficient imaging during operative procedures. The information gained from intraoperative OCT may impact surgical decision making in a high frequency of both anterior and posterior segment cases.

Evaluation of wound closure using different incision techniques with 23-gauge and 25-gauge microincision vitrectomy systems.

Purpose: To describe the anatomic and histopathologic outcomes using different incision techniques with transconjunctival 23-G and 25-G vitrectomy systems. Methods: New Zealand rabbits were randomized to either 23-G or 25-G vitrectomy surgeries using angled incisions and straight incisions. After pars plana vitrectomy, the cannulas were removed and 0.1% trypan blue was injected to evaluate for leakage. The animals were killed on day 7 and the eyes enucleated for gross analysis and histopathologic analysis by frozen section. Results: Leakage of trypan blue was noted from 10.8% and 5.7% of straight and angled incisions, respectively. There was no difference between 23-G and 25-G incisions (8.3%). On gross examination, the 25-G system resulted in 58% and 24% open external wounds for straight and angled incisions, respectively (P = 0.04). The 23-G system resulted in 83% and 39% open external wounds with straight and angled incisions, respectively (P = 0.017). The average wound area after the 23-G surgery was 223.1 &mgr;m2 and 115.7 &mgr;m2 for straight versus angled incisions, respectively (P = 0.02). The average wound area formed after the 25-G surgery was 160.3 &mgr;m2 and 85.2 &mgr;m2 for straight versus angled incisions, respectively (P = 0.001). Conclusions: Outcomes were similar for 23-G angled incisions, 25-G straight incisions, and 25-G angled incisions.

Intrasurgical Dynamics Of Macular Hole Surgery: An Assessment of Surgery-induced Ultrastructural Alterations with Intraoperative Optical Coherence Tomography

Purpose: To evaluate the intrasurgical retinal architectural and macular hole (MH) geometric alterations that occur during surgical MH repair using intraoperative optical coherence tomography. Methods: A retrospective, multisurgeon, single-center, consecutive case series of 21 eyes undergoing surgical repair for MH with concurrent intraoperative optical coherence tomography using a custom microscope–mounted optical coherence tomography system was performed. All patients underwent surgical repair with pars plana vitrectomy, membrane peel, and gas tamponade. A novel three-dimensional segmentation algorithm was used for volumetric analysis of intrasurgical changes of MH geometry after surgical repair. Intraoperative optical coherence tomographic characteristics analyzed included MH volume, minimum diameter, base area, and hole height. Outer retinal architecture changes were analyzed both quantitatively and qualitatively. Results: All 21 eyes were successfully imaged with intraoperative optical coherence tomography. Nineteen of 21 eyes had images of sufficient signal strength to allow for quantitative analysis. Significant changes were noted in MH geometry after internal limiting membrane peeling including increased MH volume, increased base area, and decreased top area (all P < 0.03). Additionally, increased subretinal hyporeflectance was noted by expansion of the height between the inner segment/outer segment and retinal pigment epithelium bands (P = 0.008). Peeling methods and surgeon experience did not correlate with the magnitude of architectural alterations. Macular hole algorithm measurements and alterations were associated with visual outcome and MH closure. Conclusion: Significant alterations occur in MH geometry and outer retinal structure after internal limiting membrane peeling. These changes are subclinical and unable to be appreciated with en face surgical microscope viewing and require intraoperative optical coherence tomography for visualization. Preliminary analysis of these measurements identified an association with visual outcome and successful MH closure. The functional significance of these changes deserves further study.

Determination of Feasibility and Utility of Microscope-Integrated Optical Coherence Tomography During Ophthalmic Surgery: The DISCOVER Study RESCAN Results

IMPORTANCE Optical coherence tomography (OCT) has transformed the clinical management of a myriad of ophthalmic conditions. Applying OCT to ophthalmic surgery may have implications for surgical decision making and patient outcomes. OBJECTIVE To assess the feasibility and effect on surgical decision making of a microscope-integrated intraoperative OCT (iOCT) system. DESIGN, SETTING, AND PARTICIPANTS Report highlighting the 1-year results (March 2014-February 2015) of the RESCAN 700 portion of the DISCOVER (Determination of Feasibility of Intraoperative Spectral Domain Microscope Combined/Integrated OCT Visualization During En Face Retinal and Ophthalmic Surgery) study, a single-site, multisurgeon, prospective consecutive case series regarding this investigational device. Participants included patients undergoing ophthalmic surgery. Data on clinical characteristics were collected, and iOCT was performed during surgical milestones, as directed by the operating surgeon. A surgeon questionnaire was issued to each surgeon and was completed after each case to evaluate the role of iOCT during surgery and its particular role in select surgical procedures. MAIN OUTCOMES AND MEASURES Percentage of cases with successful acquisition of iOCT (ie, feasibility). Percentage of cases in which iOCT altered surgical decision making (ie, utility). RESULTS During year 1 of the DISCOVER study, a total of 227 eyes (91 anterior segment cases and 136 posterior segment cases) underwent imaging with the RESCAN 700 system. Successful imaging (eg, the ability to acquire an OCT image of the tissue of interest) was obtained for 224 of 227 eyes (99% [95% CI, 98%-100%]). During lamellar keratoplasty, the iOCT data provided information that altered the surgeons decision making in 38% of the cases (eg, complete graft apposition when the surgeon believed there was interface fluid). In membrane peeling procedures, iOCT information was discordant with the surgeons impression of membrane peel completeness in 19% of cases (eg, lack of residual membrane or presence of occult membrane), thus affecting additional surgical maneuvers. CONCLUSIONS AND RELEVANCE The DISCOVER study demonstrates the feasibility of real-time iOCT with a microscope-integrated iOCT system for ophthalmic surgery. The information gained from iOCT appears to allow surgeons to assess subtle details in a unique perspective from standard en face visualization, which can affect surgical decision making some of the time, although the effect of these changes in decision making on outcomes remains unknown. A prospective randomized masked trial is needed to confirm these results.

