that $6,118 were expended per quality-adjusted life year (QALY) gained, a justiÞable value based on guidelines by which treatments costing less than the per capita gross domestic product per QALY are deemed very cost-effective.246

Hypertension has a suggestive negative inßuence on response to grid laser for ME associated with BRVO.277

13.4.1.2Subthreshold Grid Laser Treatment

Conventional GL treatment produces visible burns and chorioretinal scars. Subthreshold grid laser (SGL) is a modiÞcation of this approach using a diode laser with wavelength 810 nm.219 In SGL, micropulses of laser energy are applied rather than continuous laser burns. This technique limits the spread of laser energy and causes less collateral damage to the surrounding tissue. Different studies have employed different laser settings. Laser exposures have varied from 0.2 to 0.3 s, duty cycles from 10Ð15%, patterns used from noncontiguous spots to contiguous spots, and treatment number from one to several.219,221 Laser power is determined by adjusting the setting in the continuous mode until a medium-white burn is achieved in an area of macular edema, then converting to the micropulse mode. With this approach, the laser burns are invisible.219

In general, results with SGL are similar to those obtained with conventional GL without the retinal scarring but with somewhat slower onset of macular thinning. Whereas a single threshold GL treatment produces a macular thinning response complete by 6 months, with SGL the response is not complete for 12 months, although the amplitude of response is as large as with threshold laser treatment.219

Combining SGL with IVTI has improved visual outcomes and sped reduction in edema, but only pilot studies have been done.221 A similar approach using a Nd:YLF laser (wavelength 527 nm, 1.7 ms pulse,100 Hz train) is undergoing a clinical trial in BRVO with ME.26

13.4.1.3Sector Panretinal Laser Photocoagulation

Sector panretinal laser photocoagulation (PRP) for macular edema associated with BRVO has been

described in case reports and small case series.119 In one series of Þve patients, ME regressed in all patients. In the absence of a control group, it is not possible to know if this outcome is an improvement over the natural history.148 Sector PRP was a part of the treatment regime in a study of intravitreal bevacizumab injections for ME associated with BRVO.144 It was used in the eyes with ten or more disc diameters (DD) of ischemia as a prophylaxis against retinal neovascularization, but it may have contributed to the effect of the injectional therapy on the ME too.144 The rationale is to eliminate regions of ischemic retina that may be a source of VEGF contributing to macular edema.119

Sector PRP has also been described in a case of ischemic BRVO with vitreomacular traction and ME with the intent of surgery being to induce PVD. The intended change occurred, but whether the treatment was responsible for the favorable outcome is not possible to say.120

13.4.1.4Intravitreal Injection

of Anti-vascular Endothelial Growth Factor Drugs

Treatment with anti-VEGF drugs is rational because VEGF levels are elevated in eyes with BRVO and ME and VEGF levels correlate with area of capillary nonperfusion and severity of ME.197,216 VEGF theoretically could exacerbate microangiopathy and ischemia, which could be prevented with anti-VEGF drugs.3,283

Ranibizumab and bevacizumab are directed against an epitope common to all VEGF isoforms.3 Bevacizumab is a full-length monoclonal antibody derived from a mouse that has been humanized. It was designed for intravenous treatment of metastatic colorectal cancer, but is used extensively and efÞcaciously in off-label treatment of retinal diseases in which elevated VEGF plays a role. Bevacizumab penetrates all layers of the retina after intravitreal injection in animal models. With a molecular weight of 149 kDa, its aqueous half-life after intravitreal injection is 9.8 days.150 Ranibizumab is a monoclonal antibody fragment from a mouse that has been humanized and afÞnity-matured for tighter binding to VEGF. It has a molecular weight of 48 kDa and a half-life after intravitreal injection of

between 3 and 9 days. Pegaptanib is a ribonucleic acid aptamer directed against an epitope found only in VEGF165304 It blocks VEGF165 selectively.304 The clinical usefulness of all three antiVEGF drugs in macular edema associated with BRVO has been established in case reports, series, and clinical trials.14,91,243,261,304

The published treatments vary by drug and by injection regimen. The experience is greatest with bevacizumab and ranibizumab. Less information

has been published for pegaptanib. Various reinjection regimens have been used including a series of 2Ð6 monthly injections followed by pro re nata (prn) injections, a regimen of monthly injections until edema resolves or futility is reached followed by prn injections that depend on VA and OCT central subÞeld mean thickness (CSMT), a prn regimen from the beginning, injections given according to complicated schedules or based on OCT thresholds (Table 13.4), and a regimen based

Fig. 13.7 Mean change in best corrected visual acuity letter score in the BRAVO clinical trial for the two treatment groups (ranibizumab 0.3 and 0.5 mg) and the sham group at monthly intervals through month 6.*P < 0.0001 versus sham.

