S. Michels

Promising new treatments for neovascular age-related macular degeneration.

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.

Anecortave acetate for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration

Purpose Anecortave acetate is a novel angiostatic cortisene being evaluated clinically for treatment of exudative age-related macular degeneration (ARMD). A randomized, placebo-controlled, efficacy and safety dose duration study of anecortave acetate for depot suspension (3 mg, 15 mg, 30 mg) in this patient population was completed in June 2003. As part of this trial, 128 patients with subfoveal choroidal neovascularization (CNV) secondary to ARMD were enrolled and treated for up to 2 years by 18 clinical sites in the United States and European Union. Methods Study patients were evaluated clinically with detailed ophthalmic examinations, general physical examinations, assessments of best-corrected logMAR visual acuity, and angiographic evaluations. The Digital Angiography Reading Center (New York City, NY) assessed lesion eligibility while the clinical investigators assessed overall patient eligibility prior to treatment. As part of this study, study medication was delivered as a posterior juxtascleral depot using a specially designed curved cannula at 6-month intervals if in the masked investigators opinion the patients lesion could benefit from additional treatment. Results The 2-year efficacy results of this placebo-controlled study demonstrated that RE-TAANE 15 mg (anecortave acetate for depot suspension) was statistically superior to placebo for stabilization of vision (<3 logMAR line change from baseline) and for inhibition of neovascular lesion growth. There were no serious treatment-related safety issues associated with either the study medication or the procedure for administration. Conclusions Anecortave acetate 15 mg for depot suspension is clinically efficacious compared to placebo for treatment of subfoveal exudative ARMD lesions when administered at 6-month intervals as a posterior juxtascleral depot.

Intravitreales Bevacizumab vs. Verteporfin und intravitreales Triamcinolon Acetonid bei Patienten mit neovaskulärer AMD

AIM The aim of this study was to compare intravitreal bevacizumab (IVB) and verteporfin therapy in combination with 4 mg intravitreal triamcinolone (PDT-IVTA) in patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS A total of 30 eyes of 30 patients with neovascular AMD were included in a prospective, randomized study. Ten eyes received PDT-IVTA with a standard light fluence of 50 J/cm(2) (SPDT-IVTA), ten were treated with PDT-IVTA with a reduced light fluence of 25 J/cm(2) (RPDT-IVTA) and ten received IVB. The main outcome was evaluated using early treatment diabetic retinopathy study (ETDRS) visual acuity, fluorescein angiography and optical coherence tomography (OCT) at baseline as well as at day 1, week 1, 1 month and 3 months after therapy. RESULTS At the beginning of therapy, the distribution of the groups was balanced. After 3 months, the SPDT-IVTA group showed a non-significant vision loss of seven letters (p<0.3) while a vision loss of 0.5 letters (p<0.9) was found in the RPDT-IVTA group. At the same time, the IVB group had a vision improvement of 11.8 letters (p<0.001). This vision improvement was statistically significant compared to the results of both PDT-IVTA groups (p<0.005). Central retinal thickness (CRT) decreased up to month 3 in the SPDT-IVTA group by 132 microm, in the RPDT-IVTA group by 78 mum and in the IVB group by 138 microm, (p<0.05 in the three groups). No significant difference in the decrease of CRT was found between the treatment groups after 3 months. CONCLUSION IVB shows significantly better results in vision improvement in the short-term compared to the two PDT-IVTA groups. Within 3 months, all groups showed a comparable decrease in CRT. Long-term follow-up is required to evaluate the safety and treatment efficacy of all treatment modalities.

