randomized clinical trial of topical betaxolol for persistent macular edema after vitrectomy and...

Randomized Clinical Trial of TopicalBetaxolol for Persistent Macular Edema After

Vitrectomy and Epiretinal Membrane Removal

HIROSHI KOBAYASHI, MD, PHD, KAORI KOBAYASHI, MD, PHD,AND SATOSHI OKINAMI, MD, PHD

● PURPOSE: To report the efficacy and safety of topicalbetaxolol for treatment of persistent macular edema.● DESIGN: Randomized clinical trial.● METHODS: Thirty-seven eyes (37 patients) with best-corrected visual acuity between 20/200 and 20/50 andmacular edema that remained for 3 months after vitrec-tomy and removal of epiretinal membrane were prospec-tively, randomly assigned to receive betaxolol or placebo.Nineteen eyes of 19 patients received betaxolol twicedaily, and 18 eyes of 18 patients received placebo as arandomized comparison group. The patients were fol-lowed up for 6 months. This study evaluated the effect ofbetaxolol on best-corrected visual acuity and area ofmacular edema, which was digitally measured on serialfluorescein angiogram. Calculations of mean best-cor-rected visual acuity were based on logarithm of theminimal angle of resolution (logMAR). To assesschanges in area of edema, the initial (pretreatment) sizeof the edema was set to 100%, and all posttreatmentmeasurements were normalized relative to the initial size.● RESULTS: Mean best-corrected visual acuity at baselinewas 0.216 (20 of 92.6) and 0.244 (20 of 82.0) in thetreatment and control group, respectively. Mean area ofmacular edema was 2.271 � 1.629 mm2 and 2.273 �1.209 mm2 in the treatment and control group; there wasno significant difference. The visual acuity at 6 monthsafter the start of the follow-up was 0.471 (20 of 42.5) inthe treatment group and 0.236 (20 of 84.7) in thecontrol group. Mean changes in logMAR of visual acuityfor 3- and 6-month follow-up were �0.282 � 0.191 and�0.337 � 0.197 in the treatment group, and �0.016 �0.186 and �0.015 � 0.267 in the control group; asignificant difference was found (P <.0001; P <.0001).Areas of macular edema at 6 months after the start of the

follow-up were 1.492 � 1.357 mm2 in the treatmentgroup and 2.125 � 1.434 mm2in the control group.Mean change in area of the edema for 6 months were76.5% � 24.1% and 63.4% � 28.3% in the treatmentgroup and 92.9% � 15.4% and 87.4% � 25.6% in thecontrol group; treated patients showed a significantlylarger reduction than untreated patients at each exami-nation (P � .0193; P � .0102). No complicationassociated with treatment or placebo was found.● CONCLUSIONS: Topical betaxolol appeared to have afavorable treatment effect in eyes with macular edemathat remained after vitrectomy and removal of epiretinalmembrane. Further investigation of more cases andlonger follow-up are needed. (Am J Ophthalmol 2003;136:244–251. © 2003 by Elsevier Inc. All rightsreserved.)

B ETAXOLOL, A �1-SELECTIVE ADRENOCEPTOR ANTAG-

onist, is widely used in the treatment of glaucoma. Inaddition to its ocular hypotensive effects, betaxolol

has may act as a retinal neuroprotective agent1–6 andvasodilator,7–12 acting by Ca2�channel blockade.

Macular edema results from breakdown of the blood-retinal barrier, leading to accumulation of intracellularfluid as well as extracellular fluid.13–19 Macular edemaoccurs in a variety of pathologic conditions, includingdiabetic retinopathy, central and branch retinal veinocclusions, hypertensive retinopathy, uveitis, retinitis pig-mentosa, and other nutritional and metabolic diseases, aswell as after cataract surgery, retinal detachment surgery,vitrectomy, and glaucoma procedures.

The first step in managing macular edema is treating theprimary disease. Various other treatments have been triedwith very limited success. These include treatment withcorticosteroid,20 carbonic anhydrase inhibitor,21,22 photo-coagulation,23–25 hyperbaric oxygen,26,27 and vitrec-tomy.28,29

The pathogenesis of macular edema is frequently multi-factorial background. To study the efficacy of a drug formacular edema, an ideal subject should be macular edema

Accepted for publication Jan 23, 2003.InternetAdvance publication at ajo.com Feb 27, 2003.From the Department of Ophthalmology, Saga Medical School, Saga,

Japan.Inquiries to Hiroshi Kobayashi, MD, PhD, Department of Ophthal-

mology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan;fax: (�81) 952-33-3696); e-mail: [email protected]

© 2003 BY ELSEVIER INC. ALL RIGHTS RESERVED.244 0002-9394/03/$30.00doi:10.1016/S0002-9394(03)00151-X

that results from a single cause, and the cause should beremoved. In this study, we chose patients who underwentvitrectomy and removal of epiretinal membrane and hadedema showing no tendency to resolve 3 months aftersurgery. The purpose of this study is to determine theefficacy and safety of topical bexolol for treating macularedema.

DESIGN

THIS IS A RANDOMIZED CLINICAL STUDY.

METHODS

THIRTY-SEVEN PATIENTS WITH MACULAR EDEMA AFTER

removal of epiretinal membrane who fulfilled the criteriafor this study were enrolled. Indications for were (1)undergoing vitrectomy and removal of epiretinal mem-brane for treatment of epiretinal membrane and macularedema, (2) the presence of macular edema, which wasworse or unchanged 3 months postoperatively comparedwith immediately after surgery, and (3) visual acuity of20/200 to 20/50. Vitrectomy and epiretinal membraneremoval essentially was the same in all eyes. Any patientswith preexisting ocular disease (that is, glaucoma, highmyopia, chronic inflammatory, or neoplastic disorders)were excluded as were those with systemic disorders(diabetes, uncontrolled hypertension) or a known life-threatening disease at enrollment into the study. The studywas approved by an Institutional Review Board. Patientswere informed of the purpose of our study and providedtheir signed consent to participate. Thirty-seven patientswere prospectively randomly assigned to receive betaxololor placebo. The patients were randomized using computer-generated numbers: 0 is to receive topical betaxolol, and 1is to receive placebo. The patients’ randomization statewas masked to the treating doctor. Within a week afterrandom assignments, treatment was to begin.

To evaluate the effects and safeaty of treatment, allrecruited patients underwent a detailed ophthalmic exam-ination, including slit-lamp biomicroscopy and confocalscanning laser tomography. Best-corrected visual acuitywas measured using the Early Treatment Diabetic Retinop-athy Study (ETDRS) chart, and the log of the minimalangle of resolution (logMAR) was calculated and used forall statistical analysis. A pretreatment fluorescein angio-gram was obtained within 1 week of commencing treat-ment. After the start of follow-up, the patients werereviewed at 0.5, 1, 2, 3, 4, 5, and 6 months and then every2 months. Visual function was assessed at every visit, andangiography scheduled for the visits at 1, 2, 3, 4, 5, 6, 9, 12,18, and 24 months. An increase or decrease in visual acuitywas defined as a change of greater than 0.2 of logMARvisual acuity. Goldmann tonometry was used to determine

intraocular pressure (IOP). Three measurements wererecorded in each eye, and the mean of the three was usedin the calculations. The IOP was measured at 10:00 AM andat 5:00 PM at baseline and 6-month visits, and IOPmeasurements were performed at 10:00 AM at the othervisits. Safety was evaluated by determining the incidenceof treatment-related complications and adverse reactionsfor both treatment and control groups. The patients wereregularly questioned and examined for side effects. Assess-ment of outcomes, including visual acuity, angiographicinterpretation, assessment of complications and adverseevents, was performed in a masked fashion.

Area of macular edema is defined as the area of hyper-fluorescence on the angiogram. Fundus angiograms wereobtained using a high-resolution digital fundus imagingsystem based on a Canon UVi fundus camera (Canon,Tokyo, Japan). In each angiogram, one picture was se-lected to show the extent of the macular edema and theoptic disk. The image was analyzed with UTHSCSAImage Tool 32-bit image analysis program (developed atthe University of Texas Health Science Center at SanAntonio).30 After applying sharpening and contrast-en-hancing image filters, the outline of the edema was drawnon the image manually and the membrane surface wascalculated. The outline of the optic disk was simulta-neously drawn and saved. To calculate for magnificationerrors, the disk/edema ratio was calculated for each image.The initial (pretreatment) size of the macular edema wasset to 100%, and all posttreatment measurements werenormalized relative to the initial size. Measurements wererepeated five times. When repeated measurement was doneon the same picture, statistical analysis of the reproduc-ibility of this measuring method showed a high correlationcoefficient of 0.995. A change of less than 20% wasconsidered as unchanged.

All patients underwent phacoemulsification and poly-acrylic intraocular lens implantation (MA60BM; Alcon,Fort Worth, Texas, USA). A standard three-port parsplana vitrectomy was performed in all patients. Weachieved a complete posterior vitreous detachment duringpars plana vitrectomy using a soft-tipped needle andremoved basal vitreous as much as possible with indenta-tion. Epiretinal membranes were removed with a slightlybent microvitreoretinal blade and microforceps; their ab-sence was then verified. No internal limiting membraneremoval or gas tamponade was employed.

For statistical analysis, if the difference in the percent ofpatients who have a significant improvement between thetreatment and control groups is 33%, each group needs 18patients, as the power is 80% (� � 0.05). Values arepresented as the mean � SD and as the range, or thefrequencies. For all two-by-two comparisons, the Fisherexact test was used. Other comparisons of frequencydistributions were performed using the �2 test for indepen-dence. Unless otherwise specified, data were analyzed by

BETAXOLOL FOR MACULAR EDEMAVOL. 136, NO. 2 245

unpaired two-sided t tests. A level of P �.05 was acceptedas statistically significant.

For the pairing of both groups, age, sex, visual acuity,area of macular edema and area, volume at baseline, andduration from the surgery to the start of follow-up wereused for matching. We studied a correlation between thepaired observations. If these observations were correlated,the F-test was used to study two population variances.

CASE REPORT

A 64-YEAR-OLD WOMAN HAD DECREASED VISION IN HER

left eye for 6 months. Ocular history was unremarkable.Results of examination showed best-corrected visual acuityof 20/20 in the right eye and 20/100 in the left eye. Fundusexamination showed the presence of epiretinal membrane

over the macular region in the left eye. Fluoresceinangiography showed macular edema and leakage fromvessels in the macular region (Figure 1). A pars planavitrectomy and removal of epiretinal membrane was per-formed. After 1 month, best-corrected visual acuity im-proved to 20/50. Macular edema showed a gradualaggravation. Three months after the surgery, visual acuitydecreased to 20/200 and the area of the macular edema was4.188 mm2. The patient was randomly assigned and begantreatment. The edema gradually resolved. Three monthslater, visual acuity improved to 20/40 and the area of themacular edema decreased to 0.523 mm2. The macularedema showed a further resolution. Six months after thestart of treatment, visual acuity was 20/25 and the area ofthe edema was 0.273 mm2. After completion of the6-month follow-up, the code was broken and it was learnedthat the patient had received topical betaxolol.

FIGURE 1. (A, B) Fluorescein angiographs of a 67-year-old woman before and 3 months after vitrectomy and removal of epiretinalmembrane (before the start of betaxolol treatment). (C, D) Three and 6 months after the start of betaxolol treatment.

AMERICAN JOURNAL OF OPHTHALMOLOGY246 AUGUST 2003

RESULTS

BASELINE DATA ARE SUMMARIZED IN TABLE 1. NINETEEN

eyes of 19 patients and 18 eyes of 18 patients were enrolledand followed up for 6 months in the treatment group andcontrol group, respectively. The duration between thesurgery and the start of the follow-up was 12.9 � 1.0 weeksin the treatment group and 12.8 � 1.0 weeks in the controlgroup; there was no difference between the two groups. Atbaseline mean best-corrected visual acuity was 0.216 (20/

92.6) and 0.244 (20/82.0) in the treatment and controlgroup, respectively (Table 1). Baseline best-corrected vi-sual acuity was slightly poorer in the treatment groupcompared with the control group, but the difference oflogMAR best-corrected visual acuity was not statisticallysignificant. Mean area of macular edema at baseline was2.271 � 1.629 mm2 in the treatment group and 2.273 �1.209 mm2in the control group (Table 1).

The mean area of macular edema at 6 months after thestart of follow-up was 1.492 � 1.357 mm2 and 2.125 �

TABLE 2. Change in Area of Macular Edema

Treatment Group Control Group P Value

Number of patients 19 18

Area of macular edema (mm2)

Baseline 2.271 � 1.629 (0.543–6.123) 2.273 � 1.209 (1.023–5.354) NS

1 month 2.064 � 1.579 (0.437–6.033) 2.194 � 1.278 (1.030–5.289) NS

3 months 1.818 � 1.551 (0–5.328) 2.178 � 1.326 (0.732–5.553) NS

6 months 1.492 � 1.357 (0–5.078) 2.125 � 1.434 (0.432–5.218) NS

Change in area of macular

edema (%)

1 month 88.6 � 21.8 (53.6–117.6) 98.4 � 11.3 (77.5–113.2) NS

3 months 76.5 � 24.1 (0–103.6) 92.9 � 15.4 (66.5–110.5) .0193

6 months 63.4 � 28.3 (0–98.7) 87.4 � 25.6 (32.7–125.4) .0102

Number of eyes with change in

area of macular edema for

6 months (%)

�60% 8 (42.1%) 4 (22.2%) .0402

60% to 79% 6 (31.6%) 2 (11.1%)

81% to 120% 5 (26.3%) 11 (61.1%)

121% to 140% 0 (0.0%) 1 (5.6%)

�141% 0 (0.0%) 0 (0.0%)

NS � not significant.

TABLE 1. Demographics of Patient Groups

Treatment Group Control Group

Number of subjects enrolled 19 18

Men 8 (43.5%) 7 (40.4%)

Women 11 (56.5%) 12 (59.6%)

OD 11 (52.2%) 9 (50.0%)

OS 8 (47.8%) 9 (50.0%)

Age (years) 64.5 � 10.8 (46–85) 63.3 � 9.8 (48–79)

Interval from surgery to the start

of follow-up (weeks)

12.9 � 1.0 (12–15) 12.8 � 1.0 (12–15)

Area of edema (mm2) 6.097 � 6.283 (0.778–25.124) 6.604 � 6.908 (0.887–25.442)

Best-corrected visual 0.176 (20/113.6) 0.154 (20/129.9)

acuity (range) (0.1–0.5) (0.1–0.5)

LogMAR visual acuity 0.612 � 0.272 0.576 � 0.259

Log MAR � logarithm of the minimal angle of resolution; OD � right eye; OS � left eye.


1.434 mm2in the treatment and control groups, respec-tively (Table 2). Mean changes of area of the edema for 3and 6 months were 76.5% � 24.1% and 63.4% � 28.3%in the treatment group and 92.9% � 15.4% and 87.4% �25.6% in the control group. The reduction in the size ofmacular edema for 3 and 6 months in the treatment groupwas significantly larger than in the control group (P �.0193; P � .0102).

In the treatment group, 14 patients (74%) showed asignificant resolution of macular edema, and five (26%)showed stable fluorescein angiographic appearance at 6months after the start of follow-up (Table 2). In thecontrol group, six patients (33%) showed a significantresolution of macular edema.

In the treated eyes, mean best-corrected visual acuitybefore and 3 and 6 months after the start of treatment was0.216 (20/92.6), 0.415 (20/48.2), and 0.471 (20/42.5),respectively (Table 3); there was a significant improve-ment in best-corrected visual acuity for 3 and 6 months (P

� .0008; P � .0001). In the control eyes, best-correctedvisual acuity before and 3 and 6 months after the start offollow-up was 0.244 (20/82.0), 0.254 (20/78.7), and 0.236(20/84.7); no significant change in visual acuity was foundfor any follow-up duration. A change in logMAR visualacuity for 3 and 6 months was 0.282 � 0.191 and0.337 � 0.197 in the treatment group and 0.016 �0.186 and �0.015 � 0.267 in the control group. Asignificant difference was found for a follow-up of 3 and 6months (P � .0001; P �.0001).

In treated patients, 13 patients (68%) showed a signif-icant improvement of best-corrected visual acuity, and theremaining six patients (32%) showed unchanged visualacuity for 6 months. In the control group, three patients(17%) showed a significant improvement, 11 patients(61%) unchanged visual acuity, and four patients (22%) asignificant deterioration (Table 3).

Throughout the study, patients were monitored for anypossible adverse side effects that could be attributed to the

TABLE 3. Change in Best-corrected Visual Acuity



Best-corrected visual acuity (BCVA)

Baseline BCVA 0.216 (0.1–0.5) 0.244 (0.1–0.5)

LogMAR BCVA 0.664 � 0.279 0.612 � 0.272 NS

1-month BCVA 0.283 (0.1–0.8) 0.239 (0.1–0.7)

LogMAR BCVA 0.548 � 0.241 0.621 � 0.269 NS

3-month BCVA 0.415 (0.15–0.8) 0.254 (0.05–0.8)

LogMAR BCVA 0.382 � 0.187 0.596 � 0.312 .0154

6-month BCVA 0.471 (0.02–1.0) 0.236 (0.04–0.8)

LogMAR BCVA 0.327 � 0.197 0.627 � 0.311 .0012

Change in LogMAR

best-corrected visual acuity

1 month 0.116 � 0.143 (0.477–�0.176) �0.010 � 0.152 (0.368–�0.222) .0136

3 months 0.282 � 0.191 (0.602–0) 0.016 � 0.186 (0.426–�0.477) .0001

6 months 0.337 � 0.197 (0.699–0) �0.015 � 0.267 (0.477–�0.574) �.0001

Number of eyes with change in

LogMAR best-corrected visual

acuity for 6 months

�0.6 3 (15.8%) 0 (0.0%) .0003

0.401 to 0.6 5 (26.3%) 2 (11.1%)

0.201 to 0.4 8 (42.1%) 1 (5.6%)

0.2 to �0.2 3 (15.8%) 11 (61.1%)

�0.201 to �0.4 0 (0.0%) 3 (16.7%)

�0.401 to �0.6 0 (0.0%) 1 (5.6%)

Number of eyes with best-corrected

visual acuity at 6 months

�0.5 (20/40) 11 (57.9%) 3 (16.7%) .0002

0.3 to 0.4 (20/66.7 to 20/50) 6 (31.6%) 4 (22.2%)

0.1 to 0.2 (20/200 to 20/100) 2 (10.5%) 10 (55.5%)

0.06 to 0.09 (20/333.3 to 20/222.2) 0 (0.0%) 0 (0.0%)

0.01 to 0.05 (20/2000 to 20/400) 0 (0.0%) 1 (5.6%)

LogMAR � logarithm of the minimal angle of resolution; BCVA � best-corrected visual acuity; NS � not significant.


drugs. There were no significant systemic and ocularcomplications and adverse events.

Mean intraocular pressure at baseline and at 6 monthsafter the start of follow-up was 15.5 � 2.3 mm Hg and 13.9� 2.2 mm Hg in the treatment group and 15.4 � 3.0 mmHg and 15.3 � 2.7 mm Hg in the control group (Table 4).The treatment group showed a significant reduction in IOPafter administration of topical betaxolol (P � .0350). Atbaseline and at 6 months after the start of follow-up, meanheart rate was 72.3 � 8.6 beats per minute and 68.1 � 8.8beats per minute; and mean systolic pressure was 132.3 �13.1 mm Hg and 127.5 � 13. 4 mm Hg. The betaxololgroup showed a decrease in heart rate and systolic pressure;this was not statistically significant.

DISCUSSION

THIS STUDY EVALUATED THE EFFICACY OF BETAXOLOL FOR

macular edema that remained after vitrectomy and re-moval of epiretinal membrane. Betaxolol significantlyimproved visual acuity compared with untreated eyes.Patients with topical betaxolol showed a significant reduc-tion in macular edema, whereas no such effect was ob-served in untreated eyes. Betaxolol appeared to have afavorable effect in reducing macular edema. Therefore,topical betaxolol may promote resolution of macularedema and restore function.

Topically applied betaxolol was observed to reach theretina in maximal amounts within 60 minutes in rabbits.6Some of the substance was also found in the contralateralretina of the untreated eye, suggesting that the agentreaches the retina by local systemic and retinal circulation.Betaxolol penetrates the conjunctive and accumulate inthe Tenon capsule.31 In patients under long-term therapy,the periocular tissue can accumulate a greater quantity ofthe �-antagonist than is present in a daily dosage ofapplied eyedrops, manyfold higher than the maximalintraocular concentration.31 Therefore, topically appliedbetaxolol may reach the posterior segment of the eye andimprove metabolism and microcirculation of the macularregion.

