Daniel E. Croft

Prospective Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration: TREX-AMD 1-Year Results

PURPOSE To assess prospectively a treat-and-extend (TREX) management strategy compared with monthly dosing of intravitreal ranibizumab in treatment-naïve neovascular age-related macular degeneration (AMD) patients. DESIGN Phase IIIb, multicenter, randomized, controlled clinical trial. PARTICIPANTS Sixty patients with treatment-naïve neovascular AMD randomized 1:2 to monthly or TREX management. METHODS Patients with Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) from 20/32 to 20/500 (Snellen equivalent) were randomized to receive intravitreal 0.5 mg ranibizumab monthly or according to a TREX protocol. The TREX patients were treated monthly for at least 3 doses, until resolution of clinical and spectral-domain optical coherence tomography evidence of exudative disease activity; the interval between visits then was individualized according to a strict prospective protocol. MAIN OUTCOME MEASURES Mean ETDRS BCVA change from baseline. RESULTS At baseline, mean age was 77 years (range, 59-96 years), mean BCVA was 20/60 (Snellen equivalent), and mean central retinal thickness (CRT) was 511 μm. Fifty-seven eyes (95%) completed month 12, at which point mean BCVA improved by 9.2 and 10.5 letters in the monthly and TREX cohorts, respectively (P = 0.60). The mean number of injections administered through month 12 was 13.0 and 10.1 (range, 7-13) in the monthly and TREX cohorts, respectively (P < 0.0001). Among TREX patients, 7 (18%) were maximally extended, 4 (10%) demonstrated fluid at every visit, and at month 12, 18 (45%) had achieved an extension interval of 8 weeks or more; the mean maximum extension interval between injections after the first 3 monthly doses was 8.4 weeks (range, 4-12 weeks). Most TREX patients who demonstrated recurrent exudative disease activity (17/24 [71%]) were unable to extend beyond their initial maximum extension interval. CONCLUSIONS The TREX neovascular AMD management strategy used in this prospective, randomized, controlled trial resulted in visual and anatomic gains comparable with those obtained with monthly dosing.

Ranibizumab In Preproliferative (ischemic) Central Retinal Vein Occlusion: The Rubeosis Anti-vegf (rave) Trial

Purpose: To analyze the efficacy and safety of ranibizumab in eyes with preproliferative (ischemic) central retinal vein occlusion. Methods: In this prospective, phase I/II, open-label clinical trial, eyes at high risk of neovascular complications were identified; all eyes met ≥3 of 4 high-risk criteria: 1) the best-corrected visual acuity being ⩽20/200, 2) loss of the 1-2e isopter on Goldmann visual field, 3) relative afferent pupillary defect being ≥0.9 log units, and 4) electroretinogram B-wave reduction to ⩽60% of the corresponding A-wave. Monthly intravitreal ranibizumab treatment for 9 months, monthly monitoring for 3 months, and then monthly examination with pro re nata retreatment on evidence of disease activity for 24 months were performed. Therefore, the total study duration was 36 months. Results: The main outcome measures were mean change in the best-corrected visual acuity and central macular thickness by optical coherence tomography, proportion of patients with neovascular complications, and the incidence and severity of ocular and nonocular adverse events. Twenty patients were enrolled in the Rubeosis Anti-VEgf trial, and the mean number of intravitreal treatments administered through Months 24 and 36 were 14.1 and 17.2, respectively. The mean best-corrected visual acuity letters gained were +21.1 and +21.4 at 9 and 36 months, respectively. The mean central macular thickness improved −294 &mgr;m from baseline after 9 monthly treatments. Subsequently, after 3 months of observation, the mean central macular thickness increased +203 &mgr;m. On initiation of pro re nata ranibizumab retreatment, the mean central macular thickness then improved −191 &mgr;m at Month 36 compared with Month 12. Nine patients developed neovascular complications, being diagnosed after a mean of 24-month follow-up (range, 3–44 months), with 2 patients developing neovascularization after completion of the 36-month trial endpoint (at Months 42 and 44 after study enrollment). Conclusion: Intravitreal ranibizumab therapy can improve retinal anatomy and vision in eyes with severe central retinal vein occlusion. Despite significant clinical benefit with antivascular endothelial growth factor therapy, the risk of neovascular complications was not ameliorated by vascular endothelial growth factor blockade, but was merely delayed.

