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Preoperative Bevacizumab for Tractional Retinal Detachment in Proliferative Diabetic Retinopathy: A Prospective Randomized Clinical Trial

      Purpose

      To assess the effectiveness and safety of an intravitreal injection of 1.25 mg bevacizumab (IVB) as a preoperative adjunct to small-gauge pars plana vitrectomy (PPV) compared with PPV alone in eyes with tractional retinal detachment secondary to proliferative diabetic retinopathy.

      Methods

      This prospective, double-masked, randomized, multicenter, active-controlled clinical trial enrolled 224 eyes of 224 patients between November 2013 and July 2015. All eyes underwent a baseline examination including best-corrected visual acuity, color photos, optical coherence tomography, and fluorescein angiography. Data were collected on intraoperative bleeding, total surgical time, early (<1 month) postoperative vitreous hemorrhage, and mean change in best-corrected visual acuity at 12 months. P < .05 was considered statistically significant.

      Results

      A total of 214 patients (214 eyes) were randomized in a 1:1 ratio to PPV plus IVB ([study group] 102 eyes) or PPV plus sham ([control] 112 eyes). Iatrogenic retinal breaks were noted intraoperatively in 35 eyes (34.3%) in the study group, and 66 eyes (58.9%) in the control group (P = .001). Grade 2 intraoperative bleeding was noted in 32 (31.3%) eyes in the study group and 58 (51.7 %) eyes in the control group (P = .001). Endodiathermy was necessary in 28 (27.4 %) eyes in the study group, compared with 75 (66.9%) eyes in the control group (P = .0001). Mean surgical time was 71.3 ± 32.1 minutes in the study group and 83.6 ± 38.7 minutes in the control group (P = .061).

      Conclusion

      Preoperative IVB seems to reduce intraoperative bleeding, improving surgical field visualization, and reducing intraoperative and postoperative complications. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
      Proliferative diabetic retinopathy (PDR), is characterized by retinal ischemia, recurrent retinal neovascularization, and fibrous proliferation, which can lead to blindness without appropriate treatment.
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      Patients with nonclearing vitreous hemorrhage, tractional retinal detachment (TRD), or extensive fibrovascular proliferation are candidates for pars plana vitrectomy (PPV). Bleeding is one of the most common intraoperative complications of PPV. Intraoperative bleeding makes surgical maneuvers very difficult because of poor visualization. Poor visualization can prolong the total surgical time and hinder surgical outcomes. In some cases, pronounced bleeding during surgery may be uncontrollable and leads to surgical failure.
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      Complications of vitreous surgery for diabetic retinopathy. I. Intraoperative complications.
      Intravitreal injection of bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) is effective at decreasing vascular permeability and proliferation, improving diabetic macular edema and reducing the risk of intraocular bleeding in patients with PDR.
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      In eyes with advanced PDR, characterized by ample, active neovascularization and/or extensive or multiple layers of fibrovascular proliferation, an IVB injection before surgery may potentially further decrease intraoperative hemorrhage, facilitate fibrovascular membrane dissection,
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      Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy.
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      • et al.
      Preoperative intravitreal bevacizumab use as an adjuvant to diabetic vitrectomy: histopathologic findings and clinical implications.
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      A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy.
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      Preoperative injection of intravitreal bevacizumab in dense diabetic vitreous hemorrhage.
      and reduce intraoperative and postoperative ocular complications.
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      Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy.
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      Preoperative injection of intravitreal bevacizumab in dense diabetic vitreous hemorrhage.
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      The effect of adjunctive intravitreal bevacizumab for preventing post vitrectomy hemorrhage in proliferative diabetic retinopathy.
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      Experience with intravitreal bevacizumab as a preoperative adjunct in 23-G vitrectomy for advanced proliferative diabetic retinopathy.
      A meta-analysis supports the use of preoperative bevacizumab in diabetic vitrectomies
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      A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy.
      ; however, we have previously reported that TRD may occur or progress shortly following administration of IVB in patients with severe PDR.
      • Arevalo J.F.
      • Maia M.
      • Flynn Jr., H.W.
      • et al.
      Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy.
      • Arevalo J.F.
      • Sanchez J.G.
      • Saldarriaga L.
      • et al.
      Retinal detachment after bevacizumab.
      In addition, other reports show that IVB may cause TRD in cases with PDR and pre-existing preretinal fibrosis.
      • Jonas J.B.
      • Schmidbauer M.
      • Rensch F.
      Progression of tractional retinal detachment following intravitreal bevacizumab.
      Hence, there is no consensus in the retina community on the usefulness and risk/benefit ratio of IVB as an adjuvant to PPV in TRD in PDR. To provide more evidence, we conducted a randomized trial evaluating the effectiveness and safety of an intravitreal injection of 1.25 mg bevacizumab as a preoperative adjunct to small-gauge PPV in eyes with TRD secondary to PDR. We hypothesized that intravitreal injection of 1.25 mg bevacizumab as a preoperative adjunct to PPV in eyes with TRD secondary to PDR will be safe and effective. IVB (compared with sham) will decrease intraoperative bleeding at 12 months.