The vasodilating effects of betaxolol on ocular vesselshave recently been demonstrated in vivo and in vitro studiesacting via a Ca2� channel blocking activity.7–12,32–37 Changesin ocular blood flow velocity by topically applied betaxololhave been measured using various methods, includingcolor Doppler imaging method, laser Doppler velocimetry,scanning laser fluorescein angiography, fundus pulsationamplitudes measurement, and laser-speckle tissue bloodflow analysis.32–37 Retinal blood flow increases as a long-term effect of betaxolol.

The effects of betaxolol have been studied in isolatedporcine posterior ciliary artery and bovine retinal arterieswith the use of ring segment preparation.7–12 Betaxololinduced a dose-dependent dilation with a threshold as low

TABLE 4. Change of Intraocular Pressure, Heart Rate, and Blood Pressure



Intraocular pressure (mm Hg)

Baseline 15.5 � 2.3 (12–20) 15.4 � 3.0 (11–21) .9098

6 months 13.9 � 2.2 (11–18) 15.3 � 2.7 (11–21) .0918

Change in intraocular pressure

(mm Hg)

6 months 1.6 � 0.8 (3–0) �0.2 � 2.2 (2–�4) .0020

Heart rate (beats/min)

Baseline 70.9 � 9.8 (56–88) 72.6 � 11.8 (52–88) .6358

6 months 68.1 � 8.8 (58–86) 72.4 � 9.1 (60–86) .1529

Change in heart rate (beats/min)

6 months 2.8 � 4.8 (13–�5) 0.1 � 5.7 (8–�10) .1274

Systolic pressure (mm Hg)

Baseline 132.3 � 13.1 (110–152) 132.9 � 10.2 (114–148) .8778

6 months 127.5 � 13.4 (104–148) 132.2 � 10.9 (110–150) .3647

Change in systolic pressure

(mm Hg)

6 months 4.8 � 4.5 (16–�6) 0.6 � 5.7 (8–�8) .0656

Diastolic pressure (mm Hg)

Baseline 76.5 � 7.9 (64–92) 75.4 � 6.1 (66–88) .6398

6 months 76.0 � 7.1 (66–88) 75.7 � 6.2 (64–86) .8921

Change in diastolic pressure

(mm Hg)

6 months 0.5 � 2.6 (4–�4) �0.2 � 2.5 (4–�6) .4100


as 1012 M. Therefore, betaxolol may play a role inrelaxing the retinal microarteries to improve the ocularcirculation, resolve macular edema, and restore function.

Several studies have demonstrated that betaxolol canprotect retinal neurons from ischemia.1–6 Topical betaxo-lol can blunt the effects of ischemia/perfusion to theretina.4,6 Betaxolol can reduce influx of both sodium andcalcium into neurons through interaction at neurotoxinsite 2 of the sodium channel and the L-type calciumchannel, respectively. Betaxolol has been reported to raiselevels of mRNA for brain derived neurotrophic factor,6

suggesting that betaxolol can induce changes in expressionof factors that are known themselves to provide neuropro-tection to retinal neurons. Injury to neurons, includingmacular edema, has been proposed to cause cellular deathand idling neurons, whose functions reach a standstill.38 Inaddition to improvement of microcirculation and brainderived neurotrophic factor upregulation, the ability ofbetaxolol to interact with sodium channel and L-typecalcium channel may have a role in its therapeutic effectsin restoring functions of idling neurons and glia. There isa possibility that betaxolol may protect retinal neuron andglia from macular edema and restore function.

Although the sample size in each group was small, thecurrent study demonstrated that betaxolol may have afavorable effect for treating macular edema. Future study ofa large population is needed to verify this observation. Asmacular edema results from a variety of diseases andpathologic conditions, we need to study the kind ofpathologic condition resulting in macular edema for whichbetaxolol is effective. This information may be clinicallyvaluable when treating macular edema.

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randomized clinical trial of topical betaxolol for persistent macular edema after vitrectomy and...

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