3.3.2Intravitreal Pharmacotherapies

recovery. Steroids and anti-vascular endothelium growth factor (VEGF) agents are the two classes of intravitreal drugs under investigation and currently performed on the clinical practice.

3.3.2.1 Intravitreal Steroids

Steroids have been studied for a long time as a treatment option in DME, due to their anti-inflammatory properties. Several investigations highlighted the role of steroids in reducing inflammatory cytokines, VEGF expression, and leukostasis [62, 63]. There are different categories of steroids administered intravitreally, with different properties and duration of action. Nevertheless, the most frequent side effects reported from all types of steroids are the increasing of intraocular pressure and cataract progression.

Intravitreal triamcinolone acetonide (IVTA) has been used for a long time, and the data that emerged from small case series and randomized clinical trials showed in most of the cases some favorable response associated with increased risk of side effects [64–70]. An earlier randomized clinical trial (RCT), evaluating IVTA (4 mg) in refractory DME, showed a BCVA improvement in 56 % of treated eyes, compared to 26 % of untreated group, and an increased risk of cataract progression (respectively, 54 % versus 0 %) and rise in IOP, requiring topical medication (respectively, 44 % versus 3 % of the two groups) in a 2-year follow-up [69]. In another double-masked RCT, the effects of IVTA in refractory DME have been followed for 5 years, showing an improvement of 5 or more letters in 42 % of treated eyes, compared to 32 % of eyes initially treated with placebo and then switched to IVTA [71].

The Diabetic Retinopathy Clinical Research Network (DRCR.net) compared the safety and effectiveness of preservative-free IVTA to the standard care, focal/grid photocoagulation, for treatment of DME in a follow-up of 2 years and then extended at 3 years [72, 73] (Table 3.5). Patients were randomly assigned to three arms: laser photocoagulation (focal or grid), IVTA 1 mg, and IVTA 4 mg dosing regimen. At 4 months, a greater improvement in BCVA was noted in the IVTA 4 mg group, while at the first year, nonsignificant differences in BCVA were reported among the three arms. However, at the 2-year end point, mean BCVA was better in the laser group, and OCT results paralleled with the BCVA gain. At the extended 3-year follow-up, the results were consistent with those published at 2 years: BCVA change was, respectively, five letters in the laser group and 0 letters in the two IVTA groups. Regarding the side effects, an increased probability of cataract surgery was reported in, respectively, 31, 46, and 83 % of the three arms and an IOP increase of more than 10 mmHg in 4, 18, and 33 % of the three groups, respectively, at the third year. Thus, the authors concluded that IVTA did not show long-term benefits compared to laser photocoagulation in the treatment of DME. In addition, in the exploratory analysis performed on the participants of this trial, the effects of IVTA and laser on the progression of diabetic retinopathy were assessed at 3 years [74]. The results showed a reduced risk of progression of DR in the IVTA 4 mg group (21 %) compared to the IVTA 1 mg (29 %) and laser (31 %). However, the authors did not suggest the use of IVTA as a therapeutic strategy to reduce or slow down the progression of DR.

Later, the DRCR.net promoted a large RCT, evaluating the effects of two intravitreal agents (triamcinolone acetonide and ranibizumab) associated with laser photocoagulation (grid or focal) and laser alone, in center-involved DME, during a follow-up of 1 year and then extended at 2 years [76, 77]. Participants were randomized on four arms: sham injection plus laser, 0.5 mg of intravitreal ranibizumab (IVR) plus prompt laser, 0.5 mg IVR plus deferred laser, and 4 mg IVTA plus prompt laser. At the first year, the study showed that IVR plus prompt or deferred laser provided greater benefits in terms of BCVA regain than IVTA plus laser and laser alone groups; regarding the CRT reduction, the three arms evaluating IVTA or IVR plus laser revealed similar results and greater benefits than the laser alone group. These data were confirmed on the expanded 3-year follow-up. The mean change of BCVA was, respectively, +3.7 letters better in the IVR plus prompt laser, +5.8 letters better in the IVR plus deferred laser, and 1.5 letters worse in the IVTA plus laser compared to the laser alone group. In the subgroup of pseudophakic eyes, the IVTA plus laser provided greater benefits than laser alone, owing in mind the increased risk of IOP rise. Thus, the authors concluded that IVR should be considered as a validated treatment in DME with macular involvement.

Currently, the role of IVTA, alone or as adjunct to laser, could be carefully considered in some selected cases of visual loss, due to refractory or persistent DME, especially in pseudophakic eyes.

Sustained-release drug delivery devices are recent validated therapeutic approaches to release steroids with a longer duration of action, reducing the number of intravitreal injections.

Slow-release dexamethasone intravitreal implant (DEX implant) is a biodegradable device, providing 0.7 mg of preservative-free dexamethasone through a prefilled, single-use, 22-gauge applicator (Table 3.5). The DEX implant has been

recently approved by the US Food and Drug Administration (FDA) and by the European Union (EU) as a validated treatment for adult patients with chronic noninfectious posterior uveitis and macular edema following retinal vein occlusion. The safety and performance of the DEX implant have been evaluated in patients with DME [78–82] (Fig. 3.20). In a 6-month trial, patients with persistent macular edema secondary to different pathologies, including DME, retinal vein occlusion, uveitis, and Irvine-Gass syndrome, were randomly assigned to receive 350 or 700 μg of the DEX implant or sham treatment [79]. At the third month, a BCVA improvement of 10 or more letters was observed in the 35 and 24 % of the 350 and 700 μg DEX implant groups, respectively, compared to sham. Regarding the side effects, an increase in IOP of 10 mmHg or higher was shown in the 11 % of both DEX implant groups and in the 2 % of control group. A further analysis of this study, including the subgroup of patients affected by DME, has been conducted, revealing that the DEX implant might have potential as a treatment for persistent DME [80]. The results at day 90 showed a BCVA gain of ten or more letters in the 33.3, 21.1, and 12.3 % of the 350 μg DEX implant, 700 μg DEX implant, and observational group, respectively, and later maintained at day 180 in the 30, 19, and 23 % of the three arms, respectively. A great improvement in fluorescein leakage and CRT on OCT has been demonstrated also in treated eyes. An IOP increase, reaching a value of 25 mmHg or higher, was detected in the 7.5, 12.7, and 0 % of the three groups, respectively, and was effectively managed with topical medication.

