Research Article, Int J Ophthalmic Pathol Vol: 0 Issue: 0
Long-term Outcome of Laser Photocoagulation Combined with Ranibizumab Intravitreal Injection in Macular Edema Secondary to Retinal Vein Occlusion
Xiao-Bing Yu*, Song S, Xiao-Ya Gu, Chen Q, Zhang P and Dai H
Department of Ophthalmology, Beijing Hospital, National Center of Gerontology, Beijing 100730, China
*Corresponding Author : Xiao-bing Yu, MD
Department of Ophthalmology, Beijing Hospital, National Center of Gerontology, Dahua Road, Dong Dan, Beijing 100730, China
Received: May 22, 2017 Accepted: June 08, 2017 Published: June 15, 2017
Citation: Yu XB, Song S, Gu XY, Chen Q, Zhang P, et al. (2017) Long-term Outcome of Laser Photocoagulation Combined with Ranibizumab Intravitreal Injection in Macular Edema Secondary to Retinal Vein Occlusion. Int J Ophthalmic Pathol 6:3. doi: 10.4172/2324-8599.1000204
Objective: To investigate the efficacy of laser photocoagulation combined with ranibizumab intravitreal injection in macular edema secondary to retinal vein occlusion in long term.
Methods: 35 eyes with branch retinal vein occlusion (BRVO) and 37 eyes with central retinal vein occlusion (CRVO) treated with or without laser combined with ranibizumab were investigated in this retrospective study. Laser was conducted 7-10 days after the third ranibizumab injection if fluorescein angiography showed ischemic area. In BRVO, patients may receive both macular grid and local peripheral retinal laser. In CRVO, patients just received peripheral retinal laser. We estimated the changes in visual acuity, central retinal thickness (CRT), number of injections and laser over 14 months.
Results: Both BCVA and CRT improved significantly in BRVO (P<0.05) but only CRT improved significantly in CRVO (P<0.05) among 14 months. The mean number of injections was 4.06 in BRVO and 8.14 in CRVO. Mean number of macular grid and peripheral laser was 0.31 and 0.86 in BRVO. Mean number of peripheral laser was 0.41 in CRVO.
Conclusion: Laser photocoagulation was important to patients with macular edema secondary to RVO after ranibizumab injections and may reduce the number of injections relatively in long term.
Keywords: Laser photocoagulation; Ranibizumab; Vascular endothelial growth factor; Retinal vein occlusion; Macular edema; Efficacy; Central retinal thickness
Retinal vein occlusion (RVO) is a common retinal vascular disorder . Macular edema is the major complication that can cause vision loss [2,3]. The management of macular edema due to RVO has changed over time. Treatment options for macular edema with RVO include laser photocoagulation and intravitreal injections [3-6]. Laser therapy can improve oxygenation in the treated area by causing constriction of the occluded vein and the adjacent arteriole resulting decreased edema . The laser photocoagulation was considered the gold standard treatment for over two decades . However, visual recovery with laser is usually incomplete and slow. Recently, intravitreal anti-vascular endothelial growth factor (VEGF) agents have proven safe and efficacy which are considered the firstline treatment option for macular edema secondary to RVO [3,5,6,8]. However, nearly fifty percent of the patients require repeat intravitreal anti-VEGF injection up to 4 years after initiating therapy to sustain the visual gains .
Though anti-vascular endothelial growth factors (VEGF) have heralded a new era which indicates rapid recovery of vision and quality of vision, RVO patients endured huge financial burden especially in developing or underdeveloped nations. We did this study and hoped to maintain vision, reduce number of injections and the financial burden by laser combined ranibizumab injection therapy.
This retrospective study followed the principles of the Declaration of Helsinki and was approved by the Beijing Hospital Ethical Committee. The subjects in this case-only study were 72 patients (one eye per patient) who were 18 years of age or older with macular edema secondary to RVO from June 2012 to May 2016.
