Background
Branch retinal vein occlusion (BRVO) is a common sight-threatening retinal vascular disease. The prevalence rate of BRVO is 4.42 cases per 1000 people [
1,
2]. Macular edema (ME) secondary to BRVO is considered to be the main cause of visual impairment [
3]. Recently, the treatment options for BRVO include anti-vascular endothelial growth factor (VEGF), corticosteroid and macular laser [
4,
5].
It is now recognized that anti-vascular endothelial growth factor drugs are first-line treatment, but repeated injections are needed [
6], which increases the financial burden of patients. And at present, there is no consensus on the treatment regimen. The clinical trial of globular phase III (BRAVO study) confirmed the efficacy of ranibizumab in the treatment of BRVO. It is recommended that once a month, at least 6 times continuously, follow (6 + PRN) as needed [
7]. In 2015, European ophthalmologist published a consensus that monthly injections achieved the best vision, followed by three consecutive follow-up visits (3 + 3PRN) until visual acuity was stabilized [
4]. Compared with 6 + PRN regimen, the 3 + 3PRN treatment can reduce the economic burden.
Macular laser for ME secondary to BRVO has been the standard therapy since the 1980s and the BVOS studies indicated that eyes which received macular laser therapy were more likely to maintain reasonable visual acuity when compared to the untreated eyes [
8]. The long-term results showed that the beneficial effect of macular laser is obvious, but the treatment response of some patients is not sufficient. Furthermore, the side-effect of macular laser was iatrogenic paracentral scotomas probably [
9]. Anti-VEGF drugs did not have the above side effects. Therefore, in the era of anti-VEGF, whether it is necessary for macular laser is worth discussing.
Since both macular laser and ranibizumab can effectively treat macular edema, we inferred that the combination of macular laser and ranibizumab can reduce the number of injections and reduce the economic burden of patients. The purpose of this study was to evaluate whether macular laser combined with ranibizumab injection is more beneficial to ME due to BRVO in terms of functional and anatomical results and reinjection frequency compared with ranibizumab alone. Here, we report the 12-month outcomes of our study (Clinical
trials.gov identifier: NCT 03054766).
Methods
Trial design
This study was a prospective, double-blind, single-center, randomized clinical trial (1:1 for two groups) which followed the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Hospital. The study was conducted between February 2017 and August 2019.All participants signed a standard informed consent form reporting on the potential risks, benefits of the procedure, subsequent management and they could not be identified through this document.
Participants
This study included 64 patients (one eye per patient) finally from enrolled 80 patients who were diagnosed with ME due to BRVO. All patients were confirmed by the ophthalmology department of Beijing Hospital for a comprehensive examination including blood pressure, best corrected visual acuity (BCVA), intraocular pressure (IOP), slit-lamp biomicroscopy, auto refractometry, gonioscopy, optical coherence tomography (OCT), fluorescein angiography (FA) and dilated fundoscopic examinations of both eyes.
The study enrolled treatment-naïve patients older than 18 years of age suffering from ME secondary to BRVO within 12 months, the BCVA letters score at baseline between 24 and 73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (approximate Snellen chart equivalent of 20/400 and 20/40) and the Central retinal thickness (CRT) was more than 250um.The patients were then classifed into two groups based on the presence or absence of retinal non-perfusion on FFA [
10]. Patients were excluded if they met the following criteria: (1) hemi-CRVO or CRVO (2) diabetic maculopathy and/or retinopathy; (3) any other BCVA compromising ocular disease; (4) any prior intravitreal anti-VEGF or corticosteroid injections; (5) any prior retinal laser photocoagulation; (6) IOP higher than 21 mmHg; (7) history of vitrectomy; (8) history of myocardial infarction or stroke with 3 months; and (9) other major systemic disorders.
Randomization and interventions
Shuang Song generated the random allocation sequence and Peng Zhang enrolled participants and assigned participants to interventions.
