The effect of simultaneous intravitreal Ranibizumab and intravitreal extended-release dexamethasone injection on patients with naïve versus refractory retinal vein occlusion macular edema: prospective, single-center, interventional, and open-label study

The effect of simultaneous intravitreal Ranibizumab and intravitreal extended-release dexamethasone injection on patients with naïve versus refractory retinal vein occlusion macular edema: prospective, single-center, interventional, and open-label study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The effect of simultaneous intravitreal Ranibizumab and intravitreal extended-release dexamethasone injection on patients with naïve versus refractory retinal vein occlusion macular edema: prospective, single-center, interventional, and open-label study Yaoyao Sun, Jie Meng, Shanshan Li, Mingwei Zhao, Huijun Qi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2614020/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The efficacy of concurrent intravitreal Ranibizumab (IVR) and extended-release dexamethasone injections (Dex-I) in patients with naïve and refractory retinal vein occlusion macular edema (RVO-ME) was not well investigated previously. Methods This was a prospective, interventional, and open-label case series design. There were two groups: naïve and refractory patients (received ≥ 5 times of previous IVR within one year prior to enrollment) enrolled. Patients received IVR and Dex-I concurrently. IVR and Dex-I were given PRN. The mean change in best-corrected visual acuity (BCVA) was measured as main outcome. Results 63 patients (63 eyes) completed the entire follow-up (31 naïve and 32 refractory patients). At month 12, the change in BCVA was greater in the naïve group than in the refractory group (19.67 ± 11.7 (95%CI: 15.03,24.31) letters vs. 11.74 ± 11.18 (95%CI:7.32,16.16) letters, P = 0.014). There was no difference between the two groups of mean macular thickness reduction. (364.26 ± 215.29 (95%CI: 279.09,449.43)µm v.s. 410.19 ± 204.34 (95%CI: 329.35,491.02)µm, P = 0.43). The mean co-injection numbers were 2.52 ± 0.58 (95%CI:2.29,2.75) and 2.33 ± 0.55(95%CI:2.11,2.55) in both groups (P = 0.24). The retreatment interval was 115.81 ± 13.79 (95%CI: 110.36,121.27) days and 122.74 ± 14.06(95%CI: 119.93,133.56) days in both groups (P = 0.073). There was no significant difference in the incidence of glaucoma or the progression of cataracts between the two groups. Conclusion In both naïve and refractory RVO-ME patients, IVR combined with Dex-I was effective. The initial combination therapy for naïve patients demonstrated more efficient improvement in BCVA and may reduce total injection numbers. Trial registration: this study was registered with the identifier ChiCTR-INR-17011877 at https://www.chictr.org.cn/ Retinal vein occlusion macular edema prospective clinical trial anti-VEGF Dexamethasone implant Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Retinal vein occlusion (RVO), defined as an obstruction of the normal retinal venous system, is the second most common retinal vascular disorder after diabetic retinopathy. RVO affects patients over the age of 40 at a rate of 1–2% and contributes significantly to vision loss and visual handicaps [ 1 – 3 ]. RVO is classified into two types: branch RVO (BRVO) and central RVO (CRVO). RVO frequently causes retinal ischemia and macular edema, both of which are challenging to treat[ 4 , 5 ]. RVO is characterized by mechanical damage to the retinal vascular walls, followed by thrombosis, hypercoagulation, and blood stagnation. In this process, vascular endothelial growth factor(VEGF), as well as inflammation and oxidative stress, participated in the disruption of the inner blood-retinal barrier, increasing vascular permeability, retinal ischemia, and neovascularization[ 6 – 8 ]. Based on the above pathogenesis, the current treatment strategy for RVO-related macular edema (ME) primarily consists of anti-VEGF and anti-inflammatory therapy. Most current guidelines recommend anti-VEGF therapy as the first-line treatment for RVO-ME[ 9 , 10 ]. Extended-release steroids (0.7mg dexamethasone, Ozurdex®), on the other hand, have gained popularity in recent years and are now recommended as a first- or second-line approach to RVO-ME treatment[ 10 , 11 ]. Despite the fact that all of these treatments have been shown in randomized clinical trials to significantly improve best-corrected visual acuity (BCVA) and decrease central macular thickness (CMT) in patients with RVO-ME, there is still treatment non-response in either approach, and both treatments have some limitations. Anti-VEGF therapy, for example, increases the risk of intraocular injection complications and the treatment burden for patients. In real-world studies, patients' average number of injections is much lower than expected, indicating lower treatment efficacy[ 12 – 14 ]. Furthermore, when Ozurdex® (Dex-I) is injected more than three times intravitreally, the risk of cataract and glaucoma increases significantly [ 15 , 16 ]. Anti-VEGF and steroids may have a synergistic effect when used together to treat RVO-ME due to their different molecular actions, even though their precise mechanisms of action in treating RVO-ME are not fully understood. Combining the two may result in improved visual acuity, fewer injections and clinic visits, and lower total costs. The current treatment modality for combining anti-VEGF with Dex-I has yet to be investigated. According to various guidelines, Dex-I is frequently used as second-line therapy for refractory patients; thus, even when combined with anti-VEGF therapy, it is still a delayed combination therapy modality, and treatment efficacy is not always met. Furthermore, few studies have been conducted to assess the effects of initial anti-VEGF and Dex-I combination therapy[ 15 , 17 , 18 ]. Thus, comparing the effect of combination treatment on naïve patients and refractory patients is critical in the search for appropriate treatment modalities. We conducted a prospective study to compare the effect of combined intravitreal anti-VEGF treatment and DEX-I in naïve RVO-ME patients to refractory patients. Method The study design is demonstrated in Fig. 1 and this study was registered with the identifier ChiCTR-INR-17011877 at https://www.chictr.org.cn/ and the date of first trial registration was (05/07/2017). Patients The design of our study was prospective, single-center, interventional, and open-label case series. From October 2020 to October 2021, patients with ME secondary to RVO were enrolled in this study at Peking University People's Hospital's Department of Ophthalmology. A 12-month follow-up was performed on all patients. Patients were divided into two groups as 1:1 ratio: naïve patients and refractory patients who had received more than 5 anti-VEGF treatments in the previous year: 1) age > 18 years old patients; 2) patients with a primary diagnosis of RVO confirmed by color fundus photography (CFP) and fundus fluorescein angiography (FFA). 3) CMT ≥ 300 µm on spectral domain optical coherence tomography (SD-OCT). Patients with various ocular disorders such as uncontrolled glaucoma (defined as progressive visual field impairment despite receiving the most effective treatment to reduce intraocular pressure (IOP), uveitis, rhegmatogenous retinal detachment, age-related macular degeneration, epiretinal membrane, high myopia fundus changes, and ocular tumors were excluded. Any patient who had received intraocular steroid therapy within 6 months prior to enrolling was excluded. All patients provided written informed consent to participate in accordance with the Helsinki Declaration guidelines. The Medical Ethics Committee of Peking University People's Hospital approved this study. Treatment and follow up Each patient had a comprehensive ocular examination which included disease duration, best-corrected visual acuity (BCVA, as defined by the ETDRS protocol), IOP, anterior segment examination with a slit lamp, posterior segment examination, and CFP, FFA (both from Optos PLC, Dunfermline, United Kingdom), and SD-OCT (OCTA, both from Carl Zeiss Meditec AG, Jena, Germany). Patients were checked on a monthly basis. The study eyes were subjected to a standard ophthalmological examination at each visit, which included all of the above examinations except FFA. The intraocular injection was performed in accordance with the previously stated protocol[ 19 ]. Intravitreal ranibizumab (0.5mg, IVR, Lucentis®, Genentech/Roche, San Francisco, USA) was used as