The key inclusion criterion was a best-corrected visual acuity (BCVA) better than 15 (inclusive) Early Treatment Diabetic Retinopathy Study (ETDRS) letters (approximate Snellen equivalents, 20/500) at baseline and follow-up time ≧ 9 months. The key exclusion criteria included intravitreal anti-VEGF injections ≦ 3 months before baseline (either eye) and systemic anti-VEGF agents ≦ 6 months before baseline, retinal laser photocoagulation for macular edema ≦ 4 months before baseline and intraocular or periocular corticosteroid use ≦ 3 months before baseline (either eye).
All subjects were confirmed by the ophthalmology department of Beijing Hospital for a detailed examination including BCVA, intraocular pressure, slit-lamp biomicroscopy, dilated fundoscopic examinations, optical coherence tomography and fundus fluorescein angiography (FFA) of both eyes, and diagnosed with BRVO or CRVO. During every visit, they received BCVA, intraocular pressure, slitlamp biomicroscopy, dilated fundoscopic examinations and optical coherence tomography. FFA was reconducted 7-10 days after third injections and then per 3 months.
All of them received a minimum of 3 initial monthly ranibizumab 0.05mg injections. Then if there was vision loss or macular edema recurrence showed on OCT due to disease activity as judged by investigator, ranibizumab injections were again administered to the patients. Peripheral laser photocoagulation firstly was conducted 7-10 days after the third injection if FFA showed an area of nonperfusion in peripheral retina. Peripheral laser photocoagulation was performed in the relevant area with the posterior extent being 3000 μ away from the fovea. Every 3 months FFA was reconducted to evaluate retinal condition and if there was peripheral nonperfusion area, peripheral laser treatment should be reapplied. In BRVO, macular gird laser was firstly applied if OCT showed macular edema decrease 7-10 days after the third injection. If not, patients need ranibizumab injection until the macular edema decrease and CRT ≦ 250 um to receive macular grid treatment.
Efficacy and safety assessments
The BCVA was assess by certified vision examiners at every visit using ETDRS VA testing charts at an initial testing distance of 4 m. If it was not possible to perform a subjective refraction or VA testing at 4 m because VA was too poor for the patients to read ≧ 4 letters on the ETDRS chart at this distance, the refraction or VA testing were attempted at 1m.
Optical coherence tomography was performed by certified site personnel at each visit using spectral-domain OCT equipment (Heidelberg Spectralis, Heidelberg, Germany). The inner and outer retinal boundaries were segmented at predefined standardized locations to ensure standardization across the used spectral-domain OCT instruments.
Statistical analysis was performed using SPSS (version 19.0) software (SPSS, Chicago, IL, USA). Paired samples t-test was used to analyze the data of two groups. We set P-value <0.05 (two-sided) with statistical significance in this study.
A total of 72 eyes including 35 eyes with BRVO and 37 eyes with CRVO individually were enrolled in this study. In BRVO group as shown in Table 1, the mean (SD) age was 62.09(10.90) years, the baseline mean (SD) BCVA was 51.83(15.08) letters. The mean (SD) duration was 6.22(11.05) months. The mean (SD) observation time was 14.27(6.13) months. The mean (SD) baseline centre retina thickness (CRT) was 420.31(181.22) um. At the end of visit, the mean (SD) BCVA improved to 63.63(15.38) letters and 23 (65.7) patients gained ≧ 10 letters, the mean (SD) CRT decreased to 305.29(157.86) um and 26(74.3%) patients showed CRT decrease. In sum, BRVO patients received mean (SD) injections of ranibizumab 4.06 (2.66), macular grid laser treatment 0.31(0.58) times and local peripheral retinal laser treatment 0.86(0.81) over 14 months. 22 patients with local peripheral retinal laser treatment received mean 3.64 injections and 9 of them also received macular grid laser treatment. While 13 patients without laser received 4.77 injections.
|BRVO (n=35)||CRVO (n=37)|
|Mean ± SD(range)||Mean ± SD(range)|
|Age(years)||62.09 ± 10.99 (40-81)||55.05 ± 13.16 (27-84)|
|Follow-up time(months)||14.27 ± 6.13 (9-39)||14.30 ± 4.22 (9-26)|
|Duration(months)||6.22 ± 11.05 (0.1-60)||3.67 ± 4.64 (0-22)|
|Injections of ranibizumab||4.06 ± 2.66(1-10)||8.14 ± 2.96 (1-13)|
|Macular grid laser||.31 ± .58(0-2)|
|Peripheral retinal Laser||.86 ± .81(0-3)||.43 ± .56 (0-2)|
Table 1: Basic characteristics of RVO patients, BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion.
