Acta Ophthalmologica 2016
Comparative study of combined bevacizumab/ targeted photocoagulation vs bevacizumab alone for macular oedema in ischaemic branch retinal vein occlusions Yoko Tomomatsu, Takeshi Tomomatsu, Yoshihiro Takamura, Makoto Gozawa, Shogo Arimura, Yuji Takihara and Masaru Inatani Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Yoshida-Gun, Fukui-Ken, Japan
ABSTRACT. Purpose: To investigate whether targeted retinal photocoagulation (TRP) of peripheral non-perfused areas (NPAs) could prevent the recurrence of macular oedema (ME) due to branch retinal vein occlusion (BRVO) after intravitreal bevacizumab injection (IVB). Methods: Eyes received 1.25 mg IVB only (IVB group) or combined with TRP (IVB + TRP group) of NPAs, more than 5 disc areas identified by fluorescein angiography in the patients with ME secondary to BRVO. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) determined by optical coherence tomography were measured every month for 6 months. Results: Thirty-eight patients were enrolled and randomized to IVB group (n = 19) and IVB + TRP group (n = 19). Both groups showed similar thinning in CRT at 1 week after IVB, IVB + TRP group maintained thinner retina at 2 (p = 0.0072) and 3 (p = 0.0086) months compared with IVB group in whom turned to thickened almost back to baseline at 3 months. The number of reinjections in IVB group (1.58 0.69) was significantly greater (p = 0.0025) than that in IVB + TRP group (0.83 0.62). BCVA significantly improved at 6 month in IVB + TRP group (p = 0.015), but not in IVB group. Conclusion: TRP of NPAs reduced the amount of ME recurrence following IVB compared to IVB alone. Key words: best-corrected visual acuity – bevacizumab – branch retinal vein occlusion – central retinal thickness – fluorescein angiography – macular oedema – non-perfused areas – photocoagulation – vascular endothelial growth factor
Acta Ophthalmol. 2016: 94: e225–e230 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12721
Introduction Branch retinal vein occlusion (BRVO) is defined as focal occlusion of the major retinal vein; it frequently occurs at arteriovenous crossings (Jonas et al. 2010; Wong & Scott 2010). Macular oedema (ME) is the major cause of
visual disturbance associated with BRVO (Glacet-Bernard et al.1996; Arnarsson & Stef ansson 2000). Increased intravascular pressure and reduced blood flow in the macular capillaries can lead to dysfunction of the endothelial blood– retinal barrier and increased vascular
permeability, resulting in ME (Arnarsson & Stef ansson 2000). Vascular endothelial growth factor (VEGF) is thought to play an important role in the pathogenesis of ME with BRVO (Glacet-Bernard et al. 1996; Kreutzer et al. 2008; Kriechbaum et al. 2008). The ischaemic retina produces high levels of VEGF, which can exacerbate retinal vasculature leakage as well as retinal neovascularization as sustained release of VEGF in the vitreous cavity causes widespread leakage from retinal vessels (Jonas et al. 2010). Therefore, anti-VEGF drugs may play a critical role in the prevention and treatment of ME with BRVO. Recent prospective, randomized studies have demonstrated that intravitreal injections of anti-VEGF drugs are efficacious in reducing retinal thickness and improving visual acuity. (Kreutzer et al. 2008; Kriechbaum et al. 2008; Campochiaro et al. 2010, 2014; Higashiyama et al. 2013; Korobelnik et al. 2014; Yang & McKeage 2014; Pielen et al. 2015;). Currently used anti-VEGF drugs include ranibizumab, bevacizumab and aflibercept. Ranibizumab and bevacizumab are recombinant antibodies with pan-VEGF-A blocking activity. Aflibercept, VEGF-trap, is a fusion protein with high VEGF affinity attributed to binding sequences from the native VEGF receptors (Korobelnik et al. 2014; Yang & McKeage 2014). The recent prospective clinical trials including BRAVO study demonstrated
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Acta Ophthalmologica 2016
the promising effect of ranibizumab as the treatment of ME secondary to BRVO (Campochiaro et al. 2010). Bevacizumab (AvastinTM, Genentech, South San Francisco, CA, USA), a full-length humanized monoclonal antibody directed against all biologically active forms of VEGF-A, has been reported to be effective in decreasing retinal thickness and improving visual acuity when injected intravitreally for the treatment of BRVO. (Kreutzer et al. 2008; Kriechbaum et al. 2008; Higashiyama et al. 2013). Recently, anti-VEGF therapy is recognized as the gold standard treatment for ME secondary to BRVO; however, it remains clinically problematic that macular swelling tends to recur after a single injection of anti-VEGF drugs (Campochiaro et al. 2008; Chen et al. 2010; Ehlers & Fekrat 2011). Thus, frequent injections of anti-VEGF drugs are required to control ME (Chen et al. 2010; Ehlers & Fekrat 2011). However, repeated intravitreal injections raise the likelihood of adverse events such as endophthalmitis and retinal detachment. Therefore, it is clinically important to find ways to reduce the recurrence of ME after intravitreal anti-VEGF therapy. Even if VEGF levels can be reduced by intravitreal injection of bevacizumab (IVB), persistent production of VEGF from non-perfused areas (NPAs) may result in the recurrence of ME with BRVO. Targeted retinal photocoagulation (TRP) is a technique for treating NPAs confirmed by fluorescein angiography (FA), and this therapy is effective in minimizing the unwanted side-effects associated with pan-retinal photocoagulation including scotoma and peripheral vision loss (Muqit et al. 2013). We therefore designed this randomized clinical trial to determine the effect of PC for NPAs on the recurrence of ME with ischaemic BRVO after IVB.