Vertical bars are ±1SEM.

BCVA best corrected visual acuity, ETDRS Early Treatment Diabetic Retinopathy Study (Reproduced with permission from Campochiaro et al.36)

Mean change from baseline BCVA (ETDRS letters)

20

15

10

5

0

+7.3

entirely on physician discretion.36,89,91,144,241,243,304,305 In clinical practice, it is difÞcult to be rigid in a treatment regimen.

The efÞcacy of ranibizumab in the treatment of BRVO with ME was proven in the BRAVO study in which 397 patients were randomized 1:1:1 to receive baseline and then monthly intravitreal ranibizumab injections (IVRI) of 0.3, 0.5 mg, or sham injections, respectively, through 6 months. With seven initial injections and then continued, but fewer, injections through 2 years, sustained reductions in ME and improvement in BCVA through 2 years were possible. The mean change from baseline in BCVA letter score at month 6 was 16.6 (95% CI 14.7Ð18.5) and 18.3 (95% CI 16.0Ð 20.6) for the 0.3- and 0.5-mg ranibizumab groups, respectively, compared to 7.3 (95% CI 5.1Ð9.5) in the sham group (Fig. 13.7). The percentage of patients who gained 15 letters or more in BCVA letter score at month 6 was 55.2% and 61.1% for the 0.3- and 0.5-mg groups, respectively, compared to 28.8% of the sham group. The OCT center point (CPT) thickness decreased by a mean of 337 m (95% CI 376Ð299) and 345 m (95% CI 386Ð 304) in the 0.3- and 0.5-mg groups, respectively, compared to 158 m (95% CI 196Ð119) in the sham group (Fig. 13.8). These changes were statistically signiÞcant for both dosage groups compared to the sham group. The effects were rapid with statistically signiÞcant effects on VA noted by day 7.36

From months 6Ð12, patients in the BRAVO study were evaluated monthly both clinically and with OCT.28 In the 0.3- and 0.5-mg ranibizumab groups, reinjection was given if BCVA was 20/40 or less or CSMT was 250 m or greater (termed prn treatment). Those patients randomized to sham injection were given 0.5 mg ranibizumab based on the same criteria. At 12 months in the 0.3- and 0.5-mg groups, the VA and macular thinning responses observed with monthly dosing through 6 months were maintained. In the sham group treated with prn 0.5 mg ranibizumab, the VA and macular thickness had improved compared to 6 months, but not to the level of improvement of the 0.3- and 0.5-mg groups.28 SpeciÞcally, in the sham group, the mean change in letters read from baseline increased from +7.3 at 6 months to +12.1 at 12 months, which was lower than the +16.4 letters for the 0.3-mg group and the +18.3 mg for the 0.5-mg group at month 12.28

A smaller single-center study of 17 patients with BRVO and ME showed that monthly IVRI for 3 months followed by variable treatment the Þrst year and a mean of two IVRIs in the second year produced a mean improvement in BCVA from baseline to 2 years of 17.8 letters and a mean foveal thickness of 245.8 m at the end of year 2.36

The efÞcacy of intravitreal bevacizumab injection (IVBI) over 6 months of follow-up has been

Fig. 13.8 Mean change in the OCT center point thickness in the BRAVO clinical trial for the two treatment groups (ranibizumab 0.3 and 0.5 mg) and the sham group at monthly intervals through month 6. *P < 0.0001 versus sham.

Vertical bars are ±1SEM (Reproduced with permission from Campochiaro Ophthalmology36)

Table 13.5 Evidence of efÞcacy of bevacizumab in branch retinal vein occlusion with macular edema

All visual acuities are mean logMAR visual acuities except for * median initial visual acuity

N number of subjects, VA visual acuity, Ini initial, M months, logMAR logarithm of the minimum angle of resolution, CSMT central subÞeld mean thickness, VATR visual acuity to thinning ratio in ETDRS letters per 100 m of macular thinning. Because various doses of bevacizumab have not shown clinically important differences, Table 13.5 pools studies using bevacizumab at different doses

demonstrated both in treatment na•ve eyes and in eyes with a variety of previously failed treatments including intravitreal and periocular steroids, grid laser, and vitrectomy with or without AVS (Figs. 13.6 and 13.7).14,144,243,305 The evidence for efÞcacy of IVBI comes from the weight of multiple investigator-initiated studies of lower-quality design, compared to the level I BRAVO study for ranibizumab. There is no drug company nor any government health body championing the use of IVBI for RVO and providing funds for phase III randomized clinical trials involving bevacizumab (Table 13.5).

