Optimizing the Anti-VEGF Treatment Strategy for Neovascular Age-Related Macular Degeneration: From Clinical Trials to Real-Life Requirements.

This Perspective discusses the pertinence of variable dosing regimens with anti-vascular endothelial growth factor (VEGF) for neovascular age-related macular degeneration (nAMD) with regard to real-life requirements. After the initial pivotal trials of anti-VEGF therapy, the variable dosing regimens pro re nata (PRN), Treat-and-Extend, and Observe-and-Plan, a recently introduced regimen, aimed to optimize the anti-VEGF treatment strategy for nAMD. The PRN regimen showed good visual results but requires monthly monitoring visits and can therefore be difficult to implement. Moreover, application of the PRN regimen revealed inferior results in real-life circumstances due to problems with resource allocation. The Treat-and-Extend regimen uses an interval based approach and has become widely accepted for its ease of preplanning and the reduced number of office visits required. The parallel development of the Observe-and-Plan regimen demonstrated that the future need for retreatment (interval) could be reliably predicted. Studies investigating the observe-and-plan regimen also showed that this could be used in individualized fixed treatment plans, allowing for dramatically reduced clinical burden and good outcomes, thus meeting the real life requirements. This progressive development of variable dosing regimens is a response to the real-life circumstances of limited human, technical, and financial resources. This includes an individualized treatment approach, optimization of the number of retreatments, a minimal number of monitoring visits, and ease of planning ahead. The Observe-and-Plan regimen achieves this goal with good functional results. Translational Relevance: This perspective reviews the process from the pivotal clinical trials to the development of treatment regimens which are adjusted to real life requirements. The article discusses this translational process which- although not the classical interpretation of translation from fundamental to clinical research, but a subsequent process after the pivotal clinical trials - represents an important translational step from the clinical proof of efficacy to optimization in terms of patients' and clinics' needs. The related scientific procedure includes the exploration of the concept, evaluation of security, and finally proof of efficacy

Beneficial switch from aflibercept to ranibizumab for the treatment of refractory neovascular age-related macular degeneration.

The aim of this study was to evaluate the effects of switching to ranibizumab in patients with neovascular age-related macular degeneration (nAMD) refractory to aflibercept treatment and to identify predictive factors for switch response. A retrospective chart review was conducted including 32 eyes from 26 patients with refractory nAMD, who switched from monthly intravitreal aflibercept treatment (≥ 6 months) to ranibizumab. Outcome measures included changes in visual acuity (VA), intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED), and central retinal thickness (CRT), evaluated at 6 months before switch (T1), at the time of switch (T2), and 3 months post-switch (T3). There was an increase in CRT from T1 to T2, which decreased after switch from T2 to T3. Regression analysis of the changes per month observed between time points showed significant differences in PED height (p = 0.02), SRF (p = 0.01), and neuroretinal thickness as a measure for IRF (p = 0.03). No significant change was found for VA. Predictive factors for better switch response included an exacerbation between T1 and T2, thicker measurements at T2, male sex, shorter treatment duration before switch, and fewer preceding injections. No association with preceding switch was found. Patients with nAMD refractory to aflibercept benefit from switching to ranibizumab, particularly those whose condition worsened prior to the switch. This may be explained by drug tolerance to aflibercept. Our findings may facilitate making appropriate treatment decisions, potentially improving patient outcomes

Two-year outcome of an observe-and-plan regimen for neovascular age-related macular degeneration treated with Aflibercept.

The purpose of our study was to investigate the two-year outcome of Aflibercept treatment for neovascular age-related macular degeneration (nAMD), using the Observe-and-Plan regimen, an individually planned treatment regimen, based on the predictability of an individual's need for retreatment, aiming to reduce the clinical burden. Our prospective study used the Observe-and-Plan regimen with Aflibercept to treat nAMD: Three loading doses, followed by monthly observation visits until the disease-recurrence interval was determined, which then was shortened by 2 weeks in a treatment plan for the next three injections without intermediate monitoring visits. The subsequent treatment plans were adjusted according to periodically assessed disease activity. The primary outcome measures were visual acuity changes, number of injections, and number of monitoring visits. The study included 112 eyes of 102 patients with a mean age of 80.7 years (SD 7.6). Mean visual acuity (VA) improved from 61.8 ETDRS letters (20/60(+2)) at baseline, by 8.5, 8.0, and 6.2 letters at months 3, 12 and 24, respectively. Mean central retinal thickness was 438um at baseline, and reduced by 152um, 155um, and 150um at months 3, 12 and 24, respectively. The mean number of injections was 8.7 and 6.5 in the first and second year, respectively. The mean number of monitoring visits after baseline was 3.8 and 2.8 during the first and second year, respectively. The Observe-and-Plan regimen significantly improved VA, while fewer monitoring visits were needed as compared to other variable dosing regimens, thus reducing the workload for chronic care management of nAMD

