Table 1.
Characteristics and outcomes in the included studies, showing the effect of anti-vascular endothelial growth factors on retinal non-perfusion in patients with diabetic retinopathy.
| Study | Design | Number of eyes | Treatment | Follow-up | VA outcome | Imaging modality | Characterization of outcome | Outcome in non-perfusion | Location of examined ischemia |
|---|---|---|---|---|---|---|---|---|---|
| Neubauer et al. [49] | Prospective case series | 19 eyes with DME and NPDR | Bevacizumab 1.25 mg single injection | 1 month | Significant improvement in VA from 0.87 ± 0.37 to 0.13 ± 0.28 logMAR | UW-FFA |
Neutral (macula) Positive (peripheral) |
No significant change in FAZ area Significant decrease in peripheral retinal ischemia |
Macular and peripheral ischemia |
| Kook et al. [50] | Prospective case series | 126 eyes with diffuse DME and NPDR (86) or PDR (40) | Bevacizumab 1.25 mg repeated injections | 12 months | Significant improvement in VA from 40.3 ± 20.9 to 45.4 ± 18.5 ETDRS letters | FFA | Neutral | No significant change in macular ischemia | Macular ischemia |
| Lee and Koh (2009) [64] | Case report | 1 eye with PDR and vitreous hemorrhage | Bevacizumab 2.5 mg single injection and PPV/endolaser | – | VA stable to 20/400 | FFA | Negative | FAZ area increase by 24.5% | Macular ischemia |
| Michaelides et al. [51] | Prospective, randomized, controlled study |
40 in anti-VEGF group and 40 in laser group 80 eyes with DME |
Bevacizumab 1.25 mg (3 intravitreal 6-weekly injections) vs laser | 4 months | Improvement in VA from 55.7 ± 9.7 to 61.3 ± 10.4 in the bevacizumab group at month 12 | FFA | Neutral | No worsening of macular ischemia in either group (anti-VEGF or laser) | Macular ischemia |
| Goel et al. [71] | Case Report | 1 eye with diffuse DME and NPDR | Bevacizumab 1.25 mg single injection | 6 months | Decrease in VA from 20/80 to 20/200 | FFA | Negative | FAZ increased from 0.69 to 1.26 mm | Macular ischemia |
| Erol et al. [65] | Prospective case series | 29 eyes with DME | Bevacizumab 1.25 mg (3 injections) | 3 months | No significant change in VA | FFA | Negative | Significant increase in FAZ area by 13% after 3 anti-VEGF injections | Macular ischemia |
| Feucht et al. [72] | Retrospective case series | 28 eyes with DME and NPDR | Bevacizumab 1.25 mg single injection | 6–8 weeks | Not reported | FFA | Negative | FAZ area increase by 19.7% | Macular ischemia |
| Comyn et al. [52] | Prospective, randomized | 33 eyes with DME and no macular ischemia (22 Ran and 11 laser) | Ranibizumab 0.5 mg (3 monthly injections) vs laser every 12 weeks, as required | 48 weeks | Increase in VA from 70.4 ± 4.9 to 76.4 ± 8.5 in ranibizumab group, while decrease from 63.8 ± 5.7 to 62.9 ± 10.6 to laser group | FFA | Neutral | Slight increase in FAZ area, but no significant | Macular ischemia |
| Campochiaro et al. [73] | Retrospective controlled |
666 with DME 213 ran 0.3 225 ran 0.5 228 sham |
Ranibizumab 0.3 mg vs 0.5 mg vs sham | 24 months | Not reported | FFA | Neutral |
Less worsening with anti-VEGF, but no difference Stable percentage with no progression to macular ischemia in ranibizumab group |
Macular ischemia |
| Ghasemi Falavarjani et al. [66] | Prospective, non-comparative case series | 13 eyes with DME |
Bevacizumab 1.25 mgRanibizumab 0.5 mg Aflibercept 2 mg (1 injection) |
1 month | No significant change in VA | OCTA 3×3 | Neutral | No significant change in FAZ area and VD after single injection | Macular ischemia |
| Levin et al. [74] | Retrospective case series | 16 eyes with DME and NPDR (1) or PDR (15) | At least one injection (Bevacizumab 3 or Ranibizumab 12 or Aflibercept 1) | 5 months | Not reported | UW-FFA | Positive | Re-perfusion of areas of non-perfusion in 12 out of 16 eyes (75%) | Peripheral ischemia AND/OR macular ischemia |
| Douvali et al. [53] | Retrospective study |
49 patients with DME 32 non-ischemic 17 ischemic |
Ranibizumab 0.5 mg (3 injections + PRN) | 6 months | Significant improvement in VA in non-ischemic group-No change in ischemic group | FFA | Neutral | No difference in ischemic region in eyes with ischemia at baseline | Macular ischemia |
| Gill et al. [83] | Retrospective | 11 eyes with DME |
Aflibercept 2 mg (6 eyes-1 injection) Bevacizumab 1.25 mg (2 eyes-2 injections) Ranibizumab 0.5 mg (3 eyes-2 injections) |
