Paolo Lanzetta

Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials

Background: Neovascular age-related macular degeneration (AMD) has a poor prognosis if left untreated, frequently resulting in legal blindness. Ranibizumab is approved for treating neovascular AMD. However, further guidance is needed to assist ophthalmologists in clinical practice to optimise treatment outcomes. Methods: An international retina expert panel assessed evidence available from prospective, multicentre studies evaluating different ranibizumab treatment schedules (ANCHOR, MARINA, PIER, SAILOR, SUSTAIN and EXCITE) and a literature search to generate evidence-based and consensus recommendations for treatment indication and assessment, retreatment and monitoring. Results: Ranibizumab is indicated for choroidal neovascular lesions with active disease, the clinical parameters of which are outlined. Treatment initiation with three consecutive monthly injections, followed by continued monthly injections, has provided the best visual-acuity outcomes in pivotal clinical trials. If continued monthly injections are not feasible after initiation, a flexible strategy appears viable, with monthly monitoring of lesion activity recommended. Initiation regimens of fewer than three injections have not been assessed. Continuous careful monitoring with flexible retreatment may help avoid vision loss recurring. Standardised biomarkers need to be determined. Conclusion: Evidence-based guidelines will help to optimise treatment outcomes with ranibizumab in neovascular AMD.

Verteporfin plus Ranibizumab for Choroidal Neovascularization in Age-related Macular Degeneration: Twelve-month MONT BLANC Study Results

PURPOSE To compare the efficacy and safety of same-day verteporfin photodynamic therapy (PDT) and intravitreal ranibizumab combination treatment versus ranibizumab monotherapy in neovascular age-related macular degeneration. DESIGN Prospective, multicenter, double-masked, randomized, active-controlled trial. PARTICIPANTS We included 255 patients with all types of active subfoveal choroidal neovascularization. METHODS Patients were randomized 1:1 to as-needed (pro re nata; PRN) combination (standard-fluence verteporfin 6 mg/m(2) PDT and ranibizumab 0.5 mg) or PRN ranibizumab monotherapy (sham infusion [5% dextrose] PDT and ranibizumab 0.5 mg). Patients received 3 consecutive monthly injections followed by PRN retreatments based on protocol-specific retreatment criteria. MAIN OUTCOME MEASURES Mean change in best-corrected visual acuity (BCVA) from baseline to month 12, and the proportion of patients with treatment-free interval ≥3 months at any timepoint after month 2. RESULTS The mean change in BCVA at month 12 was +2.5 and +4.4 letters in the combination and monotherapy groups, respectively (P = 0.0048; difference: -1.9 letters [95% confidence interval, -5.76 to 1.86], for having achieved noninferiority with a margin of 7 letters). The proportion of patients with a treatment-free interval of ≥3 months at any timepoint after month 2 was high, but did not show a clinically relevant difference between the treatment groups. Secondary efficacy endpoints included the mean number of ranibizumab retreatments after month 2 (1.9 and 2.2 with combination and monotherapy, respectively [P = 0.1373]). The time to first ranibizumab retreatment after month 2 was delayed by 34 days (about 1 monthly visit) with combination (month 6) versus monotherapy (month 5). At month 12, mean ± standard error central retinal thickness decreased by 115.3±9.04 μm in the combination group and 107.7±11.02 μm in the monotherapy group. The mean number of verteporfin/sham PDT treatments was comparable in the 2 groups (combination, 1.7; monotherapy, 1.9). The safety profiles of the 2 groups were comparable, with a low incidence of ocular serious adverse events. CONCLUSIONS The combination PRN treatment regimen with verteporfin PDT and ranibizumab was effective in achieving BCVA gain comparable with ranibizumab monotherapy; however, the study did not show benefits with respect to reducing the number of ranibizumab retreatment over 12 months. The combination therapy was well tolerated.

TREAT-AND-EXTEND REGIMENS WITH ANTI-VEGF AGENTS IN RETINAL DISEASES: A Literature Review and Consensus Recommendations.

Purpose: A review of treat-and-extend regimens (TERs) with intravitreal anti–vascular endothelial growth factor agents in retinal diseases. Methods: There is a lack of consensus on the definition and optimal application of TER in clinical practice. This article describes the supporting evidence and subsequent development of a generic algorithm for TER dosing with anti–vascular endothelial growth factor agents, considering factors such as criteria for extension. Results: A TER algorithm was developed; TER is defined as an individualized proactive dosing regimen usually initiated by monthly injections until a maximal clinical response is observed (frequently determined by optical coherence tomography), followed by increasing intervals between injections (and evaluations) depending on disease activity. The TER regimen has emerged as an effective approach to tailoring the dosing regimen and for reducing treatment burden (visits and injections) compared with fixed monthly dosing or monthly visits with optical coherence tomography–guided regimens (as-needed or pro re nata). It is also considered a suitable approach in many retinal diseases managed with intravitreal anti–vascular endothelial growth factor therapy, given that all eyes differ in the need for repeat injections. Conclusion: It is hoped that this practical review and TER algorithm will be of benefit to health care professionals interested in the management of retinal diseases.

