Conbercept and Ranibizumab Pretreatments in Vitrectomy with Silicone Oil Infusion for Severe Diabetic Retinopathy

Abstract

Purpose:

We compared the efficacies of intravitreal ranibizumab (IVR) and intravitreal conbercept (IVC) as the adjuvant pretreatments for vitrectomy with silicone oil infusion for tractional retinal detachment (TRD) secondary to proliferative diabetic retinopathy.

Methods:

This retrospective study comprised 74 patients (79 eyes) who underwent vitrectomy with silicone oil tamponade for diabetic TRD. They received IVC (37 eyes) or IVR (42 eyes) at standard doses 3–5 days preoperatively and were followed up for ∼6 months. Anatomic success rate, intra- and postoperative complications, and visual outcomes were compared between both groups.

Results:

Initial (IVC vs. IVR: 97% vs. 98%) and final anatomic success rates (100% in each group) and mean visual acuity changes were not significantly different (P = 0.46). Intraoperative complications [iatrogenic retinal breaks (P = 0.58) and intraoperative bleeding (P = 0.66)], postoperative complications [fibrin formation (P = 0.51), postoperative preretinal bleeding (P = 0.88), progressing or persistent neovascular glaucoma (P = 0.63), progressive fibrovascular proliferation (P = 0.93), and recurrent retinal detachment (P = 0.93)], and surgical variables [surgical time (P = 0.53)] were similar between both groups.

Conclusions:

Conbercept and ranibizumab are equally effective surgical adjuvants for vitrectomy with silicone oil infusion in patients with diabetic TRD.

Introduction

Proliferative diabetic retinopathy (PDR), one of the most prevalent and severe ocular disorders, causes adult blindness. In patients with PDR, the development of a fibrovascular membrane results in vitreous hemorrhage and tractional retinal detachment (TRD), which are the typical indications for surgical intervention and can severely damage the visual function. As yet, pars plana vitrectomy is a predominant treatment of PDR.¹

Recently, the efficacy of preoperative intravitreal vascular endothelial growth factor (VEGF) inhibitors has been widely verified. It has been proved that anti-VEGF treatment before vitrectomy reduces many surgical procedures and complications, including intraoperative bleeding, iatrogenic retinal breaks, and early postoperative bleeding, the use of endodiathermy, and surgical time.^2–8 Four currently available VEGF antagonists, pegaptanib, bevacizumab, ranibizumab, and aflibercept, have been developed and verified in patients with PDR.^1,8,9 Conbercept is the newly approved member of the anti-VEGF family of drugs.¹⁰ It was developed to provide a prolonged and more potent anti-VEGF effect, and it was approved by the China Food and Drug Administration in November 2013. Similar to aflibercept, conbercept comprises VEGF-binding domains of the human VEGF receptor-1 (VEGFR-1) and VEGFR-2 in combination with the Fc portion of human immunoglobulin G-1. In addition to having a high affinity for all VEGF-A isoforms, conbercept binds to the placental growth factor (PlGF) and VEGF-B. Conbercept and aflibercept are structurally different; conbercept has an additional fourth binding VEGFR-2 domain, which is essential for receptor dimerization and for the enhancement of the association rate of VEGF to its receptor. Studies have suggested that conbercept pretreatment is an effective adjunct for vitrectomy in reducing intraoperative bleeding, escalating postoperative vitreous clear up, and attaining stable visual acuity restoration in patients with PDR.^11,12

The study aims to compare the efficacies of intravitreal conbercept (IVC) and intravitreal ranibizumab (IVR), the 2 most widely used anti-VEGF agents in China, as adjuvant treatments before vitrectomy with silicone oil infusion for TRD secondary to PDR. To the best of our knowledge, this is the first study to evaluate the therapeutic efficacy of conbercept versus ranibizumab pretreatment for vitrectomy in PDR patients with TRD.

Methods

Study design and patients

This retrospective chart review study comprised a consecutive sequence of patients with diabetes who received IVC or IVR as adjuvant treatments before vitrectomy with silicone oil infusion for TRD secondary to PDR between November 2015 and December 2016 at the First Hospital of China Medical University (Shenyang, China). The ethics committee and institutional review board of the university approved the study protocol, which was conducted in agreement with the Declaration of Helsinki. Written informed consents were obtained from the patients before the treatment.

