Analysis of factors associated with short-term elevation of intraocular pressure after Conbercept intravitreal injection

Abstract

KEYWORDS:Conbercept; intravitreal injection; ocular hypertension; influencing factor

INTRODUCTION

Intravitreal ranibizumab and conbercept are anti-vascular endothelial growth factor (anti-VEGF) agents used to treat choroidal neovascularization and retinal vascular disorders with rarely reported ocular adverse events such as intraocular inflammation, retinal tears, vitreous hemorrhage, endophthalmitis, lens changes, and intraocular pressure (IOP)[1-2]. As expected, volume driven acute ocular hypertension occurs immediately after intravitreal injection, but this increase in IOP is usually transient and easily tolerated. Some recent reports show that the continuous high IOP after each injection is different from the short-term acute high IOP, and it is also related to repeated intravitreal injection of anti-VEGF[3-4].

Treatment with intravitreal injection results in more fluid entering the intravitreal and may cause an increase in acute IOP. Transient and short-term increases in IOP following intravitreal anti-VEGF therapy have been well described in previous reports[5]. However, anti-VEGF therapy may also lead to long-term and sustained elevated IOP. There are many risk factors for chronic ocular hypertension caused by anti-VEGF treatment, including total injection times, high injection frequency, previous glaucoma and so on[1,6]. Here, we reported 269 eyes with short-term elevation IOP after conbercept intravitreal injection, and to investigate the influence factors of short-term IOP after conbercept intravitreal injection.

SUBJECTS AND METHODS

PatientsThis study was a clinical prospective observational study. This study enrolled in 269 eyes of 269 patients who were diagnosed retinopathy, and all patients receive conbercept intravitreal injection in our hospital from July 2018 to July 2019 were enrolled. There were 143 males and 126 females. There were 201 cases with age-related macular degeneration (ARMD) and 68 cases with other retinopathy patients. The average age was 62.86±11.74 years. The diagnosis was determined according to the fundus examination and fluorescein angiography. Inclusion criteria: 1) >18 years old; 2) Recent onset (<1.5mo); 3) No family history or history of glaucoma; 4) Follow up ≥ 1mo; Exclusion criteria: 1) Baseline IOP >21mmHg; 2) Axial length >26.00 mm or <22.00 mm; 3) Vitrectomy or other intraocular surgeries within half a year; 4) Other related diseases. This study followed the principles of the Helsinki Declaration and was approved by the Hospital Ethics Committee. The subject has been informed of the written consent of the study.

SurgicalandIOPMeasurementsAll patients underwent slit-lamp microscopy, IOP, best corrected visual acuity (BCVA), fundus angiography and optical coherence tomography angiography (OCTA) before surgery, which were performed by two experienced clinicians. The eye was treated with antibiotic eye drops 3d before injection. After surface anesthesia, conventional disinfection towel was used, 30G injection needle was used, 4.0 mm behind the edge of hornsclera below the temporal, vertical injection, and slowly injected 0.05 mL of conbercept (0.5 mg/0.05 mL). Non-contact pneumatic tonometer (NT-4000, NIDEK; Japan) was used to measure the IOP of patients before and after injection at 10, 30min, 2 and 4h, respectively. According to the reference[7], we divided the patients into the IOP elevation group and the IOP stable group according to whether the IOP elevation exceeded 10 mmHg at 10min after vitreous cavity injection.

RESULTS

VariationofIOPatEachTimePointThe mean IOP of the 269 patients in the study was 24.1, 20.2, 19.5 and 16.9 mmHg at 10, 30min, 2 and 4h after the injection, respectively. The IOP at each time point after the injection was 6.7, 3.1, 1.7 and 0.5 mmHg higher than that before the injection, with statistically significant differences (P<0.01). The number of eyes with IOP increased by more than 10 mmHg at each time point after surgery was 56 (20.8%), 15 (5.6%), 10 (3.7%), and 3 (1.1%), respectively. At 10min after injection, IOP in 9 eyes (3.4%) increased to more than 20 mmHg, all patients recovered to the preoperative level 4h after the operation, and no obvious abnormal IOP was observed in the follow-up observation for 1mo. It is worth mentioning that 5 of the 9 patients received more than 8 injections in total and 4 patients received more than 5 injections.

AnalysisofInfluencingFactorsIn 269 eyes of the 269 patients included in the study, 56 eyes in the group with elevated IOP and 213 eyes in the group with stable IOP were included. And the history of glaucoma was excluded in the 56 patients with elevated IOP during follow-up. Two-way ANOVA was used to compare IOP at different time points between IOP elevation group and IOP stable group. There was significant difference in IOP at different time points (Ftimes=494.197,P<0.01). There was significant difference in IOP between the two groups (Fgroups=106.452,P<0.01). There was no significant difference in age, BCVA (t=-1.634, -0.056, allP>0.05), gender, side and disease type (χ2= 2.110, 3.143, 2.235, allP>0.05) between the two groups. The number of injection (Z=-4.389,P=0.012), baseline IOP and IOP at each time point after injection (t=-5.343, -10.467, -8.933, -6.124, -4.635, allP<0.01) showed statistically significant differences (Tables 1 and 2). Multivariate and univariate Logistic regression analysis was performed on the significant factors (number of injection and baseline IOP). Finally, there was no statistical difference in the number of injection (B=-1.343,OR=1.189, 95%CI: 0.921-2.342,P=0.121), and the baseline IOP was positively correlated with the increase of IOP 10min after injection (B=-0.913,OR=0.521, 95%CI: 0.211-0.694,P=0.011; Table 3).

