Diabetic macular edema: Efficacy and safety of anti-vascular endothelial growth factor therapy

Table 1 Major trials of anti-vascular endothelial growth factor drugs for diabetic macular edema

Ref.	Drug	Design	n	Treatment regimen	Follow-up	Results
Sultan et al[24]	Pegaptanib	Phase 2/3, randomized, sham-controlled, multicenter	260 patients	(1) 0.3 mg IVP; or (2) sham injections at baseline and every 6 wk in year 1 and focal/grid laser beginning at wk 18. In year 2, (1) 0.3 mg IVP; or (2) sham up to every 6 wk PRN	2 yr	Improvement of ≥ 10 letters at 54 wk: (1) 36.8%; and (2) 19.7% (P = 0.0047). BCVA letters gained at week 102: (1) 6.1 letters; and (2) 1.3 letters (P < 0.01). No significant difference in CFT decreases at 54 and 102 wk between (1) and (2)
Macugen Diabetic Retinopathy Study Group[23]	Pegaptanib	Phase 2, randomized, double-masked, dose-ranging, controlled	172 patients	(1) 0.3 mg PEG; or (2) sham at baseline, week 6 and week 12; additional injections or focal LPC as needed for an additional 18 wk	36 wk	Mean VA at week 36: (1) 20/50; and (2) 20/63 (P = 0.04). Ten letters gained: (1) 34%; and (2) 10% (P = 0.003). CRT at week 36: (1) -68 μm; and (2) +4 μm (P = 0.02). PEG doses of 0.3, 1, 3 mg all well tolerated
Elman et al[28] (DRCR)	Ranibizumab	Randomized, prospective, multicenter	854 eyes of 691 patients	(1) 0.5 mg IVR plus prompt laser; (2) 0.5 mg IVR plus deferred laser (> 24 wk); and (3) 4 mg IVT plus prompt laser; (D) sham injection plus prompt laser	1 yr	Mean VA letter improvement at 1 yr: (1) +9 ± 1, P < 0.001; (2) +9 ± 12, P < 0.001; (3) +4 ± 13, P = 0.31; and (4) +3 ± 13
Mitchell et al[33] (RESTORE)	Ranibizumab	Randomized, prospective, multicenter	345 patients	(1) 0.5 mg IVR monthly × 3 then PRN + sham laser; (2) 0.5 mg IVR monthly × 3 then PRN + laser; and (3) sham injections + laser	12 mo	VA better for (1) and (2) from months 1 to 12 compared with (3); 12-mo VA: (1) +6.1 letters; (2) +5.9 letters; and (3) +0.8 letters (P < 0.0001 for both); BCVA 20/40 or better: (1) 53%; (2) 44.9%; and (3) 23.6%. No significant differences between (1) and (2) at 12 mo
RISE Trial[31]	Ranibizumab	Phase 3, randomized, sham-controlled, multicenter	377 patients	(1) 0.3 mg IVR; (2) 0.5 mg IVR; and (3) sham injection. All given monthly injections × 24 mo and with rescue laser available at 3 mo	2 yr	Improvement of ≥ 15 letters at 2 yr: (1) 44.8% (56/125); (2) 39.2% (49/125); and (3) 18.1% (23/127). Statistically significant for both (1) and (2) compared with (3) at P < 0.001 and P < 0.002, respectively
RIDE Trial[31]	Ranibizumab	Phase 3, randomized, sham-controlled, multicenter	382 patients	(1) 0.3 mg IVR; (2) 0.5 mg IVR; and (3) sham injection. All given monthly injections × 24 mo and with rescue laser available at 3 mo	2 yr	Improvement of ≥ 15 letters at 2 yr: (1) 33.6% (42/125); (2) 45.7% (58/127); and (3) 12.3% (16/130). Statistically significant for both (1) and (2) compared with (3) at P < 0.001
Massin et al[27] (RESOLVE)	Ranibizumab	Phase 2, randomized, sham controlled, multicenter	151 patients	(1) 0.3 mg or 0.5 mg IVR monthly × 3 mo then as needed (dose doubling allowed after 1 mo); or (2) sham injection monthly × 3 mo then as needed (as-needed rescue LPC in)	1 yr	Month 12 mean ± SD BCVA change: (1) 10.3 ± 9.1 letters; and (2) -1.4 ± 14.2 letters; P < 0.001. Gain ≥ 10 letters: (1) 60.8%; and (2) 18.4% (P < 0.001). Mean change in CFT: (1) -194.2 µm; and (2) -48.4 μm (P < 0.001)
DRCR[41]	Bevacizumab	Randomized, prospective	121 patients	(1) Focal LPC; (2) IVB 1.25 mg at baseline and 6 wk; (3) 2.5 mg IVB at baseline and 6 wk; (4) 1.25 IVB at baseline and sham at 6 wk; or (5) 1.25 IVB at baseline and 6 wk with focal LPC	24 wk	Baseline CFT: 411 μm; at 3 wk, CFT reduction greater in (2) and (3) than in (1); CFT reduced > 11% at 3 wk in 43% of IVB-treated eyes and 28% of LPC treated eyes, and at 6 wk in 37% of IVB treated eyes and 50% of LPC-treated eyes. Mean 12-wk VA improvement in (2) and (3) of 1 line better than (1). No significant short-term benefit combining IVB and laser
Michaelides et al[42], 2012 (BOLT)	Bevacizumab	Randomized, prospective	80 patients	(1) Focal/grid laser; or (2) IVB 1.25 mg at baseline, 6 and 12 wk, then as needed	24 mo	Mean gains in BCVA at 24 mo: (1) +2.5 letters; and (2) +9 letters (P = 0.005). Mean change in CFT at 24 mo; (1) -118 μm; and (2) -146 μm
Do DV et al[38], 2012 (DA VINCI)	Aflibercept	Phase 2, randomized, multicenter	221 patients	VEGF Trap-Eye (1) 0.5 mg every 4 wk (0.5q4); (2) 2 mg every 4 wk (2q4); (3) 2 mg every 8 wk after 3 initial monthly doses (2q8); (4) 2 mg dosing as needed after 3 initial monthly doses (2PRN); or (5) macular laser photocoagulation.	2 yr	Mean improvements in BCVA in the VEGF Trap-Eye groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, vs -1.3 letters for the laser group (P ≤ 0.001 vs laser)

BCVA: Best-corrected visual acuity; CFT: Central foveal thickness; DRCR: Diabetic Retinopathy Clinical Research Network; IVB: Intravitreal bevacizumab; PRN: Pro re nata; IVP: Intravitreal pegaptanib; IVR: Intravitreal ranibizumab; IVT: Intravitreal triamcinolone; LPC: Laser photocoagulation; VEGF: Vascular endothelial growth factor.