Ahmed Souka

Predicting outcomes to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular oedema: a review of the literature

Diabetic macular oedema affects visual acuity to a varying degree. The current treatment of choice is intravitreal anti-vascular endothelial growth factor (VEGF) that has proven both its anatomical and visual efficacy in several large randomised clinical trials (RCTs). Although most patients respond well to anti-VEGF agents, some, however, show a moderate or even poor response. There is no clear consensus as to how to manage these patients, or define them. In addition, identifying early in the course of treatment which patients will respond and which patients will not is paramount to any personalised treatment regimen. Most large RCTs such as RESTORE and Protocol I have attempted post hoc analyses to identify demographic, clinical, optical coherence tomography (OCT) and fluorescein angiography findings that might predict patient response. Although some factors were found to be predictive, the lack of uniformity between the different RCTs means that no consensus exists as to which of these factors can be reliably used. This review looks at the large diabetic macular oedema RCTs such as RESTORE, Protocol I, READ-2 and BOLT in an attempt to identify common prognostic indicators between the various studies. We also attempted to look at several other OCT parameters such as the inner segment-outer segment (IS-OS) layer, the external limiting membrane layer, and choroidal thickness to help determine whether they can truly predict visual outcomes in patients being treated with anti-VEGF therapy. Finally, we provide a simplified summary about which factors might be relevant in clinical practice to help guide physicians in treatment decisions.

Three-month outcomes of ziv-aflibercept in the treatment of diabetic macular oedema

Editor, S everal recent publications have indicated the safety of intravitreal ziv-aflibercept (Zaltrap, Sanofi-Aventis US, LLC, Bridgewater, New Jersey, USA), a drug FDA approved for cancer therapy, for the treatment of age-related macular degeneration (AMD) (Chhablani et al. 2015; Mansour et al. 2015). However, the data have been lacking for diabetic macular oedema with data for only two cases of refractory oedema being reported byMansour et al. (2015). We conducted a retrospective review of 14 eyes of 10 patients with na€ıve diabetic macular oedema injected with 0.05 ml (1.25 mg) of ziv-aflibercept. Patients were treated using a pro re nata treatment protocol with visual acuity (VA) and optical coherence tomography (OCT) measurements (Heidelberg Spectralis) at each monthly visit. Injections were deferred if patient had no signs of fluid on OCT and/or a visual acuity of 6/6 on the Snellen chart. Primary outcomes were central macular thickness and visual acuity after 3 months. Secondary outcomes were the presence of any local or systemic safety issues after 3 months of follow-up. The study included two males and eight females, with a mean age of 51.7 6.2 and follow-up period of 3 months. At 3 months (Table 1), visual acuity improved significantly from a baseline median of 0.79 logMAR (approximately 0.16 decimals) to 0.3 logMAR (approximately 0.5 decimals) (p = 0.013). There was a statistically significant decrease in central macular thickness (CMT) from a median of 394 lm to a median thickness of 293 lm (p = 0.001). Eight of the 14 eyes achieved a CMT <300 lm after 3 months of therapy with a mean number of injections of 2.4. In addition, 57% of patients had a visual acuity of ≥6/12 after 3 months of treatment. Approximately, 43% (6/14 eyes) of eyes did not receive an injection at 2 months because of the absence of any fluid. After 3 months of therapy, there were no signs of intraocular inflammation, infection, elevated intraocular pressure or signs of retinal toxicity on any of the follow-up visits. Both aflibercept and ziv-aflibercept contain the same fusion protein, but there are differences in osmolarity with aflibercept being an iso-osmotic solution (300 mOsm/kg), whereas ziv-aflibercept is more concentrated (1000 mOsm/kg). In addition, the 0.05 ml dose used in ziv-aflibercept contains only 1.25 mg compared to 2.0 mg in aflibercept. Several animals and in vitro studies have shown the relative safety of ziv-aflibercept for intravitreal use (Dias et al. 2014; Malik et al. 2014). In addition, two recent prospective studies have been published highlighting the safety of intravitreal ziv-aflibercept in different macular diseases (Chhablani et al. 2015; Mansour et al. 2015; de Oliveira Dias et al. 2015). Our data would seem to support the fact that ziv-aflibercept is safe as an intravitreal injection even in treatment na€ıve diabetic eyes. In addition, our data also show the efficacyof ziv-aflibercept in the treatment of diabeticmacular oedemawithapproximately 2/3 of patients achieving CMT <300 lm and showing a significant improvement in vision. Although the results would seem to be very impressive, more studies comparing between this drug with aflibercept itself and other anti-VEGF agents such as bevacizumab and ranibizumab are needed. It would seem, however, that ziv-aflibercept does seem to be an effective and cheap option for the treatment of diabetic macular oedema and may provide an alternative option tobevacizumab in thenear future.