an anti-VEGF agent, and DEX-I (0.7mg DEX; Ozurdex®, Allergan plc, Dublin, Ireland) and IVR were performed on the same day in the same surgical procedure. If one or more of the following criteria are met, retreatment is required: 1) BCVA decrease ≥ 5 letters compared to the previous visit; 2) CMT ≥ 250 µm; 3) macular edema threatening fovea or CMT increase ≥ 50 µm compared to the previous visit, or 4) new retinal cystic changes. FFA were performed every three months. The capillary nonperfusion area (NPA) on FFA was used to assess retinal ischemia. Laser photocoagulation was performed on BRVO patients with NPA ≥ 5 disk areas and CRVO patients with NPA ≥ 10 disk areas. The primary outcome was the change in BCVA 12 months after the first treatment. As a secondary efficacy analysis, CMT changes at 12 months, time intervals between retreatments, total injection times, and the proportion of elevated IOP cataracts that progress to require surgery were investigated. For the sake of the subjects' safety, the researchers believe that the subjects should withdraw from the study. Statistical Analysis Size of the sample. For the primary objectives (BCVA improved at month 12), a sample size of 90%, a two-sided alpha level of 0.05, and a dropout rate of 10% were calculated using the PASS software version 15.0. According to previous reported, at the 12-month follow-up time point after combined treatment with DEX-I and intravitreal IVR, BCVA improved by a mean of 21.3 letters in naïve patients [ 20 ] and by a mean of 9.8 letters in refractory patients [ 15 ], with a maximum standard deviation of 13.3 letters [ 15 , 20 , 21 ]. Therefore, the final sample size was determined to be 33 cases per group. Data examination. SPSS software was used to analyze the data (version 22.0). A 2-sided independent-sample t-test was used to test the primary efficacy analysis (BCVA and CMT changes). Results Demographic information From October 2020 to October 2021, 63 patients completed the entire follow-up, and 3 patients were excluded due to missing follow-up, for a total enrolled rate of 95.45%, with 34 men and 29 women having an overall mean age of 63.20 ± 11.00 years old, respectively. Demographic information for the two groups were listed in Table 1. The study was terminated due to the predicted sample size being reached Table 1 shows demographic information for the two groups. Group Patients/Eyes (No.) Male/Female(No.) Age( x̄ ±SD) BRVO/CRVO(No.) IOP(mmHg) BCVA(x̄±SD, letters) CMT(x̄±SD, µm) naïve patients’ group 31/31 18/13 63.15 ±11.32 11/20 16.0 ±11.79 47.00±20.24 559.85 ±229.84 refractory patients’ group 32/32 16/16 63.26 ±10.88 17/15 13.83 ±2.71 45.74±19.98 599.74 ±205.43 p 0.62 0.97 0.12 0.14 0.82 0.504 BCVA changes between two groups BCVA improved in both groups at the end of month 12. In the naïve patients’ group, the average BCVA improved by 19.67 ± 11.7 (95%CI: 15.03,24.31) letters compared to 11.74 ± 11.18 (95%CI:7.32,16.16) letters in the refractory patients’ group. The difference in BCVA change between the two groups was significant (P = 0.014, Fig. 2A). Figure 2B depicts the change in BCVA at each visit. At each visit, the average BCVA was higher in the naïve patients' group than in the refractory patients' group. The percentage of BCVA improvement greater than 15 letters in the naïve patients' group and refractory patients’ group were 70.97% and 34.38%, respectively, and the difference was statistically significant (p = 0.005, Fig. 2C). CMT changes between two groups CMT decreased in both groups at the end of month 12. The average CMT in the naïve patients' group was 364.26 ± 215.29 (95%CI: 279.09,449.43) µm compared to 410.19 ± 204.34 (95%CI: 329.35,491.02)µm). µm in the refractory patients' group. The difference in CMT change between the two groups was not significant (P = 0.43, Fig. 3A). Figure 3B depicts the average CMT change at each visit. Other outcomes Since patients received IVR as well as Dex-I for each administration in the operating room, there was a mean of 2.52 ± 0.58 (95%CI:2.29,2.75) in the naïve patients' group and 2.33 ± 0.55 (95%CI:2.11,2.55) in the refractory patients' group at month 12 (P = 0.24). Patients in the refractory group received an average of 6.30 ± 1.64 (95%CI:5.72,6.87) anti-VEGF injections prior to enrollment and 8.63 ± 1.57 (95%CI: 8.01, 9.25) total injections after enrollment. There were significant differences in total injection times between the two groups (2.52 ± 0.58 vs. 8.63 ± 1.57, P = 0.000). The time interval between retreatments was 115.81 ± 13.79 (95%CI: 110.36,121.27) days in naïve patients and 122.74 ± 14.06 (95%CI: 119.93,133.56) days in refractory patients (P = 0.073). In the naïve patient groups, 3 BRVO patients and 1 CRVO patient received photocoagulation based on the photocoagulation criteria mentioned above. In the refractory group, 1 BRVO and 4 CRVO patients had photocoagulation prior to enrollment, while 2 BRVO and 3 CRVO patients had photocoagulation during follow-up. Safety At 12 months, 4 eyes (12.90%) in the naïve patients' group had elevated IOP, including 1 eye with IOP ≥ 30 mmHg; and 4 eyes (12.50%) in the refractory patients' group had elevated IOP, including 2 patients with IOP ≥ 30 mmHg. The incidence of elevated IOP did not differ statistically between the two groups (P = 0.43). All patients with elevated IOP had their IOP normalized by using topical IOP-lowering medications, and none required anti-glaucoma surgery. During the follow-up period, 1 eye (3.23%) in the naïve patients' group and 4 eyes (12.5%) in the refractory patients' group experienced cataract progression (P = 0.355), and all received cataract surgery. Other ocular complications such as vitreous hemorrhage, endophthalmitis, or retinal detachment did not occur in either group nor did systemic complications. Typical cases Case 1 (Fig. 4) A 60-year-old woman presented with a 2 weeks history of right eye blur. The physical examination showed that the BCVA in her right eye was 65 letters. Macular edema was seen on SD-OCT and the CMT was 489µm. She was diagnosed with BRVO in the right eye and received IVR and DEX-I at the same time. 5 months later, she received a second co-injection. The BCVA was 85 letters, and the CMT was 214µm at the 12-month follow-up. OCT revealed macular edema prior to enrollment and macular at the 12-month follow-up. After a 12-month follow-up, the macular anatomy structure had fully recovered, with an intact ellipsoidal zone. Case 2 (Fig. 5) A 55-year-old woman presented with a month of blurred vision in the left eye. The physical examination revealed that her left eye's BCVA was 55 letters. Macular edema was seen on SD-OCT, and the CMT was 567µm. She was treated with IVR seven times but still had macular edema prior to enrollment. She also received panretinal photocoagulation prior to enrollment because of severe ischemia. During the entire follow-up, she received IVR and DEX-I at the same time twice. The BCVA was 65 letters, and the CMT was 211µm at the 12-month follow-up. OCT revealed macular edema prior to enrollment and macular at the 12-month follow-up. The macular edema was recovered after a 12-month follow-up, but the macular anatomy structure was not fully recovered. There was still some cystic structure with an irregular ellipsoidal zone and RPE. Discussion In this study, we discovered that the combination treatment improved BCVA and decreased CMT in both the naïve and refractory patient groups, with the naïve group showing greater improvement in BCVA and no increase in complications. With the growing emphasis on anti-VEGF and anti-inflammatory combination therapy for RVO-ME, the treatment modality proposed in this study is an excellent addition to the investigation of combination treatment strategies. To the best of our knowledge, this is the first study to compare the efficacy of combination treatment in naïve patients versus refractory patients. RVO-ME is thought to be caused by a breakdown of the blood-retinal barrier (BRB) with complicated pathogenesis [ 22 ]. At first, in RVO patients, hypoxia and ischemia increase VEGF expression, which leads to an increase in endothelial cell proliferation, vascular permeability, and angiogenesis. It promotes actin filament reorganization in the cytoplasm, which leads to angiogenesis[ 23 , 24 ]. However, evidence suggests that retinal ischemia cannot fully explain the pathophysiology of RVO-related macular edema. VEGF levels, for example, are not particularly high in nonischemic CRVO patients[ 25 , 26 ]. RVO-ME patients have elevated levels of