All eligible patients were randomly assigned (1:1) according to random number table to receive intravitreal ranibizumab 0.5 mg (ranibizumab monotherapy group) or intravitreal ranibizumab 0.5 mg with laser (IVR + Laser group). BCVA and CRT were the primary trigger of retreatment. Patients and investigators responsible for the treatment were both masked and the decision of re-treatment was based on the changes of BCVA and CRT. The eyes with more than 5 letters (ETDRS) loss due to disease activity or more than 100um increase of CRT would receive re-treatment every 4 weeks. The treatment protocol was similar to Gu’s study [
11].
The patients of IVR + laser group would receive macular grid laser photocoagulation 7 days after the third injection. Laser application was performed by Doctor Yu with a pan-funduscopic TransEquator lens (Volk optical Inc., Mentor, Ohio, USA) (spot size 100 μm; energy 100-300 mW; exposure time 100 msec; Volk Goldmann lense®) until soft whitening of the retina became apparent, according to the physician’s discretion. The patients of IVR group would receive sham macular grid laser photocoagulation 7 days after the third injection. Therefore, all patients who attained the criteria of re-treatment would receive re-injection of ranibizumab during follow-up period.
Study objectives
Our primary objective was to evaluate the change in BCVA and CRT in both groups after 52 weeks. Secondary objectives were to analyze the number of injections up to week 52 and the interval time from third to fourth injection.
Outcomes
Best corrected visual acuity (BCVA) improvement, central retinal thickness (CRT) reduction and the number of ranibizumab injections.
Best-corrected vision acuity
BCVA of patients was assessed with ETDRS VA testing charts by a certified examiner at baseline and every follow-up visit. The standard testing distance was 4 m, changing to 1 meter in case a patient could not read 4 letters at 4 m at least [
12].
Optical coherence tomography
SD-OCT (Heidelberg, Germany) examinations were conducted at every visit. Central retinal thickness (CRT) was measured by automated measurements provided by OCT software to measure central retinal thickness automatically.
Efficacy and safety assessments
The incidence of no matter ocular or non-ocular adverse events (AEs) and severe adverse events (SAEs) was assessed during follow-up period, and to indicate their possible relationship to ocular intravitreal injections and/or the study therapy.
Statistical analysis
Statistical analyses were performed with SAS 9.4 (SAS Institute Inc. Cary, North Carolina, USA) and statistical significance was established at two-tailed p < 0.05. Data were summarized as number (percentage), Mean ± Standard Deviation (SD) or Median (interquartile ranges [IQR]) as appropriate. T-test or non-parametric Wilcoxon test were adopted for between-group comparisons in normally or non-normally distributed continuous variables and chis-square tests for categorical variables. To analyze changes in BCVA as well as CRT, general linear models were constructed for variance analysis with baseline BCVA adjusted. Kaplan-Meier and cox proportional hazard models with covariates were constructed to compare time to the fourth injection after three initial injections. Safety analyses were conducted on the safety set. Adverse events (AEs) were summarized by reporting the number and percentage of patients with any ocular and/or non-ocular AEs.
Discussion
Both ranibizumab monotherapy and ranibizumab with laser therapy could improve BCVA and decrease CRT significantly in ME patients due to BRVO from this study. However, our results indicated that the effect between ranibizumab monotherapy and ranibizumab with laser were similar in no matter functional or anatomical benefit during 1 year. Also, the number of injections was similar (4 vs. 6) between two groups (
P = 0.0756). Some recent reports have also shown that this combination therapy can significantly improve BCVA and reduce CRT [
12‐
15], but the number of injections has not decreased, which is similar to the results of our study [
12,
13]. In the past we thought ranibizumab can neutralize upregulated intravitreal VEGF levels which contribute to ME development due to a blood-barrier breakdown in BRVO [
16], and laser can activate the pump function of retinal pigment epithelium and transport fluid out of the retinal structures to reduce CRT due to ME [
17]. Therefore, the combination therapy of ranibizumab with Laser in the treatment of macular edema has the above pathophysiological theoretical basis. Based on the above, we hypothesized that the combination of ranibizumab and laser therapy may reduce the number of injections. However, our results show that combination of macular grid photocoagulation showed no beneficial anatomical or functional effect during follow-up period, nor did it reduce the number of ranibizumab injections.
