- Email: [email protected]
Intravitreal Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: The Second Year of a Prospective Study
Intravitreal Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: The Second Year of a Prospective Study ZIAD F. BASHSHUR, ZEINA A. HADDAD, ALEXANDRE R. SCHAKAL, ROLA F. JAAFAR, ALAIN SAAD, AND BAHA’ N. NOUREDDIN ● PURPOSE: To demonstrate the efficacy of intravitreal bevacizumab for treatment of neovascular age-related macular degeneration (AMD). ● DESIGN: Prospective, open-label, nonrandomized clinical study. ● METHODS: Fifty-one patients (51 eyes) with subfoveal choroidal neovascularization (CNV) resulting from AMD participated in this study at the American University of Beirut and Hotel Dieu de France Retina Clinics. These patients had already completed 12 months of follow-up. The criteria for reinjection were presence of fluid in the macula, increased central retinal thickness (CRT) of at least 100 m, loss of at least 5 letters of vision associated with increased fluid in the macula, new classic CNV, or new macular hemorrhage. The main outcome measure was the proportion of eyes losing fewer than 15 letters of vision after 12 months. ● RESULTS: Fifty-one patients (51 eyes) completed the additional 12 months. Mean visual acuity improved from 45.7 letters at baseline to 54.3 letters at 24 months (P ⴝ .001), and 47 eyes (92.2%) lost fewer than 15 letters. Mean CRT decreased from 327.4 m at baseline to 246.6 m at 24 months (P < .001). A mean of 1.5 injections were administered over the course of the second year. No serious ocular or systemic side effects were noted. ● CONCLUSIONS: Eyes with neovascular AMD treated with intravitreal bevacizumab over 2 years had significant anatomic and functional improvement compared with baseline. Further studies are necessary to confirm the long-term efficacy and safety of this treatment. (Am J Ophthalmol 2009;148:59 – 65. © 2009 by Elsevier Inc. All rights reserved.)
See accompanying Editorial on page 1. Accepted for publication Feb 3, 2009. From the Department of Ophthalmology, American University of Beirut (Z.F.B., Z.A.H., R.F.J., B.N.N.); and the Department of Ophthalmology, Hotel Dieu de France, St Joseph University (A.R.S., A.S.), Beirut, Lebanon. Inquiries to Ziad F. Bashshur, American University of Beirut—Medical Center, P. O. Box 11-0236/B11, Beirut, Lebanon; e-mail: zb00@aub. edu.lb 0002-9394/09/$36.00 doi:10.1016/j.ajo.2009.02.006
©
2009 BY
A
NGIOGENESIS HAS A CAUSAL ROLE IN NEOVASCU-
lar age-related macular degeneration (AMD). By targeting vascular endothelial growth factor (VEGF), a key regulator in angiogenesis and a potent permeability factor, anti-VEGF agents have become foundation therapy for neovascular AMD.1 In June 2006, the United States Food and Drug Administration (FDA) approved ranibizumab for the treatment of neovascular AMD. Ranibizumab is a recombinant, humanized, monoclonal antibody fragment that targets all isoforms of VEGF-A.2 In the MARINA and ANCHOR trials, monthly intravitreal injection of ranibizumab in patients with choroidal neovascularization (CNV) resulting from AMD prevented vision loss and improved mean visual acuity (VA) over 2 years with low rates of serious side effects.3,4 The Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular AMD Treated with intraOcular Ranibizumab (PrONTO) Study suggested that less frequent treatment with ranibizumab using a variable-dosing regimen is possible if patients are monitored closely for recurrences with OCT.5 Bevacizumab is a full-length humanized monoclonal antibody against all isoforms of VEGF. It is approved by the FDA for the treatment of colorectal cancer.6 In 2005, Rosenfeld and associates published the first case report of the intravitreal use of bevacizumab for CNV.7 Since then, there have been many short-term retrospective and prospective studies suggesting that systemic and intravitreal use of bevacizumab is safe and effective for the treatment of neovascular AMD.8 –12 Although not approved by the FDA for intraocular use, the low cost and availability of bevacizumab made it appealing for the treatment of neovascular ocular diseases.13,14 In a 12-month prospective study, we showed that eyes with neovascular AMD treated with intravitreal bevacizumab had significant anatomic and functional improvement.15 We extended this study for a second year to explore further the safety and efficacy of intravitreal bevacizumab in the management of neovascular AMD.
METHODS THIS WAS A CONTINUATION OF A PROSPECTIVE, OPEN-
label, nonrandomized clinical study to test the safety and
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increase in CRT by more than 100 m from the lowest recorded value; 3) new area of classic CNV; 4) new hemorrhages; or 5) decrease of 5 letters from highest recorded BCVA associated with increased leakage on FA or OCT. Response to treatment on OCT examination was described as a dry macula if there was total absence of subretinal fluid and cystic maculopathy, or a partial response if there was persistent fluid in the macula. Eyes that showed a partial response received an additional injection 1 month after the previous injection. Eyes that continued to show a partial response after 3 consecutive monthly injections were considered to be partial responders. These eyes then were observed monthly as long as VA was stable and were reinjected according to the previously mentioned retreatment criteria. Based on data from the previous year, partial responders generally maintained a stable VA over time despite a slight amount of persistent subretinal fluid or cystic maculopathy. All intravitreal injections of bevacizumab were carried out in an office-based setting. The hospital pharmacy divided a 100-mg vial of bevacizumab (Avastin; Genentech Inc, South San Francisco, California, USA) into 1-ml tuberculin syringes under a laminar flow hood using aseptic techniques and then stored them at 2 to 8 C. Eyes were prepared with povidone iodine (5%) solution, and 0.1 ml (2.5 mg) bevacizumab was injected intravitreally through the pars plana according to a standard protocol described previously.15 An intent-to-treat strategy was used. If a patient missed a follow-up, then the last observation was carried forward to fill the missing data. The main outcome measure was the proportion of eyes that lost fewer than 15 letters (3 lines) of BCVA at 24 months compared with baseline. Secondary VA endpoints at 24 months included: 1) mean change from baseline in BCVA score, 2) the proportion of patients who gained 15 letters or more in BCVA, and 3) the proportion of patients with a Snellen VA of 20/200 or worse compared with baseline. Other secondary end- points included: 1) the effect of bevacizumab on the greatest linear dimension of CNV as assessed by FA and 2) the effect of bevacizumab on the CRT as assessed by OCT. The Student t test, the Pearson correlation, and Chisquare test were used for statistical analysis. The level of statistical significance was set at P ⬍ .05 with a 95% confidence interval.