PDR patients with TRD who received IVC or IVR as adjuvant treatments before vitrectomy with silicone oil infusion were included. The physician in charge of the patient's treatment was responsible for the decision of pretreatment with conbercept or ranibizumab and this was not based on any set of predefined criteria such as visual acuity and TRD type. The indications for vitrectomy included: (1) a macula-involving TRD; (2) macula-involving, combined TRD and rhegmatogenous retinal detachment (RRD); and (3) extramacular TRD with an adherent fibrovascular membrane triggering excessive macular traction. B-scan echography confirmed the macular status and TRD extent in patients with a preretinal hemorrhage that obscured clear fundus visualization. Exclusion criteria included: (1) TRD for >1 year; (2) a best-corrected visual acuity (BCVA) of less than hand movements; (3) any previous vitreoretinal surgeries; (4) <6 months of follow-up post initial surgery; (5) pre- or postoperative poor diabetes control [serum hemoglobin A1c (HbA1c) >9.0%]; (6) receiving anticoagulant or antiplatelet therapy; and (7) presenting abnormal coagulation-associated blood diseases.

Conbercept and ranibizumab treatment

All patients were given an intravitreal injection of conbercept (KH902; Chengdu Kanghong Biotech Co., Ltd., Sichuan, China; 0.5 mg in 0.05 mL; IVC group) or of ranibizumab (Lucentis; Novartis, Pharma AG, Switzerland, and Genentech; 0.5 mg in 0.05 mL; IVR group) 3–5 days before vitrectomy. When the intraoperative possibility for multiple breaks or incomplete traction release was noticed (caused by severe vitreoretinal adhesion), silicone oil infusion was administered. As previously described, the morphological criteria for silicone oil infusion comprise severe active fibrovascular proliferation and broad vitreous attachment around the disk, vascular arcade and extension to the periphery in a minimum of 3 quadrants, the presence of macular-off or combined traction, and RRD.⁵ The same surgeon (H.Z.) administered all injections and performed the surgeries.

Data collection

The patients' medical records and surgical notes were reviewed to extract age, gender, follow-up information, lens status, previous treatments, TRD type, coexisting complications, systemic data (including serum HbA1c level and systemic hypertension), preoperative and postoperative (6-month follow-up visit) BCVAs, operating time, anatomic success rate, and intraoperative and postoperative complications for each patient. The instrumentation used to dissect and remove fibrovascular membranes and the strategies for intraoperative hemostasis were obtained by reviewing the surgical video and summary sheets. The severity of intraoperative bleeding was graded based on the methodology for achieving hemostasis: “0” indicated self-limited bleeding without hemostatic procedures; “1” indicated intraoperative hemostasis through gentle direct depression of the bleeding point with the blunt tip of a vitreous cutter; “2” indicated hemostasis with elevated intraocular pressure (IOP); and “3” indicated hemostasis with elevated IOP and cautery of the bleeding point. On the first postoperative day, the rate and degree of the recurrent preretinal hemorrhage were monitored because silicone oil provides a clear medium. The severity of the postoperative preretinal blood was categorized into the following 3 grades: grade 1 indicated isolated clots having a total area <10 disk areas and no involvement of the posterior pole; grade 2 indicated the broad clot sheaths having a total area >10 disk areas with/without the partial involvement of the posterior pole; and grade 3 indicated the broad clot sheets having a total area >10 disk areas and overlaying the posterior pole. A standard Snellen chart was used to measure VA, and it was evaluated on a logarithm of minimal angle of resolution (logMAR) scale. Counting fingers vision and hand movements were defined as 20/2,000 and 20/20,000, respectively.¹³

Statistical analysis

Statistical analysis was performed using SPSS (v. 20.0; SPSS, Inc., Chicago, IL). All data were tested for normality using histogram graphical analysis and Kolmogorov–Smirnov numerical analysis. When the data conformed to normality, t-test was used for pairwise comparisons between the 2 groups. When the data did not conform to normality, the Mann–Whitney rank sum test was used. In cases of categorical data, Fisher's exact (where sample size was small) and chi-square tests were used. P < 0.05 was considered statistically significant.