In four retrospective and three prospective case series including a combined total of 166 patients receiving intravitreal bevacizumab injections for BRVO with ME and having 6 months follow-up data, the numbers of injections used ranged from 1

to 3.7. The weighted initial logMAR visual acuity in these series was 1.00 (Snellen 20/200) compared to 0.66 (Snellen 20/91) at 6 months. The weighted initial CSMT in these series was 495 m compared to 299 m at 6 months. The weighted VATR for these seven case series was 8.7 letters/100 m thinning, which is comparable to the 5.3 letters/100 m thinning found in the BRAVO study.

Intravitreal pegaptanib injection (IVPI) has also been suggested to be effective as serial monotherapy for BRVO with ME. At the 0.3-mg dose in an uncontrolled case series of 15 patients, IVPI reduced ME and improved VA in patients over a follow-up period of 54 weeks.304

In the short term, intravitreal injection of bevacizumab, ranibizumab, and pegaptanib reduces CSMT and improves VA, but the effects wear off and reinjections are usually necessary to main-

tain improvements (Fig. 13.9).10,14,36,90,112,212,225,243,2

64,304,305 The maximal effect of bevacizumab injection is seen by the second week and is sustained through 4Ð8 weeks. For bevacizumab, the maximal effect was reduction, but not elimination of ME after a single injection. In a series of 12 patients with BRVO and ME, the baseline central retinal thickness decreased from 673 ± SD 375 to 342 ± SD 149 at 1 month.212 The duration of action of an IVPI in BRVO appears to be at most 6 weeks and of IVBI in BRVO appears to be at

most 8 weeks.10,112,212,264

Reinjections were required in 37Ð87% of cases treated with bevacizumab in the Þrst year in various studies (Fig. 13.10).91,122,243 Due to different reinjection rules and variations in patient samples studied, the mean number of injections required by different regimens varies. For example, in the case of bevacizumab, 1.5Ð8 injections were given in the Þrst 6Ð12 months (Table 13.4) to maintain resolution of ME associated with

BRVO.14,52,90,91,112,122,144,146,147,225,243,305 In a study of

pegaptanib, the mean number of injections required over 54 weeks of follow-up was 7.2.304 Over time, the frequency of injections required to maintain macular deturgescence typically decreases.122 Although recurrence of edema and the need to reinject bevacizumab is the rule, in one study, one-quarter of patients with BRVO and ME were successfully treated with a single injection without recurrence of edema.144

For bevacizumab, 1.25-, 2.0-, and 2.5-mg dosages have been used.14,243,305 No differences in effectiveness based on VA, macular thickness, or required frequency of reinjection outcomes have been detected with various dosages.14,243,305

Some eyes with BRVO and ME fail to respond to bevacizumab or ranibizumab at all or respond only partially. The percentage of eyes in this category ranges from 24% to 35% and will depend on the regimen adopted for repeat injection. Reasons may include foveal hemorrhage, macular ischemia, macular cell death, or refractory edema.212 A deÞnition of futility of therapy is therefore important to consider (Table 13.6).

Some eyes that fail to respond to bevacizumab injections may respond to ranibizumab or

triamcinolone injections.89 Some eyes respond to bevacizumab but respond with a greater decrease in edema to triamcinolone.89

The rationale for use of anti-VEGF drugs is to reduce macular edema, although the clinically important outcome is improvement in VA. The correlation of the two outcomes is imperfect, with a correlation coefÞcient between change in OCT-measured macular thickness and change in VA at 6 months ranging from 0.40 to 0.54 in the case of bevacizumab.89,112 Macular ischemia,

Fig. 13.9 A 60-year-old hypertensive man was seen with the complaint of acute onset of blurred vision of the left eye 4 weeks before. The visual acuity of the left eye was counting Þngers. (a) Monochromatic fundus photograph of the left eye shows an inferotemporal branch vein occlusion with macular edema. (b) A frame from the mid-phase ßuorescein angiogram shows that there are areas of capillary nonperfusion (the yellow arrow), but some areas are difÞcult to evaluate because of obscuring intraretinal hemorrhage (the red oval). (c) A frame from the latephase ßuorescein angiogram shows that the clearly ischemic area lacks leakage (yellow arrow). The indeterminate area has considerable ßuorescein leakage (the red oval), a sign that the capillaries in this perifoveal area are perfused. (d) False-color map OCT shows marked thickening in the inferotemporal macula with the mean thickness of the central macula 951 m. (e) Horizontal OCT line scan shows marked edema of the outer nuclear layer and lesser cystoid edema of the inner nuclear layer. The inner segment/outer segment (IS/OS) junction cannot be seen (the yellow arrows) in the edematous area. (f) One month after a single injection of bevacizumab 1.25 mg, most of the edema has resolved, visual acuity has returned to 20/32, and the horizontal OCT line scan shows a preserved inner segment/outer segment junction (the red arrows)

R 30* ART (HS)

b

d

f

Fig. 13.9 (continued)

800Vol (mm3) Average thickness ( m)