inflammatory cytokines, growth factors, chemokines, adhesion molecules, and other substances. Inflammatory factors such as interleukin-1α, interleukin − 6, interleukin − 8, monocyte chemoattractant protein-1, and platelet-derived growth factor-AA all play important roles in the pathogenesis of RVO, according to previous researches [ 27 – 30 ]. Some inflammatory factors, such as serum amyloid A, are present throughout the disease's acute and chronic phases [ 31 ]. These pathological processes in RVO-ME suggest that anti-inflammatory therapy, in addition to anti-VEGF therapy, is important. The results of clinical trials heavily influence the treatment modality chosen for RVO-ME. Anti-VEGF therapy is commonly used in the treatment of RVO-ME. Ranibizumab has been shown in clinical trials, whether randomized controlled trials (e.g., BRAVO study) [ 32 ] or real-world studies (e.g., LUMINOUS study) [ 33 ], to improve patients' vision while reducing macular edema. Simultaneously, the GENEVA study demonstrated the efficacy of Dex-I on RVO-ME [ 16 ]. According to a recent expert consensus, intravitreal anti-VEGF should be used as first-line therapy, followed by other anti-VEGF agents or DEX in cases of persistent or recurrent ME [ 34 ]. However, there have been reports of patients who did not respond to either treatment. Despite being the first-line treatment, anti-VEGF has a high rate of non-response. The rate of non-response to anti-VEGF treatment in randomized controlled trials was 15–20% [ 35 ], and in the real world, the rate of non-response to anti-VEGF treatment for vision was up to 27.9% at 4 months and 30.2% at 12 months. In addition, 75% remained nonresponsive after one year in patients who did not respond to early treatment [ 36 ]. In other words, persistence does not guarantee success. The results of previous studies that switched from DEX-I to anti-VEGF or vice versa were not ideal. Failure to respond to anti-VEGF or DEX-I monotherapy may be due to a variety of factors. On the one hand, a single molecule may only partially address the pathogenesis of ME, especially when many components have been implicated. Tachyphylaxis or tolerance may develop after repeated administration of the same medicine [ 18 , 37 ]. Therefore, combined anti-VEGF and anti-inflammatory treatment modalities have been investigated in recent years. The use of anti-VEGF combined with DEX-I in RVO-ME eyes has been reported less frequently [ 17 , 18 , 21 , 38 ], and the few available studies did not use the same treatment paradigm. The investigation of RVO-ME treatment options is ongoing, and combination therapy is being tried more frequently, but the timing of combination therapy is not yet conclusive. Previous research has shown that when compared to anti-VEGF monotherapy, combination therapy significantly prolongs treatment duration, restores the anatomy and improves visual acuity, and reduces the number of anti-VEGF treatments [ 21 , 38 ]. After one year of combination therapy, Giuffrè et al. discovered refractory RVO-ME patients with significant improvement in CMT but not in BCVA [ 18 ]. Therefore, we conducted this prospective study to determine whether initial combination therapy was superior to delayed combination therapy in terms of functional and anatomical improvement and whether naïve patients had better BCVA outcomes. The benefit of BCVA was lower in the refractory group, which could be attributed to irreversible photoreceptor and RPE damage caused by prolonged macular edema. According to the studies, sudden ischemia can cause a surge of VEGF and inflammatory factors in a short period of time [ 30 ], so an initial combined treatment can rapidly inhibit the release of VEGF and inflammatory factors, slow the progression of the disease, and maintain better visual outcomes. On the contrary, as the macular edema disease course was prolonged in refractory patients, the macular structure appeared to be continuously damaged, and patients' visual prognosis remained poorer even after the combination treatment was administered. IVR was performed concurrently as DEX-I in this study, which simplified the treatment process and reduced the treatment burden on patients. Patients in this study were admitted to the operating room less frequently when compared to alternate or sequential treatments. The mean number of co-injections during the follow-up period was 2.52 ± 0.58 in the naïve patients' group and 2.33 ± 0.55 in the refractory patients' group, which is lower than previously reported [ 39 ]. Retreatment occurred around every 4 months in either group, which is much longer than monthly injection. Approximately 42% of patients, according to previous reports, expect to reduce the number of injections while maintaining efficacy [ 40 ]. The reduction in the number of injections in this study, compared to the refractory patients' group, not only reduced the incidence of injection-related complications such as vitreous hemorrhage and retinal detachment objectively but also reduced the financial burden on patients in the context of the Covid-19 pneumonia epidemic. The most common side effects of DEX-I treatment were increased IOP and cataract risk [ 16 ]. This study also demonstrated that the initial combination treatment was safe, with cataract and high IOP side effects roughly comparable to previously reported results [ 22 ]. In this study, IOP elevation was generally moderate, and no patients required surgery to control IOP. The small sample size is the study's main limitation, and longer follow-up clinical studies with larger sample sizes are expected in the future. Conclusion Overall, this study showed that the initial combination of IVR and DEX implant treatment contributed to the recovery of visual acuity and the resolution of macular edema in naïve patients, but long-term visual improvement must be confirmed in the future. Abbreviations IVR intravitreal Ranibizumab Dex-I extended-release dexamethasone injections RVO-ME retinal vein occlusion macular edema BCVA best-corrected visual acuity VEGF vascular endothelial growth factor CMT central macular thickness OCT optical coherence tomography CFP color fundus photography FFA fundus fluorescein angiography IOP intraocular pressure NPA nonperfusion area Declarations There were no financial disclosures or competing interests of all the authors and all the authors got consent for publication. Ethical approval and consent: All patients provided written informed consent to participate in accordance with the Helsinki Declaration guidelines. Informed consent have been obtained to publish the images in an online open-access publication. The Medical Ethics Committee of Peking University People's Hospital approved this study. All methods were carried out in accordance with relevant guidelines and regulations of retinal vein occlusion. All experimental protocols were approved by Committee of Clinical Drug Trials, Peking University People's Hospital. Informed consent was obtained from all patients and/or their legal guardian(s). Consent to publish: All the authors have approved for the submission and publishment of this manuscript. Conflict of Interest: There are no competing financial interests and conflict of interests of all the authors in relation to the work described. Acknowledgements: The authors would like to thank Professor Xiaoxin Li of Peking University People’s Hospital for helpful discussions on topics related to this work. Funding: This work was supported by the National Key R&D Program of China, No.2020YFC2008200; Beijing Residency Training Quality Improvement Project (No. Zhupei2021043). Sources of material are not available commercially. Author Contribution Statement: Huijun Qi was responsible for designing the protocol, writing the protocol and report, conducting the search, treating the patients, extracting, analyzing data and writing the manuscript. Yaoyao Sun was responsible for conducting the research, treating the patients, analyzing data and writing the manuscript. Jie Meng and Shanshan Li were responsible for the registration, design and statistics of this study. Mingwei Zhao was responsible for conducting the research, treating the patients and writing the manuscript. Data availability statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Please contact Dr. Yaoyao Sun, [email protected] for the raw data. 