3 months | Not reported | OCTA 3 × 3 | Positive | Significant decrease in FAZ area | Macular ischemia |
| Michalska-Malecka and Heinke Knudsen [76] | Retrospective case reports | 3 eyes with DME and DR | Aflibercept 2 mg (3 monthly injections and 2 bimonthly) | 1 month after last injection | Not reported | OCTA 3 × 3 | Neutral |
No re-perfusion noted - No change in VD |
Macular ischemia |
| Chandra et al. [54] | Case report | 1 eyes with DME and PDR | Ranibizumab 0.5 mg (3 monthly injections) | 1 month after last injection | Improvement in VA from 6/12 to 6/9 | WF-FFA | Positive | Regression of neovascularization-Improvement in retinal perfusion in previous ischemic areas | Peripheral ischemia |
| Moon et al. [67] | Retrospective case series | 67 eyes with DME and NPDR (37 eyes) or PDR (30 eyes) |
At least 3 injections of Bevacizumab (64) Aflibercept (2) Ranibizumab (1) |
12 months | No significant difference in VA | OCTA 3 × 3 | Neutral | No significant difference in FAZ area and VD in SCP, but significant increase in DCP VD, while no difference in DCP FAZ area | Macular ischemia |
| Karst et al. [75] | Prospective, randomized | 240 eyes with DME |
Ranibizumab 0.5 mg (3 injections and PRN)−83 eyes Ran + laser 83 Laser alone 74 |
36 months | Not reported | Neutral | No change in FAZ area, no difference in capillary loss in 3 groups | Macular ischemia | |
| Gupta et al. [77] | Case report | 1 eye with PDR without DME | Ranibizumab 0.3 mg (1 injection) | 12 months | Not reported | UW-FFA | Positive | Regression of neovascularization-No progression of retinal non-perfusion | Peripheral ischemia |
| Bonnin et al. [16] | Retrospective case series | 18 with DME and NPDR (15 eyes) or PDR (3 eyes) |
3 monthly injections of Ranibizumab (13) Aflibercept (5) |
3 months | Significant improvement in VA from 0.53 ± 0.28 at baseline to 0.26 ± 0.18 logMAR at month 3 | UW-FFA | Neutral |
No re-perfusion noted one month after 3 injections DRSS score improved at least one level in 61% of eyes Regression of neovascularization in PDR eyes |
Peripheral ischemia |
| Busch et al. [55] | Retrospective case series | 23 eyes with DME and NPDR (14 eyes) or PDR (9 eyes) | Aflibercept 2 mg (1–3 injections and PRN) | 8.5 ± 5.6 months | Significant improvement in VA from 0.28 ± 0.23 to 0.15 ± 0.22 logMAR | OCTA 3 × 3 | Neutral | No significant change in FAZ area in both SCP and DCP | Macular ischemia |
| Wykoff et al. [81] | Retrospective controlled | 466 eyes with DME | Aflibercept 2 mg 2q4 (130) vs 2q8 (126) vs laser (129) | 100 weeks | Not reported | WF-FFA | Positive | Improvement in retinal perfusion in aflibercept more than laser | Macular and peripheral ischemia |
| Sorour et al. [78] | Retrospective case series | 46 eyes with DME and 9 eyes with PDR |
Bevacizumab 45.7% Aflibercept 42.4% Ranibizumab 11.9% |
1–3 months | Not reported | OCTA 3 × 3 and 6 × 6 | Neutral | No significant change in VD in both SCP and DCP | Macular ischemia |
| Filek et al. [82] | Prospective study | 30 eyes with DME | Ranibizumab 0.5 mg (3 monthly injections and PRN) | 24 months | Not reported | UW-FFA (Optos) | Positive | The mean perfused ratio was significantly improved | Peripheral /macular ischemia |
| Babiuch et al. [68] | Prospective study | 20 eyes with DME | Aflibercept 2 mg monthly until resolution of fluid and then bimontlhy | 6 months | No significant change in VA | OCTA 3 × 3 | Neutral |
No change in FAZ area No change in VD |
Macular ischemia |
| Hsieh et al. [56] | Retrospective study | 50 eyes DME | Ranibizumab 0.5 mg (3 injections) | 3 months | Significant improvement in VA from 0.73 ± 0.39 to 0.56 ± 0.39 logMAR | OCTA 3 × 3 | Positive | Significant decrease in FAZ area and increase in VD | Macular ischemia |
| Couturier et al. [57] | Prospective case series | 7 eyes with NPDR and 3 eyes with PDR | Ranibizumab 0.5 mg (8 eyes) or Aflibercept 2 mg (2 eyes) (3 monthly injections) | 3 months |
Significant improvement in VA from 64.40 ± 9.39 to 73.50 ± 8.47 ETDRS letters |
UW-FFA OCTA 3 × 3 WF-OCTA |
Neutral |
No change in retinal capillary density in FAZ No change in peripheral ischemia No re-perfusion was detected |
Macular and peripheral ischemia |
