Week 36

Week 52

Fig. 2. Changes in retinal neovascularization after pegaptanib. First row, Baseline visit shows magnification of retinal neovascularization elsewhere (NVE) (A), the location of the neovascularization along the inferotemporal arcade (red-free photograph) (B), areas of capillary nonperfusion in the earlyphase frame (fluorescein angiogram) (C), and leakage from the NVE in the late-phase frame (fluorescein angiogram) (D). Second row, At week 36, after 6 periodic pegaptanib injections and 6 weeks since the most recent injection, there is seen regression of NVE on red-free photographs (A, B), less apparent microaneurysms in the early phase (C), and regression of leakage from NVE in the late phase (D). Third row, 52 weeks after study entry and 22 weeks since the last pegaptanib injection, there is seen reappearance of NVE on red-free photographs (A, B) and reappearance of leakage from NVE in earlyand late-phase frames (C) (from Macugen Diabetic Retinopathy Study Group (104) ).

efficacy of pegaptanib compared with non-treatment control (sham injection) for the treatment of DME with foveal involvement.

Clinical Experience with Bevacizumab in Diabetic Retinopathy

Several published studies have demonstrated a biological effect of intravitreal bevacizumab in proliferative diabetic retinopathy and diabetic macular edema. The majority of these studies are limited by their retrospective nature and short follow-up period.

Avery and colleagues retrospectively evaluated the use of intravitreal bevacizumab in patients with retinal neovascularization due to proliferative diabetic retinopathy (96). In 44 eyes treated with intravitreal bevacizumab (6.2 g–1.25 mg), retinal neovascularization demonstrated on fluorescein angiography had complete (or at least partial) reduction in leakage within 1 week after the injection. Complete resolution of angiographic leakage from neovascularization of the disc was noted in 19 of 26(73%) eyes, and leakage of iris neovascularization completely resolved in 9 of 11 (82%) eyes. The leakage was noted to diminish as early as 24 h after injection. Recurrence of fluorescein leakage varied and was seen as early as 2 weeks in one case, whereas in other cases, no recurrent leakage was noted at the last available follow-up of 11 weeks. No ocular or systemic adverse events were noted.

412 Do et al.

Retrospective case series of bevacizumab as an adjunct for intraoperative use in diabetic tractional retinal detachment repair (105) or in eyes with proliferative retinopathy and non-clearing vitreous hemorrhage (97) have been reported. Similarly, intracameral injection of bevacizumab for iris rubeosis (106, 107) has been noted to have a beneficial short-term effect. Although there was a regression of the rubeotic vessels present as early as 1 week after injection, no persistent effect on intraocular pressure in cases of neovascular glaucoma is yet proven.

In a prospective, consecutive, non-comparative case series, 51 consecutive patients (26 females and 25 males; mean age, 64 years) with diffuse diabetic macular oedema were treated with intravitreal bevacizumab (108). Inclusion criteria were determined independently of the size of oedema, retinal thickness, VA, age, metabolic control, type of diabetes, or previous treatments beyond a 6-month period. All patients had undergone previous treatments, such as focal laser therapy (35%), full-scatter panretinal laser therapy (37%), vitrectomy (12%), and intravitreal triamcinolone (33%). Sixteen patients (70%) received at least two intravitreal injections of bevacizumab during the study period. Mean central retinal thickness by OCT was 501 m (range, 252–1,031 m) at baseline and decreased to 425+/− 180 m at 2 weeks (P = 0.002) after bevacizumab, 416+/− 180 m at 6 weeks (P = 0.001), and 377+/− 117 m at 12 weeks (P = 0.001). VA, as measured by ETDRS letters, did not improve significantly through the follow-up period.

A phase II randomized multicenter clinical trial of intravitreal bevacizumab for diabetic macular oedema was performed by the Diabetic Retinopathy Clinical Research Network (DRCR.net) (110). This study involved 121 eyes from 121 individuals with diabetic macular oedema involving the center of the macula based on clinical examination, best-corrected Snellen VA equivalent ranging from 20/32 to 20/320, OCT central subfield thickness (CST) greater than or equal to 275 m, and no history of treatment for DME in the prior 3 months. Of the 121 subjects, 109 met criteria for inclusion in the analyses. Subjects were randomized to 1 of 5 treatment groups, with 19–24 subjects per group: (A) focal laser photocoagulation at baseline, (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks, (C) intravitreal injection of 2.5mg of bevacizumab at baseline and 6 weeks, (D) intravitreal injection of 1.25mg of bevacizumab at baseline and sham injection at 6 weeks, or (E) intravitreal injection of 1.25mg of bevacizumab at baseline and 6 weeks with focal photocoagulation at 3 weeks. Follow-up visits were performed at 3, 6, 9, 12, 18, 24, 41, and 70 weeks, and a report was published for analysis of central subfield thickness (CST) and VA during the first 12 weeks (110).

Both the 1.25and 2.5 mg bevacizumab-treated eyes had a greater reduction in central retinal thickness at 3 weeks, compared to the control group receiving photocoagulation. However, the photocoagulation group showed improvement in these parameters with longer follow-up, so that there were no meaningful differences in CST observed for bevacizumab compared to photocoagulation after the 3-week time point. About half of the eyes demonstrated what was deemed to be a response to bevacizumab (greater than an 11% decrease in retinal thickness compared to baseline). With regard to VA, there was an approximately 1 line greater improvement with both bevacizumab doses on average compared to photocoagulation throughout the 12 weeks.

In the 12 week time-frame, there was not a large difference in effect between the 2 doses of bevacizumab. Interestingly, the reduction in retinal thickness associated with bevacizumab at 3 weeks appeared to plateau or decrease in most eyes between the