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Citation: Qiao G, Dong WJ, Dai Y, Jiang ZH, Guo HK. Diabetic macular edema in proliferative stage treated with anti-vascular endothelial growth factor agent and triamcinolone acetonide by laser-based strategies. Int J Ophthalmol 2017;10(7):1113-1119

Diabetic macular edema in proliferative stage treated with anti-vascular endothelial growth factor agent and triamcinolone acetonide by laser-based strategies

Gang Qiao^1,2,3, Wan-Jiang Dong², Yan Dai³, Zhen-Hua Jiang³, Hai-Ke Guo¹

¹Department of Ophthalmology, Guangdong General Hospital Affiliated to Southern Medical University, Guangzhou 510515, Guangdong Province, China

²Department of Ophthalmology, Mianyang Wan-Jiang Eye Hospital, Mianyang 621000, Sichuan Province, China

³Department of Ophthalmology, Mianyang Central Hospital, Mianyang 621000, Sichuan Province, China

Correspondence to: Hai-Ke Guo. Department of Ophthalmology, Guangdong General Hospital Affiliated to Southern Medical University, Guangzhou 510515, Guangdong Province, China. qiaogang3@163.com; guohaike@hotmail.com

Received: 2016-09-08 Accepted: 2017-02-13

Abstract

AIM: To appraise the effect of treatment for diabetic macular edema (DME) in proliferative stage with sufficient panrentinal photocoagulation (PRP) therapy and intravitreal injections (IV) Conbercept and posterior subtenon’s triamcinolone acetonide (STTA) sequential therapy.

METHODS: This prospective clinical randomized controlled trial of cross-over design was conducted in three phases. The participants included cases of DME in proliferative stage. They were divided into two groups and treated with PRP before enrollment. Group A were treated with IV-Conbercept 0.5 mg for one month in the 1^st phase. Group B were treated with STTA 40 mg (twice per two weeks). The interventions were exchanged in the second phase (2mo) between the two groups. In the third phase (3-6mo) no other treatment was given. Best corrected visual acuity (BCVA), central macular thickness (CMT) measured by OCT and complications were compared.

RESULTS: After phase I: in Group A, BCVA improved from 0.201±0.17 to 0.37±0.24 (F=5.88, P=0.004). CMT changed from 449±155.10 to 304.1±84.70 μm (F=14.9, P<0.01). In Group B, BCVA changed from 0.195±0.19 to 0.26±0.20 (F=0.76, P=0.41) while CMT changed from 463.82±152.92 to 366.00±115.40 μm (F=3.70, P<0.03). The improvement of BCVA was better in Group A (P<0.05). After phase II: in Group A, BCVA raised to 0.47±0.27 (F=0.26, P<0.01), CMT reduced to 260.67±62.97 μm (F=-188.3, P<0.01); in Group B, BCVA raised to 0.51±0.26 (F=0.31, P<0.01), CMT reduced to 261.93±50.15 μm (F=-201.9, P<0.01). But there were no difference between two groups (P>0.05). After phase III: in Group A, BCVA maintained 0.42±0.25 (F=0.22, P=0.001), CMT maintained 267.8±58.34 μm, (F=-0.27, P<0.01); in Group B, BCVA was 0.47±0.25 (F=-0.27, P<0.01), CMT was 272.71±49.16 μm (F=-191.1, P<0.01). No serious complications happened in all phases.

CONCLUSION: PRP+Conbercept is better than PRP+STTA in DME with proliferative stage but PRP+Conbercept+STTA sequential therapy may be a wiser choice for persistent effectiveness on anatomical as well as functional status.

KEYWORDS: Conbercept; sequential therapy; cross-over design; diabetic macular edema

DOI:10.18240/ijo.2017.07.15

INTRODUCTION

Diabetes mellitus (DM) is not only epidemic in developed country but also in developing country^[1]. At present, there are 110 million diabetic persons in China, which are the most cases in a developing country^[2]. Diabetic retinopathy (DR), a microvascular complication of diabetes, is more than 35% of diabetes^[3]. The average rate of proliferative diabetic retinopathy (PDR), one of serious complications of DR, is 3.3%-7.4%. Diabetic macular edema (DME), another serious complication of DR, occurs with a large proportion in DR also^[4]. The two main serious complications of DR constitute the major causes of visual loss in diabetics in China.