In CRVO group as shown in Table 1, the mean (SD) age was 55.05.09(13.17) years, the baseline mean (SD) BCVA was 48.08(17.14) letters. The mean (SD) duration was 3.67(4.64) months. The mean (SD) observation time was 14.30(4.22) months. The mean (SD) baseline centre retina thickness (CRT) was 623.73(245.34) um. At the end of visit, the mean (SD) BCVA improved to 51.92(21.70) letters and 19 (51.4%) patients gained ≧ 10 letters, the mean (SD) CRT decreased to 328.62(237.65) μm and 32(91.4%) patients showed CRT decrease. In sum, CRVO patients received mean (SD) injections of ranibizumab 8.14(3.0) and peripheral photocoagulation treatment 0.41(0.55) over 14 months. Among them, 15 patients with peripheral photocoagulation treatment received mean 7.73 injections.22 patients without laser received 8.41 injections.
As shown in Table 2, analyzing the changes of BCVA and CRT, it was found that both BCVA and CRT improved significantly in BRVO group. However, only CRT improved significantly in CRVO group though BCVA increased 3.8 letters but had not significant difference.
|BRVO (n=35)||CRVO (n=37)|
|Mean ± SD||P||95%CI||Mean ± SD||P||95%CI|
|BCVA baseline||51.83 ± 15.09||<0.001*||6.61-17.0||48.08 ± 17.14||0.34||-4.21-11.89|
|BCVA after treatment||63.63 ± 15.38||51.92 ± 21.70|
|CRT baseline||420.31 ± 181.22||0.006*||36.07-193.99||623.73 ± 245.34||<0.001*||187.51-402.71|
|CRT after treatment||305.29 ± 157.86||328.62 ± 237.65|
Table 2: The changes of vision acuity and CRT, BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; BCVA: Best corrected visual acuity; CRT: Centre retina thickness.*Paired sample t-test, P<0.05.
Discussion and Conclusion
The study evaluated the individualized 3+PRN therapy of ranibizumab, mainly based on VA and CRT changes, with or without laser photocoagulation in patients with visual impairment due to macular edema secondary to RVO. It was found that over 14 months, RVO patients gained BCVA improvement and CRT decrease evidently after the combined therapy of laser photocoagulation and ranibizumab intravitreal injection.
In this study, BRVO patients received 4.06 ranibizumab injections among 14 months with nearly 12 letters gains and 115 um CRT decrease significantly of which 68.6% patients showed CRT decrease and macular edema improvement. Similarly Pece and his associations indicated that 17 patients diagnosed with BRVO received 3.6 ranibizumab injections and 48.5% patients showed CRT decrease and macular edema improvement with 3+ PRN therapies over 12 months . Comparing with that study, the patients received 3+PRN+laser therapy in this study received relatively similar ranibizumab injections, gained better functional and anatomical improvement in much longer time.