efficacy of intravitreal bevacizumab for the treatment of CNV resulting from AMD. Starting in September 2005, 60 patients with neovascular AMD were enrolled at the American University of Beirut Medical Center and Hotel Dieu de France Medical Center. Fifty-one patients completed the first 12 months, and the results already have been reported.15 Inclusion criteria at the initiation of the study were: 1) age 50 years or older; 2) best-corrected visual acuity (BCVA), using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, between 20/40 and 20/400 (Snellen equivalent); 3) subfoveal CNV secondary to AMD diagnosed by fluorescein angiography (FA) with a size no more than 5400 m in greatest linear dimension; and 4) subretinal fluid, cystic maculopathy, or 1-mm central retinal thickness (CRT) of at least 250 m on OCT. All lesion types were included except for retinal angiomatous proliferation because it was thought these lesions may respond differently to anti-VEGF treatment. Patients were excluded if they had: 1) prior treatment for CNV; 2) any scarring or hemorrhage involving the fovea; 3) any ocular media opacities that affect good-quality angiograms or OCT; 4) any other ocular condition affecting vision; and 5) history of a cardiovascular, cerebrovascular, or peripheral vascular event in the 6 months before enrollment. The Institutional Review Board at the American University of Beirut Medical Center approved extension of the study for another 12 months. The 51 patients who completed the first 12 months were invited to take part in the extension. They signed a study consent form in which the procedure and treatment options were explained thoroughly. Patients also were reminded of the off-label use of intravitreal bevacizumab. Patients were seen monthly during the second year. At each visit, BCVA was measured with ETDRS charts at 4 m according to ETDRS refraction protocol. A slit-lamp examination of the anterior segment, dilated fundus examination, and OCT also were performed at every follow-up visit. FA was performed every 2 months. Patients were observed for any systemic thromboembolic events or ocular complications and had their blood pressure measured at every visit. The greatest linear dimension of the CNV was determined using FA and the incorporated measuring software (ImageNet 2000; Topcon, Tokyo, Japan). OCT (Stratus OCT; Carl Zeiss Meditec, Dublin, California, USA) was used to measure 1-mm CRT and to create a macular retinal map from 6 consecutive slow diagonal 6-mm scans that intersected at the fovea. CRT and greatest linear dimension measurements were interpreted and confirmed by 2 of the investigators (Z.F.B. and A.R.S.). As with the first 12 months, a variable-dosing regimen was used during the second year. Intravitreal reinjections of bevacizumab were administered according to the following criteria: 1) recurrence of subretinal fluid or cystic maculopathy on OCT in a previously dry lesion; 2) 60
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RESULTS ALL 51 PATIENTS WHO WERE ENROLLED IN THE STUDY
extension completed the additional 12 months for a total of 24 months of follow-up. However, 1 patient missed months 13 and 14 because of an unrelated illness. The average age of these 51 patients at baseline was 72.2 years. Twenty-two were women and 29 were men. OF
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FIGURE 1. Graph showing the mean gain in visual acuity over 24 months of 51 eyes treated with intravitreal bevacizumab for subfoveal choroidal neovascularization (CNV) in age-related macular degeneration (AMD).
FIGURE 2. Graph showing the mean change in central retinal thickness over 24 months of 51 eyes treated with intravitreal bevacizumab for subfoveal CNV in AMD.
● VISUAL ACUITY, CENTRAL RETINAL THICKNESS, AND LESION SIZE: Mean baseline BCVA was 45.7 letters
(Snellen equivalent, 20/125⫹1). By month 24, mean BCVA was 54.3 letters (Snellen equivalent, 20/80⫺1) with a mean gain of 8.4 letters from baseline (P ⫽ .001). There was no statistically significant difference between mean BCVA at 12 months (53.1 letters) and 24 months (P ⫽ .35). Mean BCVA generally improved markedly by month 1 after the first injection and remained stable through the 24 months of follow-up (Figure 1). Using the Pearson correlation, there was a significant correlation between BCVA at 24 months and baseline BCVA (r ⫽ 0.527; P ⬍ .0001). Compared with baseline, 47 eyes (92.2%) avoided losing 15 letters of BCVA by 24 months. Forty-one eyes (82.4%) avoided losing any letters of BCVA, 22 eyes (43.1%) gained at least 15 letters, and 6 eyes (11.8%) gained at least 30 letters by 24 months. At 24 months, 4 eyes (7.8%) had lost more than 15 letters. One eye (2%) had a Snellen equivalent vision of 20/40 or better at baseline, which VOL. 148, NO. 1
FIGURE 3. Graph showing the mean change in the greatest linear dimension of subfoveal CNV over 24 months of 51 eyes treated with intravitreal bevacizumab for neovascular AMD.
FIGURE 4. Bar graph showing the distribution of the total number of intravitreal bevacizumab injections given during the second year to 51 eyes with subfoveal CNV resulting from AMD.
increased to 14 eyes (27.5%) by 24 months (P ⫽ .0008). However, 20 eyes (39.2%) had a Snellen equivalent vision of 20/200 or worse at baseline, which decreased to 13 eyes (25.5%) at 24 months (P ⫽ .20). Four eyes lost more than 15 letters of vision during the first 12 months. Although they maintained a dry macula, they gradually began to lose vision and to show progressive subfoveal fibrosis or retinal pigment epithelial (RPE) atrophy. During the second year, 1 of these 4 eyes lost an additional 10 letters of BCVA compared with baseline. This was the patient who missed follow-up at month 13 and 14. She sought treatment for a submacular hemorrhage, and then a disciform scar developed despite treatment. Compared with month 12, 14 eyes (27.5%) gained 5 letter or more of BCVA by month 24. Among these 14 eyes, 4 gained 15 letters or more. However, 2 eyes lost more than 15 letters of BCVA during the second year compared with month 12. This was attributed to worsen-
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TABLE. Visual Acuity, Central Retinal Thickness, and Lesion Size of Eyes with Neovascular Age-Related Macular Degeneration of Patients Who Were Either Partial or Complete Responders to Intravitreal Bevacizumab BCVA (No. of Letters)
Partial responders (n ⫽ 14) Complete responders (n ⫽ 37) P valuea
At Baseline
At 24 Months
52.3 46.9 .081
56.7 59.3 .551
CRT (m) Change
⫹4.4 ⫹10.2 .26
At Baseline
At 24 Months
326.8 327.6 .968
243.3 247.8 .5357
GLD (m) Change
⫺94.7 ⫺75.5 .35
At Baseline
At 24 Months
2010.7 2951.1 .004
1920.2 2617.4 .033
Change
⫺103.6 ⫺382.2 .01
BCVA ⫽ best-corrected visual acuity; CRT ⫽ central retinal thickness; GLD ⫽ greatest linear dimension of the lesion. Student t test.