      Methods

      This prospective, double-masked, randomized, multicenter, active-controlled clinical trial (http://clinicaltrials.gov/show/NCT01976923) was conducted by the Pan-American Collaborative Retina Study (PACORES) Group at 13 clinical sites from 9 countries. Institutional review board/ethics committee approval was granted prospectively and patient informed consent was obtained for this study at all institutions. The off-label use of the drug and its potential risks and benefits were discussed extensively with all patients. This study adhered to the 1964 Declaration of Helsinki for research involving human subjects.

       Eligibility Criteria for Participants

       Patient eligibility

      Patients were included if they were 18 years or older with type 1 or 2 diabetes mellitus and PDR and TRD threatening or involving the macula, with or without a rhegmatogenous component, and with or without vitreous hemorrhage (VH). Eyes with dense VH that prevented visualization of the macula pre-PPV were included in the study if macular-involving TRD was present on ultrasound imaging. Eyes with or without diabetic macular edema were included. Participants who had both eyes involved also were eligible, but only one eye was allowed to enroll in the study.

       Ocular exclusion criteria

      The following exclusions applied to the study eye only (ie, they may have been present for the nonstudy eye): TRD was considered to be due to a cause other than diabetes; an ocular condition such that, in the opinion of the investigator, visual acuity loss would not improve from resolution of TRD (eg, foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition, optic atrophy); an ocular condition (other than diabetes) that, in the opinion of the investigator, might affect retinal status or alter visual acuity during the course of the study (eg, retinal vein occlusion, uveitis or other ocular inflammatory disease, glaucoma); history of treatment for diabetic macular edema or diabetic retinopathy at any time in the past 4 months with anti–vascular endothelial growth factor drugs; history of major ocular surgery (including vitrectomy, scleral buckle, any intraocular surgery [except cataract surgery]) within the prior 4 months of randomization; history of neodymium-doped yttrium aluminium garnet (YAG) capsulotomy performed within 2 months before randomization; intraocular pressure either equal to or more than 25 mm Hg; or evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

       Systemic exclusion criteria

      Patients with the following systemic conditions were excluded: significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplantation; a condition that, in the opinion of the investigator, would preclude participation in the study (eg, unstable medical status including hypertension, cardiovascular disease, and glycemic control); participation in an investigational trial within 30 days of randomization that involved treatment with any drug that had not received regulatory approval at the time of study entry; known allergy to any component of the study drug; blood pressure >180/110 mm Hg (systolic above 180 or diastolic above 110); major surgery within 28 days before randomization or major surgery planned during the following 6 months to randomization; myocardial infarction, other cardiac events requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months before randomization; or systemic anti–vascular endothelial growth factor treatment within 4 months before randomization. For women of childbearing potential: pregnant or lactating or intending to become pregnant within 12 months from inclusion in the study. Patients were excluded if they were expecting to move out of the area of the clinical center to an area not covered by another clinical center during the first 12 months of the study. Patients with a history of blood diseases associated with abnormal coagulation and those on anticoagulant therapy also were excluded.

       Randomization and Masking Procedure

      Patients were randomized in a 1:1 ratio to small-gauge PPV plus IVB (study group) or small-gauge PPV plus sham injection (control group). Randomization was done by means of an Internet-based randomization generator (http://www.randomization.com) using the method of randomly permuted blocks. Each patient received 1 preoperative intravitreal injection (bevacizumab or sham) between 3 and 5 days before the surgery. The procedure was done by a retina specialist not involved in patient treatment or follow-up. The total follow-up period was 12 months. Study patients were masked to the treatment given. At baseline and at each follow-up visit, personnel masked to the type of treatment (control arm or study arm) performed best-corrected visual acuity (BCVA) testing and ophthalmic examination, including slit-lamp biomicroscopy and applanation tonometry. Optical coherence tomography (OCT), fluorescein angiography, and fundus color photographs also were done by masked personal according to the examination schedule.

       Control Arm

      A sham intravitreal injection was scheduled 3 to 5 days before surgery. The patient was prepared for intravitreal injection in the usual manner but only pressure with the hub of the syringe without the needle was applied 3.5 mm from the limbus under sterile conditions. PPV was scheduled 3 to 5 days after the sham intravitreal injection.

       Study Arm

      An intravitreal injection of 1.25 mg/0.1 mL was scheduled and performed (3 to 5 days) before surgery.

       Anti–Vascular Endothelial Growth Factor Injection Technique

      Patients who underwent IVB (or sham) received a thorough explanation of the off-label use of the drug, the potential risks of thromboembolic events, endophthalmitis, and uveitis. Written informed consent was obtained from all patients before the IVB injection, as well as before small-gauge PPV.
      A sterile lid speculum was used to separate the lids after topical anesthesia (proparacaine hydrochloride 4%). A 5% povidone iodine solution was used to disinfect the entire conjunctival surface, and 1.25 mg/0.05 mL of bevacizumab was injected using a 30-gauge needle inserted through the inferotemporal pars plana 3.5 mm from the limbus. At baseline and at each follow-up visit, personnel masked to the type of treatment (control arm or study arm) measured BCVA using Early Treatment Diabetic Retinopathy Study (ETDRS) charts.