When DME occur in stage of proliferative retinopathy, treatment becomes more difficult^[5-6]. The main treatment modalities are panretinal or focal laser treatment, intravitreal injections of anti-vascular endothelial growth factor (VEGF) or triamcinolone acetonide (TA) and pars plana vitrectomy (PPV)^[7-8]. Although management of DME has country specific preferred practice pattern (PPP)^[9], managment protocols for DME in PDR after panrentinal photocoagulation (PRP) treatment is debatable.

Conbercept, a new medicine of China, has been demonstrated an excellent antiangiogenic effect for choroidal neovascularization caused by age-related macular degeneration compared with other imported anti-VEGF drugs such as Lucentis or Aflibercept^[10-12]. But the effect on DME in PDR has not been previously reported.

So, a clinical research was designed to explore this problem by laser-based strategies and intravitreal injections (IV)Conbercept combined with posterior subtenon’s triamcinolone acetonide (STTA) sequential therapy.

SUBJECTS AND METHODS

Study Design The study was a prospective, single-center, randomized controlled clinical trial by cross-over design. It included Chinese patients with DME in PDR stage from Mianyang Central Hospital in Mianyang, China. Written informed consent was obtained from all participants. The study was approved by the Institutional Review Board of the hospitals. The sample size were estimated by SPSS Statistical Package. The cross-over scheme were designed for every patient who could accept the same treatment after the clinical trial in accordance with the tenets of the Declaration of Helsinki and following the principles of minimally invasive, low cost and easy processing. This clinical trial was divided into three phases: PRP+Conbercept and PRP+STTA were contrasted in phase I, the effect of sequential therapies were compared in phase II and the persistent effects were oberserved in phase III.

Subjects The study population consisted of patients aged ≥18y with type 1 or 2 DM, hemoglobin (Hb) A1c ≤10%. Inclusion criteria were as follows: 1) patients with PDR who were treated with PRP, and not having PPV surgery in last six months; 2) DME detected on slit lamp biomicroscopy according to ETDRS criteria, leakage confirmed by intravenous fundus fluorescein angiography (FFA; TOPCOM-TRC 50DX, Japan), central macular thickness (CMT) ≥250 μm on optical coherence tomography (OCT; TOPCOM-3D OCT-2000, Japan).

Exclusion criteria were as follows: 1) rubeosis, glaucoma [intraocular pressure (IOP) greater than 29 mm Hg], significant cataract (which does not allow complete ocular examination and proposed measurements) and any condition that might interfere with assessment of the progression of macular oedema; 2) other retinal vascular diseases; 3) impaired renal function demonstrated by receiving dialysis or uncontrolled hypertension showing values of blood pressure (BP) greater than 90 mm Hg (diastolic BP) or 165 mm Hg (systolic BP); 4) patients who had received any investigational drug or device prior to screening; 5) subjects who had suffered PPV for vitreous hemorrhage or tractional retinal detachment ≤6mo; 6) any contraindication for intravitreal or subtenon’s injections.

Intervention We randomised the eyes into two treatment groups (A and B) by using a randomisation table. A flow diagram of patient progress in different phases of the study is shown in Figure 1. An eye was subjected to PRP treatment if leakage or capillary non-perfusion was confirmed by FFA before ocular injections commenced.

Gang Qiao1

Figure 1 Flow diagram of cross-over design clinical research.

Patients were examined before commencing intervention (baseline), at phase I (1wk, 1mo), at phase II (1.25mo, 2mo) and phase III (3mo, 6mo). At each visit, best corrected visual acuity (BCVA) was noted using the intemational visual chart (decimal), CMT were measureed by OCT. In addition, refraction, slit-lamp examination, tonometry and ophthalmoscopy were carried out. FFA, measurement of BP and HbA1c tests at baseline and at follow-ups.