a
ing RPE atrophy. However, these 2 eyes lost only 3 and 5 letters compared with baseline. Mean baseline CRT was 327.4 m. By month 24, mean CRT was 246.6 m and had decreased by 80.8 m compared with baseline (P ⬍ .001). There was no significant difference between mean CRT at 12 months (227.8 m) and 24 months (P ⫽ .19). As with BCVA, CRT improved significantly after the first injection and then stabilized (Figure 2). Using the Pearson correlation, there was no statistically significant correlation between baseline CRT and final VA at 24 months (r ⫽ ⫺0.300; P ⫽ .11). There was also no significant correlation between mean change in CRT during the second year and mean change in BCVA (r ⫽ ⫺0.362; P ⫽ .51). This is illustrated in the 14 eyes that gained 5 letters or more of BCVA during the second year. Mean BCVA improved from 48.3 letters at month 12 to 59.6 letters (⫹11.3 letters) at month 24 (P ⬍ .001), whereas mean CRT was 196.6 m at month 12 and increased to 220.4 m (⫹23.8 m) at month 24 (P ⫽ .38). The mean greatest linear dimension of the CNV at baseline was 2693 m, which decreased to 2387 m at 24 months (P ⬍ .001). There was no statistically significant difference between mean greatest linear dimension at 12 months (2426 m) and 24 months (P ⫽ .11). Unlike BCVA and CRT, greatest linear dimension improved more gradually during the first year and then stabilized (Figure 3). The Pearson correlation showed a significant correlation between baseline greatest linear dimension and BCVA at 24 months (r ⫽ ⫺0.562; P ⬍ .001). Eyes with baseline greatest linear dimension of more than 3500 m had a mean baseline BCVA of 38.5 letters (Snellen equivalent, 20/160⫺1), which became 37.7 letters (Snellen equivalent of 20/160⫺2) at 24 months (P ⫽ .91). Eyes with greatest linear dimension of less than 3500 m had a mean baseline BCVA of 48.0 letters (Snellen equivalent, 20/ 100⫺2), which improved to 59.9 letters (Snellen equivalent, 20/63) at 24 months (P ⬍ .001).
Pearson correlation, there was no correlation between total injections per eye during the second year and baseline CRT (r ⫽ ⫺0.082; P ⫽ .57) or baseline BCVA (r ⫽ 0.199; P ⫽ .16). However, there was a significant correlation between number of injections and baseline greatest linear dimension of the CNV (r ⫽ ⫺0.427; P ⫽ .002). Twenty eyes (39.2%) did not require any injections in the second year and 1 of these 20 eyes received a single treatment during the entire 2 years. The mean baseline greatest linear dimension in these 20 eyes was 3450.1 m, whereas it was 2204.1 m for the remaining 31 eyes (P ⫽ .003). A total of 79 injections were given during the second year (Figure 4). Sixty-six (83.5%) of these 79 injections were given for the reappearance of subretinal fluid or cystic maculopathy in a previously dry lesion or for an increase in CRT of more than 100 m not associated with any change in BCVA. Nine (11.4%) of the 79 injections were for decrease of 5 letters or more of BCVA associated with increased leakage on OCT. Four injections (6.3%) were for the appearance of new hemorrhages (these eyes had associated increase in fluid on OCT but no loss of vision). None of the eyes showed a new CNV on angiography. ● PARTIAL RESPONDERS: Of the 51 eyes, 4 showed a partial response at the initiation of therapy that increased to 7 by the end of the first 12 months. During the next 12 months, an additional 7 eyes began to show a partial response. This occurred at month 14 in 3 patients, at month 16 in 3 patients, and at month 18 in 1 patient. These eyes were reinjected when CRT increased more than 100 m from the lowest recorded value. By 24 months, 4 of these 14 eyes had gained 15 letters or more compared with baseline and 9 avoided losing 15 letters. One patient lost 26 letters compared with baseline; however, she was the patient who missed 2 of her follow-up appointments (month 13 and 14). There was no statistically significant difference between complete responders and partial responders with respect to mean BCVA and CRT at baseline and 24 months. The mean baseline greatest linear dimension of the CNV in partial responders was 2010.7 m and that of complete responders was 2951.1 m (P ⫽ .004). However, mean greatest linear dimension decreased 349.3 m compared with baseline in
● NUMBER OF INJECTIONS: An average of 3.4 injections (range, 1 to 8) was given in the first 12 months, and this decreased to 1.5 injections (range, 0 to 7) during the second year (P ⬍ .001). There was a mean of 165.8 days between injections during the second year. Using the
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complete responders and 49.4 m in partial responders by 12 months (P ⫽ .002). By 24 months, mean greatest linear dimension decreased 382.2 m compared with baseline in complete responders and 103.6 m in partial responders (P ⫽ .01). Partial responders received a mean of 6.8 injections over 24 months vs 4.3 injections for complete responders (P ⫽ .009). The Table shows mean BCVA, CRT, and greatest linear dimension in complete responders and partial responders at baseline and 24 months. ● PHAKIC STATUS:
At baseline, 20 eyes (39.2%) were phakic and 31 eyes (60.8%) were pseudophakic. None of the pseudophakic eyes had a damaged posterior capsule. By 24 months, phakic eyes had a BCVA of 55.5 letters vs 53.8 letters for pseudophakic eyes (P ⫽ .54). CRT was 257.1 m and 218.9 m for pseudophakic and phakic eyes, respectively (P ⫽ .09). Pseudophakic eyes required 5.1 injections over 24 months, whereas phakic eyes needed 4.6 injections (P ⫽ .48). Five patients were noted to have progression of nuclear sclerosis and lost a mean of 6.6 letters of BCVA (range, 3 to 12 letters) from the highest recorded BCVA. No evidence of lens trauma was noted and the status of the macula was stable on OCT and FA. These 5 eyes received a mean of 7.2 injections over 24 months vs 4.7 injections for the remaining 46 eyes. One pseudophakic eye lost 4 letters of BCVA because of posterior capsular opacification. None of these patients had any procedures to correct their condition because the patients did not request it, nor did the condition obstruct adequate view or imaging of the macula.
● SAFETY:
By the end of the 24 months, 1 patient required coronary artery bypass surgery for unstable angina; however, no ocular side effects were reported for any patient. All patients maintained a stable blood pressure as recorded during the follow-up visits. Complete blood count and urine analysis were not carried out routinely after each injection as was done during the first year.
DISCUSSION AN INTERMITTENT DOSING REGIMEN OF INTRAVITREAL
bevacizumab was used to treat 51 eyes with neovascular AMD initially over 12 months15 and then was extended another 12 months for a total of 24 months. This treatment regimen resulted in a rapid gain in VA and decrease in CRT after the first month with stability and minor fluctuations over the remainder of the study. Lesion size, represented by the greatest linear dimension of the CNV, showed a more gradual improvement during the first year and stabilized over the second year. It may be that intravitreal bevacizumab rapidly improves macular anatomy by decreasing leakage from the CNV and by inhibiting further angiogenesis.16 Mature vessels in CNV probably do VOL. 148, NO. 1
not respond to anti-VEGF therapy and may explain why the CNV does not resolve completely.17 Similar to our findings at 12 months,15 good baseline VA and smaller lesions generally resulted in better VA at 24 months. However, the high correlation between decrease in CRT and gain in VA that was noted during the first year15 was not present in the second year. This may imply that gains in BCVA can occur in some eyes several months after CRT has stabilized, whereas decrease in BCVA seems to be the result of RPE atrophy, subretinal fibrosis, or progression of cataract. Optical coherence tomography is indispensable in an intermittent dosing regimen. It was possible to detect most recurrences on OCT before any change in VA or other clinical findings. Although we used 2.5 mg, the 1.25-mg dose may have equal efficacy.18 Fewer treatments were necessary during the second year, and some eyes required no treatments. These eyes tended to have a larger lesion at baseline with more fibrous tissue. However, smaller lesions consisted primarily of active CNV that may have required anti-VEGF therapy for a longer time to stabilize. A concerning finding was the number of partial responders, which seems to increase with time. Partial responders did not have a worse visual outcome than complete responders. Longer follow-up is necessary to determine if VA in partial responders will deteriorate and if the number of partial responders will continue to increase. Perhaps CNV in partial responders were somewhat resistant to anti-VEGF therapy, which is why they did not show the same reduction in lesion size as complete responders. Possible mechanisms for resistance to anti-VEGF therapy include a change to alternative pathways of angiogenesis that do not rely on VEGF-A or a change in the CNV to more mature VEGF-independent vessels.19 –22 There is evidence that the basement membrane of endothelial cells persists after endothelial cell death, which acts as a scaffold for rapid regrowth of vessels during gaps in treatment.21 This may speak against intermittent dosing as the best regimen to control CNV. We were concerned that pseudophakic eyes would require more injections and possibly may have worse control of the CNV. Several studies show that bevacizumab can be detected in the anterior chamber shortly after an intravitreal injection.23,24 We assumed that the absence of the barrier function of the natural crystalline lens would allow more bevacizumab to diffuse into the anterior chamber and therefore may clear out of the vitreous faster than in phakic eyes and lead to more frequent recurrences. There were no significant differences between phakic and pseudophakic eyes at 24 months. A few eyes had progression of their cataract, but the sample size was too small to determine if this was because of more frequent injections or because of natural progression of nuclear sclerosis.
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We did not observe any ocular side effects related to intravitreal bevacizumab injection25,26 over 24 months. One patient did have coronary artery bypass surgery because of unstable angina. It is not possible to determine if this was the result of anti-VEGF therapy. The incidence of complications with this treatment seems low, and a much larger randomized study is necessary to document the incidence of any ocular or systemic side effects. More importantly, this treatment seems to be indefinite, and at this time, we do not know what issues may develop with prolonged intravitreal use of bevacizumab. One of the worst immediate ocular complications may be endophthalmitis, but it seems that performing this procedure in an office setting is safe.
In conclusion, intravitreal bevacizumab for neovascular AMD over 24 months achieved functional stability with anatomic improvement. The treatment seems to be safe and well tolerated. However, it may be needed indefinitely, and some eyes may continue to deteriorate despite anatomic improvement. The issue of tachyphylaxis may become more prominent with repeated injections.27 There also is the question of whether continuous treatment is better than an intermittent treatment regimen.28 Future large, randomized, multicenter studies need to address the ideal dose and dosing regimen and need to compare this treatment with other VEGF inhibitors regarding efficacy and safety.
THIS STUDY WAS SUPPORTED BY THE DEPARTMENT OF OPHTHALMOLOGY, AMERICAN UNIVERSITY OF BEIRUT MEDICAL Center, Beirut, Lebanon. The authors indicate no financial conflict of interest. Involved in design of study (Z.F.B., B.N.N.); conduct of study (Z.F.B., Z.A.H., A.R.S., A.S.); data collection (Z.A.H., R.F.J., A.S.); management, analysis, and interpretation of data (Z.F.B., Z.A.H., R.F.J.); preparation (Z.F.B., Z.A.H.), review (Z.F.B., B.N.N., A.R.S.), and approval of the manuscript (Z.F.B., Z.A.H., A.R.S., R.F.J., A.S., B.N.N.). This study was approved by the Institutional Review Board at the American University of Beirut Medical Center and was in adherence to the tenets of the Declaration of Helsinki. The authors thank Dr Ziad Mahfoud, American University of Beirut Medical Center, Beirut, Lebanon, for his assistance in statistical analysis.
10. Spaide RF, Laud K, Fine H, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to agerelated macular degeneration. Retina 2006;26:383–390. 11. 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. 12. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–372. 13. Rosenfeld PJ. Intravitreal Avastin: the low cost alternative to Lucentis? Am J Ophthalmol 2006;142:141–143. 14. Steinbrook R. The price of sight—ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 2006;355:1409 –1412. 15. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol 2008;145:249 –256. 16. Wang Y, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis 2004;7:335–345. 17. Grunewald M, Avraham I, Dor Y, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006;124:175–189. 18. Arevalo JF, Fromow-Guerra J, Sanchez JG, et al. Primary intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American Collaborative Retina Study Group at 12 months follow-up. Retina 2008;28:1387–1394. 19. Ton NC, Jayson GC. Resistance to anti-VEGF agents. Curr Pharmaceut Des 2004;10:51– 64. 20. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967–974. 21. Abdollahi A, Klatky L, Huber PE. Endostatin: the logic of antiangiogenic therapy. Drug Resist Updat 2005;8:59 –74.
REFERENCES 1. Ng EW, Adamis AP. Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol 2005;40:352–368. 2. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multi-dose study. Ophthalmology 2006;113:633– 642. 3. Rosenfeld PJ, Brown DM, Heier JS, et al, Marina Study Group. Ranibizumab for neovascular age-related macular degeneration. N Eng J Med 2006;355:1419 –1431. 4. Brown DM, Kaiser PK, Michels M, et al, Anchor Study Group. Ranibizumab versus Verteporfin for neovascular age-related macular degeneration. N Eng J Med 2006;355: 1432–1444. 5. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable-dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007;143:566 –583. 6. Mulcahy MF, Benson AB III. Bevacizumab in the treatment of colorectal cancer. Expert Opin Biol Ther 2005;5:997–1005. 7. Rosenfeld PJ, Moshfghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascularization age-related macular degeneration. Ophthalmic Surg Laser Imaging 2005; 36:331–335. 8. Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: 12-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035–1047. 9. Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142:1–9.
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22. Van Kempen LC, Leenders WP. Tumors can adapt to anti-angiogenic therapy depending on the stromal context: lessons from endothelial cell biology. Eur J Cell Biol 2006;85:61– 68. 23. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114:855– 859. 24. Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol 2008;146: 508 –512. 25. Fung AE, Rosenfeld PJ, Reichel E. The international intravitreal bevacizumab safety survey: using the internet
to assess drug safety worldwide. Br J Ophthalmol 2006;90:1344 –1349. 26. Van Wijngaarden P, Coster D, Williams K. Inhibitors of ocular neovascularization promises and potential problems. JAMA 2005;293:1509 –1513. 27. Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008;115:2199 –2205. 28. Arias L, Caminal JM, Casas L, et al. A study comparing two protocols of treatment with intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Br J Ophthalmol 2008;92:1636 –1641.
REPORTING VISUAL ACUITIES The AJO encourages authors to report the visual acuity in the manuscript using the same nomenclature that was used in gathering the data provided they were recorded in one of the methods listed here. This table of equivalent visual acuities is provided to the readers as an aid to interpret visual acuity findings in familiar units. Table of Equivalent Visual Acuity Measurements Snellen Visual Acuities 4 Meters
6 Meters
20 Feet
Decimal Fraction
LogMAR
4/40 4/32 4/25 4/20 4/16 4/12.6 4/10 4/8 4/6.3 4/5 4/4 4/3.2 4/2.5 4/2
6/60 6/48 6/38 6/30 6/24 6/20 6/15 6/12 6/10 6/7.5 6/6 6/5 6/3.75 6/3
20/200 20/160 20/125 20/100 20/80 20/63 20/50 20/40 20/32 20/25 20/20 20/16 20/12.5 20/10
0.10 0.125 0.16 0.20 0.25 0.32 0.40 0.50 0.63 0.80 1.00 1.25 1.60 2.00
⫹1.0 ⫹0.9 ⫹0.8 ⫹0.7 ⫹0.6 ⫹0.5 ⫹0.4 ⫹0.3 ⫹0.2 ⫹0.1 0.0 ⫺0.1 ⫺0.2 ⫺0.3
From Ferris FL III, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol 1982;94:91–96.