Our results showed that there was no significant difference in the injection interval (the interval between the third and fourth injections) after combined macular grid photocoagulation, and there was no significant difference in the number of injections between the two groups within 1 year. The results showed that combined macular grid photocoagulation could not prolong the injection interval in the short term and could not reduce the injection times in the long term. We speculate that it may be related to the increase of intraocular inflammatory factors in the short term after laser treatment. So it needs to be injected more times to inhibit these inflammatory factors, since ranibizumab can not only inhibit VEGF but also inhibit inflammatory factors [
18,
19]. There is only one macular laser in this study, it is speculated that the more times of macular laser, the more times of injection may be needed, so combined macular grid photocoagulation is not recommended.
Based on the above results, considering the retinal damage caused by macular laser and the economic burden of patients, we suggest that there is no need to combine macular grid photocoagulation in the treatment of macular edema secondary to BRVO in the future. From two-years results of the BRIGHTER study, ranibizumab was initially applied three times a monthly, followed by a VA stabilization criteria-driven PRN treatment regimen. Laser was performed on the same day ≥30 min before ranibizumab injection in the combination group; they observed a significant BCVA gain and CRT reduction but there was no significant difference between the two groups, and there was no difference in the number of injections [
13]. In their retrospective analysis, Farese showed that the combination therapy was more effective and required fewer injections. Laser was applied 2 weeks after bevacizumab injection [
20]. They indicated that the strongest bevacizumab effect and CRT reduction was 2 weeks after anti-VEGF injections and that might be the most effective time point for laser treatment [
20]. Their results showed that the average number of injections was 2.73 in combination therapy and 3.13 in bevacizumab alone therapy [
20]. In our study, ranibizumab was also administered three times on a monthly basis, followed by a VA and CRT stabilization criteria-driven PRN treatment regimen, and Laser was performed 1 week after the third injection. We thought that the decrease of CRT is the most obvious after three injections of ranibizumab, and it is the best to be treated with laser 1 week after the third injection. As shown in Appendix
6 and
7 of this study, although there was a significant difference in the reduction of macular edema between the two groups within 1 year (285.6 vs 395.6 μm), there was no significant change in visual acuity (18.8 vs.18.7). Therefore, we believe that the improvement of visual acuity is not completely proportional to the reduction of macular edema, indicating that both BCVA and CRT may be more appropriate as criteria for retreatment. In addition, the efficacy time of bevacizumab was 6 weeks, while that of ranibizumab was 4 weeks [
20]. These differences may lead to more injections in our studies. Different anti-VEGF efficacy time and different retreatment criteria may be the reasons for the different results of our study and Farese study [
20].
Our results showed that there was no difference in improvement of visual acuity, reduction of macular edema and injection times within 1 year regardless of whether ischemia or whether combined with laser therapy. In previous similar studies, Callizo focused on BRVO patients with non-ischemic macular edema [
12], while Tadayoni divided BRVO patients into macular ischemic and non-ischemic groups [
13]. These above are different from our grouping criteria, in which BRVO patients are grouped according to whether the retina is ischemic or not, and macular ischemia is not involved. In the past, it was considered that the visual acuity prognosis of retinal non-ischemic BRVO was better than that of ischemic type, and that of macular non-ischemic BRVO was better than that of ischemic type [
13,
21]. However, recent studies have shown that with the intervention of anti-VEGF therapy, the visual prognosis of ischemic and non-ischemic BRVO is the same [
13]. It is speculated that the possible reason is that the level of VEGF in macular edema due to BRVO is significantly increased. After 3 consecutive anti-VEGF treatments, the level of VEGF in BRVO of ischemic group and non-ischemic group decreased significantly, macular edema could disappear quickly, and visual acuity could be recovered quickly, which may be the reason for the same visual acuity prognosis in both groups. In addition, after three consecutive anti-VEGF treatments combined with macular grid photocoagulation, the laser may further reduce VEGF, but the effect is weak, which may be the reason for the same number of injections between the two groups.
The main limitation of this study is the number of patients is relatively small and the single center. Second,the follow-up period is only 1 year, which is relatively short. Therefore, larger number of patients is needed to be followed up for a longer time to confirm this result in the future.
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