Electric-field control of domain wall nucleation and pinning in a metallic ferromagnet

The electric (E) field control of magnetic properties opens the prospects of an alternative to magnetic field or electric current activation to control magnetization. Multilayers with perpendicular magnetic anisotropy (PMA) have proven to be particularly sensitive to the influence of an E-field due to the interfacial origin of their anisotropy. In these systems, E-field effects have been recently applied to assist magnetization switching and control domain wall (DW) velocity. Here we report on two new applications of the E-field in a similar material : controlling DW nucleation and stopping DW propagation at the edge of the electrode

Reducing the clinical burden of ranibizumab treatment for neovascular age-related macular degeneration using an individually planned regimen.

AIMS: The purpose of this study was to clinically validate an individually planned treatment regimen for neovascular age-related macular degeneration (nAMD), termed, observe and plan. This regimen was based on the predictability of an individual's need for retreatment and aimed to reduce the clinical burden, while obtaining good functional results. METHODS: This was a prospective case series that included 104 patients (115 eyes) with treatment-naive nAMD. Following three loading doses of ranibizumab, monthly observation visits allowed the disease recurrence interval to be determined. The recurrence interval was reduced by 2 weeks to give the retreatment interval for the next three injections. Periodical control visits (at least every 6 months) allowed the effectiveness of the treatment to be assessed and individual intervals adjusted. RESULTS: Mean visual acuity (VA) improved by 8.7 and 9.8 letters in months 3 and 12, respectively. The mean number of injections during the 12-month study was 7.8, while the mean number of ophthalmic examinations between months 3 and 12 was 3.97. The mean treatment interval after the loading doses was 1.97 months. CONCLUSIONS: The observe-and-plan regimen significantly improved VA. This was obtained with fewer clinic visits compared with other regimens, which could ease the burden of nAMD treatment. TRIAL REGISTRATION NUMBER: Commission cantonale (VD) d'éthique de la recherché Clinique, Université de Lausanne, Protocole 351/11

Resolution of foveal detachment in dome-shaped macula after treatment by spironolactone: report of two cases and mini-review of the literature.

Dome-shaped macula (DSM) was recently described in myopic patients as a convex protrusion of the macula within a posterior pole staphyloma. The pathogenesis of DSM and the development of associated serous foveal detachment (SFD) remain unclear. The obstruction of choroidal outflow and compressive changes of choroidal capillaries have been proposed as causative factors. In this paper, we report two cases of patients with chronic SFD associated with DSM treated with oral spironolactone. After treatment, there was a complete resolution of SFD in both patients. To the best of our knowledge, this is the first report of successful treatment of SFD in DSM by a mineralocorticoid receptor antagonist

Antidepressant medication and ocular factors in association with the need for anti-VEGF retreatment in neovascular age-related macular degeneration.

Vascular endothelial growth factor (VEGF) is a key player in the pathogenesis of neovascular age-related macular degeneration (nAMD) and is also involved in the final common pathway of antidepressant medication. This study investigated the relationship between the need for anti-VEGF retreatment in patients with nAMD and antidepressant medication, and the potential impact of ocular structural factors. Data from two identical prospective 2-year treatment protocols using ranibizumab or aflibercept in a variable-dosing regimen ('Observe-and-Plan') were analysed. Retreatment requirement was compared with antidepressant medication intake (primary outcome) and a variety of ocular factors from baseline and from month 3 response (secondary outcomes), using univariate and multivariate analyses. Of the 206 included patients (227 eyes), 19 were on antidepressant medication. Their nAMD eyes significantly more often had pigment epithelium detachment (PED, p=0.04). Multivariate analysis revealed a significant association between anti-VEGF retreatment requirement and antidepressant medication use (p=0.027), as well as thicker central retinal thickness at month 3 (p<0.0001) and month 3 PED height (p=0.001). This study provides evidence that treatment with antidepressant medication increases the anti-VEGF retreatment requirement in patients with nAMD, possibly through the interplay of antidepressant medication, depression status and VEGF levels

Ranibizumab treatment history as predictor of the switch-response to aflibercept: evidence for drug tolerance.