       PPV Surgical Technique

      Under local anesthesia and intravenous sedation or general anesthesia, the eye was prepared with a 5% povidone iodine solution and draped in the usual fashion. Standard 3-port 23-, 25-, or 27-small-gauge PPV was performed in the usual fashion. Intraoperative maneuvers to deal with fibrovascular tissue dissection and retinal reattachment was left to each surgeon's preference. Intraocular tamponade and the need for laser photocoagulation was also left to each surgeon's discretion. The severity of intraoperative bleeding was noted as follows: grade 0, none; grade 1, minor bleeding stopping spontaneously or with transient bottle/pressure elevation; and grade 2, moderate to severe bleeding requiring endodiathermy or with formation of broad sheets of clots.
      • Sohn E.H.
      • He S.
      • Kim L.A.
      • et al.
      Angiofibrotic response to vascular endothelial growth factor inhibition in diabetic retinal detachment: report no. 1.
      The total surgical time also was noted.

       Examination Schedule

      Participants were examined at day 1, week 2, month 1, month 3, month 6, and month 12. At each of these visits, the patient underwent measurement of BCVA with ETDRS charts and ophthalmic examination, including slit-lamp biomicroscopy and applanation tonometry. Mean change in BCVA at 12 months was calculated. OCT was used to measure baseline central retinal thickness (CRT) and fluorescein angiography was performed before surgery. Dilated color fundus images of the posterior pole, optic nerve, and macula were acquired at each visit. Ultrasound in the presence of VH also was performed to verify or rule out TRD as needed.
      The following variables were used for primary outcome comparisons: intraoperative bleeding, total surgical time, early (<1 month) postoperative VH, and mean change in BCVA at 12 months. Secondary outcome comparisons: number of endodiathermy applications, intraoperative retinal breaks, change in central macular thickness, proportion of eyes gaining at least 2 lines (10 letters) of ETDRS BCVA.

       Statistical Analysis

      Data were collected in an Excel 2011 spreadsheet (Microsoft, Redmond, Washington, USA). Statistical analysis was performed using MedCalc Software for Windows V.8.2.0.3 (MedCalc, Mariakerke, Belgium). To determine a significant difference in proportion of postoperative VH that occurred between cases (6%) with injection of IVB and controls (19%) without injection as per Ahmadieh et al
      • Ahmadieh H.
      • Shoeibi N.
      • Entezari M.
      • Monshizadeh R.
      Intravitreal bevacizumab for prevention of early post vitrectomy hemorrhage in diabetic patients: a randomized clinical trial.
      and to achieve 80% power and 95% 2-sided confidence level with equal ratio of controls to cases, at least 102 cases and 102 controls were required. The initial total sample required with 10% drop-out was 224 (112 cases and 112 controls). ETDRS BCVA was converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analysis. An increase or decrease in BCVA was defined as a change of ≥2 lines (10 letters) of ETDRS vision before logMAR conversion. The paired-samples t-test was used to compare the CRT and BCVA with baseline values. Correlation was considered significant when P was less than 0.05.

      Results

      A total of 224 patients (224 eyes) patients were initially enrolled in this study. However, 10 participants (10 eyes) were not eligible for analysis because they did not meet the criteria for the study. Five of these patients were lost before undergoing randomization, 3 patients requested withdrawal from the study and 2 were withdrawn by the site. A total of 214 patients (214 eyes) patients were included and randomized in a 1:1 ratio to PPV plus sham injection (control group, 112 eyes) or PPV plus IVB (study group, 102 eyes). In the study group, 7 (6.8%) eyes underwent 27-gauge PPV, 15 (14.7%) 25-gauge PPV, and 80 (78.4%) 23-gauge PPV. In the control group, 6 (5.3%) eyes underwent 27-gauge PPV, 12 (10.7%) 25-gauge PPV, and 94 (83.9%) eyes underwent 23-gauge PPV. The gender distribution, age, and major systemic data between groups were not significantly different (Table 1). In the study group, 96 of 102 eyes (94.12%) had the retina reattached (Figure 1, Figure 2, Figure 3). In the control group, 98 of 112 eyes (87.5%) had the retina reattached by the end of follow-up with 1 procedure. This difference was not statistically significant (P = .097).
      Table 1Baseline Characteristics of Patients Who Received Intravitreal Bevacizumab Before Surgery vs Preoperative Sham Injection for Tractional Retinal Detachment Secondary to Proliferative Diabetic Retinopathy
      Study Group (n = 102)Control Group (n = 112)P
      Age, y (mean ± SD)59.5 ± 11.061.3 ± 10.0.32
      Gender, male (%)6254.29
      Hypertension (%)8194.007
      Statistically significant (P < .05).
      Systemic glycemic control, n (%)
       Insulin9 (9)21 (19).06
       Oral hypoglycemic12 (12)17 (15).65
       Combined therapy81 (79)74 (66).06
      HbA1c at time of surgery8.5 ± 2.18.9 ± 2.5.60
      Previous history of PRP79 (77.4)92 (82.1).46
      VH at presentation (n/%)
       Dense55 (53.0)63 (56.2).76
       Moderate4 (3.9)5 (4.4).73
       Mild15 (14.7)5 (4.4).018
      Statistically significant (P < .05).
       No28 (27.4)39 (34.8).31
      Lens status
       Phakic73 (71.6)85 (76.0).56
       Pseudophakic29 (28.4)27 (24.0).57
      HbA1c = glycosylated hemoglobin; PRP = pan-retinal photocoagulation; VH = vitreous hemorrhage.
      Values represent number and percentages (n/%); study group received intravitreal bevacizumab before surgery; control group received a preoperative sham injection.
      a Statistically significant (P < .05).
      Figure thumbnail gr1
      Figure 1(A) A 39-year-old man with type 2 diabetes showing extensive tractional retinal detachment and fibrovascular proliferation in the left eye and visual acuity (VA) of 20/400. (B) Three days after preoperative intravitreal bevacizumab and 1 day before surgery. Note significant vascular reabsorption on fibrovascular proliferations. (C) Twelve months after 25-gauge pars plana vitrectomy with intraocular gas tamponade the retina remained attached, and the postoperative VA was 20/70.
      Figure thumbnail gr2
      Figure 2(A) A 54-year-old man with type 2 diabetes. His visual acuity (VA) was 20/800. Note extensive neovascularization and fibrovascular traction along the vascular arcade with foveal involvement. (B) He received intravitreal bevacizumab 4 days before surgery. (C) One year after 25-gauge pars plana vitrectomy and C3F8 14% gas as endotamponade, his retina remained attached, and his VA improved to 20/100.
      Figure thumbnail gr3
      Figure 3(A) A 27-year-old man with type 2 diabetes showing vitreous hemorrhage and tractional retinal detachment in the right eye and visual acuity of 20/400. (B) He received intravitreal bevacizumab 5 days before vitrectomy. (B) At 5 months after surgery, the retina remained attached, and visual acuity improved to 20/80.