Nonvisible subthreshold micropulse diode laser (810 nm) treatment of central serous chorioretinopathy: A pilot study

Purpose To verify the efficacy of nonvisible micropulse diode laser irradiation in the treatment of central serous chorioretinopathy (CSC). Methods Twenty-two patients with CSC for a total of 24 eyes with a disease duration longer than 3 months were included in a prospective study. Patients underwent Early Treatment Diabetic Retinopathy Study visual acuity (VA) examination, dilated ophthalmoscopy fluorescein angiography and optical coherence tomography before treatment and during follow-up. Treatment with a micropulse diode laser was given with a duty cycle of 15%. Multiple spots were placed over and adjacent to the area of retinal pigment epithelium leak or decompensation. Results Mean follow-up was 14 months (range 3–36 months). Powers used ranged from 1 to 2 W (mean 1.35 W). Mean number of spots was 215 (range 90–400). Fourteen eyes were treated once, nine eyes received two to three treatments, and one eye had five treatments during a follow-up of 3 years. Subretinal fluid was resolved or improved in two third of cases 1 month after laser treatment, and in three-quarters at the end of follow-up. Mean retinal thickness was 328 μm, 197 μm, and 168 μm before, 1 month after irradiation, and at the end of follow-up, respectively. No evidence of RPE or retinal changes due to laser treatment were discernible in most of the eyes. Median VA was 20/32 (range 20/100–20/20) before treatment and 20/25 (range 20/200–20/20) at the end of the follow-up. Conclusions Nonvisible micropulse diode laser may have efficacy in the treatment of CSC. A randomized study with larger series is needed.

Myopic choroidal neovascularisation: current concepts and update on clinical management

Choroidal neovascularisation (CNV) is a common vision-threatening complication of myopia and pathological myopia. Despite significant advances in understanding the epidemiology, pathogenesis and natural history of myopic CNV, there is no standard definition of myopic CNV and its relationship to axial length and other myopic degenerative changes. Several treatments are available to ophthalmologists, but with the advent of new therapies there is a need for further consensus and clinical management recommendations. Verteporfin photodynamic therapy has been an established treatment for subfoveal myopic CNV for many years, but this treatment does not restore visual acuity and is associated with long-term chorioretinal atrophy. More recently, clinical trials investigating the efficacy and safety of anti-vascular endothelial growth factor agents in patients with myopic CNV have demonstrated substantial visual acuity gains and quality of life increases compared with photodynamic therapy. These enhanced outcomes provide updated evidence-based clinical management guidelines of myopic CNV, and increase the need for a generally accepted definition for myopic CNV. This review critically summarises the latest myopic CNV literature in the context of clinical experience and recommends a myopic CNV treatment algorithm.

The effects of a flexible visual acuity-driven ranibizumab treatment regimen in age-related macular degeneration: outcomes of a drug and disease model.

PURPOSE Differences in treatment responses to ranibizumab injections observed within trials involving monthly (MARINA and ANCHOR studies) and quarterly (PIER study) treatment suggest that an individualized treatment regimen may be effective in neovascular age-related macular degeneration. In the present study, a drug and disease model was used to evaluate the impact of an individualized, flexible treatment regimen on disease progression. METHODS For visual acuity (VA), a model was developed on the 12-month data from ANCHOR, MARINA, and PIER. Data from untreated patients were used to model patient-specific disease progression in terms of VA loss. Data from treated patients from the period after the three initial injections were used to model the effect of predicted ranibizumab vitreous concentration on VA loss. The model was checked by comparing simulations of VA outcomes after monthly and quarterly injections during this period with trial data. A flexible VA-guided regimen (after the three initial injections) in which treatment is initiated by loss of >5 letters from best previously observed VA scores was simulated. RESULTS Simulated monthly and quarterly VA-guided regimens showed good agreement with trial data. Simulation of VA-driven individualized treatment suggests that this regimen, on average, sustains the initial gains in VA seen in clinical trials at month 3. The model predicted that, on average, to maintain initial VA gains, an estimated 5.1 ranibizumab injections are needed during the 9 months after the three initial monthly injections, which amounts to a total of 8.1 injections during the first year. CONCLUSIONS A flexible, individualized VA-guided regimen after the three initial injections may sustain vision improvement with ranibizumab and could improve cost-effectiveness and convenience and reduce drug administration-associated risks.

Immediate intraocular pressure response to selective laser trabeculoplasty

BACKGROUND/AIMS Selective laser trabeculoplasty targets the pigmented trabecular meshwork cells without damage to the trabecular meshwork architecture in vitro. A study was conducted in vivo of eight eyes with uncontrolled open angle glaucoma to ascertain the immediate intraocular response to selective laser trabeculoplasty. METHODS The trabecular meshwork of each eye was treated 360° with a frequency doubled Q-switched Nd:YAG laser. Intraocular pressure was measured 1, 2, 24 hours and 1, 4, 6 weeks after treatment. RESULTS The average preoperative intraocular pressure was 26.6 (SD 7) mm Hg (range 18–37). Two hours and 6 weeks respectively after selective trabeculoplasty intraocular pressure was reduced in all the eyes treated with an average fall of 10.6 (5.2) mm Hg or 39.9%. A pressure spike of 10 mm Hg verified in one eye 1 hour after treatment. CONCLUSIONS Selective laser trabeculoplasty decreased intraocular pressure by an amount similar to that achieved with standard trabeculoplasty. Additional study is needed to determine whether the beneficial effect is sustained over a longer period of follow up.

