A randomized, open-label, multicenter study of switching to brolucizumab with or without a loading dose for patients with suboptimal anatomically controlled neovascular age-related macular degeneration-the FALCON study.

BACKGROUND: Treatment initiation with brolucizumab, a new potent anti-vascular endothelial growth factor (VEGF) agent, is typically performed with three monthly injections (loading dose) and has been well studied in treatment-naïve patients. However, no clinical data are available yet on whether or not anti-VEGF pretreated patients also benefit from a loading dose. In the clinical setting, different heterogeneous treatment patterns are used as no clinical trial has addressed this so far in a head-to-head comparison. Therefore, the FALCON study is investigating whether patients with unsatisfactory response to previous anti-VEGF treatments benefit from a loading dose at the switch to brolucizumab treatment. METHODS: FALCON is a 52-week, two-arm, randomized, open-label, multicenter, multinational study in patients with residually active neovascular age-related macular degeneration (nAMD) who will be randomized 1:1 and started with brolucizumab 6 mg loading (three monthly loading doses) or brolucizumab 6 mg non-loading (one initial injection) and consecutive treatment every 12 weeks, respectively. The primary objective is to demonstrate non-inferiority of the non-loading vs. loading arm in mean change of best-corrected visual acuity (BCVA) from baseline to the mean value at week 40 to week 52. Secondary objectives include the assessment of anatomical outcomes, treatment intervals, safety and tolerability. RESULTS: FALCON will be the first study to assess treatment initiation with an anti-VEGF agent in a switch situation with or without loading dose in patients with nAMD. CONCLUSIONS: The results will support the optimization of treatment of patients with previous unsatisfactory anti-VEGF response. Therefore, we expect to see an impact on current clinical practice which has been established for more than a decade. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04679935, date of registration-22-Dec 2020; EUDRACT number: 2019-004763-53, date of registration-03 Dec 2019.

[Strategies of Intravitreal Injections with Anti-VEGF: "Pro re Nata versus Treat and Extend"]. / Injektionsstrategien bei der Anwendung intravitrealer VEGF-Inhibitoren: "Pro Re Nata versus Treat and Extend".

The goal of this report is to provide a review on different strategies for the use of pro re nata (PRN) and treat and extend (T&E) regimens with intravitreal anti-VEGF agents (bevacizumab, ranibizumab or aflibercept) in patients with retinal diseases such as neovascular AMD, diabetic macular oedema and macular oedema due to retinal vein occlusion. The main focus is to present the effectiveness and visual outcomes of both PRN and T&E regimens in the main pivotal trials and studies based on currently available evidence. We also discuss the advantages and disadvantages of both regimens, as well as monitoring and treatment of the disease, including treatment intervals and injection frequency. Currently there is increasing interest in establishing a regimen which offers the best visual outcome with lower injection frequency, and with reduced treatment burden by individualising treatment intervals and minimising the number of clinic visits and costs. Studies have shown that the PRN regimens in a clinical setting are insufficient in assuring the best visual outcome. The PRN regime requires frequent clinic visits to monitor disease status and intravitreal treatment if needed in a reactive approach. Individualised T&E regimens can improve visual outcome and require fewer injections than those administered in a monthly regimen and fewer monitoring visits than those in a PRN regimen.

[Retinal Vein Occlusion - Which Treatment When?] / Retinaler Venenverschluss ­ wann, womit und wie therapieren?

According to the latest findings, macular oedema due to retinal vein occlusion is best treated safely and effectively with near-term intravitreal anti-VEGF therapy (aflibercept, bevacizumab [off label], ranibizumab). After an initial upload of 3 monthly injections of anti-VEGF, the decision on re-injection should be based on OCT (rather than on visual acuity). After initial monthly injections, the "pro-re-nata" (PRN) and the "treat-and-extend" regimens have been predominantly used in the further course of therapy. Taking into account the side effect spectrum (in particular cataract progression, increased intraocular pressure), intravitreal therapy with a dexamethasone implant may be a reasonable alternative. The prognosis for visual acuity and the decline in macular oedema depend on starting treatment early and continuing it consistently. Before starting treatment, as well as during treatment, fluorescein angiography is necessary to detect ischemic retinal areas. There is evidence that early targeted laser coagulation of ischemic retina may reduce the frequency of necessary injections and improve the response of the oedema to therapy. Significant retinal ischemia may lead to proliferations, rubeosis iridis and secondary glaucoma and therefore requires laser treatment.

Cathepsin proteases promote angiogenic sprouting and laser-induced choroidal neovascularisation in mice.