Systemisches und intravitreales Bevacizumab (Avastin®) bei neovaskulärer altersbezogener Makuladegeneration

SummaryA number of experimental and clinical studies have show the important role of the vascular endothelial growth factor (VEGF) in most neovascular and exudative ocular diseases. The therapeutic concept of an anti-VEGF therapy has been most promising in a number of prospective controlled clinical trials. In the treatment of neovascular age-related macular degeneration (AMD) intravitreal anti-VEGF therapy has shown not only to stabilize vision in most patients, but also to improve vision in a significant number of patients. Bevacizumab (Avastin®) is a monoclonal antibody designed to bind all isoforms of VEGF. It has been primarily developed for the systemic treatment of colon cancer in oncology. But several prospective and retrospective case series evaluating the use of systemic and intravitreal bevacizumab in neovascular AMD and other neovascular and exudative ocular diseases have shown most promising results. Despite the fact that results of large, prospective, long-term studies are currently unavailable, a number of studies have shown anatomic, functional and safety results up to 6 months similar to other anti-VEGF drugs. An approval of bevacizumab in ophthalmology by regulatory agencies cannot be expected in the near future. Similar to a number of drugs in clinical use, bevacizumab will remain available in ophthalmology only as off label treatment or in clinical trials. To clarify the role of bevacizumab for the treatment of a number of neovascular and exudative eye diseases, prospective long-term studies are necessary.ZusammenfassungDie wichtige Rolle des vaskulären endothelialen Wachstumsfaktors (VEGF) bei vielen neovaskulären und exsudativen Erkrankungen des Auges hat sich in den letzten Jahren in zahlreichen experimentellen und klinischen Studien herausgestellt. Das therapeutische Konzept der Anti-VEGF-Therapie zeigte sich in zahlreichen prospektiven, kontrollierten Studien mit unterschiedlichen Anti-VEGF-Präparaten als viel versprechend. Besonders bei der neovaskulären altersbezogenen Makuladegeneration (AMD) scheint es möglich geworden zu sein, nicht nur den Visusverlust zu verlangsamen, sondern in einem nicht unerheblichen Anteil der Patienten eine Visusverbesserung zu erreichen. Bevacizumab (Avastin®) ist ein monoklonaler Antikörper, der alle Isoformen des VEGF bindet. Er wurde primär für die systemische Therapie in der Onkologie entwickelt. Prospektive und retrospektive Fallserien zur systemischen und intravitrealen Anwendung von Bevacizumab bei der neovaskulären AMD aber auch bei anderen neovaskulären und exsudativen Erkrankungen des Auges haben sehr viel versprechende Ergebnisse bei insgesamt gutem Sicherheitsprofil gezeigt. Es ist jedoch nicht davon auszugehen, dass Bevacizumab in nächster Zukunft eine Zulassung für die Anwendung in der Augenheilkunde erhalten wird. Wie bei vielen anderen Präparaten in der Augenheilkunde wird die Behandlung mit Bevacizumab weiterhin nur off label oder in klinischen Studien möglich sein. Um die Rolle von Bevacizumab bei der Behandlung verschiedener Augenerkrankungen abschließend bewerten zu können, bleiben jedoch prospektive Langzeitstudien abzuwarten.

Intravitreales Bevacizumab vs. Verteporfin und intravitreales Triamcinolon Acetonid bei Patienten mit neovaskulärer AMD@@@Intravitreal bevacizumab versus verteporfin and intravitreal triamcinolone acetonide in patients with neovascular age-related macula degeneration