In the first phase, patients in Group A were treated with IV-Conbercept 0.5 mg and patients in Group B were treated with STTA 40 mg (twice, per two weeks). In the second phase (sequential therapy), the therapeutic schemes were switched between groups. In the third phase no other treatment was given and patients were monitored.

Treatment Technique In all patients, intraocular injections were performed under sterile conditions in the surgery unit following standardized procedures. A volume of 0.05 mL containing Conbercept 0.5 mg (KH902; Chengdu Kanghong Biotech Co., Ltd., Sichuan Province, China) was injected at 3.5-mm distance from the limbus through the inferotemporal pars plana.

For posterior STTA injection under topical anesthesia, 40 mg TA (Kenacort A, 40 mg/mL; Bristol Myers Squibb Srl, Italy) in a 1-mL volume was injected into the inferotemporal quadrant using a 27-gauge cannula through a conjunctival opening.

Statistical Analysis Statistical analysis was performed using the statistical package Statistical Package for Social Sciences (SPSS) Version 20 (SPSS, Chicago, IL, USA). Data were expressed in frequency, percentage, mean ± standard deviation, median and 25% quartile as applicable. Analysis of variance (ANOVA) was used to compare between groups and paired t-test was used to compare with each group. A two tailed P value of less than 0.05 was considered significant.

RESULTS

Baseline Characteristics Preoperative clinical characteristics of patients in both groups are given in Table 1. Of the 40 patients (58 eyes), 23 were men and 17 were women, and all of them completed the 6mo follow-up. The mean age was 61.9 (SD 5.9) (range 52 to 73)y. The mean duration of diabetes was 6.44 (SD 2.69) (range 4 to 15)y. The mean HbA1c at baseline visit was 7.5% (SD 1.3%). Before treatment, the mean BCVA was similar in two groups (0.20 in Group A and 0.19 in Group B). Mean CMT was also similar (449 μm in Group A and 464 μm in Group B).

Table 1 Clinical characteristics of the groups mean±SD

Characteristics	Group A	Group B	t	P
Age (a)	61.9±6.1	61.8±5.8	0.09	0.93
Duration of DM (a)	6.3±2.8	6.63±2.61	-0.50	0.62
HbA1c (%)	7.5±1.3	7.50±1.22	0.02	0.98
BCVA (median, 25% quartile)	0.20±0.17 (0.18, 0.02)	0.19±0.19 (0.18, 0.02)	0.12	0.91
CMT (μm)	449±155.1	463.8±152.9	-0.37	0.72
IOP (mm Hg)	17.6±3.1	17.4±2.7	0.33	0.74
PPV suffered (eyes)	7	9	-	-
PRP replenished (eyes)	6	5	-	-

Outcomes of the First Phase Group A was effective in BCVA (F=5.88, P=0.004) and CMT (F=14.9, P<0.01). Group B was effective in CMT (F=3.70, P=0.03). BCVA of Group A (0.38±0.25) was different from Group B (0.23±0.22) after treatment 1wk (t=2.25, P=0.03). CMT of Group A (310.20±96.60 μm) was also different from Group B after treatment 1wk (t=-3.06, P=0.003) (Table 2). It indicated that IV-Conbercept was better in visual improvement and promoting macular edema absorption in early stage. After treatment 1mo, there were no difference (t=1.84, P=0.07) in BCVA between Group A (0.37±0.24) and Group B (0.26±0.20). But there were different (t=-2.34, P=0.02) in CMT between Group A (304.1±84.7 μm) and Group B (366.0±115.4 μm). It indicated IV-Conbercept was better in promoting macular edema absorption in this phase than STTA, but not better in visual improvement.