Short-Term Effects of Early Switching to Ranibizumab or Aflibercept in Diabetic Macular Edema Cases With Non-Response to Bevacizumab

BACKGROUND AND OBJECTIVES To study the effect of early switching to ranibizumab (Lucentis; Genentech, South San Francisco, CA) or aflibercept (Eylea; Regeneron, Tarrytown, NY) in cases of diabetic macular edema (DME) that have shown no response to bevacizumab (Avastin; Genentech, South San Francisco, CA). PATIENTS AND METHODS A retrospective study involving 59 eyes of 45 patients with DME previously treated with bevacizumab. Patients were switched either to ranibizumab or aflibercept. Detailed ophthalmological examination, best-corrected visual acuity (BCVA), and optical coherence tomography (Spectralis; Heidelberg Engineering, Heidelberg, Germany) were performed prior to and 1 month post-switch. RESULTS Fifty-nine eyes of 45 patients were included in the study, of whom 14 patients (17 eyes) were switched to aflibercept and 31 patients (42 eyes) were switched to ranibizumab. Post-switch, there was a statistically significant improvement in the BCVA in the combined group (aflibercept and ranibizumab), as well as in the ranibizumab group alone. In addition, there was a statistically significant decrease in the central subfield thickness (CST) in the combined group, as well as in the ranibizumab and aflibercept groups individually. There was no significant difference with regard to the change in macular thickness or BCVA between the aflibercept and ranibizumab groups. In addition, neither the pre-switch central macular thickness, previous number of injections, nor the pre-switch visual acuity affected the response to switching. CONCLUSION Aflibercept and ranibizumab both appear to be effective for patients showing no initial response to bevacizumab. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:230-236.].

Long-term safety and efficacy of ziv-aflibercept in retinal diseases

Aims To investigate the long-term safety of intravitreal ziv-aflibercept in eyes receiving six or more intravitreal injections of ziv-aflibercept, an off-label substitute to the approved aflibercept. Methods Consecutive patients with retinal disease receiving six or more of intravitreal 0.05 mL ziv-aflibercept (1.25 mg) injections were followed monthly in three centres. Outcome measures were best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution (logMar)) and central macular thickness (CMT) on spectral domain optical coherence tomography and monitoring for ocular inflammation, progression of lens opacities and intraocular pressure rise. Paired comparison was done using Wilcoxon signed-rank test calculator. Results Sixty-five eyes of 60 consecutive patients received a mean of 8.4 (6–17) intravitreal injections with a baseline mean logMAR BCVA of 0.98±0.56 and CMT 432.7±163.0 μm and followed for a mean of 9.2 months (range 6–18 months). After the sixth injection, mean BCVA improved to 0.57±0.36 (p=0.001) and CMT decreased to 274.8±117.8 μm (p=0.0001). At the 9-month follow-up, mean BCVA improved to 0.62±0.37 (p=0.0004) and mean CMT decreased to 292.0±160.9 μm (p<0.01) in 19 eyes. At 1 year, mean BCVA was 0.73±0.52 and CMT 311.6±232.5 μm in seven eyes. Intraocular pressures did not increase after injections. One subject developed transient mild iritis at the fourth injection but not on subsequent injections. No lens opacity progression or endophthalmitis was noted. Systemic adverse effects were not registered. Conclusions Repeated intravitreal injections of ziv-aflibercept appear tolerable, safe and efficacious in the therapy of retinal disease.