Spontaneous resolution of a shallow detachment of the macula in a highly myopic eye

PURPOSE To report a case of pathologic myopia with shallow detachment of the macula and anatomic reattachment after spontaneous posterior vitreous separation. DESIGN Observational case report. METHODS A 66-year-old woman with pathologic myopia presented with decreased vision of 20/400 in her left eye. Biomicroscopy showed myopic chorioretinal changes, posterior staphyloma, and a shallow macular elevation. Optical coherence tomography was performed at the initial and follow-up examinations. RESULTS Initial optical coherence tomography revealed a retinal detachment, retinoschisis, and incomplete posterior vitreous detachment. One and one-half years after the initial visit the patients best-corrected visual acuity improved to 20/200, and optical coherence tomography disclosed macular reattachment, release of vitreous adhesions, and restoration of normal retinal tomographic appearance. CONCLUSIONS Spontaneous resolution of chronic shallow detachment of the macula in highly myopic eyes may occur and can be attributed to spontaneous posterior vitreous detachment.

Indocyanine green angiography in central serous chorioretinopathy

Purpose. To analyse images obtained by indocyanine green angiography in central serous chorioretinopathy (CSC). Methods. Ninety patients affected with CSC were examined using indocyanine green angiography. Results. CSC was detected in 127 of the 180 eyes examined. Leakage points were detected in 99 eyes with fluorescein angiography; in 85 of these eyes, they corresponded o hyperfluorescence with indocyanine green angiography, while a hyperfluorescence of the neuroepithelial detachment was seen in 21 eyes. Areas of choriodal hyperpermeability were seen in all 127 eyes with CSC and in 9 fellow eyes. With ICG angiography, the appearance of pigment epithelial detachments was similar to that previously described (early hyperfluorescence and later hypofluorescence), and was seen in 47 eyes. In 103 eyes, hypofluorescence lesions of various sizes, were detected which became more marked in the later stages. These lesions corresponded to retinal pigment epithelium lesions in fluorescein angiography, mainly hyperfluorescence caused by window defect. We were also able to observe RPE atrophic tracts in 31 eyes. These tracts appeared hyperfluorescent in 11 eyes where a minimal amount of RPE atrophy was present and hypofluorescent in 20 eyes in which the tract had marked RPE atrophy. Conclusion. The results obtained confirm the finding of choriodal hyperpermeability and subretinal diffusion of ICG, which indicate involvement of the choroid in CSC. The observation of progressively hypofluorescent lesions corresponding to retinal pigment epithelium alterations suggests that there may be as yet unknown interactions of pigment epithelium and ICG.

Light panretinal photocoagulation (LPRP) versus classic panretinal photocoagulation (CPRP) in proliferative diabetic retinopathy.

Purpose. We misled to verify whether a panretinal photocoagulation (PRP) performed using low levels of ARGON laser energy (light PRP) has the same efficacy as a PRP performed in a conventional fashion using argon green wavelengths (classic PRP) in eyes with high-risk proliferative diabetic retinopathy (HRPDR). Furthermore, we misled to compare the session number performed and the side effects produced by the two techniques. Methods. Sixty-five eyes with HRPDR of 50 consecutive patients were enrolled in a prospective randomized controlled trial. In eyes selected for light PRP, a very light biomicroscopic effect on the retina was obtained for each spot. In eyes assigned to classic PRP, each spot produced a white-yellow biomicroscopic effect. Mean follow-up was 22.4 months ±9.7 in the light PRP and 21.6 months ±9.3 in the classic PRP group (p = 0.727). Results. The initial mean logMAR visual acuity (VA) in the light PRP group was 0.12 ± 0.13 and in the classic PRP group 0.14 ± 0.15 (p = 0.493). The final mean VA in the former was 0.18 ± 0.25, and in the latter 0.27 ± 0.30 (p = 0.231). Median power was 235 mW (100–540 mW) for light and 420 mW (200–950 mW) for classic PRP (p < 0.001). Regression of HRPDR at the end of the follow-up was obtained in 30/31 eyes (97%) treated with classic PRP and in 31/34 eyes (91%) treated with light PRP (p = 0.615). The total mean session number was 7.4 ± 2.4 for light and 9.9 ± 2.2 for the classic PRP group (p < 0.001). Complications were more frequent in the classic PRP group. Conclusions. The efficacy of Light PRP is similar to that of classic Light PRP in eyes with HRPDR. Light PRP is associated with fewer complications and allows the reduction of the number of treatment sessions.