       Intraoperative Complications

      Some degree of intraoperative bleeding was noted in 69 (67.6%) eyes in the study group and in 100 (89.2%) eyes in the control group (P = .0002). Of these eyes, grade 2 intraoperative bleeding was present in 32 (31.3%) eyes in the study group and 58 (51.7%) eyes in the control group (P = .004). There was a mean of 1.5 ± 2.2 (range, 0 to 7) endodiathermy applications in the study group, and 3.6 ± 3.1 (range, 0 to 10) in the control group. This difference was not statistically significant (P = .062). The use of endodiathermy applications was statistically significantly lower in the study group (28 [27.4%] eyes) compared with the control group (75 [66.9 %] eyes) (P = .0001).
      At least 1 iatrogenic retinal break either along the TRD, or elsewhere was noted intraoperatively in 35 eyes (34.3%) in the study group, and 66 eyes (58.9 %) in the control group (P = .0005). Mean operating time was 71.3 ± 32.1 minutes (range, 35 to 150 minutes) in the study group and 83.6 ± 38.7 minutes (range, 35 to 185 minutes) in the control group. The study group had a shorter mean surgical time than the control group, but the difference was not statistically significant (P = .061). Silicone oil tamponade at the end of surgery was required in 24 (23.5%) eyes in the study group, and 48 (42.8%) eyes in the control group (P = .003) (Table 2).
      Table 2Comparative Variables in Patients Who Received Intravitreal Bevacizumab Before Surgery vs Preoperative Sham Injection for Tractional Retinal Detachment Secondary to Proliferative Diabetic Retinopathy
      Study Group (n = 102)Control Group (n = 112)P
      Intraoperative bleeding69 (67.6)100 (89.2).0002
      Statistically significant (P < .05).
      Grade 2 IB32 (31.3)58 (51.7).004
      Statistically significant (P < .05).
      Endodiathermy28 (27.4)75 (66.9).0001
      Statistically significant (P < .05).
      Iatrogenic retinal break35 (34.3)66 (58.9).0005
      Statistically significant (P < .05).
      Silicone oil tamponade24 (23.5)48 (42.8).003
      Statistically significant (P < .05).
      Early (<1 mo) postoperative VH29 (28.4)48 (42.8).028
      Statistically significant (P < .05).
      Values represent number and percentages (n/%); study group received intravitreal bevacizumab before surgery; control group received a preoperative sham injection.
      IB = intraoperative bleeding; VH = vitreous hemorrhage.
      a Statistically significant (P < .05).

