Ranibizumab versus Verteporfin for Neovascular Age-Related Macular Degeneration
David M. Brown, M.D., Peter K. Kaiser, M.D., Mark Michels, M.D., Gisele Soubrane, M.D., Jeffrey S. Heier, M.D., Robert Y. Kim, M.D., Judy P. Sy, Ph.D., Susan Schneider, M.D., for the ANCHOR Study Group
Background We compared ranibizumab — a recombinant, humanized,monoclonal antibody Fab that neutralizes all active forms ofvascular endothelial growth factor A — with photodynamictherapy with verteporfin in the treatment of predominantly classicneovascular age-related macular degeneration.
Methods During the first year of this 2-year, multicenter, double-blindstudy, we randomly assigned patients in a 1:1:1 ratio to receivemonthly intravitreal injections of ranibizumab (0.3 mg or 0.5mg) plus sham verteporfin therapy or monthly sham injectionsplus active verteporfin therapy. The primary end point was theproportion of patients losing fewer than 15 letters from baselinevisual acuity at 12 months.
Results Of the 423 patients enrolled, 94.3% of those given 0.3mg of ranibizumab and 96.4% of those given 0.5 mg lost fewerthan 15 letters, as compared with 64.3% of those in the verteporfingroup (P<0.001 for each comparison). Visual acuity improvedby 15 letters or more in 35.7% of the 0.3-mg group and 40.3%of the 0.5-mg group, as compared with 5.6% of the verteporfingroup (P<0.001 for each comparison). Mean visual acuity increasedby 8.5 letters in the 0.3-mg group and 11.3 letters in the 0.5-mggroup, as compared with a decrease of 9.5 letters in the verteporfingroup (P<0.001 for each comparison). Among 140 patients treatedwith 0.5 mg of ranibizumab, presumed endophthalmitis occurredin 2 patients (1.4%) and serious uveitis in 1 (0.7%).
Conclusions Ranibizumab was superior to verteporfin as intravitrealtreatment of predominantly classic neovascular age-related maculardegeneration, with low rates of serious ocular adverse events.Treatment improved visual acuity on average at 1 year. (ClinicalTrials.govnumber, NCT00061594
[ClinicalTrials.gov]
.)
Age-related macular degeneration is a leading cause of severeand irreversible vision loss in the developed world among people50 years of age or older.1,2,3,4 The neovascular form of thedisease is characterized by the growth of abnormal, choroidalblood vessels beneath the macula, which causes severe loss ofvision.5 Two main patterns of choroidal neovascularization thatare associated with age-related macular degeneration, as seenon fluorescein angiography, are classic (in which intenselybright fluorescence is seen in early phases of the angiogramand leaks in late phases) and occult (in which leakage is lessintense and appears in the late phases of disease).6 Choroidalneovascular lesions that are predominantly (50% or more) classicin composition cause more severe and more rapid loss of visionthan do lesions that are minimally (less than 50%) classic oroccult.7,8
Photodynamic therapy with verteporfin9,10,11,12 and intravitrealadministration of pegaptanib sodium are approved by the Foodand Drug Administration (FDA) and the European Agency for theEvaluation of Medicinal Products for the treatment of neovascularage-related macular degeneration.13 Neither treatment has resultedin clinically significant improvements in visual acuity.
Ranibizumab — a recombinant, humanized monoclonal antibodyFab that neutralizes all active forms of vascular endothelialgrowth factor A (VEGF-A) — was recently approved by theFood and Drug Administration for the treatment of this condition.Elsewhere in this issue of the Journal, Rosenfeld et al. reporton a phase 3 study, called the Minimally Classic/Occult Trialof the Anti-VEGF Antibody Ranibizumab in the Treatment of NeovascularAge-Related Macular Degeneration (MARINA),14 which demonstratedthat monthly intravitreal injections of ranibizumab preventedthe loss of visual acuity in approximately 95% of patients andimproved visual acuity in one quarter to one third of treatedpatients during 24 months of treatment. In a similar manner,the addition of ranibizumab to verteporfin photodynamic therapyin patients with predominantly classic choroidal neovascularizationwas associated with a reduction in the loss of visual acuity,as compared with verteporfin therapy alone, and with an improvementin visual acuity over baseline in many patients.15 We reportthe first-year results of a 2-year, phase 3 study, which comparedthe efficacy and safety of repeated intravitreal injectionsof ranibizumab with that of photodynamic therapy with verteporfinin patients with predominantly classic lesions associated withneovascular age-related macular degeneration.
