Intravitreal Bevacizumab for Refractory Pseudophakic Cystoid Macular Edema

Intravitreal Bevacizumab for Refractory Pseudophakic Cystoid Macular Edema The Pan-American Collaborative Retina Study Group Results J. Fernando Arevalo, MD, FACS,1 Mauricio Maia, MD,2 Rafael A. Garcia-Amaris, MD,1 Jose A. Roca, MD,3 Juan G. Sanchez, MD,1 Maria H. Berrocal, MD,4 Lihteh Wu, MD,5 for the Pan-American Collaborative Retina Study Group (PACORES)* Objective: To determine the feasibility, safety, and clinical effect of intravitreal (IVT) bevacizumab (Avastin; Genentech, Inc., San Francisco, CA) in patients with refractory cystoid macular edema (CME) after cataract surgery. Design: Interventional, retrospective, multicenter study. Participants: Thirty-six eyes of 31 patients with refractory CME after cataract surgery and with a mean age of 68.2 years (range, 67– 87 years). Methods: Patients were treated with at least 1 IVT injection of 1.25 or 2.5 mg bevacizumab. Patients were followed up for 12 months. Main Outcome Measures: Best-corrected visual acuity (BCVA) and central macular thickness (CMT) by optical coherence tomography (OCT). Results: Twenty-six eyes (72.2%) demonstrated improvement of BCVA (ⱖ2 Early Treatment Diabetic Retinopathy Study [ETDRS] lines), and no eye experienced worsening of visual acuity (ⱖ2 ETDRS lines). Mean baseline BCVA was 20/200 (0.96 logarithm of the minimum angle of resolution [logMAR] units), and the mean 12-month BCVA was 20/80 (0.62 logMAR units; P⬍0.0001). Optical coherence tomography demonstrated that mean CMT at baseline was 499.9 ␮m (range, 298 –784 ␮m) and decreased to a mean of 286.1 ␮m (range, 168 – 499 ␮m) at 12 months (P⬍0.0001). Four (11%) eyes received 2 injections, 10 (27.8%) eyes received 3 injections, 10 (27.8%) eyes received 4 injections, 1 (2.8%) eye received 5 injections, and 1 (2.8%) eye received 6 injections. The mean number of injections was 2.7 (range, 1– 6), and the mean interval between injections was 15.1 weeks (range, 4 – 45 weeks). No ocular or systemic adverse events were observed. Conclusions: Short-term results suggest that IVT bevacizumab is well tolerated in patients with refractory pseudophakic CME. Treated eyes had a significant improvement in BCVA and decrease in macular thickness by OCT at 12 months. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2009;116:1481–1487 © 2009 by the American Academy of Ophthalmology. *Group members listed online in Appendix 1 (available at http://aaojournal.org).

Despite recent advances in cataract surgery technique and instrumentation, pseudophakic cystoid macular edema (CME) remains a relatively frequent complication of cataract surgery even after uncomplicated surgery.1 Pseudophakic CME develops angiographically after uneventful cataract surgery in up to 60% of patients who have undergone intracapsular extraction1,2 and in up to 20% to 30% of patients after extracapsular cataract extraction/phacoemulsification.1,3 However, clinically significant CME, defined as a Snellen visual acuity of 20/40 or worse with characteristic petaloid perifoveal macular edema, occurs in between 0% and 13% of patients.1,3 In most patients, pseudophakic CME resolves spontaneously, with 50% to 75% of patients achieving improved © 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.

vision within 6 months and with only a minority of patients experiencing permanent visual morbidity.2,4 Over the years, numerous treatment options have been used in an attempt to treat pseudophakic CME, including the use of systemic, periocular, intravitreal, and topical corticosteroids1,4 –5; oral and topical nonsteroidal anti-inflammatory drugs (NSAIDs)1,6; oral and topical carbonic anhydrase inhibitors1; laser surgery7; hyperbaric therapy8; and pars plana vitrectomy.9 The pathogenesis of CME after cataract surgery remains obscure. Among the multiple factors of potential clinical importance are vitreous traction, vascular instability, relative ocular hypotony, inflammation, and ultraviolet radiation.1,3,4,6 Most investigators agree that inflammation is the major etiologic factor in the development of CME after ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2009.04.006

