Intravitreal Bevacizumab (Avastin) for Neovascular Age-related Macular Degeneration: A Short-term Study

5. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383– 390. 6. Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495– 511. 7. Sakaguchi H, Ikuno Y, Gomi F, et al. Intravitreal injection of bevacizumab for choroidal neovascularization associated with pathological myopia. Br J Ophthalmol 2007;91:161–165.

TABLE 1. Intravitreal Bevacizumab (Avastin) for Neovascular Age-related Macular Degeneration: Clinical Characteristics of Patients n ⫽ 102

Female:male Age (years) Eye right:left Previous treatment None PDT Anecortave acetate Triamcinolone PDT and Anecortave acetate PDT and Triamcinolone No. of patients receiving 1 injection 2 injections 3 injections 4 injections 5 injections

Intravitreal Bevacizumab (Avastin) for Neovascular Age-related Macular Degeneration: A Short-term Study Christine Y. Chen, MBBS, Tien Y. Wong, MBBS, PhD, FRANZCO, and Wilson J. Heriot, MBBS, FRANZCO To report the short-term study of intravitreal bevacizumab (Avastin) in the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Interventional, consecutive, prospective case series. METHODS: One hundred and two eyes of 102 patients with neovascular AMD received monthly intravitreal bevacizumab (Avastin) (1.25 mg) until resolution of macular edema, subretinal fluid, and/or pigment epithelial detachment. Outcome measures included visual acuity (VA) and central retinal thickness as defined from optical coherence tomography (OCT). RESULTS: Mean VA was 20/80 and OCT central retinal thickness was 251.0 ⴞ 74.6 ␮m before injection and improved to 20/63 and 214.9 ⴞ 41.7 ␮m at six weeks (P < .001), 20/50 and 204.8 ⴞ 33.6 ␮m at 10 weeks (P < .001), and remained stable at 20/50 and 210 ␮m after 14 weeks (P < .05). No significant ocular or systemic side effects were observed. CONCLUSIONS: Intravitreal bevacizumab (Avastin) appears to be beneficial and well tolerated in the treatment of neovascular AMD in the short term. Further comparative evaluation against other antivascular endothelial growth factor (VEGF) agents and dosing schedule is warranted. (Am J Ophthalmol 2007;143:510 –512. © 2007 by Elsevier Inc. All rights reserved.) PURPOSE:

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PDT ⫽ photodynamic therapy.

V

ASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)

plays an integral part in the formation of abnormal blood vessels including the development of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Inhibition of VEGF is a possible treatment for CNV. Bevacizumab (Avastin, Genentech, Inc, South San Francisco, California, USA) is a humanized monoclonal antibody to VEGF, designed and approved for intravenous administration for the treatment of metastatic colorectal cancer. Clinical trials of ranibizumab (Lucentis, Genentech, Inc), an antibody binding site fragment that is derived from the same murine anti-VEGF antibody as bevacizumab, have shown promising results in the treatment of CNV secondary to AMD.1 Recently, several small clinical series using intravitreal bevacizumab for the treatment of CNV secondary to AMD have been reported.2–5 These studies show promising results, with reports of considerable improvement in visual acuity (VA), reduction in retinal thickening as detected from optical coherence tomography (OCT), and no marked short-term toxicity. This report documents the short-term outcome of intravitreal bevacizumab treatment in an interventional, consecutive, prospective case series of 102 eyes from 102 patients. All patients had CNV secondary to AMD and were treated by the senior author (W.J.H.). Neither pegaptanib nor ranibizumab were available as alternative therapies in Australia outside study centers. Photodynamic therapy (PDT) was only reimbursed for predominantly classic CNV. The off-label use of bevacizumab was offered

Accepted for publication Oct 2, 2006. From the Center for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia (C.Y.C., T.Y.W.); the Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia (C.Y.C., T.Y.W.); and the Eye Surgery Associates, Cabrini Medical Centre, Malvern, Victoria, Australia (W.J.H.). Inquiries to Wilson J. Heriot, MBBS, FRANZCO, Eye Surgery Associates, Cabrini Medical Centre, Malvern, Victoria 3144, Australia; e-mail: [email protected]

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TABLE 2. Intravitreal Bevacizumab (Avastin) for Neovascular Age-related Macular Degeneration: Snellen Visual Acuity and Optical Coherence Tomography Retinal Thickness Changes Before and After Injection