Patients and Methods This clinical trial was approved by the University of Fukui Institutional Review Board and was consistent with the tenets of the Declaration of Helsinki. The protocol and the safety and efficacy implications of the interventions were explained to all participants before enrolment. All patients provided informed consent. This study was reg-
e226
istered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) of Japan (UMIN ID 000009689; date of access and registration, 2013/01/10). Patients with unilateral acute major BRVO who were at least 35 years old and had a reduction in best-corrected visual acuity (BCVA) of between 20/30 and 20/320 due to ME were eligible for this clinical trial. ME was defined as a central retinal thickness (CRT) of ≥250 lm in the central subfield based on optical coherence tomography (Cirrus OCT, Carl Zeiss Meditec, Dublin, CA). FA was performed after the major haemorrhage was absorbed and was evaluated to distinguish between nonperfusion and blocked fluorescence. When leakage from capillary retinal vessels corresponding to ME was confirmed and the presence of NPAs (>5 disc areas) was identified by FA, the patient was invited to participate in this study (Koss et al. 2012). FA was performed by experienced photographers with a Kowa VX-10i fundus camera (Kowa, Nagoya, Japan). A montage was manually created from the fields. The number of pixels in NPAs was measured on FA images, stored in the Claio image filing system (PSC, Ehime, Japan), and divided by the number of pixels in the total area of the optic disc. The inclusion and exclusion criteria were shown in Table 1. Patients who gave consent were screened for inclusion in the study based on their medical history, slitlamp examination, BCVA and IOP values, dilated funduscopic examination, OCT evaluation and FA. Patients were randomized 1:1 to IVB alone (IVB group), or combination treatment consisting of TRP for NPAs followed by IVB, and subsequent intra-ocular injection (IVB + TRP group) (Fig. 1). In both IVB group and IVB + TRP group, IVB was commonly scheduled at 4 weeks after determination of enrolment in the study. TRP was carried out at 2 weeks before IVB in the IVB + TRP group using retinal photocoagulator MC-300 (NIDEK, Co. Ltd., Aichi, Japan) under the following conditions: (1) NPAs confirmed by FA were selectively coagulated (2) the laser power 200 mW, the duration of exposure 200 msec in yellow wavelength (577 nm) (3) Coagulation spot size was adjusted to 200 lm with a space the size of approximately 1 coagulation
spot size between each of the spot parts (4) TRP was carried out by one trained ophthalmologist (M.G) (Takamura et al. 2014). The research investigator was not involved in the randomization process. Although the patients and study physicians were not masked to the therapeutic modality, the OCT technician, study optometrist, and all statisticians were all masked with respect to treatment allocation. If both eyes were eligible for the study, the eye with the worse BCVA was treated first and enrolled in the study. Patients were eligible to receive additional IVB no more than every 1 month if the retreatment criterion of CRT of >250 lm was met. Additional IVB was performed at 2 weeks after the determination of retreatment. TRP was administered to NPAs 3000 lm away from the centre of the fovea. Two weeks after TRP, 1.25 mg of bevacizumab in 0.05 ml was injected intravitreally with a 30-gauge needle through the superotemporal quadrant under sterile conditions. Standard procedures for injections included the application of topical anaesthetic, the insertion of a lid speculum, and cleaning the conjunctiva with povidone–iodine. The primary objective of this study was to investigate the effect of TRP for peripheral ischaemic areas on the mean average changes in BCVA and CRT measured by Cirrus OCT after IVB. BCVA was measured at the same time. CRT was calculated as the average retinal thickness within a circle having a 500-lm radius; the circle was centred on the fovea. We calculated that a sample size of 19 subjects in each group, assuming a dropout rate of approximately 10%, would provide 90% power to demonstrate, at a 1-sided a-level of 0.025, superiority of combination therapy with TRP compared to IVB monotherapy with respect to the mean change in CRT from baseline to month 6. After a comprehensive ophthalmic examination, BCVA and CRT were measured at screening 2 weeks before intra-ocular injection, on days 0 and 7, and every month post-IVB until 6 months. BCVA was measured with a Landolt chart (converted to logarithm of the minimum angle of resolution (logMAR)), and retinal thickness was measured using Cirrus OCT. The significance of differences between the two study groups in
Acta Ophthalmologica 2016
Table 1. Summary of key inclusion and exclusion criteria. Key inclusion criteria
Key exclusion criteria
Signs of significant ischaemia following BRVO* (>5 disc areas of non-perfusion). BCVA† at baseline of between 20/30 and 20/320.