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Biosketch Ziad Bashshur, MD, is an Associate Professor of Clinical Ophthalmology at the American University of Beirut (AUB), Beirut, Lebanon. He completed his ophthalmology residency at AUB in 1998 followed by a Vitreoretinal Fellowship in 1999 from the University of Virginia. Dr Bashshur’s major research interests include retinal vascular diseases and neovascular age-related macular degeneration. He has been a guest reviewer for the American Journal of Ophthalmology, the Archives of Ophthalmology, and Acta Ophthalmologica.
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See accompanying Editorial on page 1. Accepted for publication Feb 3, 2009. From the Department of Ophthalmology, American University of Beirut (Z.F.B., Z.A.H., R.F.J., B.N.N.); and the Department of Ophthalmology, Hotel Dieu de France, St Joseph University (A.R.S., A.S.), Beirut, Lebanon. Inquiries to Ziad F. Bashshur, American University of Beirut—Medical Center, P. O. Box 11-0236/B11, Beirut, Lebanon; e-mail: zb00@aub. edu.lb 0002-9394/09/$36.00 doi:10.1016/j.ajo.2009.02.006
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2009 BY
A
NGIOGENESIS HAS A CAUSAL ROLE IN NEOVASCU-
lar age-related macular degeneration (AMD). By targeting vascular endothelial growth factor (VEGF), a key regulator in angiogenesis and a potent permeability factor, anti-VEGF agents have become foundation therapy for neovascular AMD.1 In June 2006, the United States Food and Drug Administration (FDA) approved ranibizumab for the treatment of neovascular AMD. Ranibizumab is a recombinant, humanized, monoclonal antibody fragment that targets all isoforms of VEGF-A.2 In the MARINA and ANCHOR trials, monthly intravitreal injection of ranibizumab in patients with choroidal neovascularization (CNV) resulting from AMD prevented vision loss and improved mean visual acuity (VA) over 2 years with low rates of serious side effects.3,4 The Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular AMD Treated with intraOcular Ranibizumab (PrONTO) Study suggested that less frequent treatment with ranibizumab using a variable-dosing regimen is possible if patients are monitored closely for recurrences with OCT.5 Bevacizumab is a full-length humanized monoclonal antibody against all isoforms of VEGF. It is approved by the FDA for the treatment of colorectal cancer.6 In 2005, Rosenfeld and associates published the first case report of the intravitreal use of bevacizumab for CNV.7 Since then, there have been many short-term retrospective and prospective studies suggesting that systemic and intravitreal use of bevacizumab is safe and effective for the treatment of neovascular AMD.8 –12 Although not approved by the FDA for intraocular use, the low cost and availability of bevacizumab made it appealing for the treatment of neovascular ocular diseases.13,14 In a 12-month prospective study, we showed that eyes with neovascular AMD treated with intravitreal bevacizumab had significant anatomic and functional improvement.15 We extended this study for a second year to explore further the safety and efficacy of intravitreal bevacizumab in the management of neovascular AMD.
METHODS THIS WAS A CONTINUATION OF A PROSPECTIVE, OPEN-
label, nonrandomized clinical study to test the safety and
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increase in CRT by more than 100 m from the lowest recorded value; 3) new area of classic CNV; 4) new hemorrhages; or 5) decrease of 5 letters from highest recorded BCVA associated with increased leakage on FA or OCT. Response to treatment on OCT examination was described as a dry macula if there was total absence of subretinal fluid and cystic maculopathy, or a partial response if there was persistent fluid in the macula. Eyes that showed a partial response received an additional injection 1 month after the previous injection. Eyes that continued to show a partial response after 3 consecutive monthly injections were considered to be partial responders. These eyes then were observed monthly as long as VA was stable and were reinjected according to the previously mentioned retreatment criteria. Based on data from the previous year, partial responders generally maintained a stable VA over time despite a slight amount of persistent subretinal fluid or cystic maculopathy. All intravitreal injections of bevacizumab were carried out in an office-based setting. The hospital pharmacy divided a 100-mg vial of bevacizumab (Avastin; Genentech Inc, South San Francisco, California, USA) into 1-ml tuberculin syringes under a laminar flow hood using aseptic techniques and then stored them at 2 to 8 C. Eyes were prepared with povidone iodine (5%) solution, and 0.1 ml (2.5 mg) bevacizumab was injected intravitreally through the pars plana according to a standard protocol described previously.15 An intent-to-treat strategy was used. If a patient missed a follow-up, then the last observation was carried forward to fill the missing data. The main outcome measure was the proportion of eyes that lost fewer than 15 letters (3 lines) of BCVA at 24 months compared with baseline. Secondary VA endpoints at 24 months included: 1) mean change from baseline in BCVA score, 2) the proportion of patients who gained 15 letters or more in BCVA, and 3) the proportion of patients with a Snellen VA of 20/200 or worse compared with baseline. Other secondary end- points included: 1) the effect of bevacizumab on the greatest linear dimension of CNV as assessed by FA and 2) the effect of bevacizumab on the CRT as assessed by OCT. The Student t test, the Pearson correlation, and Chisquare test were used for statistical analysis. The level of statistical significance was set at P ⬍ .05 with a 95% confidence interval.
efficacy of intravitreal bevacizumab for the treatment of CNV resulting from AMD. Starting in September 2005, 60 patients with neovascular AMD were enrolled at the American University of Beirut Medical Center and Hotel Dieu de France Medical Center. Fifty-one patients completed the first 12 months, and the results already have been reported.15 Inclusion criteria at the initiation of the study were: 1) age 50 years or older; 2) best-corrected visual acuity (BCVA), using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, between 20/40 and 20/400 (Snellen equivalent); 3) subfoveal CNV secondary to AMD diagnosed by fluorescein angiography (FA) with a size no more than 5400 m in greatest linear dimension; and 4) subretinal fluid, cystic maculopathy, or 1-mm central retinal thickness (CRT) of at least 250 m on OCT. All lesion types were included except for retinal angiomatous proliferation because it was thought these lesions may respond differently to anti-VEGF treatment. Patients were excluded if they had: 1) prior treatment for CNV; 2) any scarring or hemorrhage involving the fovea; 3) any ocular media opacities that affect good-quality angiograms or OCT; 4) any other ocular condition affecting vision; and 5) history of a cardiovascular, cerebrovascular, or peripheral vascular event in the 6 months before enrollment. The Institutional Review Board at the American University of Beirut Medical Center approved extension of the study for another 12 months. The 51 patients who completed the first 12 months were invited to take part in the extension. They signed a study consent form in which the procedure and treatment options were explained thoroughly. Patients also were reminded of the off-label use of intravitreal bevacizumab. Patients were seen monthly during the second year. At each visit, BCVA was measured with ETDRS charts at 4 m according to ETDRS refraction protocol. A slit-lamp examination of the anterior segment, dilated fundus examination, and OCT also were performed at every follow-up visit. FA was performed every 2 months. Patients were observed for any systemic thromboembolic events or ocular complications and had their blood pressure measured at every visit. The greatest linear dimension of the CNV was determined using FA and the incorporated measuring software (ImageNet 2000; Topcon, Tokyo, Japan). OCT (Stratus OCT; Carl Zeiss Meditec, Dublin, California, USA) was used to measure 1-mm CRT and to create a macular retinal map from 6 consecutive slow diagonal 6-mm scans that intersected at the fovea. CRT and greatest linear dimension measurements were interpreted and confirmed by 2 of the investigators (Z.F.B. and A.R.S.). As with the first 12 months, a variable-dosing regimen was used during the second year. Intravitreal reinjections of bevacizumab were administered according to the following criteria: 1) recurrence of subretinal fluid or cystic maculopathy on OCT in a previously dry lesion; 2) 60
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RESULTS ALL 51 PATIENTS WHO WERE ENROLLED IN THE STUDY
extension completed the additional 12 months for a total of 24 months of follow-up. However, 1 patient missed months 13 and 14 because of an unrelated illness. The average age of these 51 patients at baseline was 72.2 years. Twenty-two were women and 29 were men. OF
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FIGURE 1. Graph showing the mean gain in visual acuity over 24 months of 51 eyes treated with intravitreal bevacizumab for subfoveal choroidal neovascularization (CNV) in age-related macular degeneration (AMD).