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Noma H, Funatsu H, Yamasaki M, Tsukamoto H, Mimura T, Sone T, Jian K, Sakamoto I, Nakano K, Yamashita H et al : Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6 . Am J Ophthalmol 2005, 140 (2):256-261. Yoshimura T, Sonoda KH, Sugahara M, Mochizuki Y, Enaida H, Oshima Y, Ueno A, Hata Y, Yoshida H, Ishibashi T: Comprehensive analysis of inflammatory immune mediators in vitreoretinal diseases . PLoS One 2009, 4 (12):e8158. Feng J, Zhao T, Zhang Y, Ma Y, Jiang Y: Differences in aqueous concentrations of cytokines in macular edema secondary to branch and central retinal vein occlusion . PLoS One 2013, 8 (7):e68149. Varma R, Bressler NM, Suner I, Lee P, Dolan CM, Ward J, Colman S, Rubio RG, Bravo, Groups CS: Improved vision-related function after ranibizumab for macular edema after retinal vein occlusion: results from the BRAVO and CRUISE trials . Ophthalmology 2012, 119 (10):2108-2118. Pearce I, Clemens A, Brent MH, Lu L, Gallego-Pinazo R, Minnella AM, Creuzot-Garcher C, Spital G, Sakamoto T, Dunger-Baldauf C et al : Real-world outcomes with ranibizumab in branch retinal vein occlusion: The prospective, global, LUMINOUS study . PLoS One 2020, 15 (6):e0234739. Pulido JS, Flaxel CJ, Adelman RA, Hyman L, Folk JC, Olsen TW: Retinal Vein Occlusions Preferred Practice Pattern((R)) Guidelines . Ophthalmology 2016, 123 (1):P182-208. Bhisitkul RB, Campochiaro PA, Shapiro H, Rubio RG: Predictive value in retinal vein occlusions of early versus late or incomplete ranibizumab response defined by optical coherence tomography . Ophthalmology 2013, 120 (5):1057-1063. Menke MN, Ebneter A, Zinkernagel MS, Wolf S: Differentiation between Good and Low-Responders to Intravitreal Ranibizumab for Macular Edema Secondary to Retinal Vein Occlusion . J Ophthalmol 2016, 2016 :9875741. Binder S: Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br J Ophthalmol 2012, 96 (1):1-2. Singer MA, Bell DJ, Woods P, Pollard J, Boord T, Herro A, Porbandarwalla S: Effect of combination therapy with bevacizumab and dexamethasone intravitreal implant in patients with retinal vein occlusion . Retina 2012, 32 (7):1289-1294. Capone A, Jr., Singer MA, Dodwell DG, Dreyer RF, Oh KT, Roth DB, Walt JG, Scott LC, Hollander DA: Efficacy and safety of two or more dexamethasone intravitreal implant injections for treatment of macular edema related to retinal vein occlusion (Shasta study) . Retina 2014, 34 (2):342-351. Sivaprasad S, Oyetunde S: Impact of injection therapy on retinal patients with diabetic macular edema or retinal vein occlusion . Clin Ophthalmol 2016, 10 :939-946. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2614020","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":185172265,"identity":"dddde7f8-aaad-4c6b-b9a5-2545981dd0b6","order_by":0,"name":"Yaoyao Sun","email":"","orcid":"","institution":"Peking University People’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yaoyao","middleName":"","lastName":"Sun","suffix":""},{"id":185172266,"identity":"20db9af8-8e93-4584-b08e-5a64c8c5b780","order_by":1,"name":"Jie Meng","email":"","orcid":"","institution":"Eye Institute of Shandong","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Meng","suffix":""},{"id":185172267,"identity":"8ee16e08-16e9-4e51-a30d-038d3090f1aa","order_by":2,"name":"Shanshan Li","email":"","orcid":"","institution":"Department of Ophthalmology, Qilu Hospital of Shandong","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shanshan","middleName":"","lastName":"Li","suffix":""},{"id":185172268,"identity":"ec3e72b9-4a6b-41ae-947b-86a1351df6f1","order_by":3,"name":"Mingwei Zhao","email":"","orcid":"","institution":"Peking University People’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mingwei","middleName":"","lastName":"Zhao","suffix":""},{"id":185172269,"identity":"6488d8e3-7a70-4d14-8515-fe56bd2d2a34","order_by":4,"name":"Huijun Qi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYDCCAwwMhxkYJJgZGJgPHPhQQZoWtsSDM84QqYUZwuIxPszbQoQOvtuHNx4ubLNgN7jd8+EAbwODPL/YAfxaJM+lFRye2SbBbHDn7IYDkjsYDGfOTsCvxeAMj8FhXpCWG7kbDhieYUgwuE28lpwHBxLbSNTCcOAgMVokz7AVHOY5J8EseSPN4GDDGQnCfuE7w7z5M09ZXTLfjeTHn/9U2MjzSxPQAnIbiEiGciQIKodrsSNK6SgYBaNgFIxMAAB5XkmA0/N7AwAAAABJRU5ErkJggg==","orcid":"","institution":"Peking University People’s Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Huijun","middleName":"","lastName":"Qi","suffix":""}],"badges":[],"createdAt":"2023-02-22 01:14:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2614020/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2614020/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":34731953,"identity":"39d00d71-a078-4b19-9913-b7b8ff934b44","added_by":"auto","created_at":"2023-03-23 19:19:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":569754,"visible":true,"origin":"","legend":"\u003cp\u003eThe study design is demonstrated in Figure 1\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2614020/v1/264f21d074f2707267641f0c.png"},{"id":34734762,"identity":"530c1f12-4bb4-4b36-a7cf-57cf44680916","added_by":"auto","created_at":"2023-03-23 19:35:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":725188,"visible":true,"origin":"","legend":"\u003cp\u003eBCVA changes of two groups.\u003c/p\u003e\n\u003cp\u003e(A)The difference in BCVA change between the two groups was significant at the end of month 12 (P = 0.014, Figure 2A). (B) The change in BCVA at each visit in both groups. At each visit, the average BCVA was higher in the naïve patients' group (n=31) than in the refractory patients' group (n=32). Error bars represent the standard error of the mean. (C) There was statistically significant difference in the percentage of BCVA improvement greater than 15 letters in the naïve patients' group and refractory patients’ group (p = 0.005, * demonstrates statistically significant difference, Fig 2C).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2614020/v1/1cdc0916c443088ae3b8d13b.png"},{"id":34731957,"identity":"a7a1fb40-45a8-447a-8443-f9db704d77a3","added_by":"auto","created_at":"2023-03-23 19:19:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":351200,"visible":true,"origin":"","legend":"\u003cp\u003eCMT changes of two groups\u003c/p\u003e\n\u003cp\u003e(A)The difference in CMT change between the two groups was not significant at the end of month 12 (P=0.43). (n=31 in the naïve patients' group and n=32 in the refractory patients' group) (B) The average CMT change at each visit in both groups. Error bars represent the standard error of the mean.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-2614020/v1/dc4034403acbc8bcc99f7785.png"},{"id":34731955,"identity":"7450949e-d5f1-491e-a4b3-a979275ca3d1","added_by":"auto","created_at":"2023-03-23 19:19:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1223808,"visible":true,"origin":"","legend":"\u003cp\u003eTypical case 1.\u003c/p\u003e\n\u003cp\u003eColor fundus photo (CFP) (A) and fundus fluorescing angiography (FFA) (B)before treatment demonstrate BRVO in the right eye. The Dex residual was seen from CFP after twice co-injection (arrow, (C)). CFP and FFA on 12 month follow up demonstrated clear retina without non-perfusion area on FFA (D and E). Optical coherence tomography (OCT) of the diseased eye before treatment (F) and 12 months after treatment (G), demonstrating the process from edema to fully recovery of the macular.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-2614020/v1/5157ec2f78c32ccff1caabad.png"},{"id":34733601,"identity":"b64ab2bb-b117-47be-8e7e-50ae5fafa2ff","added_by":"auto","created_at":"2023-03-23 19:27:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":774633,"visible":true,"origin":"","legend":"\u003cp\u003eTypical case 2.\u003c/p\u003e\n\u003cp\u003eThe patient was diagnosed with CRVO in the left eye and was treated with IVR seven times. She also received pan retinal photocoagulation prior to enrollment. Color fundus photo (CFP) showed laser spots (A) and optical coherence tomography (OCT) demonstrated macular edema at the time of enrollment (B). The Dex residual was seen from CFP after twice co-injection (C, arrow). OCT on 12 months after treatment showed that even the central macular thickness is reduced, there was still some cystic structure with an irregular ellipsoidal zone and RPE (D).