       Visual Acuity Outcomes

      At baseline, the mean BCVA was comparable in both groups. In the study group, the mean BCVA improved from 20/250 (logMAR 1.1 ± 0.5) at baseline to 20/80 (logMAR 0.6 ± 0.48) at the end of follow-up (P < .0001). In the control group, baseline BCVA improved from 20/250 (logMAR 1.1 ± 1.4) at baseline to 20/100 (logMAR 0.7 ± 0.31) at the end of follow-up (P = .034). These results represent a mean gain of 4 lines of vision in the first month of follow-up, and 5 lines of vision at the end of follow-up in the study group. In the control group, a mean gain of 2 lines of vision was observed in the first postoperative month, and a mean of 4 lines of vision was observed at the end of follow-up (Figure 4). BCVA significantly improved by the end of follow-up in both groups.
      Figure thumbnail gr4
      Figure 4A mean gain of 4 lines of vision in the first month of follow-up, and 5 lines of vision at the end of follow-up in the study group. In the sham group, a mean gain of 2 lines of vision was observed in the first postoperative month, and a mean of 4 lines of vision was observed at the end of follow-up. In the study group, the mean baseline best-corrected visual acuity (BCVA) improved from 20/250, logarithm of the minimum angle of resolution (logMAR) 1.1 ± 0.5 to 20/80, logMAR 0.6 ± 0.48 at the end of follow-up (P < .0001), whereas in the control group, baseline BCVA improved from 20/250, logMAR 1.1 ± 1.4 to 20/100, logMAR 0.7 ± 0.31 (P = .034). ETDRS = Early Treatment Diabetic Retinopathy Study; IVB = intravitreal bevacizumab; VA = visual acuity.
      Each group was divided into 2 subgroups according to the presence or absence of VH before surgery to determine variability in terms of both BCVA and CRT during follow-up. In the study group, 55 (53%) eyes had some degree of VH before surgery with a mean preoperative BCVA of 20/400 (logMAR 1.3 ± 0.4), whereas in the control group, 63 (56%) eyes presented VH at baseline with a mean baseline BCVA of 20/500 (logMAR 1.4 ± 2.1). Both groups presented with a statistically significant improvement in vision at the end of follow-up, demonstrating a mean BCVA of 20/60 (logMAR 0.5 ± 2.1) for the study group (P < .0001) and 20/80 (logMAR 0.6 ± 2.1) for the control group (P = .032).
      The study group included 47 patients (eyes) with TRD without VH before surgery. This subgroup had a mean BCVA of 20/100 (logMAR 0.7 ± 1.9) at presentation, that improved to 20/60 (logMAR 0.5 ± 2.9) at the 12-month follow-up visit (P = .002). Forty-nine patients (eyes) included in the control group had TRD without VH at presentation and had a mean BCVA of 20/125 (logMAR 0. 8 ± 1.3) that improved to 20/60 (logMAR 0.6 ± 1.5) at the end of follow-up (P = .004). In both groups, there was a significant postoperative gain in vision but there was no significant difference between groups during the follow-up visits.
      In the study group, the 12-month BCVA analysis by subgroups demonstrated that 75 (73%) eyes improved 2 or more ETDRS lines of BCVA, and that BCVA remained stable in 16 (15.6%) eyes at 12 months. Eleven (10.7%) eyes experienced 2 or more ETDRS lines of BCVA at the end of follow-up. In the control group, 76 (67.8%) eyes improved by 2 or more ETDRS lines of BCVA, and BCVA remained stable in 20 (17.8%) eyes, and 16 (14.2%) eyes experienced a decrease of 2 or more lines of BCVA at the end of follow-up (Table 3).
      Table 3Change in Best-Corrected Visual Acuity From Preoperative to 12 Months Postoperatively in Patients Who Received Intravitreal Bevacizumab Before Surgery vs Preoperative Sham Injection for Tractional Retinal Detachment Secondary to Proliferative Diabetic Retinopathy
      Values represent number and percentages; P < .05 is statistically significant.
      BCVA (logMAR) ResultsStudy GroupControl GroupP
      (n/%)(n/%)
      Improved 2 or more lines75 (73)76 (67.8).555
      Remained stable16 (15.6)20 (17.8).672
      Decreased 2 or more lines11 (10.7)16 (14.2).441
      Total102 (100)112 (100)
      BCVA = best-corrected visual acuity; logMAR = logarithm of the minimal angle of resolution; n = represents number of patients.
      a Values represent number and percentages; P < .05 is statistically significant.

       Postoperative Retinal Macular Thickness

      OCT results were available for all patients who had no dense VH at presentation. OCT results were available for 47 (46.1%) eyes in the study group, and 49 (43.7%) eyes in the control group. In the study group, mean CRT decreased from 382.2 ± 116.2 μm to 334.5 ± 109.2 μm at the end of follow-up (P = .061). Mean CRT decreased from 409.4 ± 160.4 to 345.5 ± 119.2 μm at the 12-month follow-up visit in the control group (P = .089).

       Postoperative Complications

      Postoperatively, VH was observed in 29 (28.4%) eyes in the study group, and 48 (42.8%) eyes in the control group had some grade of VH within the first month after surgery (P = .028).
      There were 6 (5.8%) cases of tractional redetachment in the study group. Four (66.6%) of these patients had been treated with intraocular gas (SF6, 20%) as tamponade and 2 (33.3) eyes were under silicone oil tamponade. In the control group, 14 (12.5%) cases of redetachment were noted. Nine (64.3%) of these eyes were treated with intraocular gas (SF6, 20%) and 5 (35.7%) eyes underwent silicone oil tamponade. All cases required a second vitrectomy within 1 year. Number of re-interventions due to recurrence of TRD was lower in the IVB group, but we did not demonstrate a statistically significant difference between both groups (P = .097). There were 8 (7.8%) cases of dense recurrent VH in the study group, of which 3 (37.5%) cases required a second vitrectomy. In the control group, 26 (23.2%) patients presented with dense recurrent VH within the follow-up period. Fourteen (58.3%) of these patients required a second vitrectomy during the follow-up period. There were statistically significantly more cases of dense recurrent VH in the control group compared with the study group (P = .002). At the end of follow-up, neovascular glaucoma occurred in 3 (2.9%) eyes in the study group and 7 (6.3 %) eyes in the control group (P = .252). There were no statistical differences in the surgical outcomes and complications among the cases that underwent 23-, 25-, or 27-gauge PPV.

       Adverse Events Related to IVB

      The only adverse event related to IVB injection was that there were 3 of 102 eyes (2.9%) with progression of TRD 3 days after the injection. However, the retina was reattached with BCVA improved after PPV in all these cases. This complication was not seen in the control group.