Time Point

No. of Eyes

Mean VA

P value†

Mean Central Foveal Thickness (␮m)*

P value†

Preinjection 6 weeks 10 weeks 14 weeks 18 weeks 22 weeks 26 weeks

102 102 102 97 67 52 29

0.26 ⫾ 0.02 (20/80) 0.36 ⫾ 0.03 (20/63) 0.38 ⫾ 0.03 (20/50) 0.38 ⫾ 0.03 (20/50) 0.38 ⫾ 0.03 (20/50) 0.37 ⫾ 0.03 (20/50) 0.32 ⫾ 0.03

⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 .21

250.99 ⫾ 74.61 214.92 ⫾ 41.66 204.79 ⫾ 33.60 209.96 ⫾ 37.62 214.92 ⫾ 38.49 210.72 ⫾ 34.22 206.19 ⫾ 33.03

⬍.001 ⬍.001 ⬍.001 ⬍.001 .03 .03

OCT ⫽ optical coherence tomography; VA ⫽ visual acuity. *Central 1 mm retinal thickness on optical coherence tomography (OCT) (Stratus III OCT, Carl Zeiss, Dublin, California, USA). † Paired t test comparing VA and mean central retinal thickness with preinjection VA and mean central retinal thickness.

to patients ineligible for reimbursement for PDT or who had failed therapy. The potential risks and benefits were discussed extensively and a signed informed consent was obtained from every patient. The prospective enrollment of participants was approved by the Ethics Committee of the Cabrini Hospital, Victoria, Australia. The eyes were prepared in a standard fashion: sterile speculum, topical amethocaine, povidone/iodine 10% irrigation, subconjunctival lidocaine infiltrate inferotemporally, and pars plana intravitreal injection of bevacizumab (1.25 mg in 0.05 ml).2 After the injection, intraocular pressure and retinal artery perfusion were checked, and patients were prescribed topical antibiotics for five days. At six weeks, and then every four weeks post injection, the patients were reviewed by the senior author (W.J.H.) and received reinjections until macular edema, subretinal fluids, and/or pigment epithelial detachment (PED) resolved. LogMAR VA was converted to Snellen decimal equivalent for reporting. Central retinal thickness was assessed by OCT (Stratus III OCT, Carl Zeiss, Dublin, California, USA). We used the paired Student t test to compare mean Snellen VA and OCT retinal thickness before and after injections. Clinical characteristics of the 102 eyes examined were shown in Table 1. Of the 102 patients, 102, 102, 97, 67, 52, and 29 patients completed 6, 10, 14, 18, 22, and 26 weeks follow-up visits, respectively. The rate of injection was 0.5 per patient-months of follow-up (Table 1). Most patients attained stability or improvement of their VA (Table 2). Of those few patients with a visual decline, the change was felt to be attributable to disease progression rather than drug toxicity. Mean VA improved from 20/80 to 20/63 (P ⬍ .001) at six weeks, 20/50 (P ⬍ .001) at 10 weeks, and remained stable at 20/50 (P ⬍ .001) at 14, 18, and 22 weeks. Furthermore, mean retinal thickness improved from 251.0 ⫾ 74.6 ␮m to 214.9 ⫾ 41.7 ␮m (P ⬍ .001) at six weeks, 204.8 ⫾ 33.6 ␮m at 10 weeks (P ⬍ VOL. 143, NO. 3

.001), and stabilized at 210 ␮m (P ⬍ .05) after 14 weeks (Table 2). Although PEDs were noted to decrease in elevation in most patients, quantitative evaluation of this change could not be obtained with the current OCT software. The injection was well tolerated in all patients and no uveitis, glaucoma, or endophthalmitis, or systemic cardiovascular events were observed. In summary, we demonstrate that intravitreal bevacizumab injection on an “as required” protocol is associated with a short-term improvement in VA and a decreased central retinal thickness by OCT in patients with CNV secondary to AMD, with minimal ocular or systemic complications. The “as required” protocol appears to achieve a similar clinical effect to the four weekly protocol used in the ANCHOR and MARINA trials of ranibizumab.1 Large randomized control clinical trails comparing the efficacy and safety profiles of bevacizumab and other anti-VEGF therapies and treatment protocols are needed, particularly given the considerable differential cost to the public. THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FInancial conflict of interest. Involved in design and study (W.J.H.); Involved in collection, management, analysis and interpretation of data, and preparation of the data (C.Y.C., W.J.H.); Involved in collection of data (W.J.H.); and involved in management, statistical analysis and interpretation of the data, and preparation of the manuscript (C.Y.C., T.Y.W., W.J.H). REFERENCES

1. Preliminary results from a phase III study showed patients with wet AMD treated with Lucentis quarterly experienced a 16 letter benefit over the control group at one year. June 02, 2006. Available at www.gene.com/gene/news/press-releases/ display.do?method⫽detail&id⫽9749&categoryid⫽4. Accessed Date: June 23, 2006. 2. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of

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bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331– 335. 3. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–372. 4. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to agerelated macular degeneration. Retina 2006;26:383–390. 5. Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495–511.