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Ophthalmology Volume 116, Number 8, August 2009 cataract surgery. Inflammatory mediators (prostaglandins, cytokines, and other vasopermeability factors) induce disruption of the blood–retinal barrier after ocular surgery, resulting in increased permeability from the perifoveal capillaries, with resultant fluid accumulation in the perifoveal retina.1,10 –11 Therefore, macular edema in the setting of inflammation (e.g., pseudophakic CME), diabetes, or venous occlusion arises because of disruption of this barrier, with consequent exudation and accumulation of serous fluid.12 Vascular endothelial growth factor (VEGF) has been identified as an angiogenic inducer in a variety of in vitro and in vivo models,13 has been associated with breakdown of the blood–retinal barrier, and contributes to the onset of macular edema.10,11,14 Vascular endothelial growth factor has been demonstrated to increase retinal vessel permeability by increasing the phosphorylation of tight junction proteins. Recent studies showed elevated levels of VEGF and interleukin-6 in ocular fluids of patients with macular edema.11 Furthermore, injection of VEGF into normal primate eyes increases vascular permeability.15 In light of this information, VEGF also may be a mediator in the onset of inflammatory macular edema. Bevacizumab (Avastin; Genentech, Inc., San Francisco, CA) is a complete full-length humanized antibody that binds to all subtypes of VEGF-A and is used successfully in tumor therapy as a systemic drug.16 Recent studies have demonstrated the usefulness of an intravitreal (IVT) injection of bevacizumab in the reduction of refractory pseudophakic CME, macular edema secondary to central retinal vein occlusion, vascular permeability and fibrovascular proliferation in retinal neovascularization secondary to proliferative diabetic retinopathy, and choroidal neovascularization secondary to age related-macular degeneration.17–20 The amount of human retinal penetration for a complete full-length anti-VEGF antibody is not known at present. However, full-thickness retinal penetration of IVT bevacizumab was observed in an animal model.21,22 Additionally, IVT bevacizumab does not seem to be toxic to the albino rabbit retina at a concentration of up to 2.5 mg.23,24 Recently, the authors’ group published a retrospective study of consecutive eyes with pseudophakic CME treated with primary IVT bevacizumab as initial therapy and demonstrated both anatomic and functional significant improvement at 6 months. Twenty eyes (71.4%) demonstrated improvement of best-corrected visual acuity (BCVA; ⱖ2 Early Treatment Diabetic Retinopathy Study [ETDRS] lines), and no eye experienced worsening of BCVA.25 However, Spitzer et al26 found no improved visual function in patients with postoperative CME after IVT bevacizumab. This retrospective case series comprised 16 eyes of 16 patients with CME after cataract surgery refractory to current standard treatment who received an injection of 1.25 mg IVT bevacizumab. Although the mean retinal thickness decreased slightly, the mean visual acuity remained unchanged in the series. Visual acuity improved by 2 ETDRS lines in 1 patient, remained unchanged in 12 patients, and decreased by 2 lines in 2 patients. Therefore, the authors decided to look at their results from a different group of eyes with refractory CME after cataract surgery. The objec-

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tive of this retrospective study was to determine the feasibility, safety, and clinical effect of primary IVT bevacizumab in patients with refractory CME after cataract surgery at 12 months of follow-up.