FIGURE 2. Graph showing the mean change in central retinal thickness over 24 months of 51 eyes treated with intravitreal bevacizumab for subfoveal CNV in AMD.
● VISUAL ACUITY, CENTRAL RETINAL THICKNESS, AND LESION SIZE: Mean baseline BCVA was 45.7 letters
(Snellen equivalent, 20/125⫹1). By month 24, mean BCVA was 54.3 letters (Snellen equivalent, 20/80⫺1) with a mean gain of 8.4 letters from baseline (P ⫽ .001). There was no statistically significant difference between mean BCVA at 12 months (53.1 letters) and 24 months (P ⫽ .35). Mean BCVA generally improved markedly by month 1 after the first injection and remained stable through the 24 months of follow-up (Figure 1). Using the Pearson correlation, there was a significant correlation between BCVA at 24 months and baseline BCVA (r ⫽ 0.527; P ⬍ .0001). Compared with baseline, 47 eyes (92.2%) avoided losing 15 letters of BCVA by 24 months. Forty-one eyes (82.4%) avoided losing any letters of BCVA, 22 eyes (43.1%) gained at least 15 letters, and 6 eyes (11.8%) gained at least 30 letters by 24 months. At 24 months, 4 eyes (7.8%) had lost more than 15 letters. One eye (2%) had a Snellen equivalent vision of 20/40 or better at baseline, which VOL. 148, NO. 1
FIGURE 3. Graph showing the mean change in the greatest linear dimension of subfoveal CNV over 24 months of 51 eyes treated with intravitreal bevacizumab for neovascular AMD.
FIGURE 4. Bar graph showing the distribution of the total number of intravitreal bevacizumab injections given during the second year to 51 eyes with subfoveal CNV resulting from AMD.
increased to 14 eyes (27.5%) by 24 months (P ⫽ .0008). However, 20 eyes (39.2%) had a Snellen equivalent vision of 20/200 or worse at baseline, which decreased to 13 eyes (25.5%) at 24 months (P ⫽ .20). Four eyes lost more than 15 letters of vision during the first 12 months. Although they maintained a dry macula, they gradually began to lose vision and to show progressive subfoveal fibrosis or retinal pigment epithelial (RPE) atrophy. During the second year, 1 of these 4 eyes lost an additional 10 letters of BCVA compared with baseline. This was the patient who missed follow-up at month 13 and 14. She sought treatment for a submacular hemorrhage, and then a disciform scar developed despite treatment. Compared with month 12, 14 eyes (27.5%) gained 5 letter or more of BCVA by month 24. Among these 14 eyes, 4 gained 15 letters or more. However, 2 eyes lost more than 15 letters of BCVA during the second year compared with month 12. This was attributed to worsen-
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TABLE. Visual Acuity, Central Retinal Thickness, and Lesion Size of Eyes with Neovascular Age-Related Macular Degeneration of Patients Who Were Either Partial or Complete Responders to Intravitreal Bevacizumab BCVA (No. of Letters)
Partial responders (n ⫽ 14) Complete responders (n ⫽ 37) P valuea
At Baseline
At 24 Months
52.3 46.9 .081
56.7 59.3 .551
CRT (m) Change
⫹4.4 ⫹10.2 .26
At Baseline
At 24 Months
326.8 327.6 .968
243.3 247.8 .5357
GLD (m) Change
⫺94.7 ⫺75.5 .35
At Baseline
At 24 Months
2010.7 2951.1 .004
1920.2 2617.4 .033
Change
⫺103.6 ⫺382.2 .01
BCVA ⫽ best-corrected visual acuity; CRT ⫽ central retinal thickness; GLD ⫽ greatest linear dimension of the lesion. Student t test.
a
ing RPE atrophy. However, these 2 eyes lost only 3 and 5 letters compared with baseline. Mean baseline CRT was 327.4 m. By month 24, mean CRT was 246.6 m and had decreased by 80.8 m compared with baseline (P ⬍ .001). There was no significant difference between mean CRT at 12 months (227.8 m) and 24 months (P ⫽ .19). As with BCVA, CRT improved significantly after the first injection and then stabilized (Figure 2). Using the Pearson correlation, there was no statistically significant correlation between baseline CRT and final VA at 24 months (r ⫽ ⫺0.300; P ⫽ .11). There was also no significant correlation between mean change in CRT during the second year and mean change in BCVA (r ⫽ ⫺0.362; P ⫽ .51). This is illustrated in the 14 eyes that gained 5 letters or more of BCVA during the second year. Mean BCVA improved from 48.3 letters at month 12 to 59.6 letters (⫹11.3 letters) at month 24 (P ⬍ .001), whereas mean CRT was 196.6 m at month 12 and increased to 220.4 m (⫹23.8 m) at month 24 (P ⫽ .38). The mean greatest linear dimension of the CNV at baseline was 2693 m, which decreased to 2387 m at 24 months (P ⬍ .001). There was no statistically significant difference between mean greatest linear dimension at 12 months (2426 m) and 24 months (P ⫽ .11). Unlike BCVA and CRT, greatest linear dimension improved more gradually during the first year and then stabilized (Figure 3). The Pearson correlation showed a significant correlation between baseline greatest linear dimension and BCVA at 24 months (r ⫽ ⫺0.562; P ⬍ .001). Eyes with baseline greatest linear dimension of more than 3500 m had a mean baseline BCVA of 38.5 letters (Snellen equivalent, 20/160⫺1), which became 37.7 letters (Snellen equivalent of 20/160⫺2) at 24 months (P ⫽ .91). Eyes with greatest linear dimension of less than 3500 m had a mean baseline BCVA of 48.0 letters (Snellen equivalent, 20/ 100⫺2), which improved to 59.9 letters (Snellen equivalent, 20/63) at 24 months (P ⬍ .001).
