Combination of Grid Laser Photocoagulation and a Single Intravitreal Ranibizumab as an Efficient and Cost-Effective Treatment Option for Macular Edema Secondary to Branch Retinal Vein Occlusion

Abstract

Our prospective comparative study of 60 patients aimed to compare the efficacy and feasibility of a single injection ranibizumab versus a single grid laser photocoagulation and versus a combined treatment in macular edema secondary to branch retinal vein occlusion in Asian population. Patients were randomized 1:1:1 (n = 20/group) into grid laser (LAS), the ranibizumab (RAN), and the combination (COM) group. Outcomes were measured as best-corrected visual acuity (BCVA) and central macular thickness (CMT). There were significant differences in mean BCVA between the three groups at 1 week and 1 month (p < 0.05) and in mean CMT at 1 week and 1, 3, 6, and 12 months (p < 0.05). Overall, best results were observed in the combination group. However, the RAN and COM groups achieved very similar results. At 12 months, the CMT in all three groups was decreased compared with baseline (p < 0.05). Our results allow to conclude that the effect of early treatment with a single injection of intravitreal ranibizumab (cost reduction) and the stabilizing effect of grid laser photocoagulation is indeed an effective, feasible, and safe regiment for macular edema secondary to BRVO in Chinese patients, allowing to obviate the need for repeated intravitreal injections and thus reduce the adverse events, therapy duration, patients' malcompliance, and adverse events. A single ranibizumab therapy however is a comparable alternative.

Introduction

Branch retinal vein occlusion (BRVO) is the second most common retinal vascular disorder following diabetic retinopathy.^1

–5 In United States, the prevalence of BRVO is 0.6% in patients older than 43 years.^6,7 The Beijing Eye Study revealed a prevalence of 1.3% among people >40 years old, while the total 10-year incidence was similar to that in other studies on Caucasian populations.^8

–11 The main consequence of BRVO is a secondary macular edema, which is also the most common cause of decreased visual acuity (VA).^12
–14 Hence, the quality of life is severely reduced in patients with macula impairment compared to BRVO patients without macular impairment.^15,16

Until recently, the standard of care for macular edema resulting from BRVO was the macular grid laser photocoagulation, based on the outcomes of the Branch Vein Occlusion Study (BVOS) published 32 years ago.¹⁷ The BVOS reported that patients with macular grid photocoagulation gained over 10 letters at 36 months, compared to untreated patients. Later data showed that the effect of macular grid laser treatment does not provide measurable results in the first year of therapy, and the prognosis of the vision is not improved since the immediate ischemic damage to central photoreceptors plays the most important role in permanent VA reduction.^18
–20 The laser treatment might even lead to further and irreversible damage at early BRVO stages, since laser use on hemorrhages in the inner retina can lead to energy absorption and thus ganglion cell injury. Usually, hemorrhages dissolve spontaneously within a few months.^21

–24 Therefore, a latency of 3-month interval before the beginning of laser treatment was required in the BVOS trial.⁶ However, in the latency phase, further irreversible photoreceptor damages and macular edema may lead to a permanent vision loss. Thus, in the last decades, clinical research focused on determining new, more effective, and earlier applicable therapeutic options beyond the grid laser photocoagulation to overcome the abovementioned challenges and to improve the vision of BRVO patients more rapidly and effectively.

Intravitreal agents, such as triamcinolone, dexamethasone, and vascular endothelial growth factor (VEGF) inhibitors ranibizumab and bevacizumab, demonstrated efficacy against macular edema secondary to BRVO.^25

–29 Ranibizumab (Lucentis™; Novartis, Basel, Switzerland), a recombinant, humanized, monoclonal antibody fragment with high affinity to multiple VEGF isoforms, has been approved for the treatment of macular edema due to retinal vein occlusion in the United States, United Kingdom, and Europe.^30
–32 Ranibizumab treatment after the onset of BRVO is associated with a significant mean reduction of the central macular thickness (CMT) and with improvements in best-corrected VA (BCVA) outcomes. However, the main drawback is the need for repeated injections at regular intervals to maintain the visual gain. A greater reduction in macular edema and improvement in VA was documented with a monthly rather than with a quarterly regimen.²⁸

A number of studies on Caucasian patients reported excellent results of combination therapies of injections to grid laser for macular edema caused by diabetic retinopathy and several of them also for BRVO, where the addition of intravitreal ranibizumab to laser improved the VA and markedly decreased the edema. In addition, the combination led to significantly lower retreatment rates.^33,34 In China, often the choice of therapy lies mostly in the hand of treating ophthalmologist, and the decision of which kind of management will be used varies according to physician's expertise, experience, and preference. In addition, the economic side is very important: repetitive intravitreal injections are expensive and often avoided due to the high costs. Corresponding studies comparing the laser versus ranibizumab versus combination on Asian populations are so far not available, which is astonishing regarding the relatively high incidence rate, especially in patients over 40 years of age.

