a key determinant of a successful glaucoma filtering surgery ( gfs ) is the healing response of the sclera , tenon tissue , and conjunctiva . histologically , functional blebs show low inflammatory response with scattered conjunctival epithelium cells and fibroblasts , whereas dysfunctional blebs are characterized by dense collagen tissues and corkscrew blood vessels . agents that modify the healing process have been used to improve the success of gfs . antiproliferative agents such as 5-fluoroacil ( 5-fu ) and mitomycin - c ( mmc ) inhibit the proliferation of fibroblasts . both intraoperative use and postoperative use of these two agents however , the use of these antiproliferative agents can lead to very thin blebs that are prone to leakage , hypotony , and higher incidence of endophthalmitis [ 3 , 4 ] . other modulating agents such as growth factors inhibitors have been investigated for their potential use in gfs . among these , antitransforming growth factor-2 ( tgf-2 ) has shown promising results in experimental studies but has failed to show any superiority to placebo group in clinical trial . in addition to inflammation and fibroblast proliferation , angiogenesis also plays an integral role in the wound healing process . the level of vascular endothelium growth factor ( vegf ) has been shown to be upregulated in the aqueous humour of human and rabbit eyes after trabeculectomy . case series have shown that postoperative subconjunctival injection of bevacizumab ( scb ) decreased the bleb vascularity and iop . at the time of writing , three published prospective studies have evaluated the adjunct use of scb in trabeculectomy and phacotrabeculectomy for patients with open angle glaucoma ( oag ) [ 810 ] . the study by grewal and associates is a prospective noncomparative case series of twelve trabeculectomies augmented with scb ( 1.25  mg ) immediately at the end of the surgery . mmc and 5-fu were not used . at six months , successful outcome ( iop between 616  mmhg ) was achieved in eleven out of the twelve eyes . in their study , blebs increased their vascularity after 3 months . the authors hypothesized that the use of scb might decrease the incidence of cystic thin blebs , frequently noted after mmc augmented trabeculectomies . the study by nilforushan and associates is a randomized comparative study comparing the uses of scb and mmc in trabeculectomy surgery . thirty - six eyes were randomized to receive either scb ( 2.5  mg ) or mmc ( 0.02% for 3 minutes ) . the eyes that received scb had a statistically higher iop level compared to the eyes that received mmc ( 13.6  3.2  mmhg versus 9.6  2.7  mmhg ) . in their study , the study by sengupta and associates is a randomized study comparing the uses of mmc ( 0.03% for 3 minutes ) , direct intraoperative bevacizumab application on the scleral using a sponge and three doses of scb ( 1.25  mg ) in patients undergoing phacotrabeculectomy . in their study , the patients randomized to the scb group received two doses of scb during the surgery and the third dose at one week . at six months , they reported a higher rate of success ( iop less than 18  mmhg ) in the scb group compared to those of the other two groups ( 90% versus 60% ) . we intend to examine the use of scb in the postoperative management of combined cataract and glaucoma surgery including both trabeculectomy and nonpenetrating glaucoma surgery ( npgs ) . the study was a retrospective review of patients who had glaucoma filtering surgery ( gfs ) and subconjunctival bevacizumab injection ( scb ) as part of their postoperative management . all patients have given written informed consent to receive scb . all surgeries and postoperative followups the study subjects were identified through searching a computerized internal medical database by typing the keywords such as  subconjunctival bevacizumab , a control group was selected matching the demographic data and surgical procedures of the scb group . subjects from the control group received similar postoperative management as the scb group with the exception of subconjunctival bevacizumab injection . demographics data , types of gfs , intraocular pressure ( iop ) and the number of topical iop - lowering medications used pre- and postsurgery , the frequency and timing of scb injections , other interventions used in the postoperative period , and complications were recorded .   