      Discussion

      This randomized study demonstrates that preoperative intravitreal injection of bevacizumab might be helpful to facilitate vitrectomy in cases of TRD secondary to advanced PDR. IVB as a preoperative adjunct in cases of severe PDR seems to be beneficial and aid in rapid clearing of VH and reduces the surgical time by mitigating intraoperative bleeding.
      • Spaide R.F.
      • Fisher Y.L.
      Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage.
      TRD in PDR is challenging because of the thin ischemic retina and extensive neovascularization. Intravitreal anti-angiogenic therapy is being widely used for neovascular complications of PDR.
      • Zhao L.Q.
      • Zhu H.
      • Zhao P.Q.
      • Hu Y.Q.
      A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy.
      • Avery R.L.
      Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment.
      • Pokroy R.
      • Desai U.R.
      • Du E.
      • Li Y.
      • Edwards P.
      Bevacizumab prior to vitrectomy for diabetic tractional retinal detachment.
      • Oshima Y.
      • Sakaguchi H.
      • Gomi F.
      • Tano Y.
      Regression of iris neovascularization after intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy.
      • Isaacs T.
      • Barry C.
      Rapid resolution of severe disc new vessels in proliferative diabetic retinopathy following a single intravitreal injection of bevacizumab.
      Surgical outcomes may limit visual prognosis of the disease and it could be compromised by intraoperative and postoperative complications. Perioperative VH resulting in the formation of adherent fibrinous clots may necessitate frequent application of diathermy and exchange of instruments. Severe intraoperative hemorrhages represent the main obstacle in the surgical removal of preretinal tissue, and it may interfere with completion of the surgical procedure in nearly 4 % of cases.
      • Oyakawa R.T.
      • Schachat A.P.
      • Michels R.G.
      • Rice T.A.
      Complications of vitreous surgery for diabetic retinopathy. I. Intraoperative complications.
      Conversely, a bloodless field allows for better visibility facilitating completion of surgery.
      In our study, we observed that grade 2 intraoperative bleeding was statistically significantly lower in the study group compared with the control group (P = .001). The reduced risk of intraoperative bleeding also may decrease the use of endodiathermy that represents less trauma in a previously damaged and ischemic retina. In our study, the endodiathermy was necessary in 28 (27.4%) eyes in the study group compared with 75 (66.9%) eyes in the control group (P = .0001). In addition, the decrease of intraoperative bleeding also may facilitate removal of the fibrovascular membranes with less damage to subjacent retina. We also observed that the eyes in the study group had a lower incidence of intraoperative iatrogenic retinal breaks than eyes in the control group (sham).
      Previously, a lower incidence of intraoperative retinal tears had been observed in the IVB-PPV group compared with the conventional PPV group, possibly due to minimal intraoperative bleeding and improved retinal visualization during surgery.
      • Gupta A.
      • Bansal R.
      • Gupta V.
      • Dogra M.R.
      Six-month visual outcome after pars plana vitrectomy in proliferative diabetic retinopathy with or without single preoperative injection of intravitreal bevacizumab.
      • Yeoh J.
      • Williams C.
      • Allen P.
      • et al.
      Avastin as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy: a prospective case series.
      • El-Batarny A.M.
      Intravitreal bevacizumab as an adjunctive therapy before diabetic vitrectomy.
      • Rizzo S.
      • Genovesi-Ebert F.
      • Di Bartolo E.
      • Vento A.
      • Miniaci S.
      • Williams G.
      Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR).
      Gupta et al
      • Gupta A.
      • Bansal R.
      • Gupta V.
      • Dogra M.R.
      Six-month visual outcome after pars plana vitrectomy in proliferative diabetic retinopathy with or without single preoperative injection of intravitreal bevacizumab.
      evaluated the effect of a single preoperative injection of IVB on visual outcome in patients undergoing PPV for PDR. Intraoperatively, they described an incidence of iatrogenic retinal breaks comparable in the 2 groups (20 [21.3%] vs 15 [17.2%]) in groups A and B, respectively. However, the authors
      • Gupta A.
      • Bansal R.
      • Gupta V.
      • Dogra M.R.
      Six-month visual outcome after pars plana vitrectomy in proliferative diabetic retinopathy with or without single preoperative injection of intravitreal bevacizumab.
      describe the presence of TRD in 42 eyes in the IVB group (44.7 %) and 31 eyes (35.6 %) in the control group. Recently Dong et al
      • Dong F.
      • Yu C.
      • Ding H.
      • Shen L.
      • Lou D.
      Evaluation of intravitreal ranibizumab on the surgical outcome for diabetic retinopathy with tractional retinal detachment.
      investigated intravitreal injection of ranibizumab (IVR) on the surgical outcome for diabetic patients who had TRD but in patients who did not receive any preoperative retinal photocoagulation. They
      • Dong F.
      • Yu C.
      • Ding H.
      • Shen L.
      • Lou D.
      Evaluation of intravitreal ranibizumab on the surgical outcome for diabetic retinopathy with tractional retinal detachment.