\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-2614020/v1/17a0487245f8e9cf14059baf.png"},{"id":43519618,"identity":"9a164070-a0ab-4864-acd9-969fa1912d94","added_by":"auto","created_at":"2023-09-22 08:07:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3847584,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2614020/v1/e0d2848b-837e-434a-b0a4-86b910c6ffa1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The effect of simultaneous intravitreal Ranibizumab and intravitreal extended-release dexamethasone injection on patients with naïve versus refractory retinal vein occlusion macular edema: prospective, single-center, interventional, and open-label study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRetinal vein occlusion (RVO), defined as an obstruction of the normal retinal venous system, is the second most common retinal vascular disorder after diabetic retinopathy. RVO affects patients over the age of 40 at a rate of 1–2% and contributes significantly to vision loss and visual handicaps [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. RVO is classified into two types: branch RVO (BRVO) and central RVO (CRVO). RVO frequently causes retinal ischemia and macular edema, both of which are challenging to treat[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRVO is characterized by mechanical damage to the retinal vascular walls, followed by thrombosis, hypercoagulation, and blood stagnation. In this process, vascular endothelial growth factor(VEGF), as well as inflammation and oxidative stress, participated in the disruption of the inner blood-retinal barrier, increasing vascular permeability, retinal ischemia, and neovascularization[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Based on the above pathogenesis, the current treatment strategy for RVO-related macular edema (ME) primarily consists of anti-VEGF and anti-inflammatory therapy. Most current guidelines recommend anti-VEGF therapy as the first-line treatment for RVO-ME[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Extended-release steroids (0.7mg dexamethasone, Ozurdex®), on the other hand, have gained popularity in recent years and are now recommended as a first- or second-line approach to RVO-ME treatment[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Despite the fact that all of these treatments have been shown in randomized clinical trials to significantly improve best-corrected visual acuity (BCVA) and decrease central macular thickness (CMT) in patients with RVO-ME, there is still treatment non-response in either approach, and both treatments have some limitations. Anti-VEGF therapy, for example, increases the risk of intraocular injection complications and the treatment burden for patients. In real-world studies, patients' average number of injections is much lower than expected, indicating lower treatment efficacy[\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e–\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, when Ozurdex® (Dex-I) is injected more than three times intravitreally, the risk of cataract and glaucoma increases significantly [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Anti-VEGF and steroids may have a synergistic effect when used together to treat RVO-ME due to their different molecular actions, even though their precise mechanisms of action in treating RVO-ME are not fully understood. Combining the two may result in improved visual acuity, fewer injections and clinic visits, and lower total costs.\u003c/p\u003e \u003cp\u003eThe current treatment modality for combining anti-VEGF with Dex-I has yet to be investigated. According to various guidelines, Dex-I is frequently used as second-line therapy for refractory patients; thus, even when combined with anti-VEGF therapy, it is still a delayed combination therapy modality, and treatment efficacy is not always met. Furthermore, few studies have been conducted to assess the effects of initial anti-VEGF and Dex-I combination therapy[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Thus, comparing the effect of combination treatment on naïve patients and refractory patients is critical in the search for appropriate treatment modalities. We conducted a prospective study to compare the effect of combined intravitreal anti-VEGF treatment and DEX-I in naïve RVO-ME patients to refractory patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e "},{"header":"Method","content":"\u003cp\u003eThe study design is demonstrated in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and this study was registered with the identifier ChiCTR-INR-17011877 at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.chictr.org.cn/\u003c/span\u003e\u003c/span\u003e and the date of first trial registration was (05/07/2017).\u003c/p\u003e\n\u003ch2\u003ePatients\u003c/h2\u003e\n\u003cp\u003eThe design of our study was prospective, single-center, interventional, and open-label case series. From October 2020 to October 2021, patients with ME secondary to RVO were enrolled in this study at Peking University People\u0026apos;s Hospital\u0026apos;s Department of Ophthalmology. A 12-month follow-up was performed on all patients. Patients were divided into two groups as 1:1 ratio: na\u0026iuml;ve patients and refractory patients who had received more than 5 anti-VEGF treatments in the previous year: 1) age\u0026thinsp;\u0026gt;\u0026thinsp;18 years old patients; 2) patients with a primary diagnosis of RVO confirmed by color fundus photography (CFP) and fundus fluorescein angiography (FFA). 3) CMT\u0026thinsp;\u0026ge;\u0026thinsp;300 \u0026micro;m on spectral domain optical coherence tomography (SD-OCT). Patients with various ocular disorders such as uncontrolled glaucoma (defined as progressive visual field impairment despite receiving the most effective treatment to reduce intraocular pressure (IOP), uveitis, rhegmatogenous retinal detachment, age-related macular degeneration, epiretinal membrane, high myopia fundus changes, and ocular tumors were excluded. Any patient who had received intraocular steroid therapy within 6 months prior to enrolling was excluded. All patients provided written informed consent to participate in accordance with the Helsinki Declaration guidelines. The Medical Ethics Committee of Peking University People\u0026apos;s Hospital approved this study.\u003c/p\u003e\n\u003ch2\u003eTreatment and follow up\u003c/h2\u003e\n\u003cp\u003eEach patient had a comprehensive ocular examination which included disease duration, best-corrected visual acuity (BCVA, as defined by the ETDRS protocol), IOP, anterior segment examination with a slit lamp, posterior segment examination, and CFP, FFA (both from Optos PLC, Dunfermline, United Kingdom), and SD-OCT (OCTA, both from Carl Zeiss Meditec AG, Jena, Germany). Patients were checked on a monthly basis. The study eyes were subjected to a standard ophthalmological examination at each visit, which included all of the above examinations except FFA. The intraocular injection was performed in accordance with the previously stated protocol[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Intravitreal ranibizumab (0.5mg, IVR, Lucentis\u0026reg;, Genentech/Roche, San Francisco, USA) was used as an anti-VEGF agent, and DEX-I (0.7mg DEX; Ozurdex\u0026reg;, Allergan plc, Dublin, Ireland) and IVR were performed on the same day in the same surgical procedure.\u003c/p\u003e\n\u003cp\u003eIf one or more of the following criteria are met, retreatment is required: 1) BCVA decrease\u0026thinsp;\u0026ge;\u0026thinsp;5 letters compared to the previous visit; 2) CMT\u0026thinsp;\u0026ge;\u0026thinsp;250 \u0026micro;m; 3) macular edema threatening fovea or CMT increase\u0026thinsp;\u0026ge;\u0026thinsp;50 \u0026micro;m compared to the previous visit, or 4) new retinal cystic changes. FFA were performed every three months. The capillary nonperfusion area (NPA) on FFA was used to assess retinal ischemia. Laser photocoagulation was performed on BRVO patients with NPA\u0026thinsp;\u0026ge;\u0026thinsp;5 disk areas and CRVO patients with NPA\u0026thinsp;\u0026ge;\u0026thinsp;10 disk areas. The primary outcome was the change in BCVA 12 months after the first treatment. As a secondary efficacy analysis, CMT changes at 12 months, time intervals between retreatments, total injection times, and the proportion of elevated IOP cataracts that progress to require surgery were investigated. For the sake of the subjects\u0026apos; safety, the researchers believe that the subjects should withdraw from the study.\u003c/p\u003e\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eSize of the sample. For the primary objectives (BCVA improved at month 12), a sample size of 90%, a two-sided alpha level of 0.05, and a dropout rate of 10% were calculated using the PASS software version 15.0. According to previous reported, at the 12-month follow-up time point after combined treatment with DEX-I and intravitreal IVR, BCVA improved by a mean of 21.3 letters in na\u0026iuml;ve patients [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e] and by a mean of 9.8 letters in refractory patients [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e], with a maximum standard deviation of 13.3 letters [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, the final sample size was determined to be 33 cases per group.