Progressive retinal nonperfusion in ischemic central retinal vein occlusion.

Background: Serial wide-field fluorescein angiography was performed on eyes with preproliferative (ischemic) central retinal vein occlusion to evaluate retinal perfusion. Methods: Serial wide-field fluorescein angiography was performed on 12 preproliferative central retinal vein occlusion eyes in the 3-year Rubeosis Anti-VEGF (RAVE) trial using the Staurenghi lens (Ocular Staurenghi 230SLO Retina Lens) with a scanning laser ophthalmoscope (Heidelberg HRA Spectralis). “Disk area” was defined anatomically for each eye. Results: Mean total field of gradable retina was 290 disk areas (range, 178–452). All eyes demonstrated extensive areas of retinal nonperfusion; at baseline, mean area of retinal perfusion was 106 disk areas (range, 37–129), correlating with a mean of 46.5% perfused retinal area (range, 19.1–56.4%). The area of retinal nonperfusion increased in all eyes with a mean loss of approximately 8.1% of perfused retinal area per year (range, 4.3–12.4%), which corresponded to a mean 15-disk areas (range, 12–35) of retina evolving from perfused to nonperfused annually. The extent of baseline and final nonperfusion was not significantly different between eyes that developed neovascularization and eyes that did not. Conclusion: In this population of severe central retinal vein occlusion eyes, profound retinal nonperfusion was observed with wide-field fluorescein angiography at baseline and the extent of nonperfusion progressed while undergoing anti-vascular endothelial growth factor therapy.

SAVE (Super-dose Anti-VEGF) Trial: 2.0 mg Ranibizumab for Recalcitrant Neovascular Age-Related Macular Degeneration: 1-Year Results

OBJECTIVES To assess durability of visual and anatomic gains with 2.0 mg ranibizumab in recalcitrant neovascular age-related macular degeneration (AMD). METHODS Phase I-II trial of 88 patients with recalcitrant neovascular AMD treated as needed every 4 (cohort A) or 6 weeks (cohort B) following three monthly doses. ETDRS refraction and spectral-domain OCT-guided as-needed re-treatments. RESULTS Seventy-nine patients completed the 12-month endpoint and were given 11.6 (cohort A) and 8.6 (cohort B) mean treatments. Mean best corrected visual acuity gains of 4.1 letters following three monthly doses were sustained for 12 months for both cohorts. Anatomic improvements were sustained for 12 months for cohort A, but not for cohort B; cohort B demonstrated a gradual increase in mean central retinal thickness (P = .03). CONCLUSION Visual and anatomic gains achieved with 2.0 mg ranibizumab in recalcitrant neovascular AMD were sustained for 1 year with monthly treatment. In comparison, anatomic gains were diminished with less than monthly treatment.

Comparison of spectral-domain and time-domain optical coherence tomography in the detection of neovascular age-related macular degeneration activity