We thus aimed to assess the efficacy of a single injection of ranibizumab, a single injection in combination with the grid laser photocoagulation, and with the laser alone. All options would be more attractive in aspects of patients' compliance, adverse events, and economics. We further wanted to analyze whether the significantly better results of the combination treatment in Caucasians are directly translatable to the Asian population.

Materials and Methods

We conducted a single center, prospective, comparative clinical study to evaluate the efficiency of the commonly but arbitrarily used methods in patients with chronic macular edema secondary to BRVO: grid laser photocoagulation, intravitreal ranibizumab, and a combination of both. This study was performed from November 1st 2013 to December 31st 2014 at the Shanghai East Hospital (Shanghai, China). The study was approved by the Ethics Committee of the Shanghai East Hospital and was conducted in accordance with the Declaration of Helsinki. All patients provided an informed consent before participation in the study.

Patients and grouping

Patients were enrolled with a painless vision loss or metamorphopsia for at least 2 months due to persistent macular edema secondary to acute BRVO. All patients underwent a scrupulous ophthalmologic investigation before the study, with focus on the retinal hemorrhage in the affected retina's quadrant (supplied by the occluded vein), edema, exudates, and engorged, tortuous venous system. Inclusion criteria were as follows: (1) VA ranging from 1/20 to 20/40 (assessed with Snellen charts) and (2) CMT 0 to μm measured by optical coherence tomography (OCT; Model 3000; Carl Zeiss Meditec, Inc., Dublin, CA). Exclusion criteria included the following: (1) other present (ophthalmologic) disease that could compromise the VA, induce ocular inflammation, or be associated with uncontrolled glaucoma; (2) intraocular surgery less than a month before the study; (3) recent history of myocardial infarction or stroke; severe unstable systemic disease; (4) previous treatments with laser photocoagulation or other intervention for macular edema due to BRVO; or (5) uncontrolled blood pressure.

Out of 72 identified patients, 63 met the inclusion criteria. Due to 3 dropouts, 60 patients (60 eyes) with chronic macular edema secondary to BRVO were included in the study and randomized 1:1:1 into three treatment groups: laser alone (LAS), ranibizumab alone (RAN), and combination (COM) group, with 20 patients (20 eyes under study) in every group. Group assignation was performed using a random number selection system, independently prepared by a statistician.

Treatment

At baseline, all patients underwent a thorough ophthalmological examination, including BCVA, CMT, and intraocular pressure (IOP). BCVA was measured with a Snellen chart. IOP was assessed using Goldmann applanation tonometry, indirect ophthalmoscopy, slit lamp examination with +90D, and fluorescein angiography (FA). CMT was assessed by OCT.

Patients in the LAS group underwent a single grid laser photocoagulation. Patients in the RAN group underwent a single intravitreal injection of ranibizumab (0.5 mg/0.05 mL). Patients in the COM group underwent a combination therapy of single intravitreal injection of ranibizumab (0.5 mg/0.05 mL) and a grid laser treatment 7 days thereafter. Patients where no nonperfused areas were observed by FA were treated with a scatter laser photocoagulation, respectively.

Grid laser photocoagulation was performed at a spot size of 50 μm and exposure time of 0.1 seconds. The power was started at 50 mV and increased in steps of 10 mV to produce mild intensity covering areas of capillary leakage as seen on FA, 1 burn width apart. Scatter laser photocoagulation was performed at the nonperfused areas with a spot size of 200 μm, exposure time of 0.2 seconds, 1–2 burn width apart.

The intravitreal ranibizumab injection was performed under sterile conditions. After the injection, a topical antibiotic was applied.

Outcomes

The primary outcome was the time to eyesight recovery. Secondary outcomes were the time to a significant visual gain, improvements of CMT and IOP, and the number of complications. BCVA was determined as the logarithm of the minimum angle of resolution (logMAR). Patients with gain (from the baseline) of ≥ 0.3 logMAR units or ≥ 20/40 at 12 months, were considered to have a significant visual gain.

Follow-up

Follow-up was conducted at 1 week and at 1, 3, 6, and 12 months after the specific assigned treatment. Follow-up examinations included measurements of BCVA, CMT, IOP, and FA.