\u003c/p\u003e\n\u003cp\u003eData examination. SPSS software was used to analyze the data (version 22.0). A 2-sided independent-sample t-test was used to test the primary efficacy analysis (BCVA and CMT changes).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv\u003e\n \u003ch2\u003eDemographic information\u003c/h2\u003e\n \u003cp\u003eFrom October 2020 to October 2021, 63 patients completed the entire follow-up, and 3 patients were excluded due to missing follow-up, for a total enrolled rate of 95.45%, with 34 men and 29 women having an overall mean age of 63.20\u0026thinsp;\u0026plusmn;\u0026thinsp;11.00 years old, respectively. Demographic information for the two groups were listed in Table\u0026nbsp;1. The study was terminated due to the predicted sample size being reached\u003c/p\u003e\n \u003cp\u003eTable 1 shows demographic information for the two groups.\u003c/p\u003e\n \u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePatients/Eyes (No.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMale/Female(No.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAge(\u003cstrong\u003ex̄\u003c/strong\u003e\u0026plusmn;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBRVO/CRVO(No.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIOP(mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBCVA(x̄\u0026plusmn;SD, letters)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCMT(x̄\u0026plusmn;SD, \u0026micro;m)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ena\u0026iuml;ve patients\u0026rsquo; group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18/13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e63.15 \u0026plusmn;11.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11/20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.0 \u0026plusmn;11.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e47.00\u0026plusmn;20.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e559.85 \u0026plusmn;229.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003erefractory patients\u0026rsquo; group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16/16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e63.26 \u0026plusmn;10.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17/15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.83 \u0026plusmn;2.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45.74\u0026plusmn;19.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e599.74 \u0026plusmn;205.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.504\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n \u003ch2\u003eBCVA changes between two groups\u003c/h2\u003e\n \u003cp\u003eBCVA improved in both groups at the end of month 12. In the na\u0026iuml;ve patients\u0026rsquo; group, the average BCVA improved by 19.67\u0026thinsp;\u0026plusmn;\u0026thinsp;11.7 (95%CI: 15.03,24.31) letters compared to 11.74\u0026thinsp;\u0026plusmn;\u0026thinsp;11.18 (95%CI:7.32,16.16) letters in the refractory patients\u0026rsquo; group. The difference in BCVA change between the two groups was significant (P\u0026thinsp;=\u0026thinsp;0.014, Fig.\u0026nbsp;2A). Figure\u0026nbsp;2B depicts the change in BCVA at each visit. At each visit, the average BCVA was higher in the na\u0026iuml;ve patients\u0026apos; group than in the refractory patients\u0026apos; group. The percentage of BCVA improvement greater than 15 letters in the na\u0026iuml;ve patients\u0026apos; group and refractory patients\u0026rsquo; group were 70.97% and 34.38%, respectively, and the difference was statistically significant (p\u0026thinsp;=\u0026thinsp;0.005, Fig.\u0026nbsp;2C).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n \u003ch2\u003eCMT changes between two groups\u003c/h2\u003e\n \u003cp\u003eCMT decreased in both groups at the end of month 12. The average CMT in the na\u0026iuml;ve patients\u0026apos; group was 364.26\u0026thinsp;\u0026plusmn;\u0026thinsp;215.29 (95%CI: 279.09,449.43) \u0026micro;m compared to 410.19\u0026thinsp;\u0026plusmn;\u0026thinsp;204.34 (95%CI: 329.35,491.02)\u0026micro;m). \u0026micro;m in the refractory patients\u0026apos; group. The difference in CMT change between the two groups was not significant (P\u0026thinsp;=\u0026thinsp;0.43, Fig.\u0026nbsp;3A). Figure\u0026nbsp;3B depicts the average CMT change at each visit.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n \u003ch2\u003eOther outcomes\u003c/h2\u003e\n \u003cp\u003eSince patients received IVR as well as Dex-I for each administration in the operating room, there was a mean of 2.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58 (95%CI:2.29,2.75) in the na\u0026iuml;ve patients\u0026apos; group and 2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55 (95%CI:2.11,2.55) in the refractory patients\u0026apos; group at month 12 (P\u0026thinsp;=\u0026thinsp;0.24). Patients in the refractory group received an average of 6.30\u0026thinsp;\u0026plusmn;\u0026thinsp;1.64 (95%CI:5.72,6.87) anti-VEGF injections prior to enrollment and 8.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.57 (95%CI: 8.01, 9.25) total injections after enrollment. There were significant differences in total injection times between the two groups (2.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58 vs. 8.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.57, P\u0026thinsp;=\u0026thinsp;0.000). The time interval between retreatments was 115.81\u0026thinsp;\u0026plusmn;\u0026thinsp;13.79 (95%CI: 110.36,121.27) days in na\u0026iuml;ve patients and 122.74\u0026thinsp;\u0026plusmn;\u0026thinsp;14.06 (95%CI: 119.93,133.56) days in refractory patients (P\u0026thinsp;=\u0026thinsp;0.073). In the na\u0026iuml;ve patient groups, 3 BRVO patients and 1 CRVO patient received photocoagulation based on the photocoagulation criteria mentioned above. In the refractory group, 1 BRVO and 4 CRVO patients had photocoagulation prior to enrollment, while 2 BRVO and 3 CRVO patients had photocoagulation during follow-up.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n \u003ch2\u003eSafety\u003c/h2\u003e\n \u003cp\u003eAt 12 months, 4 eyes (12.90%) in the na\u0026iuml;ve patients\u0026apos; group had elevated IOP, including 1 eye with IOP\u0026thinsp;\u0026ge;\u0026thinsp;30 mmHg; and 4 eyes (12.50%) in the refractory patients\u0026apos; group had elevated IOP, including 2 patients with IOP\u0026thinsp;\u0026ge;\u0026thinsp;30 mmHg. The incidence of elevated IOP did not differ statistically between the two groups (P\u0026thinsp;=\u0026thinsp;0.43). All patients with elevated IOP had their IOP normalized by using topical IOP-lowering medications, and none required anti-glaucoma surgery. During the follow-up period, 1 eye (3.23%) in the na\u0026iuml;ve patients\u0026apos; group and 4 eyes (12.5%) in the refractory patients\u0026apos; group experienced cataract progression (P\u0026thinsp;=\u0026thinsp;0.355), and all received cataract surgery. Other ocular complications such as vitreous hemorrhage, endophthalmitis, or retinal detachment did not occur in either group nor did systemic complications.\u003c/p\u003e\n \u003cp\u003eTypical cases\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e (Fig. 4)\u003c/p\u003e\n \u003cp\u003eA 60-year-old woman presented with a 2 weeks history of right eye blur. The physical examination showed that the BCVA in her right eye was 65 letters. Macular edema was seen on SD-OCT and the CMT was 489\u0026micro;m. She was diagnosed with BRVO in the right eye and received IVR and DEX-I at the same time. 5 months later, she received a second co-injection. The BCVA was 85 letters, and the CMT was 214\u0026micro;m at the 12-month follow-up. OCT revealed macular edema prior to enrollment and macular at the 12-month follow-up. After a 12-month follow-up, the macular anatomy structure had fully recovered, with an intact ellipsoidal zone.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e(Fig.