검안 및 콘택트렌즈 학회지 2015년 제 14 권 제 2 호 Ann Optom Contact Lens 2015;14(2):84-91 ISSN 2384-0919 (Print)⋅ISSN 2384-0927 (Online)

Original Article

Treatment of Macular Edema Secondary to Branch Retinal Vein Occlusion Sunho Park, MD, Kyung Seek Choi, MD Department of Ophthalmology, Soonchunhyang University College of Medicine, Seoul, Korea

Purpose: To compare the effect and complications of treatments for macular edema secondary to branch retinal vein occlusion. Methods: Literature review using the Korean medical database and the Korean Ophthalmological Society database, Korean Journal of Ophthalmology was performed. To compare the effect, studies used consisted of patients with macular edema secondary to branch retinal vein occlusion, according to visual acuity (VA) outcomes, central macular thickness (CMT) at 1, 3, and 6 months. Results: In the three studies comparing Intravitreal Triamcinolone Acetonide (IVTA) injection with intravitreal bevacizumab (IVB) injection, IVB injection demonstrated greater improvement in CMT at 1 month. In the three studies comparing IVTA or IVB single injection with laser photocoagulation or subtenon triamcinolone acetonide (STTA) combination therapy, combination therapy demonstrated greater improvement in VA and CMT at 3 and 6 months. Conclusions: The functional and anatomical improvements are achieved by IVTA injection, IVB injection, and combination therapy for macular edema secondary to branch retinal vein occlusion. The effect of IVB and IVTA injection is nearly similar and combination therapy is more prominent than monotherapy with longer duration. Ann Optom Contact Lens 2015;14(2):84-91 Key Words: Bevacizumab, Branch retinal vein occlusion, Laser photocoagulation, Macular edema, Triamcinolone acetonide

Branch retinal vein occlusion (BRVO) is a common dis-

Various cardiovascular, thrombophilic, systemic, and ocular

ease in which the retinal vein is compressed and occluded

conditions have been considered to predispose to the devel-

due to thickening of the arterial wall, primarily where the ar-

opment of BRVO.

1

tery and vein cross. Retinal hemorrhage, vitreous hemor-

With regard to other vasoactive factors, ischemia due to

rhage, tractional retinal detachment, and macular edema due

vascular obstruction causes excessive release of vascular en-

to BRVO lead to decreased visual acuity. Of these, macular

dothelial growth factor from the retina, with consequent dis-

edema is the most common cause of decreased visual

ruption of the blood-retina barrier. This increased vascular

1-3

In BRVOs, it is thought that a combination of com-

permeability, which is proportional to the levels of vascular

pression of veins at AV crossings, degenerative changes with-

4 endothelial growth factor, causes macular edema. Macular

in venous walls, and hypercoagulability may be causative.

edema is a major cause of visual acuity loss attributable to

acuity.

BRVO.5-7 The Branch Vein Occlusion Study found that grid ￭ Received: 2015. 2. 16. ￭ Accepted: 2015. 5. 29.

￭ Revised: 2015. 4. 30.

￭ Address reprint requests to Kyung Seek Choi, MD Department of Ophthalmology, Soonchunhyang University Hospital, #59 Daesagwan-ro, Yongsan-gu, Seoul 140-743, Korea Tel: 82-2-709-9354, Fax: 82-2-710-3196 E-mail: [email protected]

photocoagulation was effective for treatment of macular edema. The Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) project showed that grid photocoagulation was the best option for standard care when used to treat mac5,8

ular edema secondary to BRVO.

Currently, several studies have demonstrated the useful-

Copyright ⓒ 2015, The Korean Optometry Society & The Korean Contact Lens Study Society Annals of Optometry and Contact Lens is an Open Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

84

- Sunho Park and Kyung Seek Choi : Treatment of Branch Retinal Vein Occlusion -

ness of intravitreal injection of triamcinolone acetonide

significant. Heterogeneity was explored using the Q test with

(IVTA) and of antivascular endothelial growth factor (anti-

2 calculated I , indicating the percentage of variability in effect

VEGF) agents, such as intravitreal injection of bevacizumab

estimates that were attributable to heterogeneity rather than

9-13

(IVB) in dealing with macular edema due to BRVO.

However, some studies have shown that effectiveness of IVTA was not maintained after 1 year despite repeat

to chance. I2 values of 50% or more were considered to indicate substantial heterogeneity. Publication bias was explored by searching for asymmetry in the funnel plot.