Methods
Study Design
The Anti-VEGF Antibody for the Treatment of Predominantly ClassicChoroidal Neovascularization in Age-Related Macular Degeneration(ANCHOR) trial was an international, multicenter, randomized,double-blind, active-treatment–controlled study. Beforethe initiation of the study, we obtained approval from institutionalreview boards or ethics committees at all clinical centers.Patients provided written informed consent for study participation.Screening lasted as long as 28 days.
For inclusion in the study, patients had to be at least 50 yearsof age; have a lesion whose total size was no more than 5400µm in greatest linear dimension in the study eye; havebest-corrected visual acuity of 20/40 to 20/320 (Snellen equivalent),assessed with the use of Early Treatment Diabetic RetinopathyStudy (ETDRS) charts; have no permanent structural damage tothe central fovea; and have had no previous treatment (includingverteporfin therapy) that might compromise an assessment ofthe study treatment. No patients were excluded because of preexistingcardiovascular, cerebrovascular, or peripheral vascular conditions.
Study Treatment
We randomly assigned eligible patients in a 1:1:1 ratio to receiveeither 0.3 or 0.5 mg of ranibizumab (Lucentis, Genentech) plussham verteporfin therapy or sham intravitreal injections plusactive verteporfin therapy. Randomization was stratified accordingto study center and to visual-acuity scores on day 0 (<45letters vs. 45 letters, with a score of 45 letters as the approximateSnellen equivalent of 20/125 vision). In the group that receivedphotodynamic therapy with verteporfin, intravenous administrationof verteporfin (Visudyne, Novartis Pharmaceuticals) was followedby laser irradiation of the macula, according to instructionsprovided in the product package insert (www.visudyne.com). Inthe ranibizumab groups, sham verteporfin therapy was achievedby an intravenous infusion of saline rather than verteporfin,followed by laser irradiation of the macula identical to thatin the active verteporfin-therapy group.
Ranibizumab was injected into the study eye at a monthly interval(ranging from 23 to 37 days, for a total of 12 injections, excludingthe injection at month 12) in the first year, beginning on day0; sham injections were administered on the same schedule. Eitherverteporfin or sham verteporfin was administered on day 0 andthen if needed on the basis of investigators' evaluation ofangiography at months 3, 6, 9, or 12.
The study was designed and analyzed by a committee composedof Dr. Brown, representing the academic investigators, and representativesof Genentech. In analyzing the data and writing this manuscript,Dr. Brown had full and unrestricted access to the data, andall coauthors contributed to the interpretation of the dataand the writing of the manuscript. The authors vouch for theaccuracy and completeness of the reported data.
Statistical Analysis
We performed efficacy analyses on an intention-to-treat basiswith the use of a last-observation-carried-forward method formissing data. Pairwise treatment comparisons were performedwith the use of statistical methods adjusting for baseline scoresof visual acuity (<45 letters vs. 45 letters) and, for lesionmorphologic end points, the baseline value of the lesion characteristic.Binary end points were analyzed with the use of the Cochranchi-square test.16 Mean changes from baseline were analyzedwith the use of analysis of variance for end points with respectto visual acuity and an analysis of covariance for morphologicend points. The Hochberg–Bonferroni multiple-comparisonprocedure17 was used to adjust for the two pairwise treatmentcomparisons of the primary end point. Safety analyses includedall treated patients.
The number of patients required for statistical significancewas determined on the basis of a 1:1:1 randomization ratio,the Pearson chi-square test for the two pairwise comparisonsof the primary end point, and the Hochberg–Bonferronimultiple-comparison procedure at an overall type I error of0.0497. We estimated that the enrollment of 426 patients wouldprovide the study with a statistical power of 96% to detecta significant difference between one or both ranibizumab groupsand the verteporfin group in the percentage of patients losingfewer than 15 letters at 12 months, assuming a rate of 84% ineach ranibizumab group and 67% in the sham verteporfin group.(See the Supplementary Appendix, available with the full textof this article at www.nejm.org, for additional informationon the study design and analysis.)
Results
Study Patients
Between June 2003 and September 2004, 423 patients were enrolledand randomly assigned to a study treatment (143 to the verteporfingroup and 140 to each of the ranibizumab groups). The dispositionof the patients is summarized in Table 1 of the Supplementary Appendix.Three patients in the group receiving 0.3 mg of ranibizumabdid not receive any treatment: one because of the patient'sdecision and two because of an investigator's decision. Morethan 90% of patients in each group (91.5% overall) were receivingtreatment at 12 months. Of a possible 12 injections of ranibizumabor sham injections, