Randomized controlled trial of intravitreal ranibizumab versus standard grid laser for macular edema...

Randomized Controlled Trial of Intravitreal RanibizumabVersus Standard Grid Laser for Macular Edema Following

Branch Retinal Vein Occlusion

MEI HONG TAN, IAN L. MCALLISTER, MARK E. GILLIES, NITIN VERMA, GAYATRI BANERJEE,LYNNE A. SMITHIES, WAN-LING WONG, AND TIEN Y. WONG

� PURPOSE: To assess the efficacy of intravitreal 0.5 mgranibizumab for the treatment of center-involving macularedema secondary to branch retinal vein occlusion (BRVO)over 1 year compared with standard-of-care grid laser.� DESIGN: A prospective randomized controlled clinicaltrial.� METHODS: A total of 36 patients with vision loss in 1eye attributable to macular edema following BRVOwere recruited from 5 institutions. Patients were random-ized 1:1 to a treatment group that received 6 monthlyinjections of 0.5 mg ranibizumab and thereafter monthlyas needed based on best-corrected visual acuity (BCVA)and central foveal thickness (CFT) assessments onoptical coherence tomography scans, or a standard-of-care group that received monthly sham injections forthe 1-year duration of the study. Grid laser was adminis-tered at 13 and 25weeks in both groups if criteria for lasertreatment were met. Main outcome measures includedmean change in BCVA in Early Treatment Diabetic Reti-nopathy Study (ETDRS) letter scores from baseline tomonth 12. Secondary outcomes included anatomicoutcomes and the percentage of patients requiring gridlaser in both groups.� RESULTS: Mean BCVA change from baseline wassignificantly greater in the treatment compared with thestandard-of-care group at 12 months (12.5 ETDRSletters vs -1.6 ETDRS letters, P [ .032). The meanCFT was significantly reduced in the treatment comparedwith standard-of-care group (361.7 mm vs 175.6 mm,P [ .025). At 13 and 25 weeks, more patients in thestandard-of-care group (68.4%, 50.0%) received grid

Accepted for publication Aug 13, 2013.From the Centre for Ophthalmology and Visual Science, Lions Eye

Institute, The University of Western Australia, Perth, Australia(M.H.T., I.L.M., L.A.S.); Department of Ophthalmology, Royal PerthHospital, Perth, Australia (M.H.T., I.L.M.); Save Sight Institute,Sydney, Australia (M.E.G.); Hobarts Eye Surgeons, School of Medicine,University of Tasmania, Tasmania, Australia (N.V.); Central SydneyEye Surgeons, Sydney, Australia (G.B.); Singapore Eye ResearchInstitute, National University of Singapore, Singapore (W.L.W.,T.Y.W.); and Centre for Eye Research Australia, Royal Victorian Eyeand Ear Hospital, Melbourne, Australia (T.Y.W.).

Inquiries to Dr Mei Hong Tan, Lions Eye Institute, Center forOphthalmology and Visual Science, University of Western Australia,Perth, Australia; e-mail: [email protected]

0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2013.08.013

� 2014 BY ELSEVIER INC.

laser than in the treatment group (6.7%, 8.3%). Nonew ocular or systemic adverse events were observed.� CONCLUSIONS: Compared with standard grid laser,intravitreal ranibizumab provided significant and sustainedbenefits in visual acuity gain and anatomic improvement ineyes with macular edema secondary to BRVO. (Am JOphthalmol 2014;157:237–247. � 2014 by ElsevierInc. All rights reserved.)

RETINAL VEIN OCCLUSION, THE SECOND MOST

common cause of retinal vascular blindness after dia-betic retinopathy, affects approximately 16 million

people worldwide.1–3 It affects approximately 1% ofindividuals below 60 years, with increases in prevalence to5% in those over 80 years.1

Branch retinal vein occlusion (BRVO) accounts for 80%of all vein occlusions.1,4 Without treatment, it can lead toa sustained loss of vision, with a reported final mean visualacuity of 20/70 with 23% of patients having a visual acuity<_20/200.5,6 The cause for the vision loss in BRVO ispredominantly attributable to macular edema.7 Since thepublication of the Branch Vein Occlusion Study (BVOS)25 years ago, grid laser photocoagulation has been the stan-dard of care for BRVO-associated macular edema.5,8 In thisstudy, treatment of macular edema following BRVO withgrid laser resulted in >_2 lines of visual acuity (VA)improvement in 65% of eyes compared with 37% ofuntreated eyes at the 3-year primary endpoint.5 In thelast 5 years, several new treatments for macular edemasecondary to BRVO have been evaluated in randomizedclinical trials.7 This included intravitreal triamcinoloneinjections,9 intravitreal dexamethasone implants,10 andinhibitors of vascular endothelial growth factor (VEGF)agents.11 Of these, anti-VEGF agents have been the mostpromising. In the Ranibizumab for the Treatment ofMacular Edema following Branch Retinal Vein Occlusion(BRAVO) study, rapid and sustained visual improvementwas seen in the first 6 months in patients who receivedmonthly 0.3 mg and 0.5 mg ranibizumab compared withsham injections. At the 6-month primary endpoint of thestudy, the mean gain from baseline best-corrected visualacuity (BCVA) letter score was 16.6 and 18.3 Early Treat-ment Diabetic Retinopathy Study (ETDRS) letters in the0.3 and 0.5 mg ranibizumab cohorts, respectively,

237ALL RIGHTS RESERVED.

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http://dx.doi.org/10.1016/j.ajo.2013.08.013

compared with 7.3 letters in the sham group.12 After theinitial 6 months, treatment with ranibizumab was givenon an as-needed basis in all patient groups in the second6-month observation period. The results from months6-12 of the study showed maintenance of the visual gainthat was achieved in the ranibizumab groups at the 1-yearendpoint. An improvement in BCVA, although to a lesserextent, was also seen in the sham group.13 However,BRAVO was limited by a study duration of only 6 monthsand did not directly compare the effectiveness of intravi-treal ranibizumab against grid laser, the current standardof care at that time. This may be relevant as a previous trial,the Standard Care versus Corticosteroid for Retinal VeinOcclusion study (SCORE), failed to show any superiorityof intravitreal triamcinolone injections over grid laser fortreating macular edema secondary to BRVO.9 This ledthe authors to recommend that grid laser should be thebenchmark against which other treatments are comparedin clinical trials investigating treatment for vision lossattributable to macular edema following BRVO.

In this randomized controlled clinical trial, we evaluatedthe efficacy and safety of monthly 0.5 mg intravitreal rani-bizumab compared to standard-of-care conventional gridlaser over a 1-year period in patients with vision loss attrib-utable to perfused macular edema following BRVO.

METHODS

� STUDY DESIGN: We conducted a 12-month, masked,randomized, placebo-controlled study across 5 centersdesigned to evaluate the efficacy and safety of monthlyintravitreal injections of 0.5 mg ranibizumab vs standardof care with conventional laser grid in patients with visionloss attributable to perfused macular edema followingBRVO (Figure 1). Patients were assessed and eligibilitydetermined by the investigating physicians at the indi-vidual study sites according to a predistributed studymanual. Recruited patients underwent baseline assessmentfor best-corrected visual acuity (BCVA) and retinal edemaprior to randomization. Patients were then randomized 1:1into 1 of 2 study groups: those treated with intravitrealinjections of 0.5 mg ranibizumab for 6 months and there-after with monthly injections as needed, in combinationwith standard of care; and those treated with standard ofcare only. Standard of care consisted of observation withlaser grid treatment being allowed at 13 and 25 weeksinto the study period according to the BVOS protocol.Sector or pan-retinal laser for neovascularization of eitherthe retina or iris was allowed at the investigating physi-cian’s discretion. The study adhered to the tenets of theDeclaration of Helsinki and was performed according tothe principles of Good Clinical Practice (Chapter 2 ofthe International Conference on Harmonization Harmo-nized Tripartite Guideline for Good Clinical Practice)

238 AMERICAN JOURNAL OF

and national regulations about clinical studies. The studyprotocol was approved by institutional review board andhealth research ethics committee at each study site (SirCharles Gairdner Hospital Human Research EthicsCommittee for the Lions Eye Institute, Perth; Royal Victo-rian Eye and Ear Hospital Human Research EthicsCommittee for the Royal Victorian Eye and Ear Hospital,Melbourne; South Eastern Sydney and Illawarra AreaHealth Service Human Research Ethics for Save SightInstitute, Sydney; Tasmania Health and Medical HumanResearch Ethics Committee for Hobart Eye Surgeons,Tasmania; and Royal Australian and New Zealand Collegeof Ophthalmologists Human Research Ethics Committeefor Central Sydney Eye Surgeons, Sydney). All patientsprovided written informed consent prior to participationin the study. The trial was registered at Australian NewZealand Clinical Trials Registry, ANZCTR (registrationnumber ACTRN12607000262404).

� STUDY POPULATION: Between August 2007 and Sep-tember 2011, 36 treatment-naı̈ve patients meeting theinclusion and exclusion criteria and presenting with unilat-eral visual loss of 6 weeks to 9 months duration secondary toperfusedmacular edema fromBRVOwere recruited into thestudy. Patients were recruited from retina clinics of theLions Eye Institute Perth, Royal Victorian Eye and EarHospital Melbourne, Save Sight Institute Sydney, CentralSydney Eye Surgeons and Hobart Eye Surgeons, Tasmania.The inclusion and exclusion criteria are summarized inTable 1. These patients comprised the intention-to-treatpopulation, in whom the last-observation-carried-forwardmethod was used for missing data for all efficacy parameters.

� RANDOMIZATION: Enrolled patients were randomlyassigned with equal probability to receive either intravi-treal ranibizumab injections or standard of care usingsequentially numbered, sealed opaque envelopes contain-ing the treatment assignment issued centrally by the trialcoordinator at the Lions Eye Institute to each study site.The treatment assignments were compiled using a list ofcomputer-generated pseudo-random numbers of variableblock size. Patients were randomized for treatment in 1eye only. Patients, evaluating physicians, certified visualacuity examiners, and staff who performed optical coher-ence tomography (OCT) and fluorescein angiographywere masked to the treatment allocation.

� FOLLOW-UP VISITS AND ASSESSMENTS: Baseline assess-ment was performed 14 days prior to randomization andthe administration of the sham or study intravitreal injec-tion. This consisted of a full ophthalmic examinationincluding BCVA measurement, tonometry, gonioscopy,dilated fundus examination, OCT assessment of themacula, fluorescein angiography, and color fundus photo-graphs. Patients also provided a full medical and drughistory and underwent a physical examination. Follow-up

JANUARY 2014OPHTHALMOLOGY

FIGURE 1. Flow diagram according to the Consolidated Standards of Reporting Trials (CONSORT) statement, showing recruit-ment, randomization, and patient flow in this study comparing intravitreal ranibizumab with standard grid laser in patients withmacular edema following branch retinal vein occlusion.

visits took place every month after the baseline assessmentand first injection for the 12-month duration of the study.At each follow-up visit, BCVA was measured and patientswere given a complete ophthalmic examination with OCTassessment of the central foveal thickness (CFT). Frommonths 1-5 after the first injection, patients received injec-tions of either ranibizumab or sham at each follow-up visit.From months 6-11, patients received an injection only ifthe prespecified anatomic and functional criteria for re-treatment were met. All patients received a telephonecall 3 days after the intravitreal injection to assess for anyocular or systemic side effects. At weeks 13 and 25, gridlaser treatment was administered to residual areas of edemaif predetermined criteria (described in the Laser GridPhotocoagulation section) were met. At month 12, fluores-cein angiography and color fundus photographs were takenin addition to the regular follow-up assessments. TheBCVA was measured using a 4-meter ETDRS backlit light-house chart by a trained vision examiner. OCT wasobtained using Stratus OCT (Carl Zeiss Meditec, Inc,Dublin, California, USA), available at the various studycenters. The Fast Macular Thickness acquisition protocolwas used to perform the scans and to determine the averagethickness of the central 1-mm subfield of the macula.

VOL. 157, NO. 1 RANIBIZUMAB VERSUS LASER FOR MAC

All adverse events, whether volunteered by the patientor detected by other means, were recorded and followedas appropriate. Patients experiencing serious adverse eventsattributed to possible anti-VEGF effects were required todiscontinue the study. Any serious adverse event occurringafter informed consent was obtained and, until 4 weeksafter the patient stopped study participation, was recordedand followed up.

� INTRAVITREAL INJECTIONS: Patients assigned to theranibizumab group received intravitreal injections of 0.5 mgranibizumab under sterile conditions in a minor proceduresroom as outpatients. Eyes assigned to the standard-of-caregroup were prepared in the same way but received sham injec-tions performed with a needleless hub of an empty syringepushed firmly against the eye to simulate an injection. Theintravitreal injection procedures were performed accordingto the Royal Australian and New Zealand College guidelinesfor intraocular injections (http://www.ranzco.edu/images/documents/policies/Guidelines_for_Performing_Intravitreal_Therapy1.pdf). Patients received their assigned treatmentwithin 14 days following baseline assessment and at eachmonthly follow-up visit thereafter, for a total of 6 injections.From months 6-12, patients were given an injection of their

239ULAR EDEMA IN VEIN OCCLUSION

http://www.ranzco.edu/images/documents/policies/Guidelines_for_Performing_Intravitreal_Therapy1.pdf



TABLE 1. Summary of Key Inclusion and Exclusion Criteria for Determining Patient Eligibility in Study Comparing IntravitrealRanibizumab With Standard Grid Laser for Treatment of Macular Edema Following Branch Retinal Vein Occlusion

Key Inclusion Criteria Key Exclusion Criteria

Patients presenting with vision loss attributable to macular edema

following BRVOa with the following characteristics:

� Duration of vision loss between 6 weeks and 9 months prior

to baseline visit

� Macular edema involving the center of the fovea

� Macula is non ischemic (<50% ischemic injury to the

perifoveolar vascular zone)

� BCVA score at baseline between 20 letters and 68 letters

measured using the ETDRS charts (approximately 20/50 to

20/400 Snellen visual acuity)

� Mean central subfield thickness >_250 mm by OCT at

baseline visit

� Clear ocular media and adequate pupillary dilation

� Signs of significant ischemia following BRVO (eg, afferent

pupillary defect; >_10 disc diameters of nonperfusion; any disc,

retinal, or iris neovascularization

� Presence of dry or wet AMD

� Presence of diabetic retinopathy

� Any other ocular condition that would prevent improvement in

visual acuity (eg, macular ischemia, underlying macular

degeneration, epiretinal membrane)

� Treatment with intravitreal corticosteroids, intravitreal

anti-VEGF agents, or macular grid laser within 3 months

preceding baseline visit

� History of retinal detachment or retinal detachment surgery or

pars plana vitrectomy

� Recent cataract extraction with phacoemulsification within

3 months preceding baseline, or a history of postoperative

complications within the last 12 months preceding baseline in

the study eye (uveitis, cyclitis, etc)

� Any active ocular infection or immune uveitis, including

infectious conjunctivitis, keratitis, scleritis, endophthalmitis

in either eye

� Recent CVA, MI, or major ischemic event within 3 months

preceding baseline visit

� Known sensitivity to any anti-VEGF drugs and sodium

fluorescein

� Women of childbearing age not on contraception or actively

breastfeeding women

AMD ¼ age-related macular degeneration; BCVA ¼ best-corrected visual acuity; BRVO ¼ branch retinal vein occlusion; CVA ¼ cerebral

vascular accident; ETDRS ¼ Early Treatment Diabetic Retinopathy Study; MI ¼ myocardial infarction; OCT ¼ optical coherence tomography;

VEGF ¼ vascular endothelial growth factor.aBRVO is defined as the clinical evidence of retinal hemorrhages and telangiectasia in 1 quadrant or less of the retina accompanied by dilation

and tortuosity of the affected venous system.

randomized treatment if 1 or more of the following criteriawere met: a loss of >_5 letters from month 5 visit; an increaseof >_150 mm in the mean central subfield thickness on OCTfrom month 5 visit or at the investigating physician’s discre-tion.

� LASER GRID PHOTOCOAGULATION: Patients wereassessed for macular laser grid treatment according to theprecedent BVOS protocol at week 13 and week 25 of thestudy by the masked investigating physician. Treatmentwith standard grid laser was given at these 2 time points ifthe following criteria were met: Snellen visual acuity of<_20/40, persistence of macular edema with mean centralsubfield thickness of >_250 mm, BCVA gain of <5 letterscompared to baseline visual acuity. Patients who did notmeet the specified criteria received sham laser in the formof 500mm, 50mW spots applied to the far peripheral retina.

� OUTCOME MEASURES: The primary efficacy outcomemeasure was the mean change from baseline BCVA letter


score between the ranibizumab group and standard-of-caregroup at 12 months. The secondary outcome measuresincluded the mean change from baseline BCVA over time,percentage of patients who gained or lost >_15 letters frombaseline BCVA, mean change from baseline CFT at12 months and over time, and the percentage of patientswith CFT <_250 mm at 12 months. Other efficacy outcomemeasures included the percentage of patients who achievedSnellen equivalent BCVA >_20/40 (70 letters) and Snellenequivalent BCVA <_20/200 (35 letters) at 12 months, thepercentage of patients with residual macular edema (CFT>_250 mm) at 12 months, and the percentage of patientsrequiring grid laser treatment at 13 weeks and 25 weeks.Safety outcomes recorded the incidence and severity of ocularand systemic adverse events and any serious adverse events.

� STATISTICALANALYSIS: Assuming a 10% improvementrate for the standard-of-care group, we calculated thesample size required to detect a 45% difference betweenthe ranibizumab group and standard-of-care group in the


TABLE 2. Patient Demographics and Baseline Ocular Characteristics of the Treatment-Naı̈ve Study Eyes in 36 Patients With MacularEdema Following Branch Retinal Vein Occlusion Enrolled in Study Comparing Treatment With Intravitreal Ranibizumab vs Standard

Grid Laser

Parameter

Baseline

Standard of Care (n ¼ 21) Ranibizumab (n ¼ 15) All (n ¼ 36)

Age (y 6 SD)a 66.7 6 10.7 69.6 6 11.6 67.9 6 11.0

Sex, n (%)

Male 9 (42.9) 8 (53.3) 17 (47.2)

Female 12 (57.1) 7 (46.7) 19 (52.8)

Race, n (%)

White 19 (90.5) 14 (93.3) 33 (91.7)

Asian 2 (9.5) 0 2 (5.6)

Aboriginal 0 1 (6.7) 1 (2.8)

Study eye characteristics:

Time (wk) from diagnosis to inclusion

Mean 6 SDa 15.1 6 8.8 17.9 6 11.3 16.3 6 9.9

Median 14 13 14

BCVA (ETDRS letters 6 SD)a 46.2 6 15.1 39.5 6 21.2 44.2 6 17.8

Area of capillary nonperfusion on FFA

(DA 6 SD)a3.2 6 3.3 3.0 6 2.1 3.1 6 2.8

CFT (mm 6 SD)a 519.2 6 183.7 615.6 6 270.1 559.4 6 225.4

IOP (mm Hg 6 SD)a 14.1 6 2.7 15.7 6 2.9 14.8 6 2.8

Phakic eye, n (%)a 17 (81.0%) 13 (86.7) 30 (83.3)

BCVA¼ best-corrected visual acuity; CFT¼ central foveal thickness; DA¼ disc area (1 disc area is approximately 1500 mm); ETDRS¼ Early

Treatment Diabetic Retinopathy Study; FFA ¼ fundus fluorescein angiography; IOP ¼ intraocular pressure; SD ¼ standard deviation.aP value was nonsignificant between treatment and control groups for all parameters.

proportion of eyes that showed visual acuity gain of greaterthan 10 letters at 1 year. A sample size of 19 patients ineach arm was estimated to give an 80% power of detectingthis difference as significant at the 2-sided 5% level if alleyes were from different subjects. Adjusting for a drop-out rate of 10%, we planned to recruit 21 eyes per group.

Statistical analysis was performed with commercial soft-ware (SPSS, ver.20; SPSS Inc, Chicago, Illinois, USA).Descriptive statistics were used to summarize patient demo-graphics and baseline ocular characteristics. Independentt test was used for comparison of means and x2 or Fisherexact test was used for comparison of proportions betweengroups. All statistical tests were 2-sided while 1-tailed test(increased power) was also presented for hypothesis withprior assumption of effect in 1 direction. Cochran-Armitage test for linear trend was used to test for a lineartrend in distribution of outcome (ordinal categories ofletters gained or loss at 12th month) across treatment types.P value < .05 was considered as statistically significant.

RESULTS

� BASELINE CHARACTERISTICS AND PATIENT DEMO-GRAPHICS: Thirty-six eyes of 36 patients were assignedrandomly to receive intravitreal injections of 0.5 mg


ranibizumab (n ¼ 15) or standard-of-care treatment (n ¼21) at 4 centers. Demographic and baseline characteristicswere well matched between the 2 groups and are listed inTable 2. No statistically significant differences were foundbetween the groups for any of the characteristics measured.The flow of patients through the study is shown in Figure 1.The average age of patients was 68 years (range 41–87years), and 53% (19 of 36 patients) were female. Therewas a predominance of white patients in the study group(92% [33 of 36 patients]). The mean time from diagnosisof BRVO to the baseline examination was 16.3 weeks(median 14, range 4-39 weeks). The majority (56% [20 of36 patients]) of patients were diagnosed <_3 months priorto inclusion into the study. The mean study eye BCVAat baseline was 44.2 ETDRS letters (range 27–75 letters);approximate Snellen equivalent 20/125. The averageCFT at baseline as measured by OCT was 559.4 mm (range263–1419 mm). The average disc area of capillary nonper-fusion seen on fluorescein angiography in the study eye was3 disc areas (range 0–10).The completion rates through to 12 months in the study

were 93.3% (14 of 15 patients) and 76.2% (16 of 21patients) for the ranibizumab group and standard-of-caregroup, respectively. The 12-month outcome measure datawere missing in a total of 6 patients. One patient fromthe ranibizumab group withdrew after being diagnosedwith metastatic pancreatic carcinoma during the course


TABLE 3. Primary and Secondary Visual Outcomes in StudyPatients at Month 12 of Study Comparing Intravitreal

Ranibizumab vs Standard Grid Laser for Treatment of

Macular Edema Following Branch Retinal Vein Occlusion

Parameter

Grid Laser

(n ¼ 21)

Ranibizumab

(n ¼ 15)

P

Value

Change from baseline BCVA

at 12 months in ETDRS

letter score:

Mean 6 SD �1.6 6 18.2 12.5 6 19.3

95% CI for mean (�9.3, 6.2) (2.8, 22.3)

Difference in means

(ranibizumab vs laser)

14.1 .032

95% CI for difference (1.09, 27.1)

Distribution of BCVA change

at 12 months, n (%)

.116a

Gain of >_15 lettersb 4 (19.0) 8 (53.0)

Gain of 10-14 letters 3 (14.3) 1 (6.7)

Gain of 5-9 letters 0 (0.0) 1 (6.7)

No change, 6 4 letters 6 (28.6) 2 (13.3)

Loss of 5-9 letters 2 (9.5) 0 (0.0)

Loss of 10-14 letters 0 (0) 2 (13.3)

Loss of >_15 lettersc 6 (28.6) 1 (6.7)

Snellen equivalent BCVA

>_ 20/40, n (%)

6 (28.6) 9 (60.0) .090d

Snellen equivalent BCVA

<_ 20/200, n (%)

1 (4.8) 0 (0.0) .999d

BCVA¼ best-corrected visual acuity; CI¼ confidence interval;

ETDRS ¼ Early Treatment Diabetic Retinopathy Study; SD ¼standard deviation.

aP trend from Cochran-Armitage test for linear trend.bP from 1-sided Fisher exact test of greater proportion of

subjects with >_15 letters gained in ranibizumab than in grid laser

group ¼ .037; P from 2-sided Fisher exact test ¼ .071.cP from 2-sided Fisher exact test of greater proportion of

subjects with >_15 letters lost in grid laser than in ranibizumab

group ¼ .200.dP from 2-sided Fisher exact test.

FIGURE 2. Graph of mean change from baseline best-correctedvisual acuity (BCVA) letter score in the study eye over time tomonth 12 in patients receiving intravitreal ranibizumab vs stan-dard grid laser for macular edema following branch retinal veinocclusion. Each plot represents the mean gain or loss in BCVAletter score compared to baseline at that particular time point inthe study eye of patients receiving intravitreal ranibizumab(represented by round plots) vs patients receiving standardgrid laser (represented by square plots). Higher BCVA letterscores were obtained in patients receiving intravitreal ranibizu-mab compared to patients receiving grid laser at all time points.The difference in BCVA letter score between the 2 groups wasstatistically significant at months 4, 7, and 12 (indicated by *P< .05). The last-observation-carried-forward was used to inputmissing data. Vertical error bars denote standard error of themean. BCVA [ best-corrected visual acuity; ETDRS [ EarlyTreatment Diabetic Retinopathy Study.

of the study. Five patients did not complete the study in thestandard-of-care group; among these, 2 patients were lost tofollow-up, 2 patients decided to discontinue their participa-tion, and 1 patient died of an unrelated cause. The lastproperly performed observation was carried forward forthese missing values.

� PRIMARY OUTCOME MEASURE AND CHANGE FROMBASELINE BEST-CORRECTED VISUAL ACUITY: Theprimary efficacy endpoint was mean change from baselineBCVA at 12 months. At 12 months, there was an improve-ment of visual acuity compared with baseline in the ranibi-zumab group by a mean of 12.5 letters (95% CI 2.8, 22.3)letters, while in the standard-of-care group there wasa mean loss of 1.6 letters (95% CI -9.3, 6.2), a differencethat was statistically significant (P ¼ .032); (Table 3,Figure 2). The improvement in BCVA in the ranibizumab


group was seen at 1 month following injection andincreased steadily at all subsequent monthly assessmentsup to the 12-month endpoint. In the standard-of-caregroup, a decrease in BCVA was seen at each time pointfrom baseline, with a maximum loss of 5 letters at 3 monthsand fewer letters lost in the subsequent months. The differ-ence in BCVA between the 2 groups was statistically signif-icant at 12 months (P ¼ .032; Figure 2). Analysis bysubgroup showed that statistically significant differencesin the mean BCVA change between the 2 treatment groupswere maintained in patients with poorer baseline vision,those with a longer duration of BRVO, and patients withthicker CFT at baseline (Table 4). In both the ranibizumaband standard-of-care groups, the mean BCVA gain at12 months was greater in patients with worse baselineBCVA and in patients who were diagnosed with BRVOfor a longer duration of 12 weeks or more prior to inclusioninto the study. Among patients who received ranibizumab,the mean improvement in BCVA at 12 months was greaterin those who had CFT >_450 mm at baseline. This was incontrast to the standard-of-care group, where patients


TABLE 4. Analysis by Subgroup of the Mean Change From Baseline Best-Corrected Visual Acuity of Study Eye at Month 12 andPercentage of Study Eyes That Gained 15 Letters or More at Month 12 in Patients Receiving Intravitreal Ranibizumab vs Standard Grid

Laser for Macular Edema Following Branch Retinal Vein Occlusion

Subgroup

Mean BCVA Change (95% CI) Gained >_15 Letters, n (%)

Grid Laser Ranibizumab Grid Laser Ranibizumab

Baseline BCVA (ETDRS letters)

<55 7.4 (�4.5 to 19.2) 27.9 (19.9 to 35.8)a 1 (20.0) 6 (85.7)

>_55 �4.4 (�13.6 to 4.9) �0.9 (�10.8 to 9.0) 4 (25.0) 2 (25.0)

Time from diagnosis to inclusion (wk)

<12 �2.4 (�17.3 to 12.6) 10.2 (�8.2 to 28.5) 3 (37.5) 3 (50.0)

>_12 8.9 (�0.2 to 18.0) 14.11 (2.49 to 25.7)a 2 (15.4) 5 (55.6)

Baseline CFT, mm

<450 2.7 (�11.6 to 17.0) 7.0 (�8.5 to 22.5) 3 (42.9) 2 (50.0)

>_450 �3.7 (�13.1 to 5.7) 14.6 (2.3 to 26.8)a 2 (14.3) 6 (54.5)

BCVA ¼ best-corrected visual acuity; CFT ¼ central foveal thickness; ETDRS ¼ Early Treatment Diabetic Retinopathy Study.aP < .05 for difference between ranibizumab and standard-of-care group within the subgroup.

with CFT with >_450 mm did worse than those with CFT<450 mm at baseline.

� SECONDARY VISUAL OUTCOME MEASURES: At12 months, a higher percentage of patients (53.0% [8 of15 patients]) in the ranibizumab group gained >_15 lettersfrom baseline BCVA compared with the standard-of-caregroup (19.0% [4 of 21 patients]; P ¼ .071, Table 3). Ahigher proportion of patients (28.6% [6 of 21 patients])in the standard-of-care group lost >_15 letters compared topatients in the ranibizumab group (6.7% [1 of 15 patients];P ¼ .200, Table 3). Subgroup analysis within the ranibizu-mab group showed that a higher percentage of patientsgained >_ 15letters among those with lower baseline vision(P ¼ .041; Table 4).

In the ranibizumab group, 60.0% (9 of 15 patients) ofpatients achieved a Snellen BCVA equivalent of >_20/40at 12 months, compared with 28.6% (6 of 21 patients) inthe standard-of-care group (Table 3). None of the patientsin the ranibizumab group had the poor outcome of SnellenBCVA equivalent of <_20/200, compared with 4.8% (1 of 21patients) of patients in the standard-of-care group. Thedifferences between the 2 treatment groups, however, didnot reach statistical significance (Table 3).

� SECONDARYANATOMICOUTCOMESAT 12MONTHS: At12 months, there was a significant difference in the meanreduction in CFT from baseline in the ranibizumab group,�361.7 mm (95% CI �510.6 to �212.7), compared withthe standard-of-care group, �175.6 mm (95% CI �253.8to �97.42) (P ¼ .025; Table 5, Figure 3). The meandecrease in CFT was significantly greater in the ranibizu-mab group than in the standard-of-care group at all timepoints apart from month 8 (Figure 3). The percentage ofpatients with CFT <_250 mm at 12 months was determined


to assess residual macular edema in each group. In the rani-bizumab group 73.3% (11 of 15 patients) of patients had noresidual edema, compared with 33.3% (7 of 21 patients) ofpatients who received standard of care (P¼ .041, Table 5).The number of patients requiring rescue laser treatment at13 and 25 weeks was examined since this gives anotherindication of the amount of residual edema not resolvedby treatment at those time points. At 13 weeks, 6.7% (1of 15 patients) of patients receiving ranibizumab requiredrescue laser compared with 68.4% (13 of 19 patients) ofpatients receiving standard of care (P ¼ .0004). At25 weeks, 8.3% (1 of 12 patients) of ranibizumab-treatedpatients required rescue laser compared with 50.0% (8 of16 patients) of patients in the standard-of-care group(P¼ .039, Table 5). Grid laser treatment was administeredby the masked investigating physician in both groups.None of the patients in either group developed iris orretinal neovascularization or received sector panretinalphotocoagulation during the study. At the 12-monthtime point collateral vessels were seen in 50% (8 of 16patients) of those in the laser group and 64% (9 of 14patients) of those in the ranibizumab group.

� SAFETY OUTCOMES AT 12 MONTHS: There were noevents of endophthalmitis, retinal tear, or retinal detach-ment during the 12-month-long treatment period. All ofthe reported ocular complaints were related to the injec-tion procedure and were self-limiting (Table 6). Amongthese, some of the most common complaints consisted ofsubconjunctival hemorrhage, foreign body sensation,watery discharge, and ocular pain. There were no reportsof serious systemic adverse events that were potentiallyassociated with systemic VEGF inhibition (Table 6). Onepatient died during the course of the study from an unre-lated cause (bronchopneumonia).


TABLE 5. Change From Baseline Study Eye Central FovealThickness at Month 12, Proportion of Patients Requiring Grid

Laser at Week 13 and 25, and Mean Number of Injections

Received in Patients Receiving Intravitreal Ranibizumab vsStandard Grid Laser for Macular Edema Following Branch

Retinal Vein Occlusion

Parameter

Grid Laser

(n ¼ 21)

Ranibizumab

(n ¼ 15)

P

Valuea

Reduction in CFT (mm)

Mean 6 SD �175.6 6 182.7 �361.7 6 294.3 .025

95% CI for mean �253.8, �97.42 �510.6, �212.7

CFT <_250 mm at

baseline, n (%)

0 (0.0) 0 (0.0) NA

CFT <_250 mm at

6 months, n (%)

5 (23.8) 10 (66.7) .017

CFT <_250 mm at

12 months, n (%)

7 (33.3) 11 (73.3) .041

Patients requiring grid

laser,b n (%)

At 13 weeks 13 (68.4) 1 (6.7) .0004

At 25 weeks 8 (50.0) 1 (8.3) .039

Mean no. injections/

patientc

Months 0–5 5.2 6.0

Months 6–11 3.7 2.13

CFT¼ central foveal thickness; CI¼ confidence interval; SD¼standard deviation.

aP value based on 2-sided Fisher exact test.bPatients received grid laser treatment at 13 weeks and

25 weeks into the study if they met prespecified criteria.cIn the first 6 months (months 0-5), standard-of-care grid laser

group received 6 monthly sham injections while ranibizumab

group received 6 monthly intravitreal injections of 0.5 mg

ranibizumab; during the latter 6-month period (months 6-11),

standard-of-care grid laser group received sham injections and

ranibizumab group received 0.5 mg ranibizumab injections if

they met prespecified criteria.

FIGURE 3. Graph of mean change from baseline central fovealthickness in the study eye over time to month 12 in patientsreceiving intravitreal ranibizumab vs standard grid laser formacular edema following branch retinal vein occlusion. Eachplot represents the mean decrease in central foveal thicknesscompared to baseline at that particular time point in the studyeye of patients receiving intravitreal ranibizumab (representedby round plots) vs patients receiving standard grid laser (repre-sented by square plots). Central foveal thickness was lower inpatients receiving intravitreal ranibizumab compared to patientsreceiving grid laser at all time points. The difference in centralfoveal thickness between the 2 groups was statistically signifi-cant at all time points except for month 8 (indicated by *P <.05; **P < .001). The last-observation-carried-forward wasused to input missing values. Vertical error bars denote standarderror of the mean.

DISCUSSION

PRIOR TO THE BRAVO STUDY, THERE WERE NUMEROUS

reports indicating the benefit of intravitreal ranibizumab intreating macular edema secondary to BRVO, but data froma randomized controlled trial were lacking. The BRAVOstudy was the first randomized controlled masked clinicaltrial to provide evidence of the efficacy of ranibizumab inpatients with macular edema from BRVO comparingintravitreal ranibizumabwith sham injections.12A limitationof the BRAVO study, however, was that it did not directlycompare the efficacy of then-current standard care forpatients with vision loss secondary to BRVO-associatedmacular edema (ie, grid laser) with intravitreal ranibizumabover a longer time period. The primary outcome of BRAVOwas assessed at 6 months, and patients who received shaminjections in the study in the initial 6 months wereallowed to receive ranibizumab in the subsequent 6-month


period, resulting in the lack of a comparator group duringthis later period.13

In our study, intravitreal ranibizumab was compared withthe current standard of care for the entire 12-month dura-tion of the study since there was no crossover between thetreatment groups. As visual acuity improvement followinglaser occurs in a more sustained fashion compared to intra-vitreal ranibizumab, this may have been relevant.5,9 TheBRAVO study did allow rescue laser after the 3-monthtime point based on BVOS recommendations, with similarcriteria for treatment being used to our study.12 In theBVOS, treated eyes gained an average of 1.33 lines of VAover the duration of the study, with the gain occurring ina sustained fashion rather than in the first 6 months asoccurred in the 2 treatment groups in the BRAVO study.5,13

As the BRAVO study allowed crossover of treatment afterthe 6-month time point, it is impossible to draw any conclu-sions concerning the efficacy of grid laser between thesecarefully matched patient groups. A longer time period isrelevant to evaluate this as macroscopic collateral vesselformation has been noted to occur in BRVO between 2and 8 months, with experimental capillary shunt vesselsbeing noted even earlier.14–16 As these are an importantpart of the vascular remodeling process that occurs aftervenous obstruction, we felt it was important allow both


TABLE 6. Key Ocular and Nonocular Adverse EventsReported in Study Patients From Months 0-12 of Study

Comparing Intravitreal Ranibizumab vs Standard Grid Laser

for Macular Edema Following Branch Retinal Vein Occlusion

Ranibizumab

(n ¼ 15)

Standard of

Care (n ¼ 21)

Ocular adverse events, n

Redness after injection, including

conjunctival hemorrhage

6 7

Eye pain/irritation/watering during

or after injection

8 7

Discharge 8 6

Floaters after injection 7 1

Corneal epithelial defect 1 0

Light sensitivity 2 1

Lid swelling 3 1

Transient loss of visiona 2 0

Itching 0 1

Photopsia 0 1

Subtotal 37 25

Nonocular adverse events, n

Palpitations 0 1

Non-ST segment myocardialc

infarction

0 1

Rash 1 0

Headache/dizziness/tiredness 4 3

Hypertension 2 0

Gastrointestinal disturbance 1 1

Chest infection 2 2

Fall 0 1

Abdominal aneurysm 0 1

Muscle pain 1 1

Necrotizing fasciitis 0 1

Pyrexia of unknown origin 0 1

Urinary tract infection 1 3

Loss of bladder function 0 1

Urethral caruncle 1 0

Colon carcinoma 1 0

Pancreatic carcinoma 0 1

Death 0 1b

Subtotal 14 19

aTransient loss of vision that is blurring or glare with visual

reduction of a short duration (not longer than 1 week) that

resolved without any intervention. Reasons typically included irri-

tation, watering, and nonspecific causes.bPatient died of bronchopneumonia.cNon ST-segment myocardial infarction refers to myocardial

infarction that is not accompanied by elevation or depression

of the ST segment on the electrocardiogram.

treatment groups time for these to fully develop and haveany relevant effect on macular edema resolution. In thisstudy collateral vessels were visible in those whocompleted the 12-month follow-up in a majority of eyes,with no significant difference between the 2 groups.

The results of this study demonstrate the greater efficacyof intravitreal ranibizumab compared with standard of care


of laser grid treatment in center-involving macular edemafollowing BRVO. We observed improvement in BCVAand reduction in OCTCFT that is in line with the BRAVOtrial. Greater improvement in BCVA from baseline wasobserved in the ranibizumab group in the first 6 months ofthe study when monthly injections were given (Figure 2).In the latter 6 months, the slope of the curve was seen toplateau on the pro re nata dosing schedule. A similar trendwas also observed in the mean CFT change where a greaterreduction in foveal thickness occurred in the first 6 monthsof the study, with a leveling of the CFT change in thesecond half of the year (Figure 3). The observed improve-ment in VA and reduction in CFT obtained with monthlyranibizumab injections were maintained, with some furtherimprovement in months 6-12 of the study, with a mean of 2injections, implying that visual improvement and stablemacular thickness can be sustained in the longer termwith a reduced injection frequency of every 8-12 weeks.The decision to inject over the second 6 months was guidedby a simple ‘‘as-required’’ OCT- and VA-based algorithm.This was in accordance with the frequency of injections re-ported in the observation period of the BRAVO study,although the retreatment paradigm used differed slightlyfrom our study.Compared to the BRAVO study, the mean BCVA gain in

the ranibizumab-treated group in our study was lower. At12 months, the mean improvement from baseline BCVAletter score in the ranibizumab group in our study was 12.5letters, while the BRAVO study reported a mean gain of18.3 letters at 12 months in their similarly treated group.This could be accounted for by the lower baseline BCVAin our patient sample (39.5 letters vs 56.0 letters inBRAVO). Visual acuity outcomes in both BRVO andcentral retinal vein occlusion have been observed to berelated to the initial visual acuity at presentation.17,18 Thepoorer baseline BCVA in this study may indicate that thepatient selection may have been weighted toward moresevere cases of venous occlusion where other factorssuch as some degree of retinal ischemia and macularintraretinal hemorrhage may have contributed to thevisual impairment in addition to macular edema. However,the proportion of treated patients who gained >_15 lettersin this study (53%) was still comparable to that seen in theequivalent treatment group in BRAVO (60%).In contrast to other studies with a grid laser intervention

group,8 we observed a modest reduction from baselineBCVA of 1.6 letters in the standard-of-care laser group at12 months and a lower percentage of patients with >_15letter gain (19%) and of patients with >_10 letter gain(33.3%) at 12 months. The mean BCVA change in thestandard-of-care group was seen to fluctuate near baselinelevels throughout the study period. The mean CFT wasseen to decrease with time, albeit at a smaller rate comparedwith the treatment group, indicating that a reduction inCFT is not necessarily accompanied by a similar extent infunctional gain. The BVOS study reported a 1.33 line


gain and 65% achieving >_2 lines gain in visual acuity inpatients treated with grid laser in the third year of study,5

whereas the SCORE BRVO study described a mean gainof 4.2 letters and 29% of patients with >_15 letter gain inthe grid laser arm at 12 months.9 Both of these studieshad higher mean BCVAs at baseline compared to our studyin the laser treatment arms. In the BVOS the VA is notstated in letters; however, 79% had a BCVA at entry of20/100 or better (50 ETDRS letter score). In the SCOREstudy the mean BCVA at entry in the laser treatment armwas 56.8 letters.5,9 In our study the laser treatment arm atentry had a BCVA of 46.2 letters and, as statedpreviously, initial BCVA does appear to be indicative offinal acuity in BRVO. The differences in outcomes seenhere in the standard-of-care laser group may be in partattributable to a confounding effect from an obvious limita-tion of this study, that is, the small sample size. The numberof patients (5) who were lost to follow-up may have hada significant impact on the results against the backgroundof a small study. Recruitment into our study was still in prog-ress when the 12-month results from the BRAVO trial werereleased.13 A decision was then undertaken to halt furtherrecruitment since the BRAVO study had provided adequateproof of efficacy of ranibizumab in treating macular edemaattributable to BRVO. This decision to cease recruitmentcontributed to the small numbers in this trial and mayalso have contributed to the lack of improvement in thegrid laser arm seen here, since the gradual improvementin visual acuity that is seen with laser treatment tends todevelop over a longer period of time.

Despite the small patient sample, we observed significantdifferences in the visual acuity outcomes and reduction inCFT comparing standard laser to treatment with ranibizu-mab, indicating that the effect of treatment was great andconsiderably superior to the current standard of care. Thepercentage of patients requiring laser treatment at 13 and25 weeks was also significantly less in the ranibizumab groupcompared with the standard-of-care group (Table 5). It islikely that using ranibizumab alone may produce similarvisual benefits to combination therapy, given that laser didnot appear to confer significant improvements to visualacuity. After 6 monthly injections, 66.7% of patientsreceiving ranibizumab had CFT <_250 mm, compared tonone at commencement of treatment. This anatomic effectwas maintained on as-required injections through themonth-12 time point, where 73.3% of patients were edema-free. However, there were approximately 25% of patientsreceiving as-required ranibizumab who had residual or persis-tent edema after 1 year of treatment. Studies of VEGF levelsin eyes with exudative diseases such as vein occlusions andneovascular age-related macular degeneration have showna correlation between the recurrence of macular fluid andincreasing VEGF levels in eyes undergoing anti-VEGFtherapy.19,20 Based on this, it has been suggested that eyeswith persistent macular fluid after an intravitreal injectionhave an overabundance of VEGF relative to the level of


anti-VEGF binding activity in the eye. Consequently, it isnot the peak levels but the trough levels of the drug that deter-mines the efficacy.21 It is possible that increasing thefrequency of treatment or continuing monthly injectionsfor a longer period may lead to the resolution of macularedema in this remainder of patients, given that such a strategywould retain higher trough levels of VEGF binding activity.The number of observed adverse events was low, but this

study was not sufficiently large to be able to make definitivesafety statements. However, there were no cases of endoph-thalmitis and no unusual or previously unrecognized compli-cations related to intravitreal injection, and no apparentincrease or trends in systemic safety events were seen.In conclusion, our trial, comparing treatment with rani-

bizumab and standard of care with grid laser over a 12-month period, provided additional evidence regarding thelonger-term use of ranibizumab in the treatment of perfusedmacular edema following BRVO.The results from this studyand the BRAVO study are such that intravitreal ranibizu-mab should now be considered the current standard ofcare for BRVO-associated macular edema that futurestudies should be judged against. Patients with macularischemia were excluded from this study, but it seems reason-able to treat those with mild to moderate degrees ofischemia. Although intravitreal ranibizumab is likely tobecome the current mainstay of treatment for macularedema secondary to BRVO in addition to grid laser photo-coagulation, there does remain the burden of repeatedinjections and the need for continued close monitoringand treatment until complete recompensation of the retinalvenous circulation occurs. As the treatment effect wears offafter a certain period, the recurrence of macular edema andneed for re-treatment with anti-VEGF occurs in significantnumber of patients. In a study that used an OCT-guidedreinjection scheme of bevacizumab for macular edema inbranch and central retinal vein occlusions, only 33% ofcentral retinal vein occlusion (CRVO) patients and 15%of BRVO patients achieved resolution of macular edemawithout necessitating further injections during the follow-up period of approximately 1 year, while 37% and 50% ofCRVO and BRVO patients, respectively, suffered recur-rences within 6months of the last injection and the remain-ing 30% and 35% of CRVO and BRVO patients,respectively, did not achieve resolution of macular edemaat any time point.22 Similar findings were seen in a pilotstudy by Campochiaro and associates23 with longerfollow-up period of 2 years, where patients with macularedema attributable to BRVO or CRVO received 3 monthlyinjections of ranibizumab and subsequent treatment wasgiven for recurrence or persistent edema when seen atbimonthly follow-up visits. Only 5 of 17 patients withBRVO and 3 of 14 patients with CRVO who completedthe study remained dry with no injections for at least 1year, while the remainder of patients required intermittentinjections for at least 2 years. Longer-term data beyond 1year from the HORIZON study suggest that frequent and


extended re-treatments are likely to be required, particu-larly in CRVO.24 At the current time, the endpoint fortreatment is still undefined and further long-term studieswill be required to address this. Thus far, available data


suggest that there is considerable variability in terms ofpatient response to treatment in retinal vein occlusionand treatment regimens need to be customized accordingto each patient’s needs.

ALL AUTHORSHAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSUREOF POTENTIAL CONFLICTS OF INTEREST.I.L.M. is on the advisory boards of Bayer andNovartis. M.E.G. received anNHMRC grant inAustralia and is on the advisory boards of Allergan, Bayer, andNovartis. T.Y.W. is on the advisory boards of and has received consultancy and speaking fees from Allergan, Bayer, Novartis, and Pfizer. Novartis Phar-maceuticals, Australia provided support for the study by providing the supply of ranibizumab. The sponsor had no role in the design, conduct, data collec-tion, or reporting of this research and does not hold any editorial rights to the publication of the study. Author contributions: Involved in design andconduct of study (I.L.M., M.E.G., T.Y.W.); collection and management of data (M.H.T., N.V., G.B., L.A.S.); analysis and interpretation of data(M.H.T., L.A.S., W.L.W.); preparation of manuscript (M.H.T., I.L.M., W.L.W.); and review and final approval of manuscript (M.H.T., I.L.M.,M.E.G., N.V., G.B., T.Y.W.). Mei Hong Tan had full access to all of the data in the study and takes responsibility for the integrity of the data and accuracyof the data analysis. Clinical trials registration: The trial was registered at AustralianNew Zealand Clinical Trials Registry, ANZCTR (registration numberACTRN12607000262404).

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9. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trialcomparing the efficacy and safety of intravitreal triamcinolonewith standard care to treat vision loss associated with macularEdema secondary to branch retinal vein occlusion: the StandardCare vs Corticosteroid for Retinal Vein Occlusion (SCORE)study report 6. Arch Ophthalmol 2009;127(9):1115–1128.

10. Haller JA, Bandello F, Belfort RJ, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant inpatients with macular edema due to retinal vein occlusion.Ophthalmology 2010;117(6):1134–1146.

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12. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab formacular edema following branch retinal vein occlusion:six-month primary end point results of a phase III study.Ophthalmology 2010;117(6):1102–1112.

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15. Ben-Nun J. Capillary blood flow in acute branch retinal veinocclusion. Retina 2001;21(5):509–512.

16. Genevois O, Paques M, Simonutti M, et al. Microvascularremodeling after occlusion-recanalization of a branch retinalvein in rats. Invest Ophthalmol Vis Sci 2004;45(2):594–600.

17. Natural history and clinical management of central retinalvein occlusion. The Central Vein Occlusion Study Group.Arch Ophthalmol 1997;115(4):486–491.

18. Rehak J, Dusek L, Chrapek O, et al. Initial visual acuity is animportant prognostic factor in patients with branch retinalvein occlusion. Ophthalmic Res 2011;45(4):204–209.

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21. Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacoki-netic rationale for dosing every 2 weeks versus 4 weeks withintravitreal ranibizumab, bevacizumab, and aflibercept(vascular endothelial growth factor Trap-eye). Retina 2012;32(3):434–457.

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http://refhub.elsevier.com/S0002-9394(13)00550-3/sref1




















































































Biosketch

Mei Hong Tan received her medical degree from Queens University of Belfast and has a PhD from University College

London for her research work on gene therapy at the Institute of Ophthalmology and Moorfields Eye Hospital, London.

She completed ophthalmology training in the Oxford Deanery in United Kingdom and was a vitreo-retinal fellow at

the Royal Perth Hospital and Lions Eye Institute, Australia. Dr Tan’s interests include retinal vascular disorders,

inherited retinal diseases and retinal imaging.

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Randomized controlled trial of intravitreal ranibizumab versus standard grid laser for macular edema...

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