      reported the outcomes in 97 patients (97 eyes) who had diabetic retinopathy with TRD enrolled to receive 23-gauge PPV. Dong et al
      • Dong F.
      • Yu C.
      • Ding H.
      • Shen L.
      • Lou D.
      Evaluation of intravitreal ranibizumab on the surgical outcome for diabetic retinopathy with tractional retinal detachment.
      assigned the patients to an experimental group (preoperative IVR plus PPV, n  =  47 eyes) and a control group (VPP, n = 50 eyes). The authors
      • Dong F.
      • Yu C.
      • Ding H.
      • Shen L.
      • Lou D.
      Evaluation of intravitreal ranibizumab on the surgical outcome for diabetic retinopathy with tractional retinal detachment.
      reported iatrogenic breaks in 5 eyes (11%) in the experimental group and in 17 eyes (34%) in the control group; the difference was statistically significant (P = .006).
      Our results concur with the outcomes of Dong et al.
      • Dong F.
      • Yu C.
      • Ding H.
      • Shen L.
      • Lou D.
      Evaluation of intravitreal ranibizumab on the surgical outcome for diabetic retinopathy with tractional retinal detachment.
      For example, we found at least one iatrogenic retinal break either along the TRD, or elsewhere intraoperatively in 35 eyes (34.3%) in the study group, and 66 eyes (58.9 %) in the control group; this difference was statistically significant (P = .001). In addition, we observed that more than 70% of the retinal tears described in the control group were along the fibrovascular traction and that they probably occurred after fibrovascular membrane peeling. Therefore, iatrogenic retinal breaks may be strongly linked to the dissection maneuver of tractional fibrovascular tissue on the retina. This lower incidence of iatrogenic retinal breaks in the study (IVB) group is an important finding that could be explained due to the significant regression of the vascular component after preoperative IVB, which could change the pathophysiology of the fibrovascular complex, making it more prone to readily separate from the retina, facilitating easier and faster dissection. The lower rate of intraoperative bleeding and the lower number of retinal breaks in the study group suggest that preoperative IVB could make TRD surgery safer and more efficacious. This observation concurs with Yeoh et al,
      • Yeoh J.
      • Williams C.
      • Allen P.
      • et al.
      Avastin as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy: a prospective case series.
      who reported that IVB was particularly useful in diabetic eyes with traction retinal detachments of short duration with active neovascularization.
      In our study, 72 (72.5%) eyes in the IVB group had some degree of preoperative VH, which indicates that neovascularization was still active during IVB application. El-Sabagh et al
      • El-Sabagh H.A.
      • Abdelghaffar W.
      • Labib A.M.
      • et al.
      Preoperative intravitreal bevacizumab use as an adjuvant to diabetic vitrectomy: histopathologic findings and clinical implications.
      described a profibrotic switch in diabetic fibrovascular proliferation after IVB, and their results suggest that the vascular component of proliferation is markedly reduced post-IVB. These findings are consistent with our results, which suggest that PPV is safer and more complete when IVB is administered preoperatively. Our results concur with a previous report
      • Chen E.
      • Park C.H.
      Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy.
      that IVB as a preoperative adjunct for TRD repair in severe PDR resulted in more successful surgery with significant regression of neovascularization in the fibrovascular proliferative membranes, consequently minimizing intraoperative bleeding during segmentation and delamination of membranes. Additionally, we observed that postoperative intravitreal hemorrhage was less marked in the study group.
      In our study, there were 3/102 (2.9%) eyes with progression of TRD 3 days after IVB injection. However, BCVA improved after PPV. This complication was not seen in the control group. This rate concurs with previous reports.
      • Arevalo J.F.
      • Maia M.
      • Flynn Jr., H.W.
      • et al.
      Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy.
      • Arevalo J.F.
      • Sanchez J.G.
      • Saldarriaga L.
      • et al.
      Retinal detachment after bevacizumab.
      We have previously reported that most cases with progression or development of TRD after IVB occurs 5 days or later after the injection.
      • Arevalo J.F.
      • Sanchez J.G.
      • Saldarriaga L.
      • et al.
      Retinal detachment after bevacizumab.
      The low incidence in our study, and good visual outcomes, confirm that IVB is safe and effective even in eyes that develop contraction and progression of TRD.
      In this study, BCVA improved by 2 or more lines in 75 (73%) eyes in the study group, and 76 (67.8%) eyes in the control group by the end of follow-up (P > .05). Our results show a significant improvement in BCVA in both groups, but there was no significant difference between groups at the end of the follow-up. These findings are in concordance with previous studies.
      • Pokroy R.
      • Desai U.R.
      • Du E.
      • Li Y.
      • Edwards P.
      Bevacizumab prior to vitrectomy for diabetic tractional retinal detachment.
      • Dong F.
      • Yu C.
      • Ding H.
      • Shen L.
      • Lou D.
      Evaluation of intravitreal ranibizumab on the surgical outcome for diabetic retinopathy with tractional retinal detachment.