Table 2 Comparison of BCVA and CMT for groups in the first phase mean±SD

Phase I		Group A	Group B	t	P
BCVA (median, 25% quartile)	Baseline	0.20±0.17 (0.18, 0.02)	0.195±0.19 (0.18, 0.02)	0.12	0.91
	1wk	0.38±0.25 (0.35, 0.18)	0.23±0.22 (0.18, 0.07)	2.25	0.03
	1mo	0.37±0.24 (0.35, 0.14)	0.26±0.20 (0.23, 0.10)	1.84	0.07
Compared with baseline	F	5.88	0.76	-	-
	P	0.004	0.47	-	-
CMT (μm)	Baseline	449±155	464±153	-0.37	0.72
	1wk	310.20±96.6	404±136	-3.06	0.003
	1mo	304.1±84.7	366.0±115.4	-2.34	0.02
Compared with baseline	F	14.9	3.70	-	-
	P	<0.01	0.03	-	-

Outcomes of the Second Phase Both Group A and Group B had continuous improvement in BCVA and CMT. In the last follow-up visit of this phase, BCVA of Group A (0.47±0.27) was different from baseline BCVA (F=0.26, P<0.01). CMT of Group A (260.67±62.97 μm) was different from baseline CMT (F=-188.3, P<0.01). BCVA of Group B (0.51±0.26) was different from baseline BCVA (F=0.31, P<0.01). CMT of Group B (261.93±50.15 μm) was different from baseline CMT (F=-201.9, P<0.01). It indicated that both two therapeutic schedules made visual improvement and promoting macular edema absorption. There were no difference (P>0.05) between two groups. It indicated that the difference of two therapeutic schedule affect BCVA and CMT little in this phase. Both Group A and Group B were effective, there were no difference either firstly using anti-VEGF or firstly using TA in this sequential therapy (Table 3).

Table 3 Comparisons of BCVA and CMT for groups in the second phase mean±SD

Phase II		Group A	Group B	t	P
BCVA (median, 25% quartile)	1.25mo	0.43±0.28 (0.40, 0.15)	0.46±0.25 (0.40, 0.30)	-0.34	0.74
	2mo	0.47±0.27 (0.50, 0.19)	0.51±0.26 (0.50, 0.30)	-0.61	0.55
Compared with baseline	F	0.26	0.31	-	-
	P	<0.01	<0.01	-	-
CMT (μm)	1.25mo	281.73±81.89	269.36±60.10	0.65	0.52
	2mo	260.67±62.97	261.93±50.15	-0.08	0.93
Compared with baseline	F	-188.3	-201.9	-	-
	P	<0.01	<0.01	-	-

Outcomes of the Third Phase In follow-up 3 and 6mo, BCVA of Group A and Group B were both better than baseline data (F=0.22, P=0.001; F=-0.27, P<0.01). CMT of the two groups were thinner than baseline data (F=-181.2, P<0.01; F=-191.1, P<0.01). It indicated that the effect of laser-based strategies (sufficient PRP therapy)+IV-Conbercept+STTA sequential therapy could lasted to 6mo after treatment (Table 4).

Table 4 Comparisons of BCVA and CMT for groups in the third phase mean±SD

Phase III		Group A	Group B	t	P
BCVA (median, 25% quartile)	3mo	0.45±0.28 (0.40, 0.18)	0.48±0.26 (0.50, 0.30)	-0.41	0.69
	6mo	0.42±0.25 (0.45, 0.14)	0.47±0.25 (0.50, 0.30)	-0.75	0.45
Compared with baseline	F	0.22	-0.27	-	-
	P	0.001	<0.01	-	-
CMT (μm)	3mo	265.23±55.93	268.14±48.0	-0.21	0.83
	6mo	267.8±58.34	272.71±49.16	-0.35	0.73
Compared with baseline	F	-181.2	-191.1	-	-
	P	<0.01	<0.01	-	-

Trend Charts Analysis According to the analysis of trend charts for two therapeutic schedules (Figures 2, 3), it indicated that use of Conbercept in Group A could improve vision and macular edema got absorbed quickly. The sequential therapy of STTA in phase II could maintain this therapy effect to the last visit 6mo later. If STTA was used first the therapy effect was relatively sluggish, but the sequential therapy of IV-Conbercept in phase II rapidly improved the outcomes and this trend was maintained till the last visit also. However, there was no difference in the final effect between two groups. PRP+IV-Conbercept+STTA sequential therapy could still be effective in the third phase without any other treatment.