14

injections. Another study reported that IVTA and IVB in-

RESULTS

jections were similarly effective for BRVO-related macular edema, but the IVTA group showed a longer mean improve15 ment duration than the IVB group. Since then, several stud-

The flow chart of studies from initial results to final in-

ies have been performed addressing the efficacy for the ther-

clusions is shown in Figure 1. Of the 328 potentially relevant

apy of macular edema caused by BRVO.

studies yielded by electronic searches, 7 met all of the pre-

In this study, we performed meta-analysis of the existing

defined inclusion criteria. Seven retrospective comparative

clinical trials for therapy of BRVO to evaluate the efficacy

trials published between 2009 and 2012 were included in this

and complications of those therapy.

meta-analysis.16-22 A total of 365 participants with 365 eyes in the 7 included trials were enrolled in this meta-analysis.

MATERIALS AND METHODS

Mean patient age was 55.5 to 61.9 years, and the proportions of males were 32.7% to 56.1%. There were no statistically

We searched the following electronic databases: Korean

significant differences among trials in terms of age, but stat-

Medical Database, Korean Ophthalmological Society data-

istically significant differences among trials in gender. Same

base, Korean Journal of Ophthalmology. We used free text

therapeutic dose used on IVB and IVTA groups in all trials

and thesaurus terms, including branch retinal vein occlusion,

(Table 1).

16-22

macular edema, laser photocoagulation, triamcinolone acetonide, bevacizumab. Full articles were retrieved, when titles

1. Comparision of intravitreal bevacizumab and 16-19

search on August 1, 2013. We reviewed the corresponding

triamcinolone acetonide injection All the 4 studies reported data on BCVA at 1 month after

articles in full text. Trials were considered for inclusion if

the initial treatment. BCVA was transferred to the logarithm

they met the following criteria: (1) retrospective comparative

of the minimum angle of resolution and summarized by

trials that compared IVB vs. IVTA or Monotherapy vs.

means of meta-analysis. On BCVA change at 1 month, there

Combination therapy for macular edema caused by BRVO

was no statistically significant differences between IVB and

and/or abstracts met this objective. We performed the final

and (2) trials reporting outcome measures (Best corrected visual acuity [BCVA], central macular thickness) and (3) follow up period was at least 3month or more. And we extracted data from the included trials population characteristics (age, number of patients and eyes in study, and gender), type of intervention, intervention protocol, number of intervention and complications. The following variables were used for outcome comparisons: (1) change of BCVA (2) change of central macular thickness on 1, 3, 6 month after treatment. All statistical analyses were performed with Review Manager Version 5.1 (The Cochrane Collaboration, Oxford, England) using 2-tailed p-values and a 95% confidence interval (CI). A p-value less than 0.05 was considered to be statistically

Figure 1. Flow diagram of the literature search and study selection.

85

- 검안 및 콘택트렌즈 학회지 2015년 제 14 권 제 2 호 -

Table 1. Characteristics of the 7 included studies Author (years) 16

Kim et al (2010)

17

Kim and Park (2009) 18

Jang et al (2011)

19

Hyun and Lee (2012) 20

Lee et al (2009)

21

Cho et al (2012)

22

Lee et al (2012)

Exposure

Dose

IVB IVTA IVB‡ IVTA IVB IVTA IVB IVTA IVTA IVTA + laser IVB IVB + STTA IVB IVB + laser

1.25 mg 4 mg 1.25 mg 4 mg 1.25 mg 4 mg 1.25 mg 4 mg 4 mg 4 mg 1.25 mg 1.25 mg + 40 mg 1.25 mg 1.25 mg

Patient (n) 66 50 52 47 41 60 49

Eye (n) 33 33 22 28 25 27 17 30 20 21 30 30 31 18

Mean age (years) 57.9

Sex (%, male) 40.9

Follow-up Period (months) 6

58.3

42.0

6

56.6

32.7

6

55.5

36.2

3

58.6

56.1

6

61.9

48.3

6

59.3

44.9

6

Mean number of injection 2.27 1.21 1

1 1 1.3 1.05 2.77 2 1.5

IVTA = intravitreal triamcinolone acetonide injection; STTA = sub-tenon’s triamcinolone acetonide injection; IVB = intravitreal bevacizumab injection.

Figure 2. Diagram showing the pooled summary estimates of change on visual acuity (logarithm of the minimum angle of resolution units). BCVA = best corrected visual acuity; IVB = intravitreal bevacizumab injection; IVTA = intravitreal triamcinolone aceto2 2 nide injection; CI = confidence interval; Tau2 = tau-square statistic; Chi = chi-square statistic; df = degrees of freedom; I = 86

- Sunho Park and Kyung Seek Choi : Treatment of Branch Retinal Vein Occlusion -

I-square heterogeneity statistic; Z = Z-statistic.