Results

Patient demographics

In total, 79 eyes in 74 patients (37 and 42 eyes in the IVC and IVR groups, respectively) were included. Patient demographics and the preoperative ocular findings for the groups are shown in Table 1. No significant differences in terms of the baseline parameters were observed between both groups, including age, preoperative BCVA, bilaterality, TRD type, lens status, preexisting complications, and major systemic data. The mean follow-up periods were 11.5 ± 3.6 and 12.2 ± 3.9 months in the IVC and IVR group, respectively (P = 0.72). Six-month follow-up data were available for every patient in both groups.

Table 1.

Patient Demographics and Baseline Ocular Findings

	Preoperative (IVC group, n = 37)	Preoperative (IVR group, n = 42)	P
No. of eyes/patients	37/35	42/39
No. of men/women	19/16	21/18	0.97
Age (years)
Mean ± SD	49.7 ± 12.2	51.5 ± 13.3	0.70
Range	30–67	28–73
Bilaterality, n (%)	2 (6)	3 (8)	0.75
Preoperative BCVA
Mean Snellen equivalent (range)	20/1,000 (HM-20/63)	20/400 (HM-20/63)
LogMAR ± SD	1.41 ± 0.72	1.15 ± 0.58	0.49
Lens status
Phakia/pseudophakia	32/5	35/7	0.70
Type of RD, n (%)
TRD only	33 (89)	37 (88)	0.36
Combined TRD/RRD	4 (11)	5 (12)
Macula involved, n (%)	29 (78)	30 (71)	0.48
PVD, n (%)
None	28 (76)	30 (71)	0.67
Incomplete	9 (24)	12 (29)
Preoperative complication, n (%)
Persistent VH	17 (46)	17 (40)	0.62
INV or NVG	3 (8)	5 (12)	0.58
Previous PRP, n (%)
None	30 (81)	33 (79)	0.78
Incomplete	7 (19)	9 (21)
Systemic data
HbA1c (%) ± SD	7.8 ± 1.1	7.6 ± 1.2	0.42
Systemic hypertension, n (%)	25 (71)	32 (82)	0.28
Follow-up (months)
Mean ± SD	11.5 ± 3.6	12.2 ± 3.9	0.72
Range	6–21	6–23

IVC, intravitreal conbercept; IVR, intravitreal ranibizumab; BCVA, best-corrected visual acuity; HbA1c, hemoglobin A1c; HM, hand movements; INV, iris neovascularization; logMAR, logarithm of minimal angle of resolution; NVG, neovascular glaucoma; PRP, panretinal photocoagulation; PVD, posterior vitreous detachment; RRD, rhegmatogenous retinal detachment; SD, standard deviation; TRD, tractional retinal detachment; VH, vitreous hemorrhage.

Anatomic success rate and visual recovery

The initial anatomic success rates were 97% in the IVC group and 98% in the IVR group (Table 2). Although vitreoretinal reoperations were required for retinal reattachment, the final anatomic success rates were 100% in each group. The preoperative BCVA values ranged from hand movements to 20/63 (mean, 20/1,000 Snellen equivalents) in the IVC group and to 20/63 (mean, Snellen equivalents of 20/400) in the IVR group. The mean postoperative BCVAs were Snellen equivalents of 20/143 in the IVC group and Snellen equivalents of 20/105 in the IVR group. The mean postoperative BCVAs improved more significantly than the mean preoperative BCVAs in the groups (P < 0.001); however, no significant difference in terms of the mean preoperative BCVAs was observed between the groups (P = 0.49). Moreover, no significant difference in terms of the overall mean BCVA changes preoperatively and 6 months postoperatively (logMAR units, −0.58 in the IVC group versus −0.37 in the IVR group) was observed between both groups (P = 0.46).

Table 2.