Cysteine cathepsins are a family of proteases involved in intracellular protein turnover and extracellular matrix degradation. Cathepsin B (Ctsb) and cathepsin Z (Ctsz) promote tumorigenesis and Ctsb is a known modulator of tumor angiogenesis. We therefore investigated the angiomodulatory function of these cathepsins in vitro as well as in a mouse model of laser-induced choroidal neovascularization (laser-CNV). Ctsb(-/-), Ctsz(-/-), Ctsb/Ctsz double-knockout (Ctsb/z DKO), and wild type (WT) mice underwent argon laser treatment to induce choroidal neovascularization (CNV). The neovascularized area was quantified individually for each lesion at 14 days after laser coagulation. In vitro the effects of cathepsin inhibitors on angiogenesis were analysed by endothelial cell (EC) spheroid sprouting and EC invadosome assays. Retinas from cathepsin KO mice did not show gross morphological abnormalities. In the laser CNV model, however, Ctsb/z DKO mice displayed a significantly reduced neovascularized area compared to WT (0.027 mm(2) vs. 0.052 mm(2); p = 0.012), while single knockouts did not differ significantly from WT. In line, VEGF-induced EC spheroid sprouting and invadosome formation were not significantly altered by a specific cathepsin B inhibitor alone, but significantly suppressed when more than one cathepsin was inhibited. Our results demonstrate that laser-CNV formation is significantly reduced in Ctsb/z DKO mice. In line, EC sprouting and invadosome formation are blunted when more than one cathepsin is inhibited in vitro. These results reveal an angiomodulatory potential of cathepsins with partial functional redundancies between different cathepsin family members.

[Clinical diagnostics and therapy for non-arteritic central retinal artery occlusion]. / Diagnostik und Therapie beim nicht arteriitischen Zentralarterienverschluss.

Central retinal artery occlusion (CRAO) is an ophthalmological emergency situation. Known risk factors are arterial hypertension, cardial arrhythmia, arteriosclerosis, hypercholesterolemia and diabetes. Elderly patients should be examined for an arteritic genesis. Young patients (< 45 years) without typical risk factors may suffer from thrombophilia. There is no uniform recommendation on how to treat non-arteritic CRAO. Many different interventions have been suggested in the literature, i. e., massaging the eye, systemic or local reduction of intraocular pressure, anticoagulation, either systemically administered venous thrombolysis or supraselective intra-arterial thrombolysis. In this review we present the causes of CRAO and diagnostic means to detect causes; we also critically discuss previously described therapeutic options. It is our aim to provide a guide through the necessary interdisciplinary diagnostics in co-operation with internal medicine and neurology and to recommend a multimodal therapy in patients with non-arteritic CRAO.

[Intravitreal drug therapy for retinal vein occlusion--pathophysiological mechanisms and routinely used drugs]. / Intravitreale Medikamenteneingabe bei retinalem Venenverschluss--pathophysiologische Mechanismen und angewandte Substanzen.

The novel therapeutic principle of intravitreal drug therapy for retinal vein occlusion has become an integrated constituent of clinical practice over the last years. The two substance classes that have been evaluated in large randomised clinical trials so far are corticosteroids and inhibitors of vascular endothelial growth factor (VEGF). The reported treatment success of these intravitreally administered substances has lead not only to a paradigm shift in clinical care but has also advanced our understanding of the underlying pathophysiological principles of retinal vein occlusions. In this review the different substances are discussed, their mechanisms of action are analysed and the results of the large clinical trials available to date are critically evaluated. Furthermore, an approach to integrate these novel treatment options into the existing treatment regimes for retinal vein occlusions is suggested.

[Work sampling in ophthalmological clinical studies. A multicenter field study]. / Zeiterfassung in ophthalmologischen klinischen Studien. Eine multizentrische Feldstudie.

BACKGROUND: Work in clinical studies is generally more elaborate and therefore more time-consuming in comparison to the clinical routine. The purpose of this study was to systematically investigate the time consumption in the German ophthalmological clinical trial centers. METHODS: The members of the working group of the German Ophthalmology Society clinical study centers (Arbeitsgemeinschaft DOG Klinische Studienzentren) were asked to fill in three questionnaires about best estimations for the time spent on study-related procedures and administration. Additionally, work sampling was performed for each employee at each study center over a period of 3 weeks. RESULTS: The questionnaires were completed by 9 of the 11 centers. Overall, 5504 working hours were recorded. On an average working day, the time spent for both documentation and administration averaged 4 h each. Operative interventions consumed a significant amount of time (2.8 h), as did ophthalmological examinations (2.5 h) and obtaining informed consent (1.5 h). The recorded time consumption for visual acuity testing, informed consent and documentation was well aligned with the best estimates of the three questionnaires. By contrast, interventions, ophthalmological examinations and biomaterial sample handling were underrated in the best estimations. DISCUSSION: A considerable amount of time in clinical studies is spent on documentation and administration. From work sampling, ophthalmological examinations and biomaterial sampling turned out to be surprisingly time consuming. This is probably due to preparation and postprocessing tasks. It is important to consider this when calculating the overall costs of a clinical study. In addition, many administrative activities cannot be attributed to specific patients and can therefore not be compensated on the basis of case payments alone. Additional remuneration is required to fully cover the costs in an ophthalmological study center.