      • Oshima Y.
      • Shima C.
      • Wakabayashi T.
      • Kusaka S.
      • et al.
      Microincision vitrectomy surgery and intravitreal bevacizumab as a surgical adjunct to treat diabetic traction retinal detachment.
      Compared with the control group, patients who received preoperative IVB had lower use of silicone oil as internal tamponade, suggesting that the surgical procedure was less complex. We found that silicone oil tamponade at the end of surgery was required in 24 (23.5%) eyes in the study group and 48 (42.8%) eyes in the control group (P = .003). Dong et al
      • Dong F.
      • Yu C.
      • Ding H.
      • Shen L.
      • Lou D.
      Evaluation of intravitreal ranibizumab on the surgical outcome for diabetic retinopathy with tractional retinal detachment.
      report similar outcomes, performing silicone oil tamponade in 22 eyes (47%) in the IVR group and 37 (74%) eyes in the control group (P = .006). Our results also demonstrated that the postoperative incidence of neovascular glaucoma did not differ between the study group and the control group.
      The strength of our study is that it is a prospective randomized clinical trial. However, the multicentric nature is a limitation, as multiple surgeons from several centers participated with a nonstandardized surgical technique including all available gauges for minimally invasive vitrectomy. However, the number of patients is significant for a surgical trial, and the results document the benefits of IVB to facilitate PPV in TRD in PDR.
      In summary, we demonstrated that preoperative intravitreal bevacizumab as an adjuvant to small-gauge PPV may be helpful and beneficial for patients with TRD secondary to severe PDR. Preoperative IVB seems to reduce intraoperative bleeding, improving surgical visual field visualization and reducing intraoperative and postoperative complications, including iatrogenic retinal tears and postoperative bleeding. However, retinal reattachment rates were also similar between both groups. In addition, neither the postoperative BCVA nor the proportion of eyes with improved BCVA were significantly different between groups at the end of follow-up. These outcomes indicate that preoperative IVB may not be a determining factor for postoperative BCVA, as previous studies have reported.
      • El-Batarny A.M.
      Intravitreal bevacizumab as an adjunctive therapy before diabetic vitrectomy.
      • Dong F.
      • Yu C.
      • Ding H.
      • Shen L.
      • Lou D.
      Evaluation of intravitreal ranibizumab on the surgical outcome for diabetic retinopathy with tractional retinal detachment.
      • Modarres M.
      • Nazari H.
      • Falavarjani K.G.
      • Naseripour M.
      • Hashemi M.
      • Parvaresh M.M.
      Intravitreal injection of bevacizumab before vitrectomy for proliferative diabetic retinopathy.
      All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. The authors indicate no financial support or financial conflict of interest. All authors attest that they meet the current ICMJE requirements to qualify as authors. Dr Arevalo obtained his PhD at Faculty of Health Sciences, Stellenbosch University, Stellenbosch, South Africa. This article is part of his PhD on “Intravitreal Bevacizumab as Anti–vascular Endothelial Growth Factor in the Management of Complications of Diabetic Retinopathy.”
      Pan-American Collaborative Retina Study (PACORES)
      Members of the Pan-American Collaborative Retina Study (PACORES): J. F. Arevalo (principal investigator [PI]), T. Y. A. Liu, The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA; L. Wu (PI), Asociados de Macula, Vitreo y Retina de Costa Rica, San Jose, Costa Rica; A. F. Lasave (PI), Clinica Oftalmologica Centro Caracas and the Arevalo-Coutinho Foundation for Research in Ophthalmology, Caracas, Venezuela; M. Farah (PI), M. Maia, F. M. Penha, E. B. Rodrigues, Universidade Federal de São Paulo - Departamento de Oftalmologia - Instituto da Visão - Sao Paulo, Brazil; V. Morales-Canton (PI), J. Fromow-Guerra, J.L. Guerrero-Naranjo, J. Dalma-Weiszhausz, R Velez-Montoya, H. Quiroz-Mercado, Asociación para Evitar la Ceguera en México, Mexico City, Mexico; F. J. Rodriguez (PI), F. E. Gomez, A. C. Brieke, A. Goveto, Fundacion Oftalmologica Nacional, Universidad del Rosario, Bogota, Colombia; M.H. Berrocal (PI), V. Cruz-Villegas, University of Puerto Rico, San Juan, Puerto Rico; F. Graue-Wiechers (PI), D. Lozano-Rechy, E. Fulda-Graue, Fundacion Conde Valenciana, Mexico City, Mexico; J.A. Roca (PI), A. Hernández, Clínica Ricardo Palma, Lima, Peru; M. J. Saravia (PI), A. Schlaen, J. Rojas, M. Ingolotti, Hospital Universitario Austral, Buenos Aires, Argentina; M. Avila (PI), L. Carla, Universidade Federal de Goiás- Departamento de Oftalmologia - Goiânia, Brazil; J. Cardillo (PI), R. Jorge, Hospital de Olhos de Araraquara, and the Universidade de Sao Paulo, Sao Paulo, Brazil; C. Carpentier (PI), J. Verdaguer T., J.I. Verdaguer D., G. Sepúlveda, Fundacion Oftalmologica Los Andes, Santiago de Chile, Chile; A. Alezzandrini (PI), B. Garcia, M. Zas, OFTALMOS, Catedra de Oftalmologia, Universidad de Buenos Aires, Buenos Aires, Argentina; R. Gallego-Pinazo (PI), M. Diaz-Llopis, R. Dolz-Marco, Hospital La Fe, Universidad de Valencia, Spain; M. Figueroa (PI), I. Contreras, D. Ruiz-Casas, Hospital Universitario Ramón y Cajal, Departamento de Retina, and VISSUM Madrid, Madrid, Spain.

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