Purpose: To compare the sensitivity of commonly used time-domain (TD-OCT) and spectral-domain optical coherence tomography platforms and scanning modalities in the management of neovascular age-related macular degeneration in a population with a high prevalence of exudative disease activity. Methods: Fifty consecutive patients within the prospective SAVE (Super-dose Anti-Vascular Endothelial growth factor) trial, which analyzed the utility of 2.0 mg intravitreal ranibizumab for the treatment of recalcitrant neovascular age-related macular degeneration, were enrolled in a comparison trial of 3 different optical coherence tomography (OCT) platforms. Stratus TD-OCT radial scan (Carl Zeiss Meditec, Inc) was compared with 3 Heidelberg Spectralis Heidelberg Retinal Angiograph+OCT (Heidelberg Engineering) acquisition settings (radial, 7-line raster, volumetric) and 2 Cirrus high definition (HD)-OCT (Carl Zeiss Meditec, Inc) acquisition settings (5-line raster, volumetric). Results: Using every imaging platform and acquisition setting, evidence of exudative disease activity was positively identified in 163 of 191 patient visits (85.3%). Intraretinal cysts were identified in 83 of 191 visits (43.5%), and subretinal fluid was identified in 116 of 191 visits (60.7%). Of these positive visits, the Stratus TD-OCT radial scanning technology demonstrated a significantly lower rate of detection (71.8%) when compared with the Spectralis HRA+OCT spectral domain scanning modalities (radial 87.1%, P < 0.001; 7-line raster 92.0%, P < 0.001; volumetric 94.5%, P < 0.001) or the Cirrus HD-OCT spectral domain scanning modalities (5-line raster 81.6%, P = 0.001; volumetric 92.0%, P < 0.001). Intraretinal cysts and subretinal fluid were identified in 83 visits (43.5%) and 116 visits (60.7%), respectively, with 36 eyes (18.8%) having fluid in both locations. No individual imaging modality demonstrated a diagnostic advantage for detecting subretinal fluid versus intraretinal cysts (e.g., Cirrus volume detected 86.7% of intraretinal cysts and 88.8% of subretinal fluid, P = 0.33). Conclusion: In this neovascular age-related macular degeneration patient population, spectral-domain ocular coherence tomography was a superior diagnostic tool when compared with TD-OCT, with each spectral domain platform and acquisition setting identifying significantly more exudative disease activity. The two spectral domain platforms (Cirrus and Spectralis) were not directly compared because identical image acquisition parameters were not used. No individual imaging modality demonstrated a diagnostic advantage for detecting subretinal fluid versus intraretinal cysts.

Aflibercept for pigment epithelial detachment for previously treated neovascular age-related macular degeneration

OBJECTIVE Assess the efficacy of intravitreal aflibercept on pigment epithelial detachments (PED) associated with previously treated patients with neovascular age-related macular degeneration (AMD). DESIGN Retrospective study. PARTICIPANTS Sixty eyes. METHODS Patients with persistent PED who were treated with intravitreal aflibercept (2.0 mg) with ≥2 previous injections of bevacizumab (1.25 mg) or ranibizumab (0.5 mg) were analyzed. RESULTS Mean number of prior injections was 24.8 during a mean of 32 months of management (range 3-77 months). Baseline mean PED height was 258 µm (range 80-687 µm), which decreased at 1, 6, and 12 months upon switching to aflibercept to 226 µm (-14%, range 34-701 µm), 215 µm (-18%, range 0-666 µm), and 208 µm (-22%, range 0-752 µm), respectively. The majority of eyes experienced a decrease in PED height after switching to aflibercept: 50/58 (86%), 38/47 (81%), and 37/47 (79%) at months 1, 6, and 12, respectively. Reduction in PED height was weakly correlated with improved visual acuity (R(2) = 0.11). CONCLUSIONS Intravitreal aflibercept resulted in significant reduction in PED height in previously treated eyes with neovascular AMD.

Neovascular age-related macular degeneration management in the third year: Final results from the TREX-AMD randomised trial

Background/Aims Prospectively evaluate outcomes in the third year of neovascular age-related macular degeneration (AMD) management using ranibizumab with continued treat and extend (TREX) dosing compared with monthly visits with retreatment upon evidence of exudative disease activity (PRN, pro re nata). Methods Subjects with treatment-naïve neovascular AMD were randomised 1:2 to Monthly or TREX and managed through 2 years. In the third year, subjects randomised to Monthly were managed PRN while subjects randomised to TREX were continued on TREX dosing or transitioned to PRN after achieving an interval of 12 weeks between visits. Results Sixty subjects enrolled and 46 (77%) completed month 36 (M36). Transition from Monthly to PRN was associated with a decline in best corrected visual acuity (BCVA) (+10.5 letters (month 24) to +5.4 (M36, p=0.09)); three (15%) subjects required no dosing during year 3, and 47% (114/243) of possible PRN injections were delivered, yielding a mean of 6.1 injections during year 3. Among the 9 (23%) TREX subjects transitioned to PRN, the need for ongoing anti-vascular endothelial growth factor retreatments was small, with 4 (4%) intravitreal injections being delivered among 106 PRN visits; this subgroup displayed an inferior BCVA trajectory compared with the remainder of subjects. Outcomes among subjects continued on TREX were more favourable, with a mean gain of +5.0 letters at M36. Conclusions Upon transition to PRN, subjects randomised to monthly dosing experienced a decline in BCVA. Among subjects initially randomised to TREX who transitioned to PRN after achieving a 12-week interval between visits, the overall need for additional treatment was low. Trial registration number NCT01748292, Results.