Mitoxantrone-related acute leukemia in two MS patients.

We report two new cases of mitoxantrone-related leukemia occurring in two patients with multiple sclerosis (MS), 14 and 18 months after the last infusion of the drug. One patient was successfully treated. We were able to collect 29 other cases in the literature. Most of them were single reports but some were described within cohorts of mitoxantrone-treated MS patients. The incidence rate was 0.65% from all cohorts totalizing 2299 patients. Acute promyelocytic leukemia with the translocation t(15;17) was over-represented in the MS population in comparison with cancer patients also treated with mitoxanrone. The occurrence of leukemia was dose-independent and appeared with a mean delay of 20 months after the end of the treatment.

[Retinal artery occlusion]. / Retinaler Arterienverschluss.

Retinal artery occlusion leads to profound visual impairment in the affected eye. It is rarely caused by local ophthalmic pathologies. Most patients present with a large number of cardio- and cerebrovascular risk factors. Visual loss is the leading symptom in central retinal artery occlusion (CRAO), whereas a circumscribed visual field defect is claimed in branch retinal artery occlusion (BRAO). Although many attempts have been made to improve the course of the disease, no effective therapy is available. There is some hope that intravenous fibrinolysis could influence the natural course but the therapeutic window is small (ca. 4.5 h), and treatment efficacy is still not proven. It is important for ophthalmologists to guide the patients to a comprehensive and prompt neurological and cardiological diagnostic work-up.

[Intraoperative optical coherence tomography in retinal detachment]. / Intraoperative optische Kohärenztomographie bei Ablatio retinae.

BACKGROUND: Using intraoperative optical coherence tomography (iOCT) can be advantageous during macular surgery and lamellar keratoplasty. It is yet unknown if there is a distinct benefit in its application in retinal detachment surgery. OBJECTIVE: What can be shown using iOCT during retinal detachment surgery? Can therapeutically relevant decisions be made and do they have a prognostic implication on postoperative results? METHODS: Based on already published (11 patients/eyes) and our own new data (23 patients/eyes),findings by iOCT during retinal detachment surgery are presented. RESULTS: Outer retinal corrugations are a frequent feature in iOCT in retinal detachment. These corrugations persist during the application of heavy liquids. Even when the retina seems clinically reattached under the use of perfluoroctane, there is significant subfoveal fluid. Using perfluordecaline, there seems to be less subfoveal fluid. In patients with retinal detachment and macula off situation, subclinical full thickness macular holes seem to be more common than assumed. It is unclear if their incidence is influenced by the use of heavy liquids. They appear to have a negative predictive value regarding postoperative visual acuity. CONCLUSION: Even if there are no obvious benefits in using iOCT in retinal detachment surgery, this new technique offers deeper insights into the microarchitecture of the detached retina. Further investigations in more patients will show if the use of the iOCT will result in a better prognosis for our patients.

[Intraoperative real-time OCT in macular surgery]. / Intraoperative Echtzeit-OCT in der Makulachirurgie.

BACKGROUND: Spectral domain optical coherence tomography (SD-OCT) has become a standard diagnostic tool in the surgical management of vitreomacular interface disorders. The high-resolution cross-sectional information obtained from SD-OCT is a perfect complement to vitreoretinal surgery. It provides detailed intraoperative anatomical views that are not possible with a microscope. OBJECTIVE: To investigate the value of intraoperative real-time OCT with respect to improvement of surgical techniques in the management of vitreomacular disorders. METHODS: A review of the current literature was conducted and an analysis of own systematically evaluated data was included to provide a comprehensive overview of potential applications for the clinical use of intraoperative real-time OCT in macular surgery. RESULTS: Intraoperative real-time OCT can provide detailed visualization of epiretinal membranes and help to identify whether complete membrane removal has been achieved following surgery. In addition, it can provide qualitative and quantitative information that has previously not been available and assist in surgical decision-making. Intraoperative real-time OCT allows membrane peeling to be performed in selected cases without using retinal dyes, whereas it is not ideal for accurately guiding the surgeon while performing maneuvers. CONCLUSION: Intraoperative real-time OCT provides high-resolution visualization of the effects of surgical maneuvers on the microarchitecture of the retina and surrounding tissues and will fill a gap in the understanding of the pathophysiology and prognostic factors of vitreomacular disorders; however, with currently available systems, accurate intraoperative real-time guidance of surgical maneuvers is hindered by several limiting factors.