Surgical Procedures at the Initial Surgery and Outcomes

	Preoperative (IVC group, n = 37)	Preoperative (IVR group, n = 42)	P
Operating time (min)	69 ± 13	72 ± 15	0.53
Instrumentation for FVM removal, n (%)^a
Vitreoretinal forceps	25 (68)	30 (71)	0.71
Membrane scissors	3 (8)	3 (7)	0.87
Relaxing retinotomy, n (%)	5 (14)	5 (12)	0.83
Initial reattachment, n (%)	36 (97)	41 (98)	0.93
Final reattachment, n (%)	37 (100)	42 (100)	1.00
Postoperative BCVA^b
Mean Snellen equivalent (range)	20/143 (HM-20/32)	20/105 (HM-20/40)
LogMAR ± SD	0.83 ± 0.57	0.78 ± 0.43	0.75
Mean BCVA changes (logMAR)^c	-0.58	-0.37	0.46

FVM removal included segmentation, delamination, peeling, and dissection of the membranes for removal from the retina.

The postoperative BCVA was measured at the 6-month follow-up visit.

BCVA changes were defined as the changes between the preoperative and the 6-month postoperative BCVA in logMAR.

FVM, fibrovascular membrane; SD, standard deviation.

Surgical procedures and intraoperative complications

The main surgical techniques during vitrectomy were analogous for both groups (Table 2). The mean surgical time was 69 min for the IVC group and 72 min for the IVR group (P = 0.53). The number of instances where micro forceps and micro scissors were required to eliminate fibrovascular membranes was also similar for both groups (P = 0.71 and P = 0.87, respectively). Relaxing retinotomy was performed in 5 eyes (14%) of the IVC group and in 5 eyes (12%) of the IVR group (P = 0.83).

Table 3 summarizes the intra- and postoperative complications in the groups. Overall, the incidences of intraoperative iatrogenic retinal tears were not significantly different between both groups (P = 0.58). The tears were intraoperatively treated by endolaser photocoagulation or cryoretinopexy and were not related to the subsequent complications, for example, RRD. Hemorrhages during fibrovascular membrane manipulations occurred in both groups; self-limited bleeding or direct depression was sufficient to achieve hemostasis in most cases. The intraoperative bleeding episode severity was similar between both groups (P = 0.66).

Table 3.

Intraoperative and Postoperative Complications After the Initial Surgery

	Preoperative (IVC group, n = 37)	Preoperative (IVR group, n = 42)	P
Intraoperative complications
Iatrogenic retinal breaks, n (%)^a	6 (16)	5 (12)	0.58
Mean scores of intraoperative bleeding	1.7 ± 0.7	1.9 ± 0.8	0.66
Postoperative complications
Fibrin formation, n (%)	9 (24)	13 (31)	0.51
Mean scores of postoperative preretinal hemorrhage	1.5 ± 0.3	1.5 ± 0.4	0.88
Progressing or persistent NVG, n (%)	1 (3)	2 (5)	0.63
Progressive fibrovascular proliferation, n (%)	1 (3)	1 (2)	0.93
Recurrent retinal detachment, n (%)	1 (3)	1 (2)	0.93

Iatrogenic retinal breaks included the sclerotomy-related peripheral retinal breaks and retinal breaks encountered during posterior manipulations.

Postoperative complications and reoperation rates

Transient fibrin formation was the major postoperative complication in the anterior chamber occurring in 9 (24%) and 13 (31%) eyes in the IVC and IVR groups (P = 0.51). All fibrin formations were resolved owing to the postoperative topical steroid administrations; vision was not affected. Postoperative preretinal hyphema developed in both groups, with isolated clots and a total area <10 disk areas and without involvement of the posterior pole in most cases. The severity of postoperative preretinal bleeding was similar between both groups (P = 0.88). Neovascular glaucoma (NVG) and iris neovascularization (INV) are the most serious postoperative complications of vitreous surgery for severe PDR. Although no new INVs or NVGs occurred during the follow-ups, the preexisting INV and NVG were controlled or stabilized in 2 (66.7%) of 3 eyes in the IVC group and in 3 (60%) of 5 eyes in the IVR group postoperatively; the frequencies of these cases were not significantly different between both groups (P = 0.63).