THE ASSOCIATION OF EPIRETINAL MEMBRANE WITH MACULAR HOLE FORMATION AFTER RHEGMATOGENOUS RETINAL DETACHMENT REPAIR

Purpose: To describe the clinical and optical coherence tomography findings associated with the development of full-thickness macular holes after rhegmatogenous retinal detachment (RRD) repair. Methods: Retrospective, interventional case series. All patients who developed full-thickness macular holes after successful RRD repair from 3 clinical practices were reviewed. All cases of combined/simultaneous full-thickness macular hole and RRD were excluded. The main outcome measure was the presence of an epiretinal membrane at time of diagnosis of macular hole. Results: Twenty-five full-thickness macular holes were diagnosed after successful retinal detachment repair. Surgical approach to RRD repair included pneumatic retinopexy (6, 24%), scleral buckle alone (5, 20%), pars plana vitrectomy only (8, 32%), and combined scleral buckle and pars plana vitrectomy (6, 24%). The preceding RRD involved the macula in 19 patients (76%) before the formation of the macular hole. The median time to full-thickness macular hole diagnosis after RRD repair was 63 days (range, 4–4,080 days). An epiretinal membrane was present in all 25 (100%) macular holes. Two macular holes (8%) spontaneously closed, whereas the other 23 (92%) were successfully closed with a single surgical procedure. Mean visual acuity improved by approximately 5 lines to 20/72 (range, 20/20 to counting fingers at 1 foot) from 20/240 (range, 20/30 to hand motions) after macular hole repair (P < 0.0001). Conclusion: Full-thickness macular hole formation can occur after all types of RRD repair and is associated with an epiretinal membrane. The epiretinal membrane may play a role in the pathogenesis of secondary macular hole formation after RRD repair.

CHOROIDAL NEOVASCULARIZATION SECONDARY TO ALEXANDRITE LASER EXPOSURE.

PURPOSE To report macular photic trauma after accidental occupational exposure to a 750-nm Alexandrite laser and management of secondary choroidal neovascularization. METHODS Institutional review board-approved retrospective case report. RESULTS A 30-year-old woman presented with immediate vision loss in her left eye after direct inadvertent exposure to a single discharge from an occupational 750-nm Alexandrite laser used for laser hair removal. Baseline Snellen visual acuity was 20/40 in the involved left eye. One week after the initial exposure, the patient experienced subjective visual decline to 20/50, was treated with oral prednisone, and then developed a subretinal hemorrhage (SRH) in the setting of choroidal neovascularization 2 weeks later, or 3 weeks after initial trauma. The patient subsequently received 5 intravitreal ranibizumab injections over 25 weeks with resolution of the SRH. Final visual acuity was 20/50. CONCLUSION The present case documents development and management of subretinal hemorrhage associated with choroidal neovascularization following macular photic trauma after accidental occupational to a 750-nm Alexandrite laser.

Regulatory Factors Influencing Usage of Retinal Pharmaceuticals: A Look Both Home and Abroad

E XUDATIVE RETINAL DISEASES, INCLUDING AGErelated macular degeneration (AMD), diabetic retinopathy, and venous occlusive disease, are major contributors to vision loss globally. Fortunately, many ocular-specific treatments have been developed over the last decade and many more are in advanced-phase clinical trials with anticipated market release over the next 5 years. Although the specifics in bringing a novel pharmaceutical to market vary among countries, 2 key regulatory steps are often employed that influence the clinical availability and usage of these pharmacologic therapies.