Patients and Methods This was an interventional, retrospective multicenter study of eyes with CME after uneventful cataract surgery treated with off-label IVT bevacizumab between November 2005 and June 2007 at 5 institutions in Venezuela, Costa Rica, Puerto Rico, Peru, and Brazil. Eyes to be included in this study had to have any amount of persistent CME demonstrated on clinical examination, fluorescein angiography, and optical coherence tomography (OCT), despite having received medical treatment for at least 3 months. The clinical records were reviewed of 31 consecutive patients (36 eyes) with pseudophakic CME treated with at least 1 IVT injection of 1.25 or 2.5 mg bevacizumab who did not respond to other treatments, such as systemic, periocular, intravitreal, and topical corticosteroids or topical NSAIDs. Whether the dose of 1.25 mg or 2.5 mg was to be used to treat a patient was determined at the discretion of the treating physician. If a patient received one of the doses at baseline, the same dose was delivered throughout the study. Institutional review board/ethics committee approval and patient informed consent were obtained for this study at all 5 institutions. The off-label use of the drug and its potential risks and benefits, as well as other treatment options, was discussed extensively with all patients. Exclusion criteria included patients (eyes) with a history of any other intraocular surgery before cataract surgery, CME of other cause, uveitis, or the presence of vitreoretinal pathologic features. In addition, eyes with structural changes such as the presence of an epiretinal membrane or anterior segment changes such as vitreous or iris to the wound, broken capsule, sulcus fixated intraocular lens (IOL), and iris–IOL contact were excluded. Although not a formal exclusion criteria, patients with a history of uncontrolled hypertension and recent thromboembolic events were not usually injected with bevacizumab, but this decision was left to the discretion of the treating physician. Each patient underwent BCVA measurement with ETDRS charts, ophthalmic examination including slit-lamp biomicroscopy, and fluorescein angiography. Baseline central retinal characteristics were analyzed by OCT (Stratus III OCT; Carl Zeiss, Dublin, CA) using 6 diagonal slow 6-mm radial line scans, with software version 4.0, through a dilated pupil by a retina specialist. The retinal thickness of the 1-mm central retina was obtained using the macular thickness map for these calculations. A 0.18-ml aliquot of commercially available bevacizumab was prepared for each patient and placed in a tuberculin syringe using aseptic techniques. All aliquots were prepared at one time together and then stored at 4° C. After the eye had been prepared in a standard fashion using 5% povidone–iodine, an eyelid speculum was used to stabilize the eyelids, and the injection of 1.25 mg (0.05 ml) or 2.5 mg (0.1 ml) bevacizumab was performed 3.5 to 4 mm posterior to the limbus, through the inferotemporal pars plana with a 30-gauge needle under topical anesthesia or subconjunctival lidocaine. After the injection, intraocular pressure and retinal artery perfusion were checked, and patients were instructed to administer topical antibiotics for 7 days. Patients were examined at 1 week, 2 weeks, and 1 month after the first injection and monthly thereafter. At each visit, complete eye examination was performed, including BCVA, slit-lamp examination, intraocular pressure measurement, stereoscopic biomicroscopy of the retina, and retinal thickness measurement by OCT.

Arevalo et al 䡠 IVT Bevacizumab for Pseudophakic CME Patients were included in this consecutive series only if there was a minimum of 12 months of follow-up. Fluorescein angiography was carried out at the discretion of the examiner and not at every postinjection evaluation. Patients received reinjections when there was a recurrence of CME. Recurrence was defined as a decrease of BCVA of 2 or more ETDRS lines associated with an increase of intraretinal fluid of 50 ␮l or more resulting from macular edema on OCT, after a favorable response with complete or partial resolution (disappearance of cystic spaces with restoration of foveal anatomic features) in previous follow-up visits. Patient’s ETDRS BCVAs were transferred from their records and were converted to a logarithm of the minimum angle of resolution (logMAR) scale for analysis. A paired Student t test was used to compare mean values to analyze statistically mean retinal thickness and logMAR visual acuity. An increase or decrease in BCVA was considered to have occurred if there was a change of 2 or more ETDRS lines. Main outcome measures included changes in BCVA and OCT results. A P value ⬍0.05 was considered to be significant.