Recurrent retinal detachment that was complicated by progressive fibrovascular proliferation developed in 1 eye (3%) in the IVC group and in 1 eye (2%) in the IVR group, indicating no significant differences between both groups (P = 0.93). Both groups underwent vitreoretinal reoperations and achieved retinal reattachment.

Discussion

PDR is commonly characterized by serum leakage, retinal neovascularization, hemorrhage, and fibrovascular proliferation in the vitreous retinal interface, leading to further vitreous hemorrhage and TRD.¹⁴ One of the major factors causing neovascularization in PDR is the pro-angiogenic cytokine VEGF.¹⁵ Increased levels of VEGF are reported in the vitreous humor and fibrovascular tissues of eyes in patients with PDR.^16–18 Chen reported that preoperative intravitreal bevacizumab (IVB), a full-length recombinant humanized anti-VEGF monoclonal antibody, was helpful in facilitating vitrectomy for patients with severe PDR.¹⁹ The regression of the vascular component of fibrovascular complexes facilitates easier segmentation and delamination of membranes after anti-VEGF therapy because the membranes develop less adhesiveness toward the underlying retina, which can be easily separated from it.^5–7 Moreover, the hemodynamic retinal circulation changes (constriction and a reduced flow in new vessels) minimize the possibility of intraoperative bleeding. Less intraoperative bleeding may in turn provide a clear surgical field facilitating the operation. In addition, preoperative intravitreal VEGF inhibitors can shorten the blood reabsorption time post vitrectomy, reduce the incidence of recurrent vitreous hemorrhage, and improve BCVAs.

According to many clinical trials, it has been proved that IVB pretreatment ameliorates fundus conditions before vitrectomy for severe PDR. A meta-analysis comprising 6 randomized controlled trials and another comparative study on the clinical outcomes of vitrectomy with/without IVB pretreatment for severe PDR have proved that bevacizumab pretreatment can produce excellent clinical outcomes.⁷ The IVB pretreatment group required a shorter surgical time than the control group (P < 0.01). The postoperative results demonstrated considerable potential with shorter blood absorption times (P = 0.04), significantly lower incidences of recurrent vitreous hemorrhage (P = 0.05), and improved final BCVA values (P = 0.003) in the IVB group than the control group. Another meta-analysis by Zhang et al. involving 8 randomized controlled trials provides similar results, indicating that preoperative IVB may provide a safer and more effective vitrectomy for severe PDR.⁶

Ranibizumab is an engineered, humanized recombinant antibody fragment (Fab) that is active against all VEGF-A isoforms. A prospective, randomized, double-masked study comparing IVR and IVB as the adjuvant treatment before vitrectomy for PDR in terms of the parameters of surgical complexity suggested that IVR and IVB are equally effective surgical adjuvants.¹ No statistically significant difference between the groups in terms of iatrogenic retinal breaks, intraoperative bleeding, the use of endodiathermy and silicone oil, and mean total surgical time was observed.

Conbercept, a recombinant fusion protein, binds to all isoforms of VEGF-A and to PlGF and VEGF-B. PlGF, a member of the VEGF family, binds to the VEGFR Flt-1 and is upregulated by hypoxia, similar to VEGF. However, the studies of PlGF knockout mice show that PlGF is inessential for physiological angiogenesis in contrast to VEGF, but it plays a vital role in the angiogenesis process under pathological conditons.²⁰ PlGF has been recently implicated in early diabetic retinopathy (including retinal vascular leakage).²¹ Of specific importance for PDR, PlGF reportedly promoted retinal neovascularization in a mouse model of ischemia-induced retinopathy.²² The results of a clinical study showed a strong correlation between vitreous PlGF level and PDR disease activity with the expression of Flt-1 in human PDR membranes, suggesting that PlGF plays a pathogenic role in PDR.²³ Thus, the therapeutic targeting of PlGF with agents such as conbercept and aflibercept is possibly beneficial for treating diabetic macular edema (DME) or PDR. Conbercept achieves good visual outcomes similar to those of ranibizumab for treating DME, but displays a longer treatment interval and requires less intravitreal injections.²⁴ One potential differentiating property of conbercept is its ability to bind to PlGF and VEGF, leading to a speculation that this renders conbercept more efficacious.^10,25 The role of conbercept as an adjunct to vitrectomy for the administration of severe PDR has also been evaluated, and the preoperative IVC injection reduces the possibilities of intraoperative bleeding and is useful for the management of PDR.^11,12