Evaluation of nepafenac in prevention of macular edema following cataract surgery in patients with diabetic retinopathy

Background The purpose of this study was to evaluate nepafenac ophthalmic suspension 0.1% (Nevanac®; Alcon Research Ltd) in the prevention of macular edema following cataract surgery in diabetic retinopathy patients. Methods This was a multicenter, randomized, double-masked, vehicle-controlled study of 263 adult diabetic patients with nonproliferative diabetic retinopathy requiring cataract surgery. Patients were randomized (1:1) to instill nepafenac or vehicle three times daily beginning 1 day prior to surgery through day 90. Efficacy included the percentage of patients who developed macular edema (≥30% increase in central subfield macular thickness from baseline) and the percentage of patients with decreases of more than five letters in best-corrected visual acuity from day 7 to 90. Results A significantly lower percentage of patients in the nepafenac group developed macular edema relative to patients in the vehicle group (3.2% versus 16.7%; P < 0.001). A significantly lower percentage of patients in the nepafenac group had best-corrected visual acuity decreases of more than five letters relative to patients in the vehicle group on day 30 (P < 0.001), day 60 (P = 0.002), and day 90 (P = 0.006). The mean central subfield macular thickness and mean percent change from baseline in macular volume were also significantly lower in the nepafenac group versus the vehicle group at days 14 through 90 (P ≤ 0.005). No safety issues or trends were identified when dosing was increased to 90 days that negatively impacted the favorable benefit/risk profile of nepafenac. Conclusion Nepafenac demonstrated statistically significant and clinically relevant advantages compared with vehicle in preventing macular edema and maintaining visual acuity in diabetic patients following cataract surgery. These advantages were seen at multiple time points over the course of the 90-day therapy period. There was no clinically relevant increase in risk from 90 days dosing compared with 14 days. Therefore, with a similar safety profile and benefit in preventing macular edema and maintaining vision, the risk/benefit to the diabetic patient undergoing cataract surgery appears to be positive.

A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis.

Aim To evaluate efficacy and safety of intravitreal aflibercept injection (IAI) in subjects who were previously treated with ranibizumab and/or bevacizumab for active exudative age-related macular degeneration (AMD). Methods Patients (n=26) were enrolled in a 12-month prospective, interventional, single arm, investigator-initiated study with planned 6-month interim analysis. Patients with active exudative AMD, previously treated with ranibizumab and/or bevacizumab, were treated with 2 mg IAI every month for the first 3 months, followed by a fixed dosing schedule of 2 mg IAI every 2 months. The primary study endpoint was the mean absolute change from baseline central subfield thickness (CST) at month 12 as measured by SDOCT. Secondary outcomes included mean change from baseline best-corrected visual acuity (BCVA) score, percentage of subjects who gained or lost greater than or equal to 15 letters of vision, percentage of subjects who are 20/40 or better, percentage of subjects who are 20/200 or worse, and the incidence of adverse events (AE) and serious AEs. Results Planned 6-month interim analysis demonstrated a mean decrease in CST of 38.6 µm (p<0.001) and a mean increase in ETDRS BCVA of +5.9 letters (p<0.001). Fifteen percent of subjects experienced a greater than 15-letter improvement in visual acuity, 84.6% of patients gained visual acuity, and no patient lost 3 lines of vision from baseline. Forty-two percent of subjects were 20/40 or better, and 11.5% of subjects were 20/200 or worse at month 6. No serious ocular or systemic AEs were encountered. Conclusions IAI-treated eyes demonstrated improved short-term functional and anatomic endpoints in subjects with active exudative AMD switching from previous anti-VEGF treatment when given in a fixed dosing scheme for 6 months. Trial registration number NCT01617148.

Management of subretinal macular haemorrhage by direct administration of tissue plasminogen activator

Background/aims: Recent studies on the treatment of acute subretinal macular haemorrhage have shown that the volume of the clot and the time to evacuation have strong prognostic factors for visual outcome. A novel technique for surgical evacuation of these lesions involves direct injection of tissue plasminogen activator (t-PA) into the haematoma using pars plana vitrectomy. The aim of this study was to evaluate the clinical outcomes of this recently described procedure. Methods: 17 consecutive patients with subretinal macular haemorrhages caused by age related macular degeneration were enrolled. Patient demographics, acuities, and fluorescein angiograms were obtained for all evaluations. All patients underwent complete three port pars plana vitrectomy to enable direct cannulation of the subretinal space and injection of 48 μg of t-PA, partial fluid-air exchange, 1 hour face up supine positioning postoperatively, followed by upright positioning overnight. Results: 88% of patients within the study had stabilisation or improvement of visual acuity. Nine patients had total clearing of the macular haemorrhage and eight patients had subtotal clearing. Two patients had recurrence of the haemorrhage after the procedure and one patient underwent repair for retinal detachment. Occult lesions demonstrated similar outcomes to classic or predominately classic lesions. Nine patients required no therapy after the study to treat subfoveal neovascularisation. Conclusions: This study represents one of the largest case series to date showing that direct injection of subretinal t-PA with air-fluid exchange only and no intraoperative clot lysis period can have favourable results.