Table 1 The comparison of IOP at different time points in affected eyes mmHg)

Table 2 The parameters of the two groups

Table 3 The COX analysis of factors affecting IOP after vitreous cavity injection

DISCUSSION

Although the use of anti-VEGF drugs has increased in clinical practice, long-term safety data are still being published. The main studies on the complications of anti-VEGF treatment are mostly limited to intraocular inflammation, retinal tear, vitreous hemorrhage, endophthalmitis and lens changes. However, elevation of IOP was not found to be a complication of intravitreal injection[8-9]. With the injection of liquid into the vitreous cavity, the instantaneous increase of IOP is a phenomenon reported in the literature. Several published reports showed that IOP recovered to 25 mmHg within 30-60min after intravitreal anti-VEGF treatment, but it did not need IOP-lowering therapy[10-11]. Transient ocular hypertension immediately after intravitreal injection is a very common phenomenon, but some reports suggest that sustained high IOP after intravitreal injection of anti-VEGF is also possible[12].

At present, the anti-VEGF drugs that have been clinically approved for the treatment of neovascular ARMD and other retinopathy include pegaptanib, ranibizumab and aflibercept. There are some differences in the approved drugs all over the world. At the end of 2013, Chengdu Kanghong Pharmaceutical Group was approved by China Food and Drug Administration to use conbercept in the treatment of neovascular ARMD in China[13]. Conbercept, also known as KH902 (Chengdu Kanghong Biotechnology Co., Ltd.; Sichuan, China), is a recombinant fusion protein similar with aflibercept. It is a receptor bait composed of the second Ig domain of VEGFR-1, the third and fourth Ig domains of VEGFR-2 and the constant region (FC) of human IgG1[14]. There are some differences between conbercept and aflibercept in structure. The molecular weight of conbercept is larger, and there is one more fourth binding domain of VEGFR-2 than aflibercept. Compared with aflibercept, it has the characteristics of lower VEGF dissociation rate, higher binding affinity, lower adhesion to extracellular matrix and lower isoelectric point. As a result, it has a long clearing time[15]. Conbercept is well tolerated in clinical trials and provides visual results similar with other anti-VEGF drugs.

Previous studies have reported that eyes treated with intravitreal injection of ranizumab or bevacizumab may have sustained ocular hypertension. The probability of sustained ocular hypertension is between 3.5% and 6%, and the level of sustained ocular hypertension is between 22 - 58 mmHg[16-17]. This paper reports 269 patients with short-term elevated IOP after intravitreal injection of conbercept, and discusses the factors related to short-term elevated IOP. Our study showed that increased IOP after vitreous cavity injection was independent of disease, age and gender. This is consistent with the research results of Atchisonetal[18]. However, some researchers believe that the increased IOP after vitreous cavity injection has a certain correlation with the disease type and age, and this conclusion needs to be verified by further studies. According to Kimetal[19], the IOP of glaucoma patients injected with the anti-VEGF preparation in the glass body cavity is much higher than that of patients with normal IOP, and it takes longer for the IOP to return to the normal level. Whether glaucoma is a risk factor for increased IOP after vitreous cavity injection or not, the large fluctuation of IOP caused by repeated injections may cause great damage to the optic nerve, and therefore should be paid more attention by ophthalmologists. The results of this study showed that the baseline IOP was the main risk factor for the short-term IOP increase after the vitreous cavity injection of conbercept. The higher baseline IOP, the higher risk to gain elevation of IOP after injection.

At 10min after injection, the IOP increased to over 20 mmHg in 9 eyes, and there were 5 of the 9 patients received more than 8 injections in total and 4 patients received more than 5 injections. It is speculated that the number of injections may be related to increased IOP. In the univariate analysis, the number of injections was associated with increased IOP (P<0.01). But in the multifactor analysis, the number of injection was not associated with increased IOP (P>0.05). According to the comprehensive analysis, these conflicting results may be related to the small sample size of this study and the small difference in injection times between the two groups, which needs to be further verified by follow-up studies.

The results of Tsengetal[5]indicate that the intravitreal anti-VEGF drugs may affect the pathway of aqueous humor drainage of trabecular mesh, uveal sclera or schlemm tube, and then affect the normal aqueous humor circulation, resulting in increasing IOP. According to the research results of Sniegowskietal[20], after repeated injections into the vitreous cavity of anti-VEGF drugs, chronic inflammation and the inflammation of trabecular mesh lead to the obstruction of aqueous humor drainage and increase IOP. In addition, some researchers believe that silicone oil droplets in the injection instrument may deposit in the eyeball after multiple injections, leading to blocked outflow of aqueous humor and sustained IOP elevation[21-22]. Of course, this needs to be verified by further research.

Our research has certain limitations. It mainly includes: first, the sample size is small and the follow-up period is short; Second, the patients we include are not representative of most people; Third, the effect of corneal thickness was not considered in this study. Our results suggest that the main risk factor for short-term IOP elevation after intravitreal anti-VEGF therapy is the baseline IOP level. The higher the baseline IOP level, the higher risk to gain elevation of IOP after injection. A greater frequency of injection may be another risk factor. This provides some hints to clinicians that for patients with high IOP, glaucoma, or a greater number of injections, protective measures should be taken to prevent IOP elevation in advance, and IOP monitoring before and after operation should be taken as a routine examination item. Next, we will conduct a larger sample size and a longer follow-up period for a prospective control study to further verify the results of the study.