AIM The aim of this study was to compare intravitreal bevacizumab (IVB) and verteporfin therapy in combination with 4 mg intravitreal triamcinolone (PDT-IVTA) in patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS A total of 30 eyes of 30 patients with neovascular AMD were included in a prospective, randomized study. Ten eyes received PDT-IVTA with a standard light fluence of 50 J/cm(2) (SPDT-IVTA), ten were treated with PDT-IVTA with a reduced light fluence of 25 J/cm(2) (RPDT-IVTA) and ten received IVB. The main outcome was evaluated using early treatment diabetic retinopathy study (ETDRS) visual acuity, fluorescein angiography and optical coherence tomography (OCT) at baseline as well as at day 1, week 1, 1 month and 3 months after therapy. RESULTS At the beginning of therapy, the distribution of the groups was balanced. After 3 months, the SPDT-IVTA group showed a non-significant vision loss of seven letters (p<0.3) while a vision loss of 0.5 letters (p<0.9) was found in the RPDT-IVTA group. At the same time, the IVB group had a vision improvement of 11.8 letters (p<0.001). This vision improvement was statistically significant compared to the results of both PDT-IVTA groups (p<0.005). Central retinal thickness (CRT) decreased up to month 3 in the SPDT-IVTA group by 132 microm, in the RPDT-IVTA group by 78 mum and in the IVB group by 138 microm, (p<0.05 in the three groups). No significant difference in the decrease of CRT was found between the treatment groups after 3 months. CONCLUSION IVB shows significantly better results in vision improvement in the short-term compared to the two PDT-IVTA groups. Within 3 months, all groups showed a comparable decrease in CRT. Long-term follow-up is required to evaluate the safety and treatment efficacy of all treatment modalities.

Klinischer Einsatz eines intravitrealen Dexamethason-Implantats in der Behandlung des Makulaödems

ZusammenfassungProblemstellungDas Makulaödem ist die wesentliche Ursache für eine Visusverschlechterung nach Ast- und Zentralvenenverschlüssen (AVV, ZVV) oder bei der diabetischen Retinopathie (DRP). Die derzeitigen Therapieoptionen sind unbefriedigend oder noch nicht ausreichend untersucht. Steroide sind durch ihre gefäßabdichtenden Eigenschaften geeignet und intravitreale Injektionen (z. B. Triamcinolon) haben sich als erfolgversprechend erwiesen, müssen aber häufig wiederholt werden.Methoden und/oder PatientenPosurdex (Fa. Allergan) ist ein kleines biologisch abbaubares Polymer-Implantat (0,45 × 6,5 mm), das mittels Applikator über die Pars plana intravitreal injiziert wird, und über einen Zeitraum von 6 bis 12 Monaten wirksam sein soll (Dexamethason posterior segment drug delivery system, DEX PS DDS).ErgebnisseEine in den USA durchgeführte erste klinische Studie der Phase 2 zeigte nach 3 Monaten eine dosisabhängige Visusverbesserung und eine Abnahme der Netzhautdicke im OCT. Eine signifikante Wirksamkeit wurde bei Makulaödemen nach AVV, ZVV, DRP, Uveitis und nach Kataraktoperation gezeigt. An Komplikationen traten Augendruckanstiege und Glaskörperblutungen auf.SchlussfolgerungenEine langdauernde kontrollierte intravitreale Steroidwirkung stellt eine therapeutische Hoffnung für die Therapie des Makulaödems dar. Aus den ersten Ergebnissen kann auf eine sichere und effektive Anwendung geschlossen werden. Die klinische Bedeutung wird sich aus den Langzeitergebnissen ableiten lassen.SummaryPurposeMacular edema is the main cause for visual decline after branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO) or at diabetic retinopathy (DRP). Current therapeutic options are not yet satisfying. Intravitreal steroids (e. g. Triamcinolone acetate) are promising, but they have to be repeated often.Methods and patientsPosurdex (Allergan, Inc.) is a small biodegradable polymer-implant (0.45 × 6.5 mm), also called “dexamethasone posterior segment drug delivery system” (DEX PS DDS) and injected at pars plana with an injector intravitreally where it should be active 6 to 12 months. A phase 2 randomized multicenterstudy for treatment of macular edema due to different causes including 306 eyes in 3 groups (350 μg dexamethason, n = 100, 750 μg dexamethason, n = 101, control group, n = 105) has been finished after 6 months.ResultsThe first clinical trial showed dose dependent improvement of visual acuity and reduction of retinal thickness in OCT after 3 months of treatment. A significant potency could be observed at macular edema due to BRVO, CRVO, DRP, uveitis and after cataract surgery. Complications included rise of intraocular pressure and vitreal hemorrhage group. During observation period no other complications could be observed.ConclusionA prolonged controlled release of intravitreal steroids represents a promising therapeutic option for the treatment of macular edema. The first results of a phase 2 study represent a safe and effective treatment. Further evaluation is necessary to evaluate clinical feasibility and long term results.