Results Thirty-six eyes (31 consecutive patients) with a minimum of 12 months of follow-up were included for analysis. The patients had a mean age of 68.2 years (range, 67– 87 years), and 67.7% were female (21 women and 10 men). Patients were followed up for 12 months (Table 1). At baseline examination, all eyes had clinically significant CME that did not respond to other treatment methods (systemic, periocular, intravitreal, and topical corticosteroids; topical NSAIDs; or a combination thereof). All 36 eyes had received at least 1 alternative therapy (topical corticosteroids had been applied to 22 eyes [70.9%], intravitreal triamcinolone had been applied to 11 eyes [30.5%], topical NSAIDs had been applied to 14 Table 1. Patient Demographics Intravitreal Bevacizumab by Refractory Pseudophakic Cystoid Macular Edema No. of eyes/no. of patients Age (yrs) Mean Range Gender, no. (%) Female Male Interval from CME symptoms to IVT bevacizumab (mos) Mean Range Mean visual acuity (logMAR) Baseline (range) 3 months (range) 6 months (range) 12 months (range) Mean macular thickness by OCT (␮m) Baseline (range) 3 months (range) 6 months (range) 12 months (range)

36/31 68.2 67–87 21 (58.3) 10 (27.7)

Figure 1. Graph showing the changes in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity (BCVA) after intravitreal bevacizumab. The BCVA improved from baseline to 12 months from 0.96 (range, 0.3–1.5) to 0.62 (range, 0.0 –1.3) logarithm of the minimum angle of resolution (logMAR) units, respectively, a difference that was statistically significant (P⬍0.0001).

eyes [29.1%], periocular triamcinolone had been applied to 5 eyes [13.8%], and systemic corticosteroids had been prescribed for 3 patients [eyes; 9.6%]) before IVT injection of bevacizumab. Patients with a previous intravitreal corticosteroid injection were included only if they had received the injection at least 6 months before IVT bevacizumab. The mean interval from CME symptoms to IVT injection of bevacizumab was 10.6 months (range, 3– 60 months). Mean baseline BCVA was 20/200 (0.96 logMAR units), mean 3-month BCVA was 20/80 (0.63 logMAR units), mean 6-month BCVA was 20/80 (0.6 logMAR units), and mean 12-month BCVA was 20/80 (0.62 logMAR units). The difference between baseline and 12-month BCVA was statistically significant (P⬍0.0001; Fig 1). The 12-month BCVA analysis by subgroups demonstrated that 10 (27.8%) eyes remained stable and that 26 (72.2%) eyes improved 2 ETDRS lines of BCVA or more. No eye experienced worsening of 2 ETDRS lines of BCVA or more (Tables 1 and 2). Optical coherence tomography results were available for all 36 eyes with refractory pseudophakic CME. The mean baseline central macular thickness was 499.9 ␮m (range, 298 –784 ␮m) and decreased progressively to a mean of 320.1 ␮m (range, 185–702 ␮m) at the 3-month follow-up, to 300.2 ␮m (range, 182– 678 ␮m) at the 6-month follow-up, and to 286.1 ␮m (range, 185–702 ␮m) at the 12-month follow-up. The difference between baseline and

10.6 3–60 0.96 (0.3–1.5) 0.63 (0.0–1.4) 0.60 (0.0–1.4) 0.62 (0.0–1.3)

Table 2. Visual Acuity Outcomes (36 eyes) At 12 months

499.9 (298–784) 320.1 (185–702) 300.2 (182–678) 286.1 (168–499)

CME ⫽ cystoid macular edema; IVT ⫽ intravitreal; logMAR ⫽ logarithm of the minimum angle of resolution; OCT ⫽ optical coherence tomography.

Improved ⱖ2 ETDRS lines of BCVA Remained stable Decreased ⱖ2 ETDRS lines of BCVA

No. of Eyes

%

26 10 0

72.2 27.8 0

BCVA ⫽ best-corrected visual acuity; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study.

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Discussion

Figure 2. Graph showing the changes in macular thickness with optical coherence tomography (OCT) after intravitreal bevacizumab. The foveal thickness improved after 12 months, mean 1-mm central retinal thickness measurements decreased from 499.9 ␮m (range, 298 –784 ␮m) at baseline to 286.1 ␮m (range, 168 – 499 ␮m) at the end of follow-up, a difference that was highly significant (P⬍0.0001).