\u0026nbsp;5)\u003c/p\u003e\n \u003cp\u003eA 55-year-old woman presented with a month of blurred vision in the left eye. The physical examination revealed that her left eye\u0026apos;s BCVA was 55 letters. Macular edema was seen on SD-OCT, and the CMT was 567\u0026micro;m. She was treated with IVR seven times but still had macular edema prior to enrollment. She also received panretinal photocoagulation prior to enrollment because of severe ischemia. During the entire follow-up, she received IVR and DEX-I at the same time twice. The BCVA was 65 letters, and the CMT was 211\u0026micro;m at the 12-month follow-up. OCT revealed macular edema prior to enrollment and macular at the 12-month follow-up. The macular edema was recovered after a 12-month follow-up, but the macular anatomy structure was not fully recovered. There was still some cystic structure with an irregular ellipsoidal zone and RPE.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we discovered that the combination treatment improved BCVA and decreased CMT in both the na\u0026iuml;ve and refractory patient groups, with the na\u0026iuml;ve group showing greater improvement in BCVA and no increase in complications. With the growing emphasis on anti-VEGF and anti-inflammatory combination therapy for RVO-ME, the treatment modality proposed in this study is an excellent addition to the investigation of combination treatment strategies. To the best of our knowledge, this is the first study to compare the efficacy of combination treatment in na\u0026iuml;ve patients versus refractory patients.\u003c/p\u003e \u003cp\u003eRVO-ME is thought to be caused by a breakdown of the blood-retinal barrier (BRB) with complicated pathogenesis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. At first, in RVO patients, hypoxia and ischemia increase VEGF expression, which leads to an increase in endothelial cell proliferation, vascular permeability, and angiogenesis. It promotes actin filament reorganization in the cytoplasm, which leads to angiogenesis[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, evidence suggests that retinal ischemia cannot fully explain the pathophysiology of RVO-related macular edema. VEGF levels, for example, are not particularly high in nonischemic CRVO patients[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. RVO-ME patients have elevated levels of inflammatory cytokines, growth factors, chemokines, adhesion molecules, and other substances. Inflammatory factors such as interleukin-1α, interleukin \u0026minus;\u0026thinsp;6, interleukin \u0026minus;\u0026thinsp;8, monocyte chemoattractant protein-1, and platelet-derived growth factor-AA all play important roles in the pathogenesis of RVO, according to previous researches [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Some inflammatory factors, such as serum amyloid A, are present throughout the disease's acute and chronic phases [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. These pathological processes in RVO-ME suggest that anti-inflammatory therapy, in addition to anti-VEGF therapy, is important.\u003c/p\u003e \u003cp\u003eThe results of clinical trials heavily influence the treatment modality chosen for RVO-ME. Anti-VEGF therapy is commonly used in the treatment of RVO-ME. Ranibizumab has been shown in clinical trials, whether randomized controlled trials (e.g., BRAVO study) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] or real-world studies (e.g., LUMINOUS study) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], to improve patients' vision while reducing macular edema. Simultaneously, the GENEVA study demonstrated the efficacy of Dex-I on RVO-ME [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. According to a recent expert consensus, intravitreal anti-VEGF should be used as first-line therapy, followed by other anti-VEGF agents or DEX in cases of persistent or recurrent ME [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, there have been reports of patients who did not respond to either treatment. Despite being the first-line treatment, anti-VEGF has a high rate of non-response. The rate of non-response to anti-VEGF treatment in randomized controlled trials was 15\u0026ndash;20% [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and in the real world, the rate of non-response to anti-VEGF treatment for vision was up to 27.9% at 4 months and 30.2% at 12 months. In addition, 75% remained nonresponsive after one year in patients who did not respond to early treatment [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In other words, persistence does not guarantee success. The results of previous studies that switched from DEX-I to anti-VEGF or vice versa were not ideal. Failure to respond to anti-VEGF or DEX-I monotherapy may be due to a variety of factors. On the one hand, a single molecule may only partially address the pathogenesis of ME, especially when many components have been implicated. Tachyphylaxis or tolerance may develop after repeated administration of the same medicine [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Therefore, combined anti-VEGF and anti-inflammatory treatment modalities have been investigated in recent years.\u003c/p\u003e \u003cp\u003eThe use of anti-VEGF combined with DEX-I in RVO-ME eyes has been reported less frequently [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], and the few available studies did not use the same treatment paradigm. The investigation of RVO-ME treatment options is ongoing, and combination therapy is being tried more frequently, but the timing of combination therapy is not yet conclusive. Previous research has shown that when compared to anti-VEGF monotherapy, combination therapy significantly prolongs treatment duration, restores the anatomy and improves visual acuity, and reduces the number of anti-VEGF treatments [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. After one year of combination therapy, Giuffr\u0026egrave; et al. discovered refractory RVO-ME patients with significant improvement in CMT but not in BCVA [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Therefore, we conducted this prospective study to determine whether initial combination therapy was superior to delayed combination therapy in terms of functional and anatomical improvement and whether na\u0026iuml;ve patients had better BCVA outcomes. The benefit of BCVA was lower in the refractory group, which could be attributed to irreversible photoreceptor and RPE damage caused by prolonged macular edema. According to the studies, sudden ischemia can cause a surge of VEGF and inflammatory factors in a short period of time [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], so an initial combined treatment can rapidly inhibit the release of VEGF and inflammatory factors, slow the progression of the disease, and maintain better visual outcomes. On the contrary, as the macular edema disease course was prolonged in refractory patients, the macular structure appeared to be continuously damaged, and patients' visual prognosis remained poorer even after the combination treatment was administered.\u003c/p\u003e \u003cp\u003eIVR was performed concurrently as DEX-I in this study, which simplified the treatment process and reduced the treatment burden on patients. Patients in this study were admitted to the operating room less frequently when compared to alternate or sequential treatments. The mean number of co-injections during the follow-up period was 2.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58 in the na\u0026iuml;ve patients' group and 2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55 in the refractory patients' group, which is lower than previously reported [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Retreatment occurred around every 4 months in either group, which is much longer than monthly injection. Approximately 42% of patients, according to previous reports, expect to reduce the number of injections while maintaining efficacy [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The reduction in the number of injections in this study, compared to the refractory patients' group, not only reduced the incidence of injection-related complications such as vitreous hemorrhage and retinal detachment objectively but also reduced the financial burden on patients in the context of the Covid-19 pneumonia epidemic.\u003c/p\u003e \u003cp\u003eThe most common side effects of DEX-I treatment were increased IOP and cataract risk [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This study also demonstrated that the initial combination treatment was safe, with cataract and high IOP side effects roughly comparable to previously reported results [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In this study, IOP elevation was generally moderate, and no patients required surgery to control IOP. The small sample size is the study's main limitation, and longer follow-up clinical studies with larger sample sizes are expected in the future.