6.89 416

1027

4000.79

927

atrophy, and hemorrhage may be confounders that reduce the correlation.89,264

Concerns that pan-VEGF blockade might stunt collateral vessel growth and increase retinal ischemia have been addressed by examining ßuorescein angiography before and after antiVEGF treatment. No evidence to suggest increased ischemia has been found.10,14,55,178,194,212,2 25,227,243,276,305 In fact, retinal collaterals have been

witnessed to develop in the face of repeated intravitreal injections of bevacizumab and sometimes areas of nonperfusion decreased.225,227

Because intravitreal injections have rare but serious risks, incur expense, and sometimes do not work, the ability to predict response to treatment is important. Therefore, studies seeking baseline factors predictive of outcome with anti-VEGF therapy have been done. In a study of 40 patients with

BRVO, failure to reduce macular thickness by at least 20% after intravitreal bevacizumab injection was associated with higher aqueous levels of VEGF and PEDF.215 OCT variables have also been explored for predictive power regarding outcome. In a study of 32 patients with BRVO and ME, baseline CSMT and presence or absence of subretinal ßuid were not predictive.113 One study found that good baseline VA was a predictor of 1 year VA after IVBI.144 Two studies reported that eyes with poor baseline VA had on average the largest VA improvements after IVBI or IVRI.144,241 One study of 38 patients with BRVO and ME treated with serial IVBI found no prognostic factors.2 A positive correlation between duration

of symptoms and Þnal BCVA with a regimen of IVRI was reported.241 In another study of IVRI, the median Þnal BCVA was eight letters better in eyes with BRVO of duration less than 1 year than eyes with duration of one or more.36 Baseline OCT CSMT and subretinal ßuid status were not predictive of VA outcome in one retrospective study of 32 patients with BRVO and ME.113

Studies are inconsistent about whether ischemia predicts response to anti-VEGF injections.52,143 The visual prognosis in cases of BRVO and ME treated with IVBI was worse in cases with macular ischemia than in well-perfused cases in one study.52,143 However, in another study, 36% of nonresponders to bevacizumab were

Fig. 13.10 Images from a 74-year-old male with hypertension and open-angle glaucoma who developed a superotemporal branch retinal vein occlusion of the right eye. (a) Subfoveal hemorrhage is present (orange arrow). (b) Frame from the mid-phase ßuorescein angiogram shows perifoveal capillary disruption of approximately 90¡ extent (yellow arrow); this occlusion occurs at the secondorder crossing of a branch retinal artery over a branch retinal vein (green arrow); the Þrst-order crossing is denoted by the purple arrow. (c) Late phase of the ßuorescein angiogram shows extensive ßuorescein leakage from the microvasculature of the involved sector of retina.

(d) SD-OCT line scan shows macular cystoid edema and a hyperreßective subretinal collection of blood (orange arrow). (e) Four consecutive images taken during and after a course of 3 monthly injections of bevacizumab. The macular edema resolves within a month of the Þrst injection. The dark zone in the SLO fundus images reßects the severity of the edema which improves most after a single injection with minor further improvement by the third study (6/23/2010). The study of 10/6/2010 shows recurrence of macular edema 14 weeks after the third bevacizumab injection

eDates of bevacizumab

Bevacizumab 4/6/2010

Bevacizumab 5/5/2010

Bevacizumab 6/23/2010

Fig. 13.10 (continued)

3/31/2010

5/1/2010

6/23/2010

10/6/2010

Table 13.6 Proposed rules for futility of intravitreal anti-VEGF therapy

Futility rules

1. At least three consecutive bevacizumab injections

2. VA did not increase by at least two lines, or ME did not decrease by at least 30%

At least two consecutive monthly injections and yet CSMT does not decrease at least 50 m or 20% of the baseline CSMT and vision does not improve by at least Þve ETDRS letters

Macular edema persists after 6 monthly injections of bevacizumab 1.25 mg

VA visual acuity, ME macular edema, CSMT central subÞeld mean thickness, ETDRS Early Treatment Diabetic Retinopathy Study

nonischemic by FA.52,143 Reduction in ME seems to occur without regard to ischemia.52 For ranibizumab, whether the FAZ-border is disrupted 180¡ or more inßuences the VA Þnal outcome. The median Þnal BCVA was ten letters better in eyes with FAZ-border disruption of less than 180¡ than in eyes with 180¡ or more of FAZ-border disruption.36

A theoretical concern has been raised that anti-VEGF drugs might cause upregulation of VEGF receptors that could amplify macular edema when the drug level wanes.161,223 Rebound macular edema in excess of that observed at baseline has been reported, providing some evidence to support this mechanism.181

Patients may respond well to IVBI by OCT and VA measures and yet elect to discontinue treatment, presumably because the discomfort,