Our study results comparing IVR and IVC pretreatments in terms of intraoperative and postoperative outcomes of vitrectomy with silicone oil for patients with severe diabetic retinopathy with TRD suggest that both treatments are equally effective surgical adjuvants. No statistically significant difference was observed between both groups in terms of anatomic success rate, postoperative BCVA, the use of vitreoretinal forceps or membrane scissors, relaxing retinotomy, and operating time. Intraoperative complications, including intraoperative bleeding and iatrogenic retinal breaks, and postoperative complications, including postoperative preretinal bleeding, fibrin formation, progressing or persistent NVG, progressive fibrovascular proliferation, and recurrent retinal detachment, were also similar between both groups. Our results are consistent with a recently published article by Cui et al., comparing the efficacy and safety of vitrectomy when assisted by IVC and IVR and triamcinolone acetonide intravitreal injection for PDR.²⁶ PDR patients with vitreous hemorrhage, retinal proliferation, or TRD were included in the prospective study. At baseline, TRD was present in 7 out of 20 eyes (35.0%) in IVC group and 7 out of 19 eyes (36.8%) in IVR group, respectively. The results showed that the preoperative application of IVC and IVR had equal effect in improvement of visual acuity, operation time, incidence of iatrogenic retinal breaks, endodiathermy rate, frequency of silicone oil tamponade, vitreous clearing time, and the incidence of intraoperative bleeding, as well as in the incidence of postoperative bleeding, PRP completion rate, and reoperation probability.

However, conbercept possesses a greater binding affinity toward VEGF-A than ranibizumab; in addition, it binds to PlGF and VEGF-B; this has led other studies to suggest that it is more effective than ranibizumab as an adjuvant pretreatment in vitrectomy for PDR.^27,28 However, our data demonstrate that the 2 reagents are equally effective surgical adjuvants. It is possible that the smaller molecular weight of ranibizumab enhances its penetration into the action site, thus offsetting its lower binding affinity compared with that of conbercept.²⁹ The studies in monkeys demonstrated that post single intravitreal administration, ranibizumab can rapidly distribute into the retina (6–24 h), and the biologically effective retinal concentrations of ranibizumab have shown to be preserved for approximately a month.³⁰ These results suggest that the inhibitory effect of anti-VEGF agents on fibrovascular activity is rapid and can persist even after the elimination of vitreous effect.

To examine the effect of conbercept versus ranibizumab pretreatments for diabetic vitrectomy, we selected only patients with TRD secondary to PDR who underwent silicone oil infusion. Given that silicone oil provides a clear medium to monitor the rate and degree of recurrent preretinal hemorrhage on the first postoperative day, we were able to properly evaluate the effects of the conbercept and ranibizumab pretreatments. In a similar study on the effects of IVB pretreatment, Yeh et al. suggested that bevacizumab reduces intra- and postoperative hemorrhages.⁵

Although the present study had limitations such as its retrospective design, small sample size, unmasked investigators and patients, and nonrandomized treatment choice (conbercept or ranibizumab), our results indicated for the first time that conbercept and ranibizumab are equally effective surgical adjuvants for treating patients with TRD secondary to PDR undergoing vitrectomy with silicone oil infusion. Further multicenter, randomized controlled studies are necessary to further determine fully the efficacy and safety of conbercept and ranibizumab pretreatment for vitrectomy in patients with PDR. In addition, further studies are warranted to investigate changes in aqueous humor or vitreous levels of VEGF, PlGF, and inflammatory cytokines in PDR patients receiving IVC or IVR.

Footnotes

Acknowledgments

Liaoning Science and Technology Project (No. 2013225303, H. Z.) and Fund for Scientific Research of The First Hospital of China Medical University (No. 2014-04, H.Z.) supported this work. However, the funders played no role in the study design, data assembly or analysis, publishing decision, or article preparation.

Author Disclosure Statement

The authors declare that there are no competing interests.

References

Pakzad-Vaezi

, Albiani

D.A.

, Kirker

A.W.

, Merkur

A.B.

, Kertes

P.J.

, Eng

K.T.

, Fallah

, and Forooghian

A randomized study comparing the efficacy of bevacizumab and ranibizumab as pre-treatment for pars plana vitrectomy in proliferative diabetic retinopathy. Ophthalmic Surg. Lasers Imaging Retina. 45:521–524, 2014.

Hernandez-Da Mota

S.E.

, and Nunez-Solorio

S.M.

Experience with intravitreal bevacizumab as a preoperative adjunct in 23-G vitrectomy for advanced proliferative diabetic retinopathy. Eur. J. Ophthalmol. 20:1047–1052, 2010.

Ishikawa

, Honda

, Tsukahara

, and Negi

Preferable use of intravitreal bevacizumab as a pretreatment of vitrectomy for severe proliferative diabetic retinopathy. Eye. 23:108–111, 2009.

Rizzo

, Genovesi-Ebert

, Di Bartolo

, Vento

, Miniaci

, and Williams

Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR). Graefes Arch. Clin. Exp. Ophthalmol. 246:837–842, 2008.

Yeh

P.T.

, Yang

C.M.

, Lin

Y.C.

, Chen

M.S.

, and Yang

C.H.

Bevacizumab pretreatment in vitrectomy with silicone oil for severe diabetic retinopathy. Retina. 29:768–774, 2009.

Zhang

Z.H.

, Liu

H.Y.

, Hernandez-Da Mota

S.E.

, Romano

M.R.

, Falavarjani

K.G.

, Ahmadieh

, Xu

, and Liu

Vitrectomy with or without preoperative intravitreal bevacizumab for proliferative diabetic retinopathy: a meta-analysis of randomized controlled trials. Am. J. Ophthalmol. 156:106–115 e102, 2013.

Zhao

L.Q.

, Zhu

, Zhao

P.Q.

, and Hu

Y.Q.

A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy. Br. J. Ophthalmol. 95:1216–1222, 2011.

Simunovic

M.P.

, and Maberley

D.A.

Anti-vascular endothelial growth factor therapy for proliferative diabetic retinopathy: a systematic review and meta-analysis. Retina. 35:1931–1942, 2015.

Umanets

, Korol

, Vit

, Zavodnaya

, and Pasyechnikova

Peculiarities of vitrectomy and morphologic changes in the epiretinal membrane after intravitreal aflibercept in patients with severe proliferative diabetic retinopathy. Retinal Cases Brief Rep. 11:114–118, 2017.

10.

, Xu

, Wang

, Xu

, Liu

, Tang

, Zhang

, Tang

, Wu

, Luo

, Ke

, and Group

A.S.

Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study. Ophthalmology. 121:1740–1747, 2014.

11.

, Ren

, Wei

, Zhao

, Zhang

, Liu

, Su

, Tan

, and Li

Intravitreal conbercept (Kh902) for surgical treatment of severe proliferative diabetic retinopathy. Retina. 36:938–943, 2016.

12.

Yang

, Xu

, Wang

, Mei

, Lei

, Liu

, Zhang

, and Zhao

A Randomized controlled trial of conbercept pretreatment before vitrectomy in proliferative diabetic retinopathy. J. Ophthalmol. 2016:2473234, 2016.

13.

Oshima

, Shima

, Wakabayashi

, Kusaka

, Shiraga

, Ohji

, and Tano

Microincision vitrectomy surgery and intravitreal bevacizumab as a surgical adjunct to treat diabetic traction retinal detachment. Ophthalmology. 116:927–938, 2009.

14.

Osaadon

, Fagan

X.J.

, Lifshitz

, and Levy

A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye. 28:510–520, 2014.

15.

Witmer

A.N.