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOverall, this study showed that the initial combination of IVR and DEX implant treatment contributed to the recovery of visual acuity and the resolution of macular edema in na\u0026iuml;ve patients, but long-term visual improvement must be confirmed in the future.\u003c/p\u003e"},{"header":"Abbreviations ","content":"\u003cp\u003eIVR intravitreal Ranibizumab\u003c/p\u003e\n\u003cp\u003eDex-I extended-release dexamethasone injections\u003c/p\u003e\n\u003cp\u003eRVO-ME retinal vein occlusion macular edema\u003c/p\u003e\n\u003cp\u003eBCVA best-corrected visual acuity\u003c/p\u003e\n\u003cp\u003eVEGF vascular endothelial growth factor\u003c/p\u003e\n\u003cp\u003eCMT central macular thickness\u003c/p\u003e\n\u003cp\u003eOCT optical coherence tomography\u003c/p\u003e\n\u003cp\u003eCFP color fundus photography\u003c/p\u003e\n\u003cp\u003eFFA fundus fluorescein angiography\u003c/p\u003e\n\u003cp\u003eIOP intraocular pressure\u003c/p\u003e\n\u003cp\u003eNPA nonperfusion area\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThere were no financial disclosures or competing interests of all the authors and all the authors got consent for publication.\u003c/p\u003e\n\u003cp\u003eEthical approval and consent: All patients provided written informed consent to participate in accordance with the Helsinki Declaration guidelines. Informed consent have been obtained to publish the images in an online open-access publication. The Medical Ethics Committee of Peking University People\u0026apos;s Hospital approved this study. All methods were carried out in accordance with relevant guidelines and regulations of retinal vein occlusion. All experimental protocols were approved by Committee of Clinical Drug Trials, Peking University People\u0026apos;s Hospital. Informed consent was obtained from all patients and/or their legal guardian(s).\u003c/p\u003e\n\u003cp\u003eConsent to publish: All the authors have approved for the submission and publishment of this manuscript.\u003c/p\u003e\n\u003cp\u003eConflict of Interest: There are no competing financial interests and conflict of interests of all the authors in relation to the work described.\u003c/p\u003e\n\n\u003cp\u003eAcknowledgements: The authors would like to thank Professor Xiaoxin Li of Peking University People\u0026rsquo;s Hospital for helpful discussions on topics related to this work.\u003c/p\u003e\n\n\u003cp\u003eFunding: This work was supported by the National Key R\u0026amp;D Program of China, No.2020YFC2008200; Beijing Residency Training Quality Improvement Project (No. Zhupei2021043). Sources of material are not available commercially.\u003c/p\u003e\n\n\n\u003cp\u003eAuthor Contribution Statement: Huijun Qi was responsible for designing the protocol, writing the protocol and report, conducting the search, treating the patients, extracting, analyzing data and writing the manuscript. Yaoyao Sun was responsible for conducting the research, treating the patients, analyzing data and writing the manuscript. Jie Meng and Shanshan Li were responsible for the registration, design and statistics of this study. Mingwei Zhao was responsible for conducting the research, treating the patients and writing the manuscript.\u003c/p\u003e\n\n\u003cp\u003eData availability statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Please contact Dr. Yaoyao Sun, [email protected] for the raw data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRogers S, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, Kowalski JW, Nguyen H, Wong TY, International Eye Disease C: \u003cstrong\u003eThe prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia\u003c/strong\u003e. \u003cem\u003eOphthalmology \u003c/em\u003e2010, \u003cstrong\u003e117\u003c/strong\u003e(2):313-319 e311.\u003c/li\u003e\n\u003cli\u003eSong P, Xu Y, Zha M, Zhang Y, Rudan I: \u003cstrong\u003eGlobal epidemiology of retinal vein occlusion: a systematic review and meta-analysis of prevalence, incidence, and risk factors\u003c/strong\u003e. \u003cem\u003eJ Glob Health \u003c/em\u003e2019, \u003cstrong\u003e9\u003c/strong\u003e(1):010427.\u003c/li\u003e\n\u003cli\u003eLaouri M, Chen E, Looman M, Gallagher M: \u003cstrong\u003eThe burden of disease of retinal vein occlusion: review of the literature\u003c/strong\u003e. \u003cem\u003eEye (Lond) \u003c/em\u003e2011, \u003cstrong\u003e25\u003c/strong\u003e(8):981-988.\u003c/li\u003e\n\u003cli\u003eMcIntosh RL, Mohamed Q, Saw SM, Wong TY: \u003cstrong\u003eInterventions for branch retinal vein occlusion: an evidence-based systematic review\u003c/strong\u003e. \u003cem\u003eOphthalmology \u003c/em\u003e2007, \u003cstrong\u003e114\u003c/strong\u003e(5):835-854.\u003c/li\u003e\n\u003cli\u003eHirano Y, Suzuki N, Tomiyasu T, Kurobe R, Yasuda Y, Esaki Y, Yasukawa T, Yoshida M, Ogura Y: \u003cstrong\u003eMultimodal Imaging of Microvascular Abnormalities in Retinal Vein Occlusion\u003c/strong\u003e. \u003cem\u003eJ Clin Med \u003c/em\u003e2021, \u003cstrong\u003e10\u003c/strong\u003e(3).\u003c/li\u003e\n\u003cli\u003eJaulim A, Ahmed B, Khanam T, Chatziralli IP: \u003cstrong\u003eBranch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. 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\u003cstrong\u003e10\u003c/strong\u003e:939-946.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Retinal vein occlusion, macular edema, prospective clinical trial, anti-VEGF, Dexamethasone implant","lastPublishedDoi":"10.21203/rs.3.rs-2614020/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2614020/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\n\u003cp\u003eThe efficacy of concurrent intravitreal Ranibizumab (IVR) and extended-release dexamethasone injections (Dex-I) in patients with naïve and refractory retinal vein occlusion macular edema (RVO-ME) was not well investigated previously.\u003c/p\u003e\n\u003ch2\u003eMethods\u003c/h2\u003e\n\u003cp\u003eThis was a prospective, interventional, and open-label case series design. There were two groups: naïve and refractory patients (received ≥ 5 times of previous IVR within one year prior to enrollment) enrolled. Patients received IVR and Dex-I concurrently. IVR and Dex-I were given PRN. The mean change in best-corrected visual acuity (BCVA) was measured as main outcome.\u003c/p\u003e\n\u003ch2\u003eResults\u003c/h2\u003e\n\u003cp\u003e63 patients (63 eyes) completed the entire follow-up (31 naïve and 32 refractory patients). At month 12, the change in BCVA was greater in the naïve group than in the refractory group (19.67 ± 11.7 (95%CI: 15.03,24.31) letters vs. 11.74 ± 11.18 (95%CI:7.32,16.16) letters, P = 0.014). There was no difference between the two groups of mean macular thickness reduction. (364.26 ± 215.29 (95%CI: 279.09,449.43)µm v.s. 410.19 ± 204.34 (95%CI: 329.35,491.02)µm, P = 0.43). The mean co-injection numbers were 2.52 ± 0.58 (95%CI:2.29,2.75) and 2.33 ± 0.55(95%CI:2.11,2.55) in both groups (P = 0.24). The retreatment interval was 115.81 ± 13.79 (95%CI: 110.36,121.27) days and 122.74 ± 14.06(95%CI: 119.93,133.56) days in both groups (P = 0.073). There was no significant difference in the incidence of glaucoma or the progression of cataracts between the two groups.\u003c/p\u003e\n\u003ch2\u003eConclusion\u003c/h2\u003e\n\u003cp\u003eIn both naïve and refractory RVO-ME patients, IVR combined with Dex-I was effective. The initial combination therapy for naïve patients demonstrated more efficient improvement in BCVA and may reduce total injection numbers.\u003c/p\u003e\n\u003cp\u003eTrial registration: this study was registered with the identifier ChiCTR-INR-17011877 at https://www.chictr.org.cn/\u003c/p\u003e","manuscriptTitle":"The effect of simultaneous intravitreal Ranibizumab and intravitreal extended-release dexamethasone injection on patients with naïve versus refractory retinal vein occlusion macular edema: prospective, single-center, interventional, and open-label study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-23 19:19:40","doi":"10.21203/rs.3.rs-2614020/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4ba570bc-5f5a-4da3-854b-4e8464f9904e","owner":[],"postedDate":"March 23rd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-09-22T07:59:34+00:00","versionOfRecord":[],"versionCreatedAt":"2023-03-23 19:19:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2614020","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2614020","identity":"rs-2614020","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}