[Retinal vein occlusion : Epidemiology, classification and clinical findings]. / Retinaler Venenverschluss : Epidemiologie, Einteilung und klinische Befunde.

Since the introduction of intravitreal operative medication injections (IVOM), the therapy of retinal vein occlusion (RVO) has permanently changed. The growing acceptance of IVOM is undoubtedly due to the generally positive outcome after RVO. During the pharmaceutical trials required to obtain medication approval, extensive data were collected on the spontaneous course of the disease and the risk factors responsible for the disease. As RVO is a complication of systemic or local risk factors, these data are also useful for the therapy of the underlying risk factors. In this article the currently available data are presented and evaluated to provide the reader with key guidelines to diagnose and treat this complex syndrome.

[Retinal vein occlusion: Therapy of retinal vein occlusion]. / Retinaler Venenverschluss : Therapie des retinalen Venenverschlusses.

Treatment of retinal vein occlusion can be systemic or local. Therapeutic strategies include improved blood supply, treatment of the vision-reducing macular edema by intravitreal injection of inhibitors of vascular endothelial growth factors (VEGF) or corticosteroids and laser photocoagulation for neovascular complications. As long as head-to-head studies comparing steroids and VEGF inhibitors have not been published, none of the available intravitreally injected substances can be given priority. Well-known side effects of intravitreal steroids are cataract formation and ocular hypertension whereas VEGF inhibitors need to be frequently injected. Although therapy for retinal vein occlusion is protracted, initial long-term data indicate that treatment can be terminated in at least half of the patients . Finally, a treatment recommendation according to the current state of data is presented.

Switch of anti-VEGF agents is an option for nonresponders in the treatment of AMD.

BACKGROUND: Although anti-VEGF therapy of exudative AMD with bevacizumab and ranibizumab proved efficacious in the majority of patients, CNV activity does not respond to continued treatment after repeated injections in a considerable amount of patients. These are referred to as nonresponders. A change of the drug to bevacizumab or ranibizumab could possibly offer an alternative option for the treatment of nonresponding exudative AMD. METHODS AND MATERIALS: A total of 138 nonresponders who switched therapy from bevacizumab to ranibizumab (n=114) or vice versa (n=24) were included in a retrospective study. Visual acuity (VA) and foveal thickness before and after the switch of therapy were compared. By means of linear regression analysis, we analyzed possible prognostic factors associated with a favorable outcome for visual acuity. RESULTS: Linear regression analysis revealed a statistically significant benefit for nonresponders when treatment was changed to a different anti-VEGF drug (bevacizumab or ranibizumab). VA at the time of the switch was positively correlated with a beneficial development of VA after changing the drug. There was no significant correlation with age, macular thickness, number of injections before the switch, or the development of VA under treatment before the switch. Both patients switching to Avastin and Lucentis benefitted without statistically significant differences. CONCLUSIONS: An exchange of bevacizumab with ranibizumab or vice versa should be considered in nonresponders in the treatment of exudative AMD. Further prognostic factors may help to identify patients who might benefit from a switch. These factors should be investigated in further studies.

[Ocular ischemic syndrome]. / Okuläres Ischämiesyndrom.

Ocular ischemic syndrome (OIS) is a group of ocular diseases caused by chronic artery occlusion usually involving the internal carotid artery. Patients suffer from visual loss and pain. OIS is a rare disease which can be confounded with diabetic retinopathy or an older central retinal vein occlusion. The only therapy is to treat the neovascular complications. Due to the high mortality of OIS patients, medical and neurological examinations are mandatory. We discuss the clinical findings and diagnostic and therapeutic options of OIS patients in this paper.

[Perioperative conversion of oral anticoagulants to heparin (bridging) in ophthalmic medicine]. / Perioperative Umstellung von oralen Antikoagulanzien auf Heparin in der Augenheilkunde (Bridging).

Since topical anesthesia was introduced in ophthalmic surgery, anticoagulation therapy can often be used in patients with thromboembolic risk. But some surgical procedures with an increased risk for intraoperative bleeding necessitate changing a patient's Coumadin therapy to heparin. To reduce intraoperative bleeding and perioperative thromboembolic complications, ophthalmologists and referring general practitioners should cooperate closely.