, Vrensen

G.F.

, Van Noorden

C.J.

, and Schlingemann

R.O.

Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retinal Eye Res. 22:1–29, 2003.

16.

Aiello

L.P.

, Avery

R.L.

, Arrigg

P.G.

, Keyt

B.A.

, Jampel

H.D.

, Shah

S.T.

, Pasquale

L.R.

, Thieme

, Iwamoto

M.A.

, Park

J.E.

, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331:1480–1487, 1994.

17.

Wang

, Wang

, and Wang

Intravitreous vascular endothelial growth factor and hypoxia-inducible factor 1a in patients with proliferative diabetic retinopathy. Am. J. Ophthalmol. 148:883–889, 2009.

18.

Lim

J.I.

, Spee

, and Hinton

D.R.

A comparison of hypoxia-inducible factor-alpha in surgically excised neovascular membranes of patients with diabetes compared with idiopathic epiretinal membranes in nondiabetic patients. Retina. 30:1472–1478, 2010.

19.

Chen

, and Park

C.H.

Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy. Retina. 26:699–700, 2006.

20.

De Falco

The discovery of placenta growth factor and its biological activity. Exp. Mol. Med. 44:1–9, 2012.

21.

Huang

, He

, Johnson

, Wei

, Liu

, Wang

, Lutty

G.A.

, Duh

E.J.

, and Semba

R.D.

Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1alpha-VEGF pathway inhibition. Diabetes. 64:200–212, 2015.

22.

Carmeliet

, Moons

, Luttun

, Vincenti

, Compernolle

, De Mol

, Wu

, Bono

, Devy

, Beck

, Scholz

, Acker

, DiPalma

, Dewerchin

, Noel

, Stalmans

, Barra

, Blacher

, VandenDriessche

, Ponten

, Eriksson

, Plate

K.H.

, Foidart

J.M.

, Schaper

, Charnock-Jones

D.S.

, Hicklin

D.J.

, Herbert

J.M.

, Collen

, and Persico

M.G.

Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med. 7:575–583, 2001.

23.

Al Kahtani

, Xu

, Al Rashaed

, Wu

, Mahale

, Tian

, Abboud

E.B.

, Ghazi

N.G.

, Kozak

, Gupta

, Arevalo

J.F.

, and Duh

E.J.

Vitreous levels of placental growth factor correlate with activity of proliferative diabetic retinopathy and are not influenced by bevacizumab treatment. Eye. 31:529–536, 2017.

24.

, Rong

, Xu

, Niu

, and Wang

Comparison of 12-month therapeutic effect of conbercept and ranibizumab for diabetic macular edema: a real-life clinical practice study. BMC Ophthalmol. 17:158, 2017.

25.

, Cheng

, Li

, Yu

, Ke

, and Group

A.S.

Efficacy of intravitreal injection of conbercept in polypoidal choroidal vasculopathy: subgroup analysis of the aurora study. Retina. 36:926–937, 2016.

26.

Cui

, Chen

, Lu

, Dong

, Wei

, Jiao

, Charles

, Gu

, and Wang

Efficacy and safety of intravitreal conbercept, ranibizumab, and triamcinolone on 23-gauge vitrectomy for patients with proliferative diabetic retinopathy. J Ophthalmol. 2018:4927259, 2018.

27.

Fogli

, Del Re

, Rofi

, Posarelli

, Figus

, and Danesi

Clinical pharmacology of intravitreal anti-VEGF drugs. Eye. 32:1010–1020, 2018.

28.

, Lei

, Zhang

, Li

, Xiao

, and Hao

Pharmacokinetics of a long-lasting anti-VEGF fusion protein in rabbit. Exp. Eye Res. 97:154–159, 2012.

29.

, Sun

, Guo

, Ma

, and Zhao

Comparison of conbercept with ranibizumab for the treatment of macular edema secondary to branch retinal vein occlusion. Curr. Eye Res. 42:1174–1178, 2017.

30.

Gaudreault

, Fei

, Rusit

, Suboc

, and Shiu

Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration. Invest. Ophthalmol. Vis. Sci. 46:726–733, 2005.