12-month central macular thickness was highly significant (P⬍0.0001; Table 1; Figs 2 and 3). All eyes received an IVT injection at the initial visit. Twentytwo (61.1%) cases were treated with an IVT injection of bevacizumab at a dose of 1.25 mg, and 14 (38.9%) with a dose of 2.5 mg. Recurrences were retreated with another bevacizumab IVT injection of the same dose as the first injection at the discretion of the treating physician. Four (11%) eyes received 2 injections, 10 (27.8%) eyes received 3 injections, 10 (27.8%) eyes received 4 injections, 1 (2.8%) eye received 5 injections, and 1 (2.8%) eye received 6 injections. The mean interval between injections was 15.1 weeks (range, 4 – 45 weeks). Only 2 (5.5%) eyes received a second injection at week 4 and only 7 (19.4%) eyes received a second injection before month 3. There was no significant difference in the number of eyes that received reinjections after an IVT injection of bevacizumab at a dose of 1.25 mg (15 of 22; 68.1%) or after an IVT injection of bevacizumab at a dose of 2.5 mg (11 of 14; 78.5%). In addition, no statistically significant differences were observed in changes of BCVA and macular thickness with OCT between doses of bevacizumab used. However, there was a correlation between BCVA and macular thickness reduction with OCT after IVT bevacizumab. This study aimed to compare the response to treatment between patients with refractory CME after cataract surgery who received 1 injection with those who received 2 injections or more of IVT bevacizumab to see if there was any difference. When the mean values were compared to analyze statistically the mean retinal thickness and logMAR visual acuity (VA), a statistically significant difference (P ⫽ 0.03 for BCVA and P ⫽ 0.0001 for CMT) was found in favor of those eyes that received 2 injections or more of IVT bevacizumab. There were no episodes of inflammation or severe decrease of vision immediately after an injection. At 12 months, no ocular or systemic adverse events such as thromboembolic events (cerebrovascular accidents, transient ischemic attacks, myocardial infarctions, or peripheral vascular disease) were reported.

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Several theories exist regarding the pathogenesis of CME,1,3– 4,10 and the rationale for its treatment is dictated by the pathogenetic theory accepted by the practitioner. The theories involve changes in the perifoveal retina where the vascular permeability of the retinal capillaries is altered, leading to leakage of plasma into the central retina, which causes it to thicken because of excess interstitial fluid. The excess interstitial fluid is likely to disrupt ion fluxes, and the thickening of the macula results in stretching and distortion of neurons. There is reversible reduction in visual acuity, but over time the perturbed neurons die, which results in permanent visual loss.27 In general, cataract surgery results in varying degrees of acute intraocular inflammation caused by chemical mediators of inflammation (prostaglandins, cytokines, endotoxin, and immune complex) that can cause increased expression of VEGF,10,14 which is a potent inducer of vascular permeability that causes breakdown of the blood–retinal barrier and secondarily increases the permeability of the perifoveal capillary net.10 –11,14,27 The retina initially is resistant to the effects of local inflammatory mediators until after persistent exposure, when increased vascular permeability of the perifoveal retinal capillaries occurs and CME is manifest.6 Thus, it is reasonable to hypothesize that VEGF may contribute to the development of pseudophakic CME. Intravitreal bevacizumab has marked anatomic effects on macular edema resulting from various causes associated with increased IVT levels of VEGF.11,18,27,28 Recently, Mason et al17 reported a significant decrease in macular thickness and improvement in visual acuity in 2 eyes with refractory pseudophakic CME treated with IVT bevacizumab. A retrospective study of consecutive eyes with refractory pseudophakic CME treated with IVT bevacizumab demonstrated both anatomic and functional improvement. Patients showed a marked and progressive decrease in CME and an improvement in visual acuity throughout follow-up. The observations suggest an anatomic improvement and beneficial visual effect of bevacizumab on refractory CME after cataract surgery. Optical coherence tomography demonstrates that the reduction of foveal thickness is present at 12 months of follow-up in most patients. The mechanism for bevacizumab-induced reduction of CME may be associated with a downregulation of many cytokines and VEGF combined with conformational changes in the tight junctions of retinal vascular endothelial cell and decrease of vascular permeability.11 The 2 doses of bevacizumab evaluated in this study were 1.25 mg, which is the dose that has been used most commonly in clinical practice, and 2.5 mg, which also has been used, although less commonly. Doses lower than 1.25 mg create difficulties with dilution and the accuracy of injection of a small volume. The results of the retrospective study demonstrated the efficacy of 1.25 or 2.5 mg IVT bevacizumab as treatment for refractory pseudophakic CME, because 72.2% of eyes showed anatomic and functional improvement. In addition, these results suggest a reduced risk of VA loss in eyes with CME treated with IVT bevacizumab