Comparison between the short-term outcomes of bevacizumab and ziv-aflibercept in the treatment of primary diabetic macular oedema

non-affected fellow eyes of CSC patients showed a significantly higher mean FDfov (35.66% 4.02%; 36.09% 4.77%) in the superficial plexus compared to healthy controls (32.22% 3.94%). In addition, the FAZ was significantly smaller in CSC patients compared to healthy controls in the superficial plexus (CSC eyes affected, non-affected fellow eyes, controls: 0.15 0.07 mm; 0.15 0.07 mm; 0.21 0.06 mm; Fig. 1). We hypothesize that the decrease in the FAZ and the increase in flow in eyes of CSC patients may be interpreted as a reaction to pathological changes due to CSC such as accumulation of SRF. Continuous SRF impedes nourishment of the photoreceptor layer from the choriocapillaris and may stimulate an increase in retinal flow density (Eperon et al. 1975). Second, in contrast to many other macular diseases with accumulated SRF, the inner blood retina barrier is presumably not affected by CSC pathology and may be capable of inducing regulatory mechanisms such as vasodilatation to resorb SRF. With regards to the affected eye, the findings in the fellow eyes of CSC patients suggest that such compensatory changes in the retinal vessels may be centrally induced. Another explanation might be that clinically non-affected fellow eyes are in fact affected by the disease, however, changes are not yet accessible to current imaging methods. Optical coherence tomography angiography is a nascent technology, yet, experience and data on clinical image interpretation in CSC is growing (Costanzo et al. 2015; Teussink et al. 2015). Obviously, this preliminary study is also limited by the small sample size. In conclusion, OCT-A reveals an increase in retinal flow density and a decrease in the FAZ in affected eyes as well as unaffected fellow eyes of CSC patients. This may be interpreted as an adaptation of foveal retinal vessels in response to pathological CSC changes such as perfusion changes in the choriocapillaris, disintegrity of the RPE and subsequent accumulation of SRF.

Two-year outcomes of intravitreal ziv-aflibercept

Aim To assess the two-year outcome of intravitreal ziv-aflibercept (IVZ) in eyes with macular diseases. Methods Consecutive subjects with various macular diseases that received six or more of 0.05 mL IVZ (1.25 mg) injections with at least 1 year follow-up were included. Outcome measures were best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution) and central macular thickness (CMT) on spectral domain optical coherence tomography. Paired comparison was done using Wilcoxon signed-rank test calculator. Results 107 eyes of 91 subjects received IVZ and were followed with mean±SD follow-up interval of 1.48±0.44 months following treat and extend or pro-re-nata protocol. The distribution included neovascular macular degeneration (42 eyes), diabetic macular oedema (32 eyes) and macular oedema secondary to retinal vein occlusion (11 eyes). Fifty eyes were naive, while 57 eyes were previously treated. Combining all disease categories, CMT decreased significantly by 133.0±153.0 µm at the 24-month follow-up (P<0.001) with BCVA gain of 0.35±0.37 at the 24-month follow-up (P<0.001) with mean number of injections of 8.5 at month 12, 2.4 between 12 and 18 month and 1.7 between 18 and 24 month. Ocular and systemic adverse effects included one episode of transient uveitis and one instance of central retinal artery occlusion after 1121 injections. Conclusions IVZ appears safe and efficacious in the therapy of macular diseases through 2 years.

Safety and Efficacy of Ziv-Aflibercept in the Treatment of Refractory Diabetic Macular Edema

BACKGROUND AND OBJECTIVE To evaluate the safety and efficacy of ziv-aflibercept (Zaltrap; Sanofi-Aventis, Bridgewater, NJ/Regeneron Pharmaceuticals, Tarrytown, NY) in the treatment of refractory diabetic macular edema (DME). PATIENTS AND METHODS Retrospective case series looking at the safety of ziv-aflibercept in patients with DME refractory to previous anti-vascular endothelial growth factor (VEGF) therapy. Detailed ophthalmologic examination, best-corrected visual acuity, and optical coherence tomography measurements were performed pre-switch, as well as at each monthly follow-up visit. RESULTS The study included 34 eyes of 26 patients. The mean number of ziv-aflibercept injections post-switch was 2.03 injections. Visual acuity improved from a mean of 0.63 logMAR pre-switch to 0.51 logMAR after the first visit and 0.46 logMAR after the second visit post-switch (P < .084). Macular thickness improved from a mean of 513.79 μm to 411.79 μm (P = .006) on the first visit and 426.76 μm (P = .029) after the second visit post-switch. No adverse ocular or systemic side effects were reported on any of the follow visits. CONCLUSION Ziv-aflibercept appears to be safe and effective in patients with refractory DME previously treated with other anti-VEGF agents in the short term. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:399-405.].

Steroids in Central Retinal Vein Occlusion: Is There a Role in Current Treatment Practice?