Complications

Patients were also monitored for signs of postsurgical complications, for example, cataract, glaucoma, vitreous hemorrhage, retinal detachment, and endophthalmitis.

Statistical analysis

SPSS 19.0 for windows (IBM, Armonk, NY) was used for data analysis. Categorical data were expressed as frequency and compared using the Fisher exact test. Normally distributed continuous variables are presented as mean ± standard deviation and were compared with one-way analyses of variance, followed by post hoc. Paired t tests were used to compare pre- and postoperative VA. The value p < 0.05 was considered statistically significant.

Results

Characteristics of the patients

Between November 1st 2013 and December 31st 2014, 72 patients were screened, 63 patients included in the study (63 eyes), and after 3 dropouts, 60 patients (eyes) were randomized into 3 groups (resulting in 20 patients per treatment group). The characteristics of the patients are presented in Table 1. Age, gender distribution, baseline BCVA, CMT, IOP, and disease duration were similar among the three groups (all p > 0.05).

Table 1.

Demographic and Clinical Characteristics of Patients

	LAS	RAN	COM	p
Patients (eyes), n	20 (20)	20 (20)	20 (20)
Age, mean ± SD years	66.90 ± 6.52	69.80 ± 7.10	66.80 ± 5.09	0.49
Sex (M/F)	12/8	13/7	11/9	0.81
logMAR BCVA	0.72 ± 0.19	0.79 ± 0.27	0.85 ± 0.35	0.59
CMT (μm)	598.00 ± 133.29	555.40 ± 115.57	620.30 ± 201.53	0.64
IOP (mmhg)	15.12 ± 3.30	15.42 ± 2.38	13.88 ± 1.79	0.38
Disease duration (months)	4.2 ± 3.3	4.1 ± 2.7	4.6 ± 3.5	0.10

LAS, grid laser; RAN, ranibizumab; COM, laser + ranibizumab; SD, standard deviation; BCVA, best-corrected visual acuity; CMT, central macular thickness; IOP, intraocular pressure; Disease duration, time between onset of symptoms and screening for participation in this study; LogMAR, logarithm of the minimum angle of resolution.

Time to recovery of the VA

Figure 1 and Table 2 illustrate the measurements of BCVA along the follow-up. BCVA in the LAS group did not show significant changes from the baseline along the 12 months of post-treatment follow-up. BCVA in the RAN group improved significantly at 1 week, 1 month, and 3 months after treatment compared to the baseline BCVA (all p < 0.05); at 6 and 12 months, BCVA returned to baseline values (p = 0.05 and p = 0.11). In the COM group, BCVA was significantly improved compared with baseline BCVA at each follow-up visit over the entire period of 12 months (all p < 0.05).

FIG. 1.

BCVA improvement among three groups at all follow-ups. BCVA, best-corrected visual acuity.

Table 2.

Comparison of LogMAR Best-Corrected Visual Acuity Among LAS, RAN, and COM Group

Group	Preoperative BCVA	Postoperative BCVA
Group	Preoperative BCVA	1 Week	1 Month	3 Months	6 Months	12 Months
LAS	0.72 ± 0.19	0.73 ± 0.19	0.71 ± 0.17	0.69 ± 0.21	0.66 ± 0.22	0.67 ± 0.26
p (vs. preoperative BCVA)		0.34	0.92	0.67	0.37	0.59
RAN	0.79 ± 0.27	0.54 ± 0.18	0.46 ± 0.26	0.43 ± 0.25	0.50 ± 0.27	0.54 ± 0.30
p (vs. preoperative BCVA)		0.01	0.02	0.01	0.05	0.11
COM	0.85 ± 0.35	0.52 ± 0.19	0.44 ± 0.33	0.40 ± 0.36	0.45 ± 0.40	0.51 ± 0.39
p (vs. preoperative BCVA)		<0.01	<0.01	<0.01	0.01	0.01
P₁	0.58	0.04	0.04	0.05	0.28	0.39
P₂	0.31	0.02	0.02	0.03	0.15	0.29
P₃	0.63	0.77	0.82	0.84	0.71	0.84

Data are shown as mean ± SD (range). BCVA was present as LogMAR.

P₁ : LAS versus RAN; P₂ : LAS versus COM; P₃ : RAN versus COM.

There was no significant difference in baseline BCVA among the three groups (p = 0.59). BCVA in the RAN group was significantly better at 1 week and 1 month compared to the LAS group (all p < 0.05). From 3 to 12 months, BCVA was not significantly different between the two groups (p = 0.05, p = 0.28, p = 0.39, respectively). BCVA in the COM group was significantly better at 1 week, 1 month, and 3 months compared with the LAS group (all p < 0.05), while it was not significantly different between the two groups at 6 and 12 months (p = 0.15 and p = 0.29, respectively). There was no significant difference between the RAS and COM groups along the treatment at all times (all p > 0.05). A comparison of logMAR BCVA among the three groups is depicted in Table 2.

