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Evidence for Anti-vascular Endothelial Growth Factor Treatment of Diabetic Macular Oedema


One hundred nine subjects with DME and Snellen acuity equivalent ranging from 20/32 to 20/320 were prospectively enrolled and randomised to five groups:


DME in a large randomised Phase II clinical trial were initially reported by the DRCRnet.26


• focal photocoagulation at baseline; • intravitreal injection of 1.25 mg bevacizumab at baseline and six weeks; • intravitreal injection of 2.5 mg bevacizumab at baseline and six weeks; • intravitreal injection of 1.25 mg bevacizumab at baseline and sham injection at six weeks; or





intravitreal injection of 1.25 mg bevacizumab at baseline and six weeks with photocoagulation at three weeks.


The BCVA in the groups receiving bevacizumab alone showed a median one-line improvement at the three-week visit, which was preserved up to 12 weeks and was greater than the change in the group receiving only focal photocoagulation at baseline. A similar trend was observed in regard to CRT: comparing focal photocoagulation versus bevacizumab alone, a greater reduction in CRT was observed in the bevacizumab groups at three weeks. No significant differences in changes in BCVA or CRT between groups receiving bevacizumab 1.25 versus 2.5 mg were observed. Comparing bevacizumab groups with groups receiving combined treatment, no significant differences were observed in reduction of central subfield thickening or improvement in VA.


Lam et al. evaluated the efficacy of two dosing regimens of bevacizumab at six months of follow-up.27


Forty-eight patients were


randomised to receive three monthly intravitreal injections of 1.25 mg (n=23) or 2.5 mg (n=25) bevacizumab. At each monthly scheduled visit a significant mean CFT reduction was observed in both groups. Similarly, the mean logarithm of the minimum angle of resolution (logMAR) BCVA showed a statistically significant improvement from the baseline to final visit at six months (from 0.63 to 0.52 in the 1.25 mg group; from 0.60 to 0.47 in the 2.5 mg group). No significant difference in BCVA was observed between the two groups. No significant adverse events were reported during the study. Arevalo et al. reported the results of a retrospective, multicentre, interventional, comparative case series with a long-term follow-up extended to 24 months.28


The study


evaluated 139 eyes receiving bevacizumab intravitreal injection (1.25 mg [n=74] or 2.5 mg [n=65]). Additional injections were administered if recurrence of macular oedema was detected on OCT associated with VA loss. At one month, both groups showed a statistically significant improvement in BCVA and subsequently the gain was preserved up to the 24-months examination. The 1.25 mg group improved from 20/150 to 20/107 at one month and to 20/75 at 24 months. In the 2.5 mg group, the BCVA improved from 20/168 to 20/118 at one month and to 20/114 at the final visit.


Long-term efficacy of repeated injections of intravitreal bevacizumab 1.25 mg for the treatment of chronic DME was also reported by Kook et al.29


The study (prospective, consecutive, non-comparative case series) included 126 patients affected by chronic, diffuse, clinically significant DME in part not responsive to previous treatments. Preceding treatments included focal laser treatment (62 %), triamcinolone intravitreal injection (41 %), panretinal laser treatment (38 %), or vitrectomy (11 %). Sixty-seven and 59 patients completed the scheduled visits to six months and 12 months, respectively. At the six-month examination, the logMAR BCVA ranged from baseline value of 0.82 to 0.74, considering all patients. The mean BCVA of patients


EUROPEAN ENDOCRINOLOGY


who completed the 12-month follow-up improved similarly, from 0.82 to 0.74 logMAR. Mean CRT decreased from 463 to 374 µm after six months and to 357 µm after 12 months with a statistically significant difference. This study showed that, even in cases with chronic diffuse ischaemic DME not responding to other therapy, a successful treatment with repeated intravitreal injections of bevacizumab can be achieved over a long-term follow-up period.


Other studies compared intravitreal bevacizumab treatment with intravitreal triamcinolone or focal retinal photocoagulation in refractory DME or as primary treatment. Paccola et al. designed a randomised, prospective study in order to evaluate the anatomical response and VA outcomes after a single intravitreal injection of triamcinolone acetonide (4 mg) or bevacizumab (1.25 mg) in refractory diffuse DME.30


The study


enrolled 26 patients; at baseline, the logMAR BCVA was 0.936 and 0.937 in the triamcinolone and bevacizumab groups, respectively. At six months, the BCVA improved to 0.91 and 0.92 without achieving a significant difference; however, interim analysis at one-, two- and three-month examinations evidenced a significant improvement in the triamcinolone group compared with the bevacizumab group.


The study recruited 14 patients with bilateral long-standing DME; in each patient, one eye was selected to receive a single intravitreal injection of triamcinolone (4 mg) and the other to receive a single intravitreal bevacizumab injection (1.25 mg). The logMAR BCVA in the triamcinolone group improved significantly from 0.64 to 0.33 at one week, and the gain was subsequently preserved up to 12 weeks. At a final observation period of 24 weeks, BCVA decreased to 0.47 but was still significantly different from the baseline value. Similarly, BCVA in the bevacizumab group improved from 0.61 to 0.39 at one week and maintained the initial gain up to four weeks. At 12 weeks, BCVA returned to the initial level. No further decrease or improvement was observed in the following three months. A statistically significant difference in BCVA was observed in favour of the triamcinolone group at three and six months.


A similar prospective and comparative case series was reported by Shimura et al.31


The bevacizumab group showed a significant BCVA improvement, from 0.71 to 0.54 at six weeks; the initial gain was maintained in each following visit at 12, 24, and 36 weeks. The patients that underwent combined treatment showed a significant BCVA improvement, from 0.73 to 0.60 at six weeks. This group showed stability of BCVA at 12 weeks but loss of statistically significant improvement at six and nine months. In the macular photocoagulation group, the BCVA showed stabilisation at six weeks in comparison with the baseline value (0.60 versus 0.55) and similar values were observed at all follow-up evaluations. However, it is important to note that the three groups differed in regard to the baseline VA values. The mean values of CMT decreased significantly, in comparison with the baseline values, in all groups only at six weeks and although the reduction was greater in the bevacizumab group with respect to the other two groups, no statistically significant difference was registered during follow-up. Recently, the authors categorised the original treatment arms and the following subgroups were analysed based on CMT: 1) <250 μm; 2) 250–349 μm; and 3) ≥350 μm.33


A randomised, three-arm clinical trial comparing intravitreal bevacizumab injection (1.25 mg, n=50), alone or in combination with intravitreal triamcinolone acetonide (2 mg, n=50), versus macular laser photocoagulation (n=50) as a primary treatment of DME was published by Soheilian et al.32


Main outcome measures were changes in VA and CMT at weeks six, 12, 24, and 36. At six weeks in all subgroups, mean VA


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