Inc, New York, New York, USA] was approved for the treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) in December 2004. It is administered as vitreous injection at six-week intervals.1 Complications reported included intraocular inflammation and exogenous bacterial endophthalmitis. Systemic allergic responses have been rare.2 ● CASE 1:

A 82-year-old man with macular edema following complicated cataract extraction was given vitreous injection of 4 mg triamcinolone acetonide. This was preceded by topical proparicaine drops, povidone iodine lid scrub and fornix drops, and subconjunctival lidocaine. Following triamcinolone, he used topical levofloxacin drops. Eight weeks later, he developed occult CNV. Pegaptanib sodium 0.3 mg was administered using the same perioperative regimen. Thirty-five minutes following injection, oral angioedema and generalized urticaria developed. Epinephrine IM (0.3 ml of 1:1000), methylprednisolone 125 mg IV, and diphenhydramine 50 mg oral were administered. Worsening tongue edema, stridor, and hypertension developed. Nasal intubation was performed, and he was admitted to the medical intensive care unit where he was given ongoing systemic methylprednisolone, diphenhydramine, cimetidine, and hydroxyzine. The oropharyngeal angioedema persisted for more than 24 hours. Following two additional injections of epinephrine, the oropharyngeal edema markedly improved, allowing extubation at 36 hours. Following a sixweek refractory period, immediate hypersensitivity skin testing was performed by the epicutaneous and intradermal routes, with dilutions of 1:1000, 1:100, and 1:10, for pegaptanib, levofloxacin, fluorescein, and lidocaine with and without preservative. All skin test results were nonreactive except for the intradermal histamine control. Serum IgE antibody testing to latex by Immunocap radioallergosorbent test (RAST) assay was 0.23 kU/l, which is negative. Six weeks later, the patient received an injection of bevacizumab. Identical pre- and postinjection medications were given. He had no adverse reaction.

Vitreous Injections of Pegaptanib Sodium Triggering Allergic Reactions Andrew C. G. Steffensmeier, MD, Antoine E. Azar, MD, Jeffrey J. Fuller, MD, Barbara A. Muller, MD, and Stephen R. Russell, MD To report two cases of systemic allergic response associated with vitreous administration of pegaptanib sodium. DESIGN: Observational case report. METHODS: Two patients were treated for systemic allergic reactions associated with the administration of pegaptanib sodium. RESULTS: One patient developed a delayed and prolonged anaphylactoid reaction following administration of his first dose of intraocular pegaptanib sodium. The second patient received four injections of pegaptanib over the course of six months. He developed mild lip swelling and prolonged urticarial rash following the first injection, which subsided when pegaptanib was suspended. CONCLUSIONS: Severe hypersensitivity reactions may occur in association with vitreous administration of pegaptanib sodium and may be associated with prolonged urticaria and angioedema. Elderly individuals with comorbidities are at higher risk for fatality from severe hypersensitivity reactions in the ambulatory setting. Physicians administering pegaptanib sodium should review emergency response and airway procedures. (Am J Ophthalmol 2007;143:512–513. © 2007 by Elsevier Inc. All rights reserved.) PURPOSE:

● CASE 2:

A 87-year-old man developed generalized urticaria approximately 12 hours after initial administration of pegaptanib sodium for occult CNV. Prolonged urticaria (lasting days) was observed by the patient with associated transient (hours) lip angioedema. The symptoms occurred following each of four injections. The patient reported these symptoms after the fourth administration. The rash was observed six weeks following the fourth injection (Figure). No other changes in his medical regimen or environmental factors occurred during this time to explain the symptoms. Bevacizumab was substituted for the subsequent injection. Symptoms resolved within one week without additional treatment.

Accepted for publication Oct 4, 2006. From the Center for Macular Degeneration and Department of Ophthalmology and Visual Sciences (A.C.G.S., J.J.F., S.R.R.); and Division of Allergy and Immunology, Department of Internal Medicine (A.E.A., B.A.M.), The University of Iowa Carver College of Medicine, Iowa City, Iowa. Inquiries to Stephen R. Russell, MD, Department of Ophthalmology and Visual Sciences, The University of Iowa Carver School of Medicine, 200 Hawkins Drive, Iowa City, IA 52242; e-mail: stephen-russell@uiowa. edu

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