In our pilot study, intravitreal injection of pegaptanib did not significantly alter the size of the FAZ in participants with varying degrees of ischemia and DME. In addition, it did not lead to an overall statistically significant improvement in BCVA or CST. However, some patients showed significant benefit similar to that reported in the Phase II/III Macugen for DME study, and there was a statistically significant improvement in BCVA for those who completed the treatment course. These findings suggest that it might be rea- sonable to consider treating patients with ischemic DME with pegaptanib, despite the fact that it is not currently approved for the treatment of DME. For those who do not respond to pegaptanib, other anti-VEGF-A agents might be considered, bearing in mind that some of the anti-VEGF-A agents have approval for the treatment of DME. Our study population
The primary endpoint was the incidence of ocular and non- ocular adverse events (AEs), defined as any untoward medical occurrence not necessarily having a causal relationship with the treatment. One secondary endpoint was the incidence of ocular and nonocular serious AEs, defined as any AE resulting in, but not limited to, death, is life-threatening, hospitaliza- tion, persistent disability, or congenital anomaly. All observed and reported AEs were recorded using Medical Dictionary for Regulatory Activities (MedDRA) version 15.0 through- out the study. Other secondary endpoints included the mean number of injections per patient and efficacy of treatment as evaluated by change in BCVA from baseline to end of treat- ment. BCVA was measured using retroilluminated modified Ferris-Bailey Early TreatmentDiabetic Retinopathy Study charts starting at 4 m. Complete ophthalmological examina- tions (including slit-lamp biomicroscopy, ophthalmoscopy, tonometry, BCVA measurements, and fundus examinations) were performed at screening, baseline, each treatment visit, and at follow-up. Applanation tonometry was performed for all patients at screening and to verify postinjection intraocular pressures 30 mmHg lasting for 30 minutes post injection or for a reading of 30 mmHg at any other time.
An increase in IOP is mostly seen 45 to 60 days following intravitreal injection of DEX implant. However, a check for perfusion of the optic nerve head is advised immediately after the injection and tonometry should be performed within 30 min following the application. Regular monitoring of IOP is required afterward, and any elevation needs proper man- agement. Increases in IOP are not typically observed at the safety visits within 3 weeks after DEX implant treatment. The MEAD study revealed that both mean IOP and the prevalence of IOP elevations were highest at 1.5 to 3 months after injection. These results suggested the need for a follow- up visit at 6 to 8 weeks postinjection, and IOP mostly returned to baseline levels by 6 months after injection. 99 According to data from the SAFODEX study, which mon- itored IOP increase in eyes treated with DEX implant due to macularedema of various origin, there was a small percen- tage of patients in whom the IOP increase already occurred at 8 days and 1 month. A small percentage of late responders has also been reported in which the ﬁ rst increase in IOP was diagnosed at the third injection or later. 100
On comparing the results of the outcome measures for each pair of drugs, we found that there was a significant dif- ference in the maintained improvement in visual acuity and the decrease in the CMT at week 12 on using IVB alone or combined with IVT. While this significant difference was not observed with IVT alone, this confirms the better and maintained effect of IVB over IVT in the treatment of DME without additional benefit of combining IVT to IVB.
The corticosteroid ﬂ uocinolone acetonide (FAc) is avail- able as a sterile, non-biodegradable, intravitreal implant (Iluvien®; Alimera Sciences, Inc., Alpharetta, GA, USA) con- taining 0.19 mg FAc, which is delivered over 36 months at a rate of 0.2 μ g/day, 18 reducing the need for repeat injections. 4 The FAc implant is indicated in the US for the treatment of DME in eyes previously treated with a course of corticoster- oids without a clinically signi ﬁ cant rise in IOP. 18 In trials in eyes with DME that had prior laser photocoagulation, the 0.19 mg implant signi ﬁ cantly improved best-corrected visual acuity from as early as 3 weeks after injection, which was sustained for up to 2 years, and signi ﬁ cantly reduced foveal
Results: Central foveal volume and visual acuity mean difference before and after intra-vitral anti-VEGF injection in both groups was significant. There were no significant mean differences in central macular thickness in case groups. Comparing the mean between two groups did not show a significant difference in visual acuity, central foveal volume ( P -value: 0.69) and central macular thickness ( P - value: 0.62). There were no significant differences in the desired changes pattern of DME between two groups ( P -value: 1.00). Conclusion: This pilot study did not show any additive positive effect of RIPC on retinal outcomes especially visual acuity in T2DM patients with DME who were received anti-VEGF treatment. Keywords: Ischemic preconditioning, Type 2 diabetes mellitus, Macularedema, anti-VEGF
either ranibizumab 0.5 mg, ranibizumab 0.5 mg plus laser, or laser alone. For patients receiving ranibizumab, after two mandatory injections, patients were reinjected on a prn basis according to vision stability and OCT findings. No further injections were given if vision was stable for two consecutive visits or at 20/20. For the laser group, laser therapy was given every 3 months on a prn basis. Results showed that treatment with ranibizumab both as monotherapy or combined treatment were significantly better than laser monotherapy in terms of VA functionally and OCT findings anatomically. At 1 year, the mean average change in VA from baseline was + 6.1, + 5.9, and + 0.8 for the ranibizumab monotherapy, ranibizumab plus laser, and laser groups, respectively. Anatomically, the mean CRT decreased by 118.7 μ m, 128.3 μ m, and 61.3 μ m for the ranibizumab, combined, and laser groups, respectively. Patients received a mean of seven injections throughout the 12 months. No significant difference was observed in terms of efficacy between the ranibizumab monotherapy group and the combined ranibizumab and laser groups. Repeated intravitreal injection of ranibizumab was found to be safe with no cases of endophthalmitis. No ocular severe adverse event was observed in the ranibizumab arm, with only one case of increased intraocular pressure, which resolved spontaneously. The pooled incidence of endophthalmitis in the RESOLVE and RESTORE trials was 1.4%, which was similar to the AMD trials. Ranibizumab was not found to be associated with increased risk of cerebrovascular or cardiovascular events in DME patients over 12 months in the study.