Gang Qiao2

Figure 2 Trend chart of BCVA of Group A and Group B.

Gang Qiao3

Figure 3 Trend chart of CMT of Group A and Group B.

Complications Each patient was given only one IV-Conbercept and twice STTA injections. This resulted in low and not severe complications. The main complications included: subconjunctival hemorrhage (7 eyes in Group A, 6 eyes in Group B), intraocular hypertension in short period (8 eyes in Group A, 10 eyes in Group B). The subconjunctival hemorrhage got absorbed spontaneously in one or two weeks. The intra ocular pressure was controlled in one or two days with or without anti-glaucoma drugs.

DISCUSSION

Macular edema can occur in any stage of DR, either nonproliferative or proliferative retinopathy^[6]. It is difficult to deal with when DME in PDR stage^[13-15], particularly in PDR having been treated with PRP^[16]. This kind of DME sometimes was called refractory DME^[17]. We designed this clinical research with laser-based strategies (sufficient PRP therapy) and IV-Conbercept+STTA sequential therapy to explore a minimally invasive, low cost and easy processing new therapy for this kind of DME.

Firstly , sufficient PRP therapy is the base of all the treatment in PDR, including PDR after PPV^[18]. There is improved oxygen supply to areas of inner retina that had become oxygen-deprived because of poor perfusion of inner retinal vessels after PRP^[19]. As a result, there is a decreasing number of viable hypoxic cells in the inner retina producing VEGF and other growth factors. The new vessels generally regress and may disappear altogether, without continuous production of VEGF, although stabilization of the neovascularization with no further growth also may occur^[20]. DME may occur before or after PRP in PDR, even worsen in some cases after panretinal treatment^[21]. So pharmacotherapy with anti-VEGF or glucocorticoids sequential therapy should be used to alleviate macular edema.

VEGF inhibitors are powerful means for DME. It was hypothesized that alternative or adjunct therapies using VEGF inhibitors could be beneficial in reversing vision loss from macular edema, as observing that VEGF intraocular levels are increased in DME^[7,11]. The VEGF family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PIGF). They are potent vasopermeability factors and play key roles in pathogenesis of DME^[22-23].

Although there are several anti-VEGF drugs that target the VEGF molecule, such as direct inhibitors of the VEGF molecule including the anti-VEGF aptamer pegaptanib (Macugen; OSI Pharmaceuticals, Long Island, NY, USA)^[24], the monoclonal antibody fragment ranibizumab (Lucentis; Genentech, South San Francisco, CA, USA)^[25], and the full-length antibody bevacizumab (Avastin; Genentech)^[26]. Other anti-VEGF molecules include soluble VEGF receptor analogs, VEGF-Trap (Regeneron, Tarrytown, NY, USA)^[27], and small interfering RNAs bevasiranib (Opko Health, Miami, FL, USA) and rapamycin (Sirolimus, MacuSight, Union City, CA, USA). Soluble protein that contains extracellular VEGFR-1, VEGFR-2 sequences fused to the Fc domain of a human immunoglobulin-G1 molecule including Aflibercept (Eylea; Regeneron, Tarrytown, NY, USA; and Bayer, Leverkusen, Germany)^[28-30] and Conbercept (KH902; Chengdu Kanghong Biotech Co., Ltd., Sichuan, China)^[29]. But only Conbercept is a new medicine of China. The effect of it on DME in PDR has not been previously reported.