the types of gfs included trabeculectomy and npgs with or without phacoemulsification and posterior chamber intraocular lens implantation ( pciol ) . in both gfs procedures , a conjunctival incision was made 1.5  mm posterior to the limbus , and a half thickness 3.5  3.5  mm scleral flap was dissected toward the limbus . in npgs , a second deeper flap was dissected and excised , leaving an anterior trabeculodescemet window and the anterior wall of schlemm 's canal unroofed . in trabeculectomy surgery , a sclerostomy was created using a kelly punch , and a peripheral iridectomy was performed with vannas scissors . in both cases , mmc ( 0.2  mg / ml ) was routinely applied for 2 minutes on the bare sclera followed by thorough irrigation of conjunctival tissues with balanced salt solution , the scleral flap was closed with interrupted 10.0 nylon sutures , and the conjunctiva was closed using 10.0 biosorb using the modified wise technique . in combined gfs and cataract extraction , the anterior chamber was entered under the scleral flap with a 2.75  mm keratome , and phacoemulsification was performed using a direct chop technique followed by cortical clean - up and implantation of a foldable intraocular lens . at the end of surgery , all patients received topical moxifloxacin four times per day for one week , nonsteroidal anti - inflammatory four times per day for one week , and topical steroid tapering off for over two months .   during the postoperative follow - up period , all patients could have the following interventions at the surgeon 's discretion : subconjunctival injection of 5-fluorouracil ( 5-fu ) , laser suture lysis , bleb needling with a 30-gauge needle with or without 5-fu , laser goniopuncture , and subconjunctival injection of betamethasone or triamcinolone acetonide . needling was performed using a 30-gauge needle tip to the flap area and then beneath the flap to puncture episcleral fibrous tissue . the needle tip was passed several times beneath the flap until bleb elevation was observed . ml ) was occasionally used during the same session depending on the clinical appearance of the bleb . scleral flap sutures were lysed using an argon green laser or red laser ( 0.1  s , 400420  mw , 50  um spot size ) . goniopunctures with nd : yag laser ( 4  mj ) were performed using a latina gonioscopy contact lens . in addition to the previously mentioned interventions , all patients in the scb group also received at least one dose of scb postoperatively . after topical anesthesia , 1.25  mg ( 0.05  ml ) of bevacizumab was injected in the subconjunctival space superior to the bleb using a 30-gauge needle . main outcome measurements included iop and topical medication use recorded on the last clinical visit . the database retrieved 30 eyes of 28 patients who had scb injection following either trabeculectomy or npgs in postoperative period . matching for age , diagnosis , and surgical procedures , we selected 28 control patients who did not received scb as part of their postoperative management . demographic data and postoperative management for each group age , preoperative iop , and medications used were not significantly different in each group . the mean follow - up time was 19.6 ( 11.5 ) and 16.8 ( 8.2 ) months for the control and scb groups , respectively . the majority of patients had combined npgs with phaco - pciol ( scb group : 24/30 eyes ; control group : 20/30 eyes ) ; few patients had phacotrabeculectomy , npgs , and trabeculectomy alone ( table 1 ) .   in the control group , eight eyes from the control group did not undergo any intervention during their postoperative period . the rest of the control group ( 22/30 eyes ) underwent one or a combination of the following treatments : 5-fu injection ( 12/30 eyes ) , suture lysis ( 9/30 eyes ) , goniopuncture ( 11/30 eyes ) , needling ( 2/30 eyes ) , and subconjunctival injection of triamcinolone acedonide ( 1/30 eyes ) . patients from the scb group received similar pattern of postoperative management , but more patients underwent needling compared to those of the control group : 5-fu injection ( 10/30 eyes ) , suture lysis ( 7/30 eyes ) , goniopuncture ( 8/30 eyes ) , needling ( 5/30 eyes ) , and subconjunctival injection of triamacinolone ( 2/30 eyes ) and betamethasone ( 1/30 eyes ) . sixteen eyes of the scb group received only bevacizumab as their postoperative management with no other intervention required . compared to the control groups , the scb group had fewer patients who required different types of interventions : 14/30 eyes in the scb group versus 22/30 eyes in the control group ( table 2 ) . iop was reduced from 21.9 ( 9.8 ) mmhg preoperatively to 11.9 ( 4.7 ) mmhg on the last follow - up visit in the control group . in the scb group , the average iop was reduced from 19.6 ( 8.9 ) mmhg preoperatively to 14.0 ( 4.7 ) mmhg on the last visit . the number of iop - lowering medications was reduced from 3.1 ( 1.0 ) to 0.4 ( 0.8 ) in the control group and from 3.0 ( 1.1 ) to 0.7 ( 1.1 ) in the scb group . the reductions in number of medications and iop were statistically significant in both groups ( p < 0.001 ) . the mean final iop was slightly higher in the scb group ( 14.0  4.7  mmhg ) compared to that of the control