This study demonstrates that three months after the intra- vitreal injection of TA and the subtenon injection of TA there is a statistically significant improvement in visual acuity and an equally significant reduction in retinal thickness. Six months after IVT the patients presented a recurrence of macularedema with loss of visual acuity whereas six months after SBT injection retinal thickness and visual acuity remained stable. After one, three and six months we observed a statistically significant rise of the IOP in the eyes treated with IVT injection whereas in the SBT injection group, no statistically significant variations of the IOP were found. None of patients developed cata- ract or needed anti-glaucoma drugs during the follow-up. Macularedema is the main cause of loss of visual acuity in diabetic patients [13,14]. It may occur at any stage of the retinal disorder and is the most common cause of sight reductions in these subjects.
The present study showed that after 6 months, there was no beneficial effect of intravitreal bevacizumab for DME with subfoveal and perifoveal hard exudates in terms of visual acuity. Hard exudates increased in extent and tended to move to the foveal side, despite continuous injections. In addition to the short study period, the small number of enrolled patients is another limitation of this study. Further studies with a larger sample size and longer follow-up are required to confirm our study results as well as compare the efficacy of each and combined treatment modalities for this pattern of DME.
Since VEGF contributes to the development of macularedema, attention has recently focused on intravitreal injections of anti-VEGF antibodies. Antibodies delivered by intravitreal injection bind to VEGF and thereby decrease downstream effects on vascular leakage. Anti-VEGF antibodies were ﬁ rst used to treat patients with exudative age- related macular degeneration (AMD) with dramatic beneﬁ cial results. Because of these beneﬁ ts, anti-VEGF antibodies are now being evaluated in the treatment of macularedema.
Moreover, there was a significant correlation between the ΔVA-1d and ΔVA-1 m (Fig. 4), suggesting that it is possible to predict the BCVA 1 month after treatment by measuring the BCVA 1 day after IVR injection. Ma et al. reported that the FT 1 h after IVB injection signifi- cantly decreased compared with baseline and that a reduction in the FT 1 h after IVB was correlated signifi- cantly with the reduction in the central macular thick- ness 1 month after IVB injection in patients with both DME and macular oedema after branch retinal vein occlusion (BRVO) (total of 30 eyes). The authors specu- lated that the FT 1 month after treatment might be pre- dictable by measuring it a few hours after IVB injection .
Abstract: Diabetic retinopathy is the leading cause of blindness among individuals of working age in industrialized nations, with most of the vision loss resulting from diabeticmacularedema (DME). The formation of DME depends on the action of several growth factors and inflammatory mediators, but vascular endothelial growth factor (VEGF) appears to be critical for breaking down the blood-retinal barrier and promoting the accumulation of macularedema. Laser photocoagulation has been the standard-of-care for three decades, and although it stabilizes vision, significant gains in visual acuity after treatment are unusual. Several VEGF inhibitors (pegaptanib, aflibercept, and ranibizumab) have been initially developed and tested for the treatment of age-related macular degeneration and subsequently for DME. In Phase I, II, and III trials for DME, ranibizumab has been shown to be superior to macular laser photocoagulation and intraocular triamcinolone acetonide injections for improving visual acuity and drying the macula. As a result, ranibizumab is the only anti-VEGF drug that has been approved by the United States Food and Drug Administration for the treatment of DME. Most experts now consider intravitreal anti-VEGF therapy to be standard-of-care for DME involving the fovea.
Methods: In a randomized, double-masked multicenter trial, intravitrealpegaptanib (0.3, 1.0, or 3.0 mg/eye) was administered in patients with diabeticmacularedema every 6 weeks for 12–30 weeks. A one-compartment model with first-order absorption, distribution volume, and clearance was used to characterize the pegaptanib plasma concentration–time profile. Results: In 58 patients, increases in area under the concentration–time curve (AUC) to end of the dosing interval (AUC 0–tau ) and maximum concentration with repeat doses were 6%, indicating minimal plasma accumulation. Sex and race did not have clinically significant effects on pegaptanib exposure. In the final model, the AUC extrapolated to infinite time and maximum concentration increased by 50% in older patients (aged 68 years) relative to younger patients due to decreases in creatinine clearance (CRCL), a significant predictor of clearance. Pegaptanib clearance was reduced by 29% when CRCL decreased by 50%. The change in exposure with CRCL (range, 0–190 mL/minute) was 10-fold with 0.3–3.0 mg doses.