We choose Conbercept to treat DME because of not only its antiangiogenic effect and but also it’s low price in China. It is a humanized, soluble, VEGFR protein which comprises extracellular domain 2 of VEGFR-1 and extracellular domains 3 and 4 of VEGFR-2, all of which are combined with the Fc region of human immunoglobulin G1 simultaneously^[31]. The structural difference between Conbercept and Aflibercept is that Conbercept also contains the fourth binding domain of VEGFR-2. This fourth domain is essential for receptor dimerization and enhances the association rate of VEGF to the receptor^[32]. Previous studies have demonstrated that extracellular domain 4 of VEGFR-2 can enhance the three-dimensional structure and efficiently advance dimerization^[33-35]. Also, preclinical studies have presented higher affinity of Conbercept for VEGF than bevacizumab^[36]. Moreover, recent phase 1 (HOPE)^[37] and phase 2 (AURORA)^[38] studies have shown an antiangiogenic effect of KH902 for choroidal neovascularization caused by age-related macular degeneration.

Another drug for DME in our research was TA, which is a long-acting corticosteroid. The corticosteroids are anti-inflammatory agents that stabilize retinal capillaries and tend to reduce their permeability by enhancing the activity or density of the tight junctions in the retinal capillary endothelium^[4,13]. In addition, they inhibit and downregulate the metabolic VEGF pathway to decrease the leakage of plasma proteins into the interstitial tissue compartment and to help restore the osmotic gradient between blood and tissue compartments, which eventually resolves the edema^[39]. Subtenon’s capsule injection of corticosteroids is an established method for the treatment of various inflammatory eye diseases and offers a good therapeutic response and ocular tolerance. Its prolonged therapeutic effect has provided ophthalmologists with an alternative tool for the treatment of different diseases. There are several recent reports on the effectiveness of intravitreal or posterior STTA treatment for reducing macular thickness in DME^[14,40]. We choose the way of posterior subtenon’s injection in order to avoid the main drawbacks of IV injections, which are potential retinal toxicity, invasive characteristics of the treatment, need for recurrent injections, and risk of endophthalmitis, cataract progression, and elevated IOP^[41].

Both PRP with only anti-VEGF and PRP with only glucocorticoids may give help for DME, but the therapeutic effect can not last long. These points has been discussed in documents. In this cross-over designed randomized controlled trial (RCT), we have further demonstrated that PRP+only anti-VEGF was better than PRP+only STTA in phase I: IV-Conbercept was better in promoting macular edema absorption than STTA.

Furthermore, PRP+anti-VEGF+STTA sequential therapy showed an excellently persistent effectiveness on anatomical as well as functional status for DME in phase II and phase III. This sequential therapy, abiding by minimally invasive principle, every patient accepted only once IV and twice subtenon’s injections, the rate of complications was low, and no serious complication happened. The deficiencies of two drugs were remedied and the merits were strengthened by each other. All of the above made the final therapeutic effect enhanced and side effect reduced. In last two phases, the difference of two therapeutic schedule became little, both groups had continuous improvement in BCVA and CMT. In follow up to 6mo, compared with baseline data, BCVA of IV-Conbercept were 0.42±0.25 (F=0.22, P=0.001). CMT of IV-Conbercept 267.8±58.34 μm (F=-181.2, P<0.01); BCVA of STTA were 0.47±0.25 (F=-0.27, P<0.01). CMT of STTA 272.71±49.16 μm (F=-191.1, P<0.01).

The pathophysiology of DME is complex, involving VEGF and other inflammatory mediators^[42]. Corticosteroids decrease inflammatory cytokines and have a modest anti-VEGF effect, while anti-VEGF agents have a modest anti-inflammatory effect. Using a corticosteroid in combination with an anti-VEGF agent allows the patient to benefit with increased efficacy as well as increased duration of effect^[5]. The sequential therapy reduced DME with both anti-VEGF and anti-inflammatory effect. The progress of PDR was inhibited by PRP treatment and macular edema was improved by reducing permeability of retinal capillary endothelium with Conbercept and TA. In this RCT, PRP+IV-Conbercept+STTA sequential therapy could maintain effective even in the third phase without any other treatment.

So we can draw a conclusion that the strategy meets the requirements of minimally invasive, low cost and easy processing principles. It made visual improvement and promoting macular edema absorption, and no serious complication happened. As relative less patients and short follow-up time, more long term multi-center RCTs are needed to confirm our conclusions.