Figure 3. Diagram showing the pooled summary estimates of reduction on central macular thickness (micrometers). CM T = central macular thickness; IVB = intravitreal bevacizumab injection; IVTA = intravitreal triamcinolone acetonide injection; CI = confidence interval; Tau 2 = tau-square statistic; Chi 2 = chi-square statistic; df = degrees of freedom; I 2 = I-square heterogeneity statistic; Z = Z-statistic.

IVTA group. (Mean difference [MD]: -0.02, 95% Confidence

Data on central macular thickness at 1 month after the ini-

interval [CI]: -0.05 to 0.02, p = 0.43). All the 4 studies re-

tial treatment were available in all 4 studies. A high hetero-

ported data on BCVA at 3 months after the initial treatment.

geneity between the studies was detected (I2 = 80%).

2

High heterogeneity between studies was detected (I = 92%)

Random-effects model analysis showed that the reduction in

and therefore random effects model analysis was used. There

central macular thickness at 1 month was significantly higher

was no statistically significant differences of BCVA change

in the IVB group than in the IVTA group (MD: -55.87, CI:

at 3 months between two groups (MD: 0.06, CI: -0.07 to

-104.55 to -7.19, p = 0.02). 3 studies reported data on central

0.20, p = 0.35). Data on BCVA at 6 months after the initial

macular thickness at 3 months after the initial treatment. The

treatment were available in 3 studies. A high heterogeneity

central macular thickness change at 3 months , did not differ

2

between the studies was detected (I = 80%). Random-effects

significantly between the IVB groups and the IVTA groups

model analysis showed that the change of BCVA at 6 months

(MD: -19.77, CI: -42.76 to 3.21, p = 0.09). Data on central

did not differ significantly between the IVB groups and the

macular thickness at 6 months after the initial treatment were

IVTA groups (MD: 0.01, CI: -0.08 to 0.10, p = 0.79) (Fig. 2).

available in 3 studies. A high heterogeneity between the stud87

- 검안 및 콘택트렌즈 학회지 2015년 제 14 권 제 2 호 -

Figure 4. Diagram showing the pooled summary estimates of change on visual acuity (logarithm of the minimum angle of resolution units). BCVA = best corrected visual acuity; CI = confidence interval; Tau 2 = tau-square statistic; Chi 2 = chi-square statistic; df 2 = degrees of freedom; I = I-square heterogeneity statistic; Z = Z-statistic.

ies was detected (I2 = 92%). Random-effects model analysis

BCVA at 3 months after the initial treatment were available

showed that the reduction in central macular thickness at 6

in 3 studies. Compared with the monotherapy groups, BCVA

months did not differ significantly between the two groups.

improvement was significant in the combination therapy

(MD: 19.71, CI: -60.91 to 100.33, p = 0.63) (Fig. 3).

groups (MD: -0.10, CI: -0.16 to -0.04, p = 0.001). Data on

There was no severe complications except temporary in-

BCVA at 6 months after the initial treatment were available

traocular pressure elevation and subconjunctival hemorrhage

in 3 studies. BCVA at 6 months after combination therapy

in both groups.

was significantly increased as compared to the monotherapy group (MD: -0.14, CI: -0.22 to -0.06, p = 0.0003) (Fig. 4).

2. Comparision of monotherapy and combination 20-22

Data on central macular thickness at 1 month after the ini-

therapy

tial treatment were available in 3 studies. A high hetero-

All the 3 studies reported data on central macular thickness

geneity between the studies was detected (I = 94%). Random-

at 1 month after the initial treatment. High heterogeneity be-

effects model analysis showed that the effect of reduction in

2

2

tween studies was detected (I = 90%) and therefore random

central macular thickness did not differ significantly between

effects model analysis was used. There was no statistically

the monotherapy groups and the combination therapy

significant differences of BCVA change at 1 month between

groups. All 3 studies reported on the central macular thick-

two groups (MD: -0.06, CI: -0.19 to 0.07, p = 0.35). Data on

ness measured at 3 months after the initial treatment with

88

- Sunho Park and Kyung Seek Choi : Treatment of Branch Retinal Vein Occlusion -

Figure 5. Diagram showing the pooled summary estimates of reduction on central macular thickness (micrometers). CM T = central macular thickness; CI= confidence interval; Tau 2 = tau-square statistic; Chi 2 = chi-square statistic; df= degrees of freedom; 2 I = I-square heterogeneity statistic; Z= Z-statistic.

high heterogeneity (I2 = 52%). Random-effects model analy-

DISCUSSION

sis showed that the reduction in central macular thickness at 3 months was significantly higher in the combination therapy

Macular edema is the most common complication of

group than in the monotherapy group (MD: -38.78, CI:

BRVO, and is the most serious in terms of causing vision

-64.84 to -12.72, p = 0.004). A high heterogeneity between

loss. IVTA or IVB have been widely used and reported for

2

the studies was detected (I = 56%) at 6 months after initial

their efficacies. It has been claimed that IVTA reduces the

treatment. Random-effects model analysis showed that the

permeability effect of VEGF, and thereby reduces the leak-

reduction in central macular thickness at 6 months was sig-

age of osmotically active molecules from the vessel into the

nificantly higher in the combination therapy group than in

23 tissue. IVB directly inhibits VEGF, reduces vascular leak-

the monotherapy group (MD: -56.15, CI: -85.06 to -27.23, p

age, eliminates retinal and subretinal fluid, and improves the

= 0.0001) (Fig. 5).

hypoxic condition. However, the efficacy of IVTA or IVB is

There was no severe complications except temporary in-

still controversial. In many studies, IVTA, IVB, and the com-

traocular pressure elevation and subconjunctival hemorrhage

bination of both treatments have shown beneficial effects in

in both groups.

treatment of macular edema secondary to BRVO. Guthoff et

Based on funnel plots for the analysis of visual acuity and

al. compared the intravitreal bevacizumab with triamcinolone

central macular thickness, the left-sided asymmetry indicates

acetonide. They concluded that both treatments are effec-

a lack of smaller studies showing a reverse or smaller effect.

tive in reducing central macular thickness, but IVB is more

24

effective in improving visual acuity for 2 months. After 3 89

- 검안 및 콘택트렌즈 학회지 2015년 제 14 권 제 2 호 -

months, there is no difference in either group. Cekiç et al

The main potential limitation of our meta-analysis was that

compared the three different intravitreal treatment modal-

the number of studies which fulfilled the inclusion criteria of

ities, including intravitreal bevacizumab, intreavitreal tri-

this meta-analysis and which were eventually included into

25

amcinolone, and the combination of both. They concluded

the analysis was relatively low as was the number of study

that all treatment groups had similar therapeutic effects at

participants. This led to a relatively low number of patient in

one month, but at 6 months, the IVB group had better visual

the meta-analysis. Therefore, further clinical studies are war-

acuity. In our meta-analysis, change in BCVA at 1, 3, 6

ranted for many study participants and large population.

months after baseline did not vary significantly between the

Another limitation of this meta-analysis was that the in-

IVB group and IVTA group. And the reduction in the central

cluded studies were all retrospective comparative trials.

macular thickness at 1 month after baseline was significantly

Future work with randomized controlled trials is needed to

higher in the IVB group than in the IVTA group, while there

achieve definite results. And our meta-analysis was restricted

was no significant difference at 3, 6 months. These results are

to data from published articles, and it is possible that bias is

in agreement with other studies on the intravitreal use of bev-

introduced if studies with small or reverse effects exist but

acizumab or triamcinolone acetonide for the therapy of

were not accepted for publication. In conclusion, patients with branch retinal vein occlusion

BRVO. In our meta-analysis, the improvement in BCVA at 3, 6

experienced a nearly similar efficacy in terms of visual im-

months after baseline was significantly higher in the combi-

provement and reduction in macular edema after the intra-

nation therapy group than in the monotherapy group and the

vitreal injection of bevacizumab and triamcinolone acetonide.

reduction in central macular thickness at 3, 6 months after

And the combination therapy revealed the more significant

baseline was also significantly higher in the combination

efficacy in terms of visual improvement and reduction in

therapy group than in the mono therapy group. The results of

macular edema than the monotherapy in patients with mac-

our meta-analysis suggest that combination therapy led to an

ular edema secondary to BRVO.

increased visual acuity and corresponding reduction in cen-

Conflict of Interest

tral macular thickness for a period of 3, 6 months after initial treatment. These results are in agreement with other studies on the combination use of laser photocoagulation for the therapy of BRVO. Salinas-Alamán et al evaluated the effect

No potential conflict of interest relevant to this article was reported.

of bevacizumab associated with grid laser in macular edema 26 secondary to BRVO. In the study, IVB was administered at

REFERENCES

baseline followed by grid laser photocoagulation 1 month after. After 12 months, mean BCVA improvement and reduction of central macular thickness was significant. In a similar study by Donati et al, IVB monotherapy was compared with IVB combined with grid laser photocoagulation in patients with macular edema secondary to BRVO.

27

The improve-

ment in BCVA and the reduction in central macular thickness were significantly higher in the combination therapy group. Laser photocoagulation of the retina disrupts the retinal structure to some degree and induces the proliferation of retinal pigment epithelium and glial cells, which in turn results in scar formation in the retina, improving inner retinal hypo28-30

xia, intravascular pressure and retinochoroidal exchange.

These changes in the retina may help to inhibit further recurrence of macular edema. 90

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