group ( 11.9  4.7  mmhg ) ; however the difference was not statistically significant ( p = 0.36 ) . in fact , there were no statistical differences in final iop , the number of medications or reductions in iop between the scb and control groups ( tables 3 and 4 ) . the complications observed in the control group included one case of blebitis requiring topical antibiotic treatment , two cases of iris incarceration , and one case of bleb leak requiring medical treatment . in the scb group , three patients developed branch retinal vein occlusion ( brvo ) during their follow - up periods , two patients had choroidal detachments , and one patient had a bleb leak that required surgical repair . two of the three patients were not known for any systemic risk factors such as hypertension , diabetes , or atherosclerosis , whereas the third patient with brvo had had central retinal vein occlusion in the past ( table 5 ) . studies have shown that anti - vegf agents could modulate wound healing through antifibroblast effect in addition to its antiangiogenic role . have also demonstrated that the application of bevacizumab inhibited tenon fibroblasts proliferation , reduced collagen deposition , and induced apoptosis of fibroblasts [ 6 , 13 ] . in vivo animal studies in rabbits undergoing trabeculectomy have demonstrated the efficacy of bevacizumab in prolonging bleb survival compared to 5-fu injection . one study has also shown that the bleb survival rate was the highest in the rabbits receiving a combination of subconjunctival 5-fu and bevacizumab injections ( 100% survival rate ) compared to the rabbits receiving only one of the two injections ( 5-fu : 25% survival rate or bevacizumab : 50% survival rate ) , suggesting that a combination of antimetabolite and anti - vegf might be superior to the use of either agent alone . such synergetic effect of antimetabolite and anti - vegf has been reported in clinical trials involving patients treated for colorectal cancer where delayed wound healing was observed in the group treated with systemic bevacizumab and 5-fu compared to the group treated with 5-fu - based chemotherapy alone . clinical studies on the combined use of anti - vegf and antifibrotic agents are limited to the use of ranibizumab . in a prospective study , kahook compared the effect of combined intravitreal injection of ranibizumab and topical mmc to mmc alone in patients undergoing trabeculectomy . his study found that patients receiving a combination of mmc and anti - vegf demonstrated more diffuse bleb , but both groups had the same final iop . our comparative series attempted to illustrate the combined use of scb in addition to other postoperative interventions including the use of antimetabolites such as mmc and 5-fu . we also did not find significant advantage in terms of the final iop value or the reduction in medications . unfortunately , the difference in bleb morphology between the scb and control groups could not be compared due to lack of documentation ; whether the addition of bevacizumab would influence the bleb morphology could not be determined in this series . the optimal timing and delivery method of bevacizumab in gfs are yet to be determined . pharmacokinetics studies in rabbits have shown that both subconjunctival and intravitreal administrations of bevacizumab reached adequate intraocular concentration , whereas the topical route did not . topical use of anti - vegf is , however , sufficient in regressing corneal neovascularization . it is debatable if the topical administration of anti - vegf will be sufficient in glaucoma surgery as the target place is the subconjunctival space . topical administration has the advantage of less systemic absorption but requires frequent dosing , whereas a single intravitreal or subconjunctival injection may be sufficient as the duration of bevacizumab can be detected at least up to two weeks in aqueous humour . the duration of injection will cover the peak inflammatory and healing phase that occurs for about one week after filtering surgeries . in the prospective studies on anti - vegf use in gfs , subconjunctival injection is the most commonly used route except in one study that used intravitreal injection [ 810 , 17 ] . most of studies also used a single injection intraoperatively or postoperatively . only the study by sengupta and there is no study comparing a single use of bevacizumab to repeated injections . in our study , scb was given postoperatively when the bleb appeared to be hypervascular . this approach is reasonable as newly formed vessels depend on vegf to survive , and the inhibition of vegf will result in regression of neovascularization . clinically , decreased bleb vascularity has been observed after one single injection of bevacizumab into the bleb in some case reports as well as in our