Pearson correlation, there was no correlation between total injections per eye during the second year and baseline CRT (r ⫽ ⫺0.082; P ⫽ .57) or baseline BCVA (r ⫽ 0.199; P ⫽ .16). However, there was a significant correlation between number of injections and baseline greatest linear dimension of the CNV (r ⫽ ⫺0.427; P ⫽ .002). Twenty eyes (39.2%) did not require any injections in the second year and 1 of these 20 eyes received a single treatment during the entire 2 years. The mean baseline greatest linear dimension in these 20 eyes was 3450.1 m, whereas it was 2204.1 m for the remaining 31 eyes (P ⫽ .003). A total of 79 injections were given during the second year (Figure 4). Sixty-six (83.5%) of these 79 injections were given for the reappearance of subretinal fluid or cystic maculopathy in a previously dry lesion or for an increase in CRT of more than 100 m not associated with any change in BCVA. Nine (11.4%) of the 79 injections were for decrease of 5 letters or more of BCVA associated with increased leakage on OCT. Four injections (6.3%) were for the appearance of new hemorrhages (these eyes had associated increase in fluid on OCT but no loss of vision). None of the eyes showed a new CNV on angiography. ● PARTIAL RESPONDERS: Of the 51 eyes, 4 showed a partial response at the initiation of therapy that increased to 7 by the end of the first 12 months. During the next 12 months, an additional 7 eyes began to show a partial response. This occurred at month 14 in 3 patients, at month 16 in 3 patients, and at month 18 in 1 patient. These eyes were reinjected when CRT increased more than 100 m from the lowest recorded value. By 24 months, 4 of these 14 eyes had gained 15 letters or more compared with baseline and 9 avoided losing 15 letters. One patient lost 26 letters compared with baseline; however, she was the patient who missed 2 of her follow-up appointments (month 13 and 14). There was no statistically significant difference between complete responders and partial responders with respect to mean BCVA and CRT at baseline and 24 months. The mean baseline greatest linear dimension of the CNV in partial responders was 2010.7 m and that of complete responders was 2951.1 m (P ⫽ .004). However, mean greatest linear dimension decreased 349.3 m compared with baseline in
● NUMBER OF INJECTIONS: An average of 3.4 injections (range, 1 to 8) was given in the first 12 months, and this decreased to 1.5 injections (range, 0 to 7) during the second year (P ⬍ .001). There was a mean of 165.8 days between injections during the second year. Using the
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complete responders and 49.4 m in partial responders by 12 months (P ⫽ .002). By 24 months, mean greatest linear dimension decreased 382.2 m compared with baseline in complete responders and 103.6 m in partial responders (P ⫽ .01). Partial responders received a mean of 6.8 injections over 24 months vs 4.3 injections for complete responders (P ⫽ .009). The Table shows mean BCVA, CRT, and greatest linear dimension in complete responders and partial responders at baseline and 24 months. ● PHAKIC STATUS:
At baseline, 20 eyes (39.2%) were phakic and 31 eyes (60.8%) were pseudophakic. None of the pseudophakic eyes had a damaged posterior capsule. By 24 months, phakic eyes had a BCVA of 55.5 letters vs 53.8 letters for pseudophakic eyes (P ⫽ .54). CRT was 257.1 m and 218.9 m for pseudophakic and phakic eyes, respectively (P ⫽ .09). Pseudophakic eyes required 5.1 injections over 24 months, whereas phakic eyes needed 4.6 injections (P ⫽ .48). Five patients were noted to have progression of nuclear sclerosis and lost a mean of 6.6 letters of BCVA (range, 3 to 12 letters) from the highest recorded BCVA. No evidence of lens trauma was noted and the status of the macula was stable on OCT and FA. These 5 eyes received a mean of 7.2 injections over 24 months vs 4.7 injections for the remaining 46 eyes. One pseudophakic eye lost 4 letters of BCVA because of posterior capsular opacification. None of these patients had any procedures to correct their condition because the patients did not request it, nor did the condition obstruct adequate view or imaging of the macula.
● SAFETY:
By the end of the 24 months, 1 patient required coronary artery bypass surgery for unstable angina; however, no ocular side effects were reported for any patient. All patients maintained a stable blood pressure as recorded during the follow-up visits. Complete blood count and urine analysis were not carried out routinely after each injection as was done during the first year.
DISCUSSION AN INTERMITTENT DOSING REGIMEN OF INTRAVITREAL
bevacizumab was used to treat 51 eyes with neovascular AMD initially over 12 months15 and then was extended another 12 months for a total of 24 months. This treatment regimen resulted in a rapid gain in VA and decrease in CRT after the first month with stability and minor fluctuations over the remainder of the study. Lesion size, represented by the greatest linear dimension of the CNV, showed a more gradual improvement during the first year and stabilized over the second year. It may be that intravitreal bevacizumab rapidly improves macular anatomy by decreasing leakage from the CNV and by inhibiting further angiogenesis.16 Mature vessels in CNV probably do VOL. 148, NO. 1
not respond to anti-VEGF therapy and may explain why the CNV does not resolve completely.17 Similar to our findings at 12 months,15 good baseline VA and smaller lesions generally resulted in better VA at 24 months. However, the high correlation between decrease in CRT and gain in VA that was noted during the first year15 was not present in the second year. This may imply that gains in BCVA can occur in some eyes several months after CRT has stabilized, whereas decrease in BCVA seems to be the result of RPE atrophy, subretinal fibrosis, or progression of cataract. Optical coherence tomography is indispensable in an intermittent dosing regimen. It was possible to detect most recurrences on OCT before any change in VA or other clinical findings. Although we used 2.5 mg, the 1.25-mg dose may have equal efficacy.18 Fewer treatments were necessary during the second year, and some eyes required no treatments. These eyes tended to have a larger lesion at baseline with more fibrous tissue. However, smaller lesions consisted primarily of active CNV that may have required anti-VEGF therapy for a longer time to stabilize. A concerning finding was the number of partial responders, which seems to increase with time. Partial responders did not have a worse visual outcome than complete responders. Longer follow-up is necessary to determine if VA in partial responders will deteriorate and if the number of partial responders will continue to increase. Perhaps CNV in partial responders were somewhat resistant to anti-VEGF therapy, which is why they did not show the same reduction in lesion size as complete responders. Possible mechanisms for resistance to anti-VEGF therapy include a change to alternative pathways of angiogenesis that do not rely on VEGF-A or a change in the CNV to more mature VEGF-independent vessels.19 –22 There is evidence that the basement membrane of endothelial cells persists after endothelial cell death, which acts as a scaffold for rapid regrowth of vessels during gaps in treatment.21 This may speak against intermittent dosing as the best regimen to control CNV. We were concerned that pseudophakic eyes would require more injections and possibly may have worse control of the CNV. Several studies show that bevacizumab can be detected in the anterior chamber shortly after an intravitreal injection.23,24 We assumed that the absence of the barrier function of the natural crystalline lens would allow more bevacizumab to diffuse into the anterior chamber and therefore may clear out of the vitreous faster than in phakic eyes and lead to more frequent recurrences. There were no significant differences between phakic and pseudophakic eyes at 24 months. A few eyes had progression of their cataract, but the sample size was too small to determine if this was because of more frequent injections or because of natural progression of nuclear sclerosis.