With the current widespread use of anti-VEGFs in the treatment of central retinal vein occlusion (CRVO), the role for steroids has become greatly diminished. Recent large scale randomized control trials (RCTs) have established the efficacy and safety of anti-VEGFs in the treatment of CRVO. Steroids are known to cause elevations in intraocular pressure as well as increase the risk of cataract formation. With that in mind many ophthalmologists are injecting steroids less frequently. This paper aims to review some of the data pertaining to the use of steroids either as a first line monotherapy, adjunct therapy, or an alternative therapy to help answer the question: Is there currently any role for steroids in the management of CRVO?

Safety of 5914 intravitreal ziv-aflibercept injections

Purpose To analyse the pooled safety data of intravitreal ziv-aflibercept (IVZ) therapy for various retinal conditions. Methods This was a retrospective, observational study which included patients from 14 participating centres who received IVZ. The medical records of patients who received IVZ from March 2015 through October 2017 were evaluated. Patient demographics and ocular details were compiled. Ocular and systemic adverse events that occurred within 1 month of IVZ injections were recorded and defined as either procedure-related or drug-related. Results A total of 1704 eyes of 1562 patients received 5914 IVZ injections (mean±SD: 3.73±3.94) during a period of 2.5 years. The age of patients was 60.6±12.8 years (mean±SD) and included diverse chorioretinal pathologies. Both ocular (one case of endophthalmitis, three cases of intraocular inflammation, and one case each of conjunctival thinning/necrosis and scleral nodule) and systemic adverse events (two cases of myocardial infarction, one case of stroke and two deaths) were infrequent. Conclusion This constitutes the largest pooled safety report on IVZ use and includes patients from 14 centres distributed across the globe. It shows that IVZ has an acceptable ocular and systemic safety profile with incidences of adverse events similar to those of other vascular endothelial growth factor inhibitory drugs. The analysis supports the continued use of IVZ in various retinal disorders.

Age-related macular degeneration: using morphological predictors to modify current treatment protocols

To assess predictors of treatment response in neovascular age‐related macular degeneration (AMD) in an attempt to develop a patient‐centric treatment algorithm. We conducted a systematic search using PubMed, EMBASE and Web of Science for prognostic indicators/predictive factors with the key words: ‘age related macular degeneration’, ‘neovascular AMD’, ‘choroidal neovascular membrane (CNV)’, ‘anti‐vascular endothelial growth factor (anti‐VEGF)’, ‘aflibercept’, ‘ranibizumab’, ‘bevacizumab’, ‘randomized clinical trials’, ‘post‐hoc’, ‘prognostic’, ‘predictive’, ‘response’ ‘injection frequency, ‘treat and extend (TAE), ‘pro re nata (PRN)’, ‘bi‐monthly’ and ‘quarterly’. We only included studies that had an adequate period of follow‐up (>1 year), a single predefined treatment regimen with a predetermined re‐injection criteria, an adequate number of patients, specific morphological [optical coherence tomography (OCT)] criteria that predicted final visual outcomes and injection frequency and did not include switching from one drug to the other. We were able to identify seven prospective studies and 16 retrospective studies meeting our inclusion criteria. There are several morphological and demographic prognostic indicators that can predict response to therapy in wet AMD. Smaller CNV size, subretinal fluid (SRF), retinal angiomatous proliferation (RAP) and response to therapy at 12 weeks (visual, angiographic or OCT) can all predict good visual outcomes in patients receiving anti‐VEGF therapy. Patients with larger CNV, older age, pigment epithelial detachment (PED), intraretinal cysts (IRC) and vitreomacular adhesion (VMA) achieved less visual gains. Patients having VMA/VMT required more intensive treatment with increased treatment frequency. Patients with both posterior vitreous detachment (PVD) and SRF require infrequent injections. Patients with PED are prone to recurrences of fluid activity with a reduction in visual acuity (VA). A regimen that involves less intensive therapy and extended follow‐up intervals (4 weekly) can be suggested for patients who show adequate visual response and have both SRF and PVD at baseline. In addition, patients with poor prognostic indicators such as IRC, VMA, large CNV size, older age and poor response at 12 weeks should be extended very cautiously with the possibility of fixed monthly/bimonthly (every 2 months) treatments if they fail to achieve dryness. Patients with PED at baseline should receive monthly/bimonthly injections of anti‐VEGF therapy or can be extended very cautiously (two weekly intervals) using a TAE protocol.