Photocoagulation within the previous 12 months.
Duration of vision loss between 4 weeks and 6 months prior to baseline visit. Macular oedema involving the centre of the fovea. Mean central subfield thickness ≥250 lm by OCT‡ at baseline visit.
Active intra-ocular inflammation or infection in either eye. Uncontrolled glaucoma in either eye (intra-ocular pressure ≥24 mmHg on medication). Previous treatment with the anti-angiogenic drug used in this study. History of stroke Systolic blood pressure >160 mmHg, diastolic BP >100 mmHg, or untreated hypertension. BRVO without macular oedema. Known sensitivities to anti-VEGF§ drugs and sodium fluorescein.
* Branch retinal vein occlusion. † Best-corrected visual acuity. ‡ Optical coherence tomography. § Vascular endothelial growth factor.
CRT, BCVA and the numbers of additional IVB was analysed using Mann–Whitney U-test. CRT and BCVA at different time-points were compared using Wilcoxon signed-ranks test. Differences with p values
Comparative study of combined bevacizumab/ targeted photocoagulation vs bevacizumab alone for macular oedema in ischaemic branch retinal vein occlusions Yoko Tomomatsu, Takeshi Tomomatsu, Yoshihiro Takamura, Makoto Gozawa, Shogo Arimura, Yuji Takihara and Masaru Inatani Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Yoshida-Gun, Fukui-Ken, Japan
ABSTRACT. Purpose: To investigate whether targeted retinal photocoagulation (TRP) of peripheral non-perfused areas (NPAs) could prevent the recurrence of macular oedema (ME) due to branch retinal vein occlusion (BRVO) after intravitreal bevacizumab injection (IVB). Methods: Eyes received 1.25 mg IVB only (IVB group) or combined with TRP (IVB + TRP group) of NPAs, more than 5 disc areas identified by fluorescein angiography in the patients with ME secondary to BRVO. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) determined by optical coherence tomography were measured every month for 6 months. Results: Thirty-eight patients were enrolled and randomized to IVB group (n = 19) and IVB + TRP group (n = 19). Both groups showed similar thinning in CRT at 1 week after IVB, IVB + TRP group maintained thinner retina at 2 (p = 0.0072) and 3 (p = 0.0086) months compared with IVB group in whom turned to thickened almost back to baseline at 3 months. The number of reinjections in IVB group (1.58 0.69) was significantly greater (p = 0.0025) than that in IVB + TRP group (0.83 0.62). BCVA significantly improved at 6 month in IVB + TRP group (p = 0.015), but not in IVB group. Conclusion: TRP of NPAs reduced the amount of ME recurrence following IVB compared to IVB alone. Key words: best-corrected visual acuity – bevacizumab – branch retinal vein occlusion – central retinal thickness – fluorescein angiography – macular oedema – non-perfused areas – photocoagulation – vascular endothelial growth factor
Acta Ophthalmol. 2016: 94: e225–e230 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12721
Introduction Branch retinal vein occlusion (BRVO) is defined as focal occlusion of the major retinal vein; it frequently occurs at arteriovenous crossings (Jonas et al. 2010; Wong & Scott 2010). Macular oedema (ME) is the major cause of
visual disturbance associated with BRVO (Glacet-Bernard et al.1996; Arnarsson & Stef ansson 2000). Increased intravascular pressure and reduced blood flow in the macular capillaries can lead to dysfunction of the endothelial blood– retinal barrier and increased vascular