Arevalo et al 䡠 IVT Bevacizumab for Pseudophakic CME

Figure 3. Sequential optical coherence tomography (OCT) images from a 64-year-old man with a 4-month history of loss of vision to 20/160 in his right eye in whom refractory pseudophakic cystoid macular edema had developed. A, Horizontal OCT scan obtained through the fovea revealing loss of the normal foveal contour, diffuse macular thickening, and areas of low intraretinal reflectivity consistent with intraretinal cysts and fluid accumulation. The retinal map analysis revealed a foveal thickness of 595 ␮m. The patient underwent an intravitreal injection of bevacizumab at a dose of 2.5 mg in this eye. B, Optical coherence tomography scan revealing complete resolution of cystic spaces with restoration of foveal anatomic features at 1 month after bevacizumab injection. The retinal map analysis indicates a central foveal thickness of 260 ␮m. Visual acuity (VA) improved to 20/63. C, Six months after the injection, OCT scan showing marked improvement in foveal thickness (229 ␮m) and contour. The VA was 20/32. D, Optical coherence tomography scan showing a normal-appearing macula at 12 months after injection. Foveal thickness decreased to 202 ␮m, and visual acuity was 20/32.

(100% of eyes). Twenty-six (72.2 %) eyes received reinjections at a mean of 15 weeks. This strongly suggests that VEGF is a stimulus for retinal thickening, which is a conclusion supported by the added improvement in foveal thickness that is achieved with additional injections of bevacizumab. The anatomic and visual benefit of IVT bevacizumab was found to maintain itself over 12 months. Statistically significant differences in duration or anatomic or functional effectiveness were not found between the 2 doses of bevacizumab evaluated. In addition, the difference between the previous primary study25 and the current study (refractory group) does not seem to be significant with regard to BCVA and OCT measurements. Again, the reasons for the poor results of Spitzer et al are unclear.26 The authors hypothesize that their study may have had an important selection bias and that a group of chronic cases was treated. Therefore, irreversible complications of chronic CME (chronic serous macular detachment, retinal pigment epithelium changes, epiretinal membrane formation, and nonreversible macular changes with permanent visual loss)1,29 already may have happened.

The optimum dosing and sequence for IVT bevacizumab injections in refractory pseudophakic CME is not determined. The authors elected to defer reinjections until there was a recurrence. It is possible that a different dosing schedule, such as a series of injections every 12 weeks for an extended period followed by retreatment only for recurrences, may be superior to the method used in this study; however, the authors chose to err on the side of undertreatment until further toxicity data are obtained. Nevertheless, when the response to treatment was compared between patients with refractory CME after cataract surgery who received 1 injection with those who received 2 injections or more of IVT bevacizumab, a statistically significant difference was found regarding anatomic and functional response in favor of those eyes that received 2 injections or more. It is possible that some eyes may need multiple injections to achieve better outcomes. Further studies are needed to confirm these observations. No observable ocular side effects were found with IVT bevacizumab, such as inflammation, infection, increased intraocular pressure, retinal tear, or detachment. These re-

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Ophthalmology Volume 116, Number 8, August 2009 sults indicate that IVT bevacizumab injections may have a beneficial effect on macular thickness and VA. Therefore, in the future, this new therapeutic method may be established as alternative treatment for refractory CME after cataract surgery. Safety concerns were not detected in this study. However, the study was not powered adequately to detect safety outcomes. Further limitations of the study include that it was short-term, nonrandomized, and retrospective, all of which preclude any estimation of the long-term efficacy of IVT bevacizumab. In addition, another limitation is the lack of a control group. Therefore, it can not be excluded that the eyes would have done well on their own. The small sample size also is a limitation. However, the results were very promising and suggest the need for further investigation. In summary, short-term results suggest that IVT bevacizumab is well tolerated in patients with refractory pseudophakic CME. Treated eyes with IVT bevacizumab had a significant improvement in BCVA and showed a decrease in macular thickness by OCT in this series. The favorable results at 12 months suggest the need for further study with longer follow-up and a larger series of patients to evaluate the safety and efficacy of this treatment. Based on these data, an approximate sample size to detect a 0.2-logMAR BCVA difference in a confirmatory randomized clinical trial with a 12-month end point with an ␣ of 5% and a power of 80% would be at least 100 for each group. Refractory pseudophakic CME should be considered to be included on the list of indications for IVT bevacizumab.