Inclusion criteria were a diagnosis of type 1 or 2 dia- betes and center-involved DME treated with one or more intravitreal DEX implants and followed up for at least 6 months and a BCVA ≥30 and ≤ 80 letters [Early TreatmentDiabetic Retinopathy Study (ETDRS) charts]. Patients with ME secondary to a cause other than dia- betes mellitus, macular ischemia, a history of vitrectomy, intraocular surgery in the previous 6 months, a history of systemic corticosteroids within 6 months before base- line evaluation, uveitis, glaucoma or ocular hypertension, dense cataract, and those lost to follow-up were ex- cluded from the study. Patients with macular ischemia were excluded for their poor prognosis, which might dis- tort the results.
The pathogenesis of PCME is likely multifactorial, but inflammation appears to be the major reason. It is widely accepted that the purpose of anti-inflammatory treatment is to not only treat but also prevent the development of PCME. Topical nonsteroidal anti-inflammatory drugs are commonly used in the perioperative period of cataract surgery, but not all patients are sensitive to them. Corticosteroids have excel- lent anti-inflammatory properties and a synergistic effect when combined with nonsteroidal anti-inflammatory drugs. Triamcinolone acetonide (TA) is an anti-inflammatory drug and immunomodulator used in a variety of ocular diseases. Previous studies have suggested that intravitreal TA (IVTA) is efficacious in the treatment of refractory PCME. 5–7 However,
Two different pharmaceutical triamcinolone acetonide products were used, depending on availability: preserva- tive-free Aurocort (Aurolab, Veerapanjan, India), intend- ed for intravitreal use; or Kenalog (Bristol-Myers Squibb, Anagni, Italy), used off label. In both cases, the drug vol- ume was minimized by eliminating the solvent after di- viding the ampule in half and centrifuging the drug.
Abstract: Diabeticmacularedema (DME) has shown an increasing prevalence during the past years and is the leading cause of diabetic retinopathy blindness. Traditional treatment modalities include laser and corticosteroid therapy, which, however, either act through unclear mechanisms or cause cataracts and elevated intraocular pressure. In recent years, as the pathogenic role of VEGF in DME has been well-recognized, the intravitreal injection of anti-VEGF drugs has become the first-line treatment of DME due to their great efficacy in improving visual acuity and mitigating macularedema. Advantages have been shown for aflibercept and conbercept, the two recombinant decoy receptors that can bind VEGF with high specificity and affinity, in DME treatment in clinical trials conducted both worldwide and in People’s Republic of China. This review introduces the structural characteristics and molecular mechanisms of action of these two anti-VEGF drugs, and summarizes the clinical trials evaluating their efficacy and safety, with the hope to provide clues for designing optimal and personalized therapeutic regimens for DME patients.
tion of exudates and edema in these refractory cases was remarkable. Although the previous laser treatments might have had some beneficial effect, this may have been counter- acted by persistent vitreoretinal traction, on which laser treat- ment alone would have had no significant influence. Apart from relief of traction, induction of a PVD may also confer a secondary beneficial effect in increasing retinal oxygenation derived from the fluid phase between the neuroretina and the PHF. An increase in oxygen tension within the inner retina could have a mitigating effect on macularedema by a number of mechanisms: reduced VEGF production caus- ing decreased retinal vascular permeability; autoregulatory arteriolar vasoconstriction reducing hydrostatic pressure in capillaries and venules. There will be in turn decreased extravascular fluid flow (the Starling equation) and reduced edema formation. 18
Abstract: Diabeticmacularedema (DME) remains one of the leading causes of moderate to severe vision loss. Although laser photocoagulation was the standard of care for several years, few patients achieved significant improvements in visual acuity. As a result, several pharmacotherapies and surgeries have been investigated. The fluocinolone acetonide devices are one of the latest therapies considered for the treatment of DME. Despite bringing significant improvements in visual acuity, fluocinolone devices are associated with cataract formation, increased intraocular pressure (IOP), and surgery to lower IOP. Due to the risk of complica- tions, fluocinolone acetonide devices should be considered only in cases refractive to first-line therapies. In this review, we evaluate current and emerging therapies for DME, with special emphasis on fluocinolone acetonide intravitreal devices.
A total of 70 eyes of 42 diabetic patients were included in this prospective randomized study. The study was approved by the ethical committee of the Mitghamr Lasik and Eye Center (approval number 212015), and all patients provided written informed consent to participate according to the tenets of the Declaration of Helsinki. The patients were randomly divided into two groups; patients in group I (35 eyes) were treated with intravitreal aflibercept injection and patients in group II (35 eyes) were treated with intravitreal ranibizumab injection.