permeability, resulting in ME (Arnarsson & Stef ansson 2000). Vascular endothelial growth factor (VEGF) is thought to play an important role in the pathogenesis of ME with BRVO (Glacet-Bernard et al. 1996; Kreutzer et al. 2008; Kriechbaum et al. 2008). The ischaemic retina produces high levels of VEGF, which can exacerbate retinal vasculature leakage as well as retinal neovascularization as sustained release of VEGF in the vitreous cavity causes widespread leakage from retinal vessels (Jonas et al. 2010). Therefore, anti-VEGF drugs may play a critical role in the prevention and treatment of ME with BRVO. Recent prospective, randomized studies have demonstrated that intravitreal injections of anti-VEGF drugs are efficacious in reducing retinal thickness and improving visual acuity. (Kreutzer et al. 2008; Kriechbaum et al. 2008; Campochiaro et al. 2010, 2014; Higashiyama et al. 2013; Korobelnik et al. 2014; Yang & McKeage 2014; Pielen et al. 2015;). Currently used anti-VEGF drugs include ranibizumab, bevacizumab and aflibercept. Ranibizumab and bevacizumab are recombinant antibodies with pan-VEGF-A blocking activity. Aflibercept, VEGF-trap, is a fusion protein with high VEGF affinity attributed to binding sequences from the native VEGF receptors (Korobelnik et al. 2014; Yang & McKeage 2014). The recent prospective clinical trials including BRAVO study demonstrated
e225
Acta Ophthalmologica 2016
the promising effect of ranibizumab as the treatment of ME secondary to BRVO (Campochiaro et al. 2010). Bevacizumab (AvastinTM, Genentech, South San Francisco, CA, USA), a full-length humanized monoclonal antibody directed against all biologically active forms of VEGF-A, has been reported to be effective in decreasing retinal thickness and improving visual acuity when injected intravitreally for the treatment of BRVO. (Kreutzer et al. 2008; Kriechbaum et al. 2008; Higashiyama et al. 2013). Recently, anti-VEGF therapy is recognized as the gold standard treatment for ME secondary to BRVO; however, it remains clinically problematic that macular swelling tends to recur after a single injection of anti-VEGF drugs (Campochiaro et al. 2008; Chen et al. 2010; Ehlers & Fekrat 2011). Thus, frequent injections of anti-VEGF drugs are required to control ME (Chen et al. 2010; Ehlers & Fekrat 2011). However, repeated intravitreal injections raise the likelihood of adverse events such as endophthalmitis and retinal detachment. Therefore, it is clinically important to find ways to reduce the recurrence of ME after intravitreal anti-VEGF therapy. Even if VEGF levels can be reduced by intravitreal injection of bevacizumab (IVB), persistent production of VEGF from non-perfused areas (NPAs) may result in the recurrence of ME with BRVO. Targeted retinal photocoagulation (TRP) is a technique for treating NPAs confirmed by fluorescein angiography (FA), and this therapy is effective in minimizing the unwanted side-effects associated with pan-retinal photocoagulation including scotoma and peripheral vision loss (Muqit et al. 2013). We therefore designed this randomized clinical trial to determine the effect of PC for NPAs on the recurrence of ME with ischaemic BRVO after IVB.