Rolle der makulären Funktionsanalyse für die Bestimmung der Funktionsfähigkeit der Makula bei charakteristischen Makulapathologien

ZusammenfassungHintergrundAufgrund zunehmender Therapieoptionen für unterschiedliche Makulapathologien besteht ein zunehmendes Interesse an einer verlässlichen Bestimmung der Funktionsfähigkeit der Makula. Das Mikroperimeter 1 (MP 1, Nidek) ermöglicht eine fundusorientierte, zentrale Funktionsanalyse und verfugt zudem über eine automatische Schwellenbestimmung und eine automatische Fixationskorrektur („Eye Tracking“).Material und MethodeEs wurden prospektiv standardisierte Untersuchungen mittels makulärer Funktionsanalyse (Nidek MP 1) und optischer Kohärenztomographie (Stratus OCT) bei Patienten mit Makulaforamen und bei Patienten mit altersbedingter Makuladegeneration (AMD) sowie bei gesunden Probanden durchgeführt. Die anatomischen und funktioneilen Befunde wurden korreliert.Wir verwendeten für unsere Untersuchungen mit dem MP 1 Goldmann-III-Stimuli, eine 4-2-1-Strategie und eine unterschiedliche Anzahl von Stimuli (41–61).ErgebnisseAlle Patienten mit durchgreifendem Makulaforamen mit einem Durchmesser > 300 μm zeigten absolute Zentralskotome (ZS). In Augen mit durchgreifendem Makulaforamen mit einem Durchmesser < 300 um hatten 71,4% kein absolutes ZS. Alle durchgreifenden Makulaforamen wurden von einem relativen ZS umgeben. Eine beeinträchtigte Makulafunktion war bei Patienten mit AREDS IV-AMD feststellbar und es bestand eine Korrelation zwischen Unregelmä-ßigkeiten des retinalen Pigmentepithels und beeinträchtigter Makulafunktion. Bei einem Frühstadium einer choroidalen Neovaskularisation mit einem intakten Visus war bereits eine Beeinträchtigung der Funktion der Makula nachweisbar.SchlussfolgerungDie makuläre Funktionsprüfung mittels dem automatisierten MP 1 bietet eine präzise Bestimmung des Funktionsverlustes der Makula bei unterschiedlichen Krankheitsbildern.SummaryBackgroundAn increasing interest exists for a reliable determination of macular function. Determination of macular function provides an additional possibility for diagnostic and therapeutical process. Microperimeter 1 (MPI, Nidek) enables a fundus-orientated, central perimetry and has an automated system to control eye movements named “Eye Tracking”.Material and methodsProspective standardised examinations with Nidek MP 1 functional macular mapping and high resolution radial scans using Stratus OCT were performed in patients with macular holes and in patients with age-related macular degeneration as well as in healthy participants.Functional macular mapping was done using Goldmann III Stimuli, a 4-2-1 strategy and a different number of stimuli (41–61).ResultsAll eyes with macular holes > 300 urn diameter showed a central absolute scotoma. In eyes with macular holes < 300 um diameter 71.4% showed no central absolute scotoma. Eyes with a full-thickness macular hole were associated with a relative scotoma.In patients with AMD AREDS IV we found a diminished macular function as well as correlation between retinal pigment epithelium irregularities and diminished macular function. An impairment of macular function was observed in an early stage of a choroidal neovascularization with no visual impairment.ConclusionFunctional macular mapping provides additional information regarding functional loss in varying macular diseases.