To investigate whether tolerance to the anti-VEGF drug, ranibizumab, develops after drug exposure and to determine whether the history of treatment with ranibizumab prior to refractoriness can predict the post-switching responses to aflibercept. We retrospectively investigated neovascular age-related macular degeneration patients refractory to ranibizumab (intra- or subretinal fluid despite monthly injections for ≥6 months) who were switched to aflibercept and were followed up for at least 12 months on each of ranibizumab and aflibercept. Baseline characteristics and ranibizumab and aflibercept treatment history (number of injections during the first year and central retinal thickness [CRT]) were analyzed by univariate and multivariate correlation analyses. Ninety-eight eyes (88 patients, 70% females, mean age 77.5 years), including a high proportion of eyes with pigment epithelium detachment (63%), were treated with a mean of 26.2 injections during 36.8 months before switching to aflibercept. The number of ranibizumab injections required in the first year ( javax.xml.bind.JAXBElement@135ceeb9 =0.0002) and the presence of pigment epithelium detachment ( javax.xml.bind.JAXBElement@41f4808d =0.025) predicted the number of post-switching aflibercept injections required. The post-switching CRT change was predicted by the CRT increase from Month 3 to the switch time point ( javax.xml.bind.JAXBElement@1893b2db <0.0001). Moreover, the CRT change correlated with the visual acuity benefit post-switching ( javax.xml.bind.JAXBElement@4c54257f =0.038 and javax.xml.bind.JAXBElement@3889336a =0.004, at 3 and 12 months post-switching, respectively). Ranibizumab treatment history before switching to aflibercept correlates with the post-switching response in terms of the number of drug injections needed and CRT. Thus, drug tolerance does indeed exist and this might help to identify switching candidates

ACUTE CENTRAL SEROUS CHORIORETINOPATHY: Factors Influencing Episode Duration.

To evaluate the influence of clinical and multimodal imaging parameters on the duration of acute central serous chorioretinopathy (CSCR) episodes. Consecutive patients with first, treatment-naïve central serous chorioretinopathy episodes presenting within 20 days of symptoms onset were prospectively included. They were reevaluated 15 days to 20 days later, followed by monthly evaluation for 6 months. Subfoveal choroidal thickness (SFCT), fluorescein leakage intensity on fluorescein angiography, elevation of retinal pigment epithelium (RPE) lesions at leakage sites, focal/multifocal pattern of indocyanine green angiography (ICGA) at baseline, time-dependent pattern of subretinal fluid (SRF) resorption on OCT using volume segmentation, history of corticosteroid intake and mean blood pressure were evaluated using univariate (Log rank test) and multivariate (Cox proportional hazard regression) survival analysis. Thirty-one patients were included (26 men, 5 women, mean age: 40.0 ± 8.9 years, range: 24-58), of which 26 (84%) had episode resolution by 6 months. Using univariate analysis, episode duration was longer in cases with subfoveal choroidal thickness ≥500 μm (P = 0.0002), retinal pigment epithelium elevation at leakage sites ≥50 μm (P = 0.033), and a peak in subretinal fluid observed during follow-up (P = 0.013), and there was a near-significant association of intense fluorescein leakage (P = 0.074) with longer episodes. Using multivariate analysis, subfoveal choroidal thickness ≥500 μm (P = 0.017), retinal pigment epithelium elevation at leakage sites ≥50 μm (P = 0.010) and patient age ≥40 years (P = 0.010) were significantly and independently associated to longer episodes. Indocyanine green angiography pattern, corticosteroid intake, and blood pressure did not influence episode duration. Older age, higher subfoveal choroidal thickness, and higher degree of retinal pigment epithelium alteration at leakage sites are independent factors of longer acute central serous chorioretinopathy episodes