The efficacy and safety of the DEX implant have been assessed in vitrectomized eyes affected by DME, showing a significant improvement on BCVA, CRT, and vascular leakage in a follow-up of 26 weeks [81]. At weeks 8 and 26, the study showed a mean rise in BCVA of 6 and 3 letters and a mean reduction in CRT of 156 and 39 μm, respectively.

Currently, a randomized, placebo-controlled, clinical trial is ongoing to assess the efficacy and safety of the DEX implant in a larger study population affected by DME [82].

Intravitreal fluocinolone acetonide (IVFA) sustained drug delivery devices have been tested in DME and might have some potential in the treatment of persistent DME [83] (Table 3.5).

Retisert® (Bausch & Lomb, Rochester, NY) is a nonbiodegradable device, inserted through a pars plana incision, engineered to deliver sustained levels of fluocinolone acetonide for almost 30 months. This is a surgically implanted device in which 0.59 mg of fluocinolone acetonide is inserted in the vitreous and is released at an initial rate of nearly 0.6 μg/day and then progressively decreased to a steady rate of about 0.3–0.4 μg/day at the first month. Currently, Retisert has been approved as a validated treatment option of noninfectious, chronic, posterior uveitis [84]. The efficacy and safety of Retisert in the treatment of recurrent or persistent DME have been evaluated in a large, multicenter RCT of a 4-year follow-up, and the results at 3 years have been recently published [85]. Enrolled patients were randomly assigned Retisert or standard of care (considered as additional laser photocoagulation or observation). The results showed a BCVA improvement of 3 or more lines in the 16.8 % at the sixth month, 16.4 % at the first year, 31.8 % at the second year, and

d

h

i

j

Fig. 3.20 (a–d) A 64-year-old male, with type 2 DM since 22 years and poor metabolic control, hypertension, and dyslipidemia, complains visual acuity deterioration (BCVA 20/100). The imaging at baseline shows multiple hemorrhages and microaneurysms at the posterior pole (a, b), diffuse breakdown of the blood-retinal barrier (c), and increased central retinal thickness (d). (e–h) Six months after grid laser, a persistence of fluorescein leakage and retinal thickening is still visible, and visual acuity has not raised yet (BCVA 20/100). (i) The patient underwent one intravitreal injection of slow-release dexamethasone implant, reaching a good anatomical recovery and a mild increase in visual acuity (BCVA 20/80) at 1 month. (j) Six months after the implant, the retinal remains dry and visual acuity remains stable. Nevertheless, OCT shows photoreceptors’ loss and disorganization of the outer retina

31.1 % at the third year in the treated group. A higher rate of improvement in CRT was noticed in the treated group compared to placebo at each time point. Nevertheless, a high rate of secondary effects has been shown in the fluocinolone acetonide group: cataract extraction was performed in the 91 % of phakic eyes by 4 years, and an IOP of 30 mmHg or more was noted in the 61.4 % of treated eyes at any time, of which 33.8 % required surgical management at 4 years. Thus, the authors concluded that the fluocinolone acetonide implant could be suggested in eyes with persistent or recurrent DME.

Iluvien® (Alimera Sciences, Alpharetta, GA) is a nonbiodegradable insert, injected into the vitreous through a 25-gauge needle, which releases 0.5 or 0.2 μg/ day of fluocinolone acetonide [86]. Iluvien has been evaluated in a recent randomized clinical trial with duration of 3 years [75, 87]. Subjects, with persistent DME, were randomized into three arms: 0.2 μg/day (low dose), 0.5 μg/day (high dose), or sham injection. At month 36, the percentage of patients with a BCVA increase of 15 or more letters was, respectively, 28.7 % and 27.8 % and 18.9 % in the three groups.

To evaluate which is the category of patients that obtained more benefits from the treatment, a subgroup analysis based on the duration of DME has been developed. The analysis revealed that the benefits were markedly better for the subgroup of patients with duration of macular edema of 3 or more years. In fact, in the subgroup of patients affected by DME with 3 or more years of duration, the study showed that the percentage of patients which improved 15 letters or more was significantly higher in the group treated with the fluocinolone implant than placebo. Nevertheless, in the subgroup of patients with a mean duration of DME less than 3 years, the percentage of patients reaching the BCVA increase of 15 or more letters was not significant [75]. Thus, the authors concluded that eyes with persistent DME, refractory to previous treatments, responded better to the administration of the fluocinolone insert.

Regarding the side effects, approximately all the phakic eyes underwent cataract extraction; the rate of glaucoma requiring surgical intervention was, respectively, 4.8 and 8.1 % in lowand high-dose groups. Currently, Iluvien could be considered as a valuable treatment option in patients with persistent DME, especially in pseudophakic eyes.

Summary 3.5

There are different categories of steroids administered intravitreally, with different properties and duration of action, including triamcinolone acetonide, dexamethasone, and fluocinolone implants. The most frequent side effects reported from all types of steroids are the increasing of intraocular pressure and cataract progression. In most of the cases, the different types of steroids have been administered in persistent or refractory DME, especially in pseudophakic patients.