Patients and Methods This clinical trial was approved by the University of Fukui Institutional Review Board and was consistent with the tenets of the Declaration of Helsinki. The protocol and the safety and efficacy implications of the interventions were explained to all participants before enrolment. All patients provided informed consent. This study was reg-
e226
istered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) of Japan (UMIN ID 000009689; date of access and registration, 2013/01/10). Patients with unilateral acute major BRVO who were at least 35 years old and had a reduction in best-corrected visual acuity (BCVA) of between 20/30 and 20/320 due to ME were eligible for this clinical trial. ME was defined as a central retinal thickness (CRT) of ≥250 lm in the central subfield based on optical coherence tomography (Cirrus OCT, Carl Zeiss Meditec, Dublin, CA). FA was performed after the major haemorrhage was absorbed and was evaluated to distinguish between nonperfusion and blocked fluorescence. When leakage from capillary retinal vessels corresponding to ME was confirmed and the presence of NPAs (>5 disc areas) was identified by FA, the patient was invited to participate in this study (Koss et al. 2012). FA was performed by experienced photographers with a Kowa VX-10i fundus camera (Kowa, Nagoya, Japan). A montage was manually created from the fields. The number of pixels in NPAs was measured on FA images, stored in the Claio image filing system (PSC, Ehime, Japan), and divided by the number of pixels in the total area of the optic disc. The inclusion and exclusion criteria were shown in Table 1. Patients who gave consent were screened for inclusion in the study based on their medical history, slitlamp examination, BCVA and IOP values, dilated funduscopic examination, OCT evaluation and FA. Patients were randomized 1:1 to IVB alone (IVB group), or combination treatment consisting of TRP for NPAs followed by IVB, and subsequent intra-ocular injection (IVB + TRP group) (Fig. 1). In both IVB group and IVB + TRP group, IVB was commonly scheduled at 4 weeks after determination of enrolment in the study. TRP was carried out at 2 weeks before IVB in the IVB + TRP group using retinal photocoagulator MC-300 (NIDEK, Co. Ltd., Aichi, Japan) under the following conditions: (1) NPAs confirmed by FA were selectively coagulated (2) the laser power 200 mW, the duration of exposure 200 msec in yellow wavelength (577 nm) (3) Coagulation spot size was adjusted to 200 lm with a space the size of approximately 1 coagulation
spot size between each of the spot parts (4) TRP was carried out by one trained ophthalmologist (M.G) (Takamura et al. 2014). The research investigator was not involved in the randomization process. Although the patients and study physicians were not masked to the therapeutic modality, the OCT technician, study optometrist, and all statisticians were all masked with respect to treatment allocation. If both eyes were eligible for the study, the eye with the worse BCVA was treated first and enrolled in the study. Patients were eligible to receive additional IVB no more than every 1 month if the retreatment criterion of CRT of >250 lm was met. Additional IVB was performed at 2 weeks after the determination of retreatment. TRP was administered to NPAs 3000 lm away from the centre of the fovea. Two weeks after TRP, 1.25 mg of bevacizumab in 0.05 ml was injected intravitreally with a 30-gauge needle through the superotemporal quadrant under sterile conditions. Standard procedures for injections included the application of topical anaesthetic, the insertion of a lid speculum, and cleaning the conjunctiva with povidone–iodine. The primary objective of this study was to investigate the effect of TRP for peripheral ischaemic areas on the mean average changes in BCVA and CRT measured by Cirrus OCT after IVB. BCVA was measured at the same time. CRT was calculated as the average retinal thickness within a circle having a 500-lm radius; the circle was centred on the fovea. We calculated that a sample size of 19 subjects in each group, assuming a dropout rate of approximately 10%, would provide 90% power to demonstrate, at a 1-sided a-level of 0.025, superiority of combination therapy with TRP compared to IVB monotherapy with respect to the mean change in CRT from baseline to month 6. After a comprehensive ophthalmic examination, BCVA and CRT were measured at screening 2 weeks before intra-ocular injection, on days 0 and 7, and every month post-IVB until 6 months. BCVA was measured with a Landolt chart (converted to logarithm of the minimum angle of resolution (logMAR)), and retinal thickness was measured using Cirrus OCT. The significance of differences between the two study groups in
Acta Ophthalmologica 2016
Table 1. Summary of key inclusion and exclusion criteria. Key inclusion criteria
Key exclusion criteria
Signs of significant ischaemia following BRVO* (>5 disc areas of non-perfusion). BCVA† at baseline of between 20/30 and 20/320.
Photocoagulation within the previous 12 months.
Duration of vision loss between 4 weeks and 6 months prior to baseline visit. Macular oedema involving the centre of the fovea. Mean central subfield thickness ≥250 lm by OCT‡ at baseline visit.
Active intra-ocular inflammation or infection in either eye. Uncontrolled glaucoma in either eye (intra-ocular pressure ≥24 mmHg on medication). Previous treatment with the anti-angiogenic drug used in this study. History of stroke Systolic blood pressure >160 mmHg, diastolic BP >100 mmHg, or untreated hypertension. BRVO without macular oedema. Known sensitivities to anti-VEGF§ drugs and sodium fluorescein.
* Branch retinal vein occlusion. † Best-corrected visual acuity. ‡ Optical coherence tomography. § Vascular endothelial growth factor.
CRT, BCVA and the numbers of additional IVB was analysed using Mann–Whitney U-test. CRT and BCVA at different time-points were compared using Wilcoxon signed-ranks test. Differences with p values