References 1. Flach AJ. The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery. Trans Am Ophthalmol Soc 1998;96:557– 634. 2. Levin DS, Lim JI. Update on pseudophakic cystoid macular edema treatment options. Ophthalmol Clin North Am 2002; 15:467–72. 3. Stark WJ Jr, Maumenee AE, Fagadau W, et al. Cystoid macular edema in pseudophakia. Surv Ophthalmol 1984;28(suppl): 442–51. 4. Tranos PG, Wickremasinghe SS, Stangos NT, et al. Macular edema. Surv Ophthalmol 2004;49:470 –90. 5. Conway MD, Canakis C, Livir-Rallatos C, Peyman GA. Intravitreal triamcinolone acetonide for refractory chronic pseudophakic cystoid macular edema. J Cataract Refract Surg 2003;29:27–33. 6. Rho DS. Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac. J Cataract Refract Surg 2003;29:2378 – 84. 7. Steinert RF, Wasson PJ. Neodymium:YAG laser anterior vitreolysis for Irvine-Gass cystoid macular edema. J Cataract Refract Surg 1989;15:304 –7. 8. Ogura Y, Takahashi M, Ueno S, Honda Y. Hyperbaric oxygen treatment for chronic cystoid macular edema after branch retinal vein occlusion. Am J Ophthalmol 1987;104: 301–2. 9. Harbour JW, Smiddy WE, Rubsamen PE, et al. Pars plana vitrectomy for chronic pseudophakic cystoid macular edema. Am J Ophthalmol 1995;120:302–7. 10. Miyake K, Ibaraki N. Prostaglandins and cystoid macular edema. Surv Ophthalmol 2002;47(suppl):S203–18.

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11. Noma H, Minamoto A, Funatsu H, et al. Intravitreal levels of vascular endothelial growth factor and interleukin-6 are correlated with macular edema in branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2006;244:309 –15. 12. Cunha-Vaz JG. The blood-retinal barriers system: basic concepts and clinical evaluation. Exp Eye Res 2004;78:715–21. 13. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581– 611. 14. Kent D, Vinores SA, Campochiaro PA. Macular oedema: the role of soluble mediators. Br J Ophthalmol 2000;84: 542–5. 15. Tolentino MJ, McLeod DS, Taomoto M, et al. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol 2002;133: 373– 85. 16. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3:391– 400. 17. Mason JO III, Albert MA Jr, Vail R. Intravitreal bevacizumab (Avastin) for refractory pseudophakic cystoid macular edema. Retina 2006;26:356 –7. 18. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 2006;26: 279 – 84. 19. Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26:275– 8. 20. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–72. 21. Maturi RK, Bleau LA, Wilson DL. Electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina 2006;26:270 – 4. 22. Shahar J, Avery RL, Heilweil G, et al. Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina 2006;26:262–9. 23. Manzano RP, Peyman GA, Khan P, Kivilcim M. Testing intravitreal toxicity of bevacizumab (Avastin). Retina 2006; 26:257– 61. 24. Bakri SJ, Cameron JD, McCannel CA, et al. Absence of histologic retinal toxicity of intravitreal bevacizumab in a rabbit model. Am J Ophthalmol 2006;142:162– 4. 25. Arevalo JF, Garcia-Amaris RA, Roca JA, et al, Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab for the management of pseudophakic cystoid macular edema: pilot study of the Pan-American Collaborative Retina Study Group. J Cataract Refract Surg 2007;33:2098 – 105. 26. Spitzer MS, Ziemssen F, Yoeruek E, et al. Efficacy of intravitreal bevacizumab in treating postoperative pseudophakic cystoid macular edema. J Cataract Refract Surg 2008;34: 70 –5. 27. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 2006;142:961–9. 28. Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 2006;26:999 –1005. 29. Thach AB, Dugel PU, Flindall RJ, et al. Comparison of retrobulbar versus sub-Tenon’s corticosteroid therapy for cystoid macular edema refractory to topical medications. Ophthalmology 1997;104:2003– 8.