series of patients ( figure 1 ) . in our opinion , intravitreal or subconjunctival injection may not differ much in the management of gfs , as both methods achieve adequate aqueous concentration and have similar pharmacokinetics . intravitreal injection has the additional ocular risks of inflammation , retinal detachment , and endophthalmitis . one ongoing study is investigating the use of topical ranibizumab four times a day for one month in postoperative period for trabeculectomy ; its results may illustrate if topical treatment will be also an option in the management of glaucoma surgery . we observed three cases of branch retinal vein occlusion ( brvo ) in the group of 28 patients receiving bevacizumab . this high - incidence brvo is probably coincidental since the onset of brvo was seven to eight weeks after the injection of bevacizumab . other series on glaucoma filtering surgery did not report any vascular complication related to the use of anti - vegf agents [ 8 , 9 , 17 ] . however , brvo is a serious ocular complication , and we should still be cautious about the possible vascular side effects of anti - vegf agents . systemic use of bevacizumab is associated with various vascular events such as hypertension , hemorrhage , and thromboembolism . regarding the ocular use of bevacizumab , rare events such as retinal ischemia , central retinal artery occlusion , subretinal hemorrhages , and systemic complications such as elevated blood pressure , stroke , and myocardial infarctions have also been reported in surveys and retrospective studies [ 22 , 23 ] . pooled results from clinical trials have suggested a higher incidence of stroke in patients receiving a higher dose of ranibizumab ( 0.5  mg ) compared to that in those receiving a lower dose ( 0.3  mg ) . some studies have also shown that oag patients had elevated vegf levels in their aqueous humour and plasma compared to normal controls [ 25 , 26 ] . the presence of vegf is likely important for normal function and repair of vascular endothelium , and the blockage of vegf may lead to endothelial dysfunction [ 19 , 25 ] . although there is no definitive evidence suggesting that glaucoma patients are prone to side effect of anti - vegf agents , as their use may be more frequent in glaucoma patients , the safety profile of anti - vegf agents should be followed . in conclusion , our comparative series did not found that subconjunctival injection of bevacizumab had additional benefit in term of iop reduction . the bleb morphology could not be assessed in this series due to the retrospective nature of the study and lack of bleb description in every patient . whether bevacizumab will influence the bleb morphology and whether this influence will be clinically relevant need to be addressed by prospective studies with longer follow - up time . in our opinion , subconjunctival and intravitreal injections of anti - vegf would have the same efficacy as the pharmacokinetics of either delivery route will cover the inflammatory phase after filtering surgeries . of significance , there were three cases of brvo observed in the bevacizumab group . clinicians should monitor potential side effects of anti - vegf agents as their safety profile in glaucoma patients may not be the same as that in amd patients .
aims . to describe the use of subconjunctival bevacizumab ( scb ) injection in the combined cataract and glaucoma filtering surgery ( gfs ) 
 . methods . 
 retrospective comparative case series . 
 thirty eyes of twenty - eight patients who had gfs followed by scb injection as part of post - operative management were included ( group scb ) . 
 the types of gfs included trabeculectomy and non - penetrating glaucoma surgery ( npgs ) with mitomycin - c . 
 outcome measures included the reduction of intraocular pressure ( iop ) and medications . 
 age - matched patients who had the same types of surgery without scb were selected as a control group ( group c ) . 
 results . 
 the types of gfs were : combined cataract surgery and npgs ( scb : 20 ; c : 24 ) , phacotrabeculectomy ( scb : 6 ; c : 3 ) , npgs ( scb : 3 ; c : 2 ) and trabeculectomy alone ( scb : 1 ; c : 1 ) . 
 the average follow - up time was 16.9 ( 8.2 ) months in the scb group and 19.6 ( 11.5 ) months in the controls . 
 1.25  mg of bevacizumab was injected on average 14.1 ( range : 342 ) days post - gfs . 
 the mean iop decreased from 21.9 ( 9.8 ) to 11.9 ( 4.7 ) mmhg in the controls and from 19.6 ( 8.9 ) to 14.0 ( 4.7 ) mmhg in the scb group . 
 there was no statistically significant difference between the two groups ( p = 0.11 ) . 
 complications included three cases of branch vein occlusion in the scb group . 
 conclusions . 
 scb did not result in better outcome in term of iop reduction . 
 clinicians should monitor its side effects in glaucoma patients .