| Sugimoto et al. [58] | Prospective study | 25 eyes with DME and NPDR | Aflibercept 2 mg (3 monthly injections) | 1 week after last injection | Significant improvement in VA from 0.45 ± 0.35 to 0.40 ± 0.38 logMAR | UW-FFA | Positive | Significant decrease of the mean ischemic index | Peripheral ischemia |
| Pereira et al. [59] | Prospective case series | 5 eyes with DME and previously treated PDR | Bevacizumab 1.25 mg (6 injections) | 6 months | Significant improvement in VA from 20/180 to 20/74 |
FFA OCTA 3 × 3 and 4.5 × 4.5 |
Negative |
No changes in macular perfusion status FAZ area increase, but not significantly in FFA, while significant increase in OCTA |
Macular ischemia |
| Wykoff et al. [15] | Prospective, randomized | 40 eyes with PDR and without DME | Aflibercept 2 mg monthly (20 eyes) vs quarterly (20 eyes) | 12 months | No significant improvement in VA | UW-FFA | Neutral |
2-step DRSS score improvement in both groups Significant regression of neovascularization Significant increase of ischemic index in the whole cohort Significant increase of retinal non-perfusion in quarterly group and stable non-perfusion in monthly group Localized re-perfusion in some patients |
Peripheral and macular ischemia (total) |
| Conti et al. [69] | Prospective study | 19 eyes with DME and NPDR (15) or PDR (4) | Aflibercept 2 mg monthly until resolution of fluid and then bimonthly | 12 months | No significant improvement in VA | OCTA 6 × 6 | Neutral | No change in FAZ area No change in VD | Macular ischemia |
| Figueiredo et al. [60] | Prospective case series | 14 eyes with DME and NPDR (11 eyes) or PDR (3 eyes) | Aflibercept 2 mg monthly for 6 months and then bimonthly | 12 months | Significant improvement in VA at month 6 (6.6 ± 5.9 letters), but not at month 12 (5.0 ± 7.4 letters) | UW-FFA | Neutral |
Stability in panretinal ischemic index Significant reduction in panretinal leakage index |
Peripheral and macular ischemia (total) |
| Dastiridou et al. [79] | Prospective case series | 20 eyes with DME | Aflibercept 2 mg (3 injections) | 3 months | Not reported | OCTA 6 × 6 | Neutral |
No change in FAZ in SCP Decrease in FAZ in DCP Significant decrease in central VD, but stable VD in parafoveal area |
Macular ischemia |
| Elnahry et al. [61] | Prospective, non-comparative case series | 40 eyes with DME and NPDR (31 eyes) or PDR (9 eyes) | Bevacizumab 1,25 mg (3 monthly injections) | 3 months | Significant improvement in VA from 0.68 ± 0.34 to 0.47 ± 0.25 logMAR | OCTA 6 × 6 | Negative | Significant increase in FAZ area by 8.1% and significant decrease in VD in both SCP and DCP | Macular ischemia |
| Lee et al. [63] | Prospective study | 25 eyes with DME | Ranibizumab 0.5 mg (6 monthly injections) | 6 months | Significant improvement in VA from 67.6 ± 3.29 to 76.4 ± 1.61 letters | FFA | Neutral | No significant change in the perifoveal non-perfused area | Macular ischemia |
| Barash et al. [80] | Retrospective case series | 9 PDR and 5 DME with NPDR | Bevacizumab 1.25 mg or Aflibercept 2 mg single injection | Immediately after injection | Not reported | OCTA 3 × 3 | Negative | SCP VD dropped by 7.8% while DCP VD dropped by 3.5% immediately after injection | Macular ischemia |
| Mirshahi et al. [70] | Prospective case series | 23 eyes with DME | Bevacizumab 1.25 mg | 1 month after injection | No significant improvement in VA 0.46 ± 0.25 to 0.45 ± 0.25 logMAR | OCTA 3 × 3 | Neutral |
No significant changes in the capillary non-perfusion area, FAZ area, FD-300, or in the VD of the foveal and parafoveal SCP and DCP VD in choriocapillaris significantly increased |
Macular ischemia |
| Statler et al. [62] | Prospective | 16 eyes with persistent DME | Aflibercept 2.0 mg every 4 weeks | 24 months | Significant improvement in VA by 5.5 letters | OCTA 3 × 3 | Negative | Enlargement of FAZ and decrease in VD in superficial and deep capillary plexus | Macular ischemia |
DCP deep capillary plexus, DME diabetic macular edema, FAZ foveal avascular zone, FFA fundus fluorescein angiography, NPDR non-proliferative diabetic retinopathy, OCTA optical coherence tomography angiography, PDR proliferative diabetic retinopathy, PPV pars plana vitrectomy, SCP superficial capillary plexus, UW ultra-wide-field, VA visual acuity, VD vessel density, WF wide–field.