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We did not observe any ocular side effects related to intravitreal bevacizumab injection25,26 over 24 months. One patient did have coronary artery bypass surgery because of unstable angina. It is not possible to determine if this was the result of anti-VEGF therapy. The incidence of complications with this treatment seems low, and a much larger randomized study is necessary to document the incidence of any ocular or systemic side effects. More importantly, this treatment seems to be indefinite, and at this time, we do not know what issues may develop with prolonged intravitreal use of bevacizumab. One of the worst immediate ocular complications may be endophthalmitis, but it seems that performing this procedure in an office setting is safe.
In conclusion, intravitreal bevacizumab for neovascular AMD over 24 months achieved functional stability with anatomic improvement. The treatment seems to be safe and well tolerated. However, it may be needed indefinitely, and some eyes may continue to deteriorate despite anatomic improvement. The issue of tachyphylaxis may become more prominent with repeated injections.27 There also is the question of whether continuous treatment is better than an intermittent treatment regimen.28 Future large, randomized, multicenter studies need to address the ideal dose and dosing regimen and need to compare this treatment with other VEGF inhibitors regarding efficacy and safety.
THIS STUDY WAS SUPPORTED BY THE DEPARTMENT OF OPHTHALMOLOGY, AMERICAN UNIVERSITY OF BEIRUT MEDICAL Center, Beirut, Lebanon. The authors indicate no financial conflict of interest. Involved in design of study (Z.F.B., B.N.N.); conduct of study (Z.F.B., Z.A.H., A.R.S., A.S.); data collection (Z.A.H., R.F.J., A.S.); management, analysis, and interpretation of data (Z.F.B., Z.A.H., R.F.J.); preparation (Z.F.B., Z.A.H.), review (Z.F.B., B.N.N., A.R.S.), and approval of the manuscript (Z.F.B., Z.A.H., A.R.S., R.F.J., A.S., B.N.N.). This study was approved by the Institutional Review Board at the American University of Beirut Medical Center and was in adherence to the tenets of the Declaration of Helsinki. The authors thank Dr Ziad Mahfoud, American University of Beirut Medical Center, Beirut, Lebanon, for his assistance in statistical analysis.
10. Spaide RF, Laud K, Fine H, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to agerelated macular degeneration. Retina 2006;26:383–390. 11. 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. 12. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–372. 13. Rosenfeld PJ. Intravitreal Avastin: the low cost alternative to Lucentis? Am J Ophthalmol 2006;142:141–143. 14. Steinbrook R. The price of sight—ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 2006;355:1409 –1412. 15. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol 2008;145:249 –256. 16. Wang Y, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis 2004;7:335–345. 17. Grunewald M, Avraham I, Dor Y, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006;124:175–189. 18. Arevalo JF, Fromow-Guerra J, Sanchez JG, et al. Primary intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American Collaborative Retina Study Group at 12 months follow-up. Retina 2008;28:1387–1394. 19. Ton NC, Jayson GC. Resistance to anti-VEGF agents. Curr Pharmaceut Des 2004;10:51– 64. 20. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967–974. 21. Abdollahi A, Klatky L, Huber PE. Endostatin: the logic of antiangiogenic therapy. Drug Resist Updat 2005;8:59 –74.
REFERENCES 1. Ng EW, Adamis AP. Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol 2005;40:352–368. 2. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multi-dose study. Ophthalmology 2006;113:633– 642. 3. Rosenfeld PJ, Brown DM, Heier JS, et al, Marina Study Group. Ranibizumab for neovascular age-related macular degeneration. N Eng J Med 2006;355:1419 –1431. 4. Brown DM, Kaiser PK, Michels M, et al, Anchor Study Group. Ranibizumab versus Verteporfin for neovascular age-related macular degeneration. N Eng J Med 2006;355: 1432–1444. 5. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable-dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007;143:566 –583. 6. Mulcahy MF, Benson AB III. Bevacizumab in the treatment of colorectal cancer. Expert Opin Biol Ther 2005;5:997–1005. 7. Rosenfeld PJ, Moshfghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascularization age-related macular degeneration. Ophthalmic Surg Laser Imaging 2005; 36:331–335. 8. Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: 12-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035–1047. 9. Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142:1–9.
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22. Van Kempen LC, Leenders WP. Tumors can adapt to anti-angiogenic therapy depending on the stromal context: lessons from endothelial cell biology. Eur J Cell Biol 2006;85:61– 68. 23. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114:855– 859. 24. Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol 2008;146: 508 –512. 25. Fung AE, Rosenfeld PJ, Reichel E. The international intravitreal bevacizumab safety survey: using the internet
to assess drug safety worldwide. Br J Ophthalmol 2006;90:1344 –1349. 26. Van Wijngaarden P, Coster D, Williams K. Inhibitors of ocular neovascularization promises and potential problems. JAMA 2005;293:1509 –1513. 27. Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008;115:2199 –2205. 28. Arias L, Caminal JM, Casas L, et al. A study comparing two protocols of treatment with intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Br J Ophthalmol 2008;92:1636 –1641.
REPORTING VISUAL ACUITIES The AJO encourages authors to report the visual acuity in the manuscript using the same nomenclature that was used in gathering the data provided they were recorded in one of the methods listed here. This table of equivalent visual acuities is provided to the readers as an aid to interpret visual acuity findings in familiar units. Table of Equivalent Visual Acuity Measurements Snellen Visual Acuities 4 Meters
6 Meters
20 Feet
Decimal Fraction
LogMAR
4/40 4/32 4/25 4/20 4/16 4/12.6 4/10 4/8 4/6.3 4/5 4/4 4/3.2 4/2.5 4/2
6/60 6/48 6/38 6/30 6/24 6/20 6/15 6/12 6/10 6/7.5 6/6 6/5 6/3.75 6/3
20/200 20/160 20/125 20/100 20/80 20/63 20/50 20/40 20/32 20/25 20/20 20/16 20/12.5 20/10
0.10 0.125 0.16 0.20 0.25 0.32 0.40 0.50 0.63 0.80 1.00 1.25 1.60 2.00
⫹1.0 ⫹0.9 ⫹0.8 ⫹0.7 ⫹0.6 ⫹0.5 ⫹0.4 ⫹0.3 ⫹0.2 ⫹0.1 0.0 ⫺0.1 ⫺0.2 ⫺0.3
From Ferris FL III, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol 1982;94:91–96.
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Biosketch Ziad Bashshur, MD, is an Associate Professor of Clinical Ophthalmology at the American University of Beirut (AUB), Beirut, Lebanon. He completed his ophthalmology residency at AUB in 1998 followed by a Vitreoretinal Fellowship in 1999 from the University of Virginia. Dr Bashshur’s major research interests include retinal vascular diseases and neovascular age-related macular degeneration. He has been a guest reviewer for the American Journal of Ophthalmology, the Archives of Ophthalmology, and Acta Ophthalmologica.
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