Arevalo et al 䡠 IVT Bevacizumab for Pseudophakic CME

Footnotes and Financial Disclosures Originally received: September 25, 2008. Final revision: February 21, 2009. Accepted: April 1, 2009. Available online: June 21, 2009.

Manuscript no. 2008-1157.

1

Retina and Vitreous Service, Clinica Oftalmológica Centro Caracas, Caracas, Venezuela. 2

Departamento de Oftalmologia, Instituto da Visão, Universidade Federal de São Paulo, São Paulo, Brazil. 3

Clínica Ricardo Palma, Lima, Peru.

4

Department of Ophthalmology, University of Puerto Rico, San Juan, Puerto Rico. 5

Retina and Vitreous Service, Instituto de Cirugia Ocular, San Jose, Costa Rica.

For a complete listing of participating members of PACORES, see Appendix 1 (available at http://aaojournal.org). Presented in part at: American Academy of Ophthalmology Annual Meeting, November 2008, Atlanta, Georgia. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Supported in part by the Arevalo-Coutinho Foundation for Research in Ophthalmology, Caracas, Venezuela. Correspondence: J. Fernando Arevalo, MD, FACS, Clinica Oftalmológica Centro Caracas, Edif. Centro Caracas PH-1, Av. Panteon, San Bernardino, Caracas 1010, Venezuela. E-mail: [email protected].

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Appendix 1. Pan-American Collaborative Retina Study Group The following investigators belong to the Pan-American Collaborative Retina Study Group (PACORES): L. Wu (PI), T. Evans, Instituto de Cirugia Ocular, San Jose, Costa Rica; J. F. Arevalo (PI), J. G. Sanchez, R. A. Garcia-Amaris, D. G. Zeballos, J. V. Espinoza, Clinica Oftalmológica Centro Caracas and the Arevalo-Coutinho Foundation for Research in Ophthalmology, Caracas, Venezuela; M. Farah (PI), M. Maia, F. B. Aggio, Departamento de Oftalmologia, Instituto da Visão Universidade Federal de São Paulo, Sao Paulo, Brazil; H. Quiroz-Mercado (PI), J. Fromow-Guerra, V. Morales-Canton, J. L. Guerrero-Naranjo, Asociación para Evitar la Ceguera en México, Mexico City, Mexico; F. J. Rodriguez (PI), R. Infante,

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S. Flores, D. Medina, Fundacion Oftalmologica Nacional, Universidad del Rosario, Bogota, Colombia; M. H. Berrocal (PI), V. Cruz-Villegas, University of Puerto Rico, San Juan, Puerto Rico; F. Graue-Wiechers (PI), D. Lozano-Rechy, V. Robledo, J. L. Rodriguez-Loaiza, Fundacion Conde Valenciana, Mexico City, Mexico; J. A. Roca (PI), G. Reategui, Clínica Ricardo Palma, Lima, Peru; M. J. Saravia (PI), M. Martinez-Cartier, Hospital Universitario Austral, Buenos Aires, Argentina; M. Avila (PI), Departamento de Oftalmologia, Universidade Federal de Goiás, Goiânia, Brazil; R. A. Costa (PI), J. Cardillo, Hospital de Olhos de Araraquara, and the Universidade de São Paulo, São Paulo, Brazil; J. Verdaguer T. (PI), C. Carpentier, J. I. Verdaguer, D. L. Filsecker, G. Sepúlveda, Fundacion Oftalmologica Los Andes, Santiago de Chile, Chile. PI ⫽ principal investigator.