Though anti-VEGF agents had been considered the first-line treatment option for macular edema secondary to RVO recently , laser photocoagulation still contributed obviously to the improvement in BRVO patients. According to BVOS group suggestion, macular gird laser photocoagulation is golden standard treatment for macular edema secondary to BRVO . Tomomatsu et al. assessed the efficacy of bevacizumab (anti-VEGF agents) combined with targeted retinal photocoagulation (TRP) compared to bevacizumab alone . In this study, bevacizumab injection was performed two weeks after TRP. The authors concluded that the combination therapy help reduce recurrence of macular edema . Similarly, Azad et al. compared the efficacy of ranibizumab and laser, bevacizumab and laser with that of laser alone in the management of BRVO with macular edema . Laser was performed in the combined group 7 days after the intravitreal injection similar to our study. The authors suggested that a combination of anti-VEGF agents and early laser results in better gains in visual acuity and reduced the number of subsequent injections . The BRIGHTER study showed that there was no distinct advantage of combination therapy over ranibizumab in terms of functional or vision recovery or prevention of recurrence . Analyzing the different results, firstly we suggested that patients in our study received not only macular gird laser but also peripheral retinal laser treatment. Secondly, the laser photocoagulation was administered 7-10 days after ranibizumab injection when macular edema may decrease and laser energy reduced with less damage. Recently, with the super-wide field fundus angiography appearance, the peripheral retinal ischemic area expanded which may be omitted by traditional examination. As is known that ischemic area of retina can promote VEGF production which lead to macular edema with vision harm. Therefore, the sooner to be applied laser treatment, the better to reduce retina edema theoretically. Thirdly, the BRIGHTER study had a follow-up for only 6 months but this study for 14 months . Some studies have shown that the benefits of grid laser become evident after the first year .
It was also found that patients with macular edema secondary to CRVO received 8.1 injections, 0.43 peripheral photocoagulation applications with 3.8 letters improvement and nearly 305 um CRT decrease over 14 months. From CRYSTAL study, the mean BCVA gain of patients with duration among 3-9 month was 11.6 letters and CRT decreased 333.4 um at month 12 . Though the advantage of laser treatment was not huge in CRVO patients of our study comparing to CRYSTAL study, we suggested that the numbers of ranibizumab injection may reduce when combined laser treatment in long time. Chhablani et al. conducted the study to evaluate the efficacy of combination of peripheral laser photocoagulation (PLP) with intravitreal bevacizumab in naïve eyes with macular edema secondary to CRVO and found that early PLP in eyes with CRVO neither showed additional benefits on functional outcome nor to reduce the number of injections during the 1-year follow-up . And PLP was applied at 1 month in treatment of naïve eyes with CRVO . Similarly, RETAIN and RELATE trials also reported no benefits of laser treatment [9,17]. Shah et al. treated nine patients with ME secondary to CRVO with a single intravitreal injection of bevacizumab within 10d from diagnosis, followed 3 weeks later by pan retinal and macular grid photocoagulation . They suggested that early intravitreal bevacizumab therapy followed by pan retinal and macular grid laser may provide visually and anatomically favorable results for treatment of CRVO. They indicated that the early combined treatment may also obviate the need for repeated injection . The time chosen to apply PLP may affect the final result.
Previous studies suggested that peripheral retinal laser photocoagulation was applied for area of nonperfusion on FFA >5 disc diameters in BRVO or >10 disc diameters in CRVO [4,12]. However, this study the combined treatment criterion was different evidently and that was any area of nonperfusion on FFA. Similar to Shah’s suggestion, we indicated that early laser treatment after ranibizumab injection may reduce the damage of laser with less energy and may reduce the macular edema much effectively. That may be the reason for different conclusions comparing with previous studies [14,16]. Though macular gird laser photocoagulation could reduce macular edema of BRVO patients as shown by previous studies [4,12,13], we also insisted that peripheral retinal laser treatment was necessary for patients with peripheral retinal ischemic area and the results of this study supported our suggestion.
This study also had several limitations. It was retrospective, caseonly and lacked a control group. The number of letters signifying loss or improvement of VA activity was not defined, but just based on the investigator’s judgment. The laser treatment applications were based on both investigator’s judgment and patients’ agreement, therefore some patients refused laser treatment because of laser energy injure and received ranibizumab injections continuously which may also affect the final results. The types of ischemic or non-ischemic were not classified which may affect the final results though we thought that classification criterion of these may not accurate by traditional FFA examination. The most important disadvantage was the small sample and our group would make advanced prospective study with large population, and control group in further to support our conclusion.
In summary, 3+PRN+laser therapy over 14 months resulted in BCVA gains and CRT decrease in patients with macular edema secondary to RVO. Laser photocoagulation treatment was important to patients with macular edema secondary to RVO after intravitreal ranibizumab injections and may reduce the number of ranibizumab injections relatively in long term. Large, multicenter, randomized controlled study is needed to be conducted in the further.
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