Significant visual gain

Figure 1 and Table 2 illustrate the measurements of BCVA along the follow-up. At the 12-month follow-up, a significant visual improvement (BCVA gain ≥0.3 logMAR units) was observed in 25% (5/20) of the LAS, 40% (8/20) of the RAN, and 65% (13/20) of the COM group, compared to the respective baseline values (p = 0.036) (Table 3). The COM group had a higher number of eyes that achieved an improvement of two logMAR (p = 0.01).

Table 3.

Comparison of Visual Acuity Gain at 12 Months Among LAS, RAN, and COM Group

BCVA gain	LAS (%)	RAN (%)	COM (%)	P^*	P₁	P₂	P₃
≥0.3 LogMAR	5 (25)	8 (40)	13 (65)	0.036	0.31	0.01	0.11
≥20/40	2 (10)	6 (30)	9 (45)	0.048	0.11	0.01	0.33

P ^* compared among three groups.

P₁ : LAS versus RAN; P₂ : LAS versus COM; P₃ : RAN versus COM.

The number of eyes with a significant BCVA gain of ≥20/40 was significantly different among the three groups (p = 0.048). Two eyes (10%) in the LAS group showed an improvement of VA of 20/40, while six eyes (30%) and nine eyes (45%) in the RAN and COM groups, respectively, achieved that improvement at the final follow-up (Table 3).

Comparison of CMT

Figure 2 and Table 4 illustrate the measurements of CMT along the follow-up. The baseline CMT was similar among the three groups (598.0 ± 133.3 vs. 555.4 ± 115.6 vs. 620.3 ± 201.5 μm, p = 0.639). Compared with the baseline, CMT at the 3, 6, and 12 months follow-up visits was significantly decreased in the LAS group (all p < 0.05), while it was significantly decreased for both the RAN and COM groups (all p < 0.05) from the first week on. CTM in the RAN group was significantly lower compared to the LAS group over the entire follow-up period (all values reached p < 0.05). A series of OCT of an exemplary patient of the RAN group is shown in Figure 1. CTM in the COM group was significantly lower compared to the LAS group (all p < 0.05). There was no significant difference of CMT between the RAN and COM groups (p > 0.05).

FIG. 2.

CMT improvement among three groups at all follow-ups. CMT, central macular thickness.

Table 4.

Comparison of Central Macular Thickness Among LAS, RAN, and COM Group Microns

Group	Preoperative CMT	Postoperative BCVA
Group	Preoperative CMT	1 Week	1 Month	3 Months	6 Months	12 Months
LAS	598.00 ± 133.29	597.90 ± 131.81	584.50 ± 118.54	481.30 ± 84.04	405.40 ± 79.30	367.60 ± 70.70
p (vs. preoperative CMT)		0.97	0.12	<0.01	<0.01	<0.01
RAN	555.40 ± 115.57	397.90 ± 60.21	330.70 ± 64.12	315.70 ± 65.73	319.80 ± 73.56	295.10 ± 67.15
p (vs. preoperative CMT)		<0.01	<0.01	<0.01	<0.01	<0.01
COM	620.30 ± 201.53	397.50 ± 74.72	319.70 ± 54.36	295.40 ± 75.64	297.30 ± 83.02	284.10 ± 76.87
p (vs. preoperative CMT)		<0.01	<0.01	<0.01	<0.01	<0.01
P₁	0.54	<0.01	<0.01	<0.01	0.02	0.03
P₂	0.75	<0.01	<0.01	<0.01	0.01	0.02
P₃	0.36	0.99	0.77	0.55	0.53	0.73

P₁ : LAS versus RAN; P₂ : LAS versus COM; P₃ : RAN versus COM.

Comparison of IOP

There was no statistically significant difference of IOP between baseline and follow-up values (all p > 0.05) in all groups (Table 2).

Complications

No local or systemic complications, such as endophthalmitis, clinically evident inflammation, retinal tears, retinal detachment, or thromboembolic events, were noted at any point of time.

Subjective experiences of the patients

Patients were surveyed before the treatment and at every follow-up. The subjective experiences and changes in vision were documented and corresponded to the measured objective values. Importantly, all patients were satisfied with the treatment and did not drop out of the study–this enforces the concept of a single injection.

Discussion

Macular edema secondary to BRVO can cause vision loss due to blockage of a retinal vein branch. For many decades, treatment with grid laser photocoagulation was the gold standard. However, a sole use of the grid laser has several disadvantages, such as possible permanent damage of visual capacity if a hemorrhage is present, the latency till a laser session can be conducted, and the latency toward an improvement in patient's condition (VA). Recent years brought many positive reports on ranibizumab use for macular edema, which was associated with good initial results, but was challenging to patients' compliance due to the necessity to repetitive injections.

Both options alone and in combination have been studied and reported very effective in macular edema due to diabetic retinopathy in white race. In this study, for the first time as to our knowledge, we investigated the combined therapy using grid photocoagulation laser and single injection of ranibizumab, compared to a use of both substances alone, in the Asian population. This is urgently needed, since Asians are more at risk of developing the condition and the prevalence is almost double higher than in Caucasians.³⁵ In China, various institutions arbitrarily chose the management, as per physician's expertise or choice. In our study, we aimed to constructively, systemically, and blindly compare the efficacy and feasibility of all three treatment options, as well as the duration needed to a subjective and objective improvement and to assess the safety. We conducted a prospective, long-term follow-up study with a representative number of eyes in each treatment group.

The Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) trial demonstrated not lasting benefits of the laser treatment within 12 months.^12
–14 Further smaller trials reported that its efficacy at 9 months is comparable with no treatment.¹⁹ Thus, the results from BVOS trial of 1984 were challenged.^36,37 Still, scatter laser and grid laser are the main treatment approaches for BRVO in China. Although laser treatment leads to only very slow improvements, it gives gradual and steady effects compared to ranibizumab. It allows to avoid medical risks of intravitreal injection and the economic burden of multiple repeated injections. Ranibizumab, however, offers a rapid bettering of the VA and can be used quickly after the macular edema onset.^20,28,38,39 Due to the long persistence of the macular edema and the rapid diffusion of the drug, intravitreal injections have to be repeated often to sustain the visual improvement. Based on the prospective randomized BRAVO and HORIZON trials, 6 monthly treatments were needed during the first 6 months; from month 7 to 12 the average number of supplementary treatments was 2.8; in the second year of follow-up, the average number of repeated injections was 2.1; and an average of three injections was still needed in 50% patients of BRVO during the fourth year of follow-up.²⁸

Therefore, we hypothesized that the combined effect of early treatment with intravitreal ranibizumab and the stabilizing effect of grid laser photocoagulation could be used in an attempt to obviate the need for repeated intravitreal injections. From the economic point of view and from the patients' comfort perspective, it would be extremely beneficial to reduce the number of ranibizumab injections to one. Thus, we have chosen a regiment with a single injection of ranibizumab, followed by laser treatment.

Our results suggest that the combined intravitreal ranibizumab with the grid laser is very efficacious and safe for Asian patients and should be recommended as the primary therapeutic approach. We showed that this combination leads to a better VA and a decreased CMT at 12 months of follow-up compared to the two modalities used alone. This is an extremely positive outcome, since the combination treatment leads to a long-term efficacy of ranibizumab, comparable with reported trials in Europe and United States, where multiple injections were used. In our study, BCVA in the LAS group showed a slight improvement, but no significant difference (consistent with recent data), while there were significant differences in the mean CMT among the three groups during follow-up.

The IOP of the RAN and COM groups did not show significant changes after ranibizumab injection, suggesting that ranibizumab is mostly well tolerated. Only a few patients showed sustained elevated IOP after ranibizumab injection, suggesting that there is a subset of patients in which IOP should be monitored, but additional studies are necessary to identify the vulnerable group. Otherwise, we did not observe any adverse events, potentially also due to a comparatively low laser power setting (90–130 mV), which is a safer treatment plan.

The limitations of this study include the relatively small number of patients, the single center character, and lack of assessment of a boost dose of ranibizumab, which could help to better assess on how often the drug should be administered. In addition, although the follow-up time was fairly long, further studies with a follow-up of several years would be of great importance.

In conclusion, a combination of single ranibizumab injection and grid laser photocoagulation allows solid and safe results, comparable to multiple injections but at lower costs. A single injection alone however is a good alternative, as the outcomes do not differ much, but place the patient at a lower risk for complications, malcompliance, and costs. Additional multicenter long-term trials are necessary to confirm these results and to demonstrate the efficacy and safety of the combined approach, as well as to address further optimizing, such as a potential reduction of VEGF dose or laser power.

Ethics Approval

This study was approved by the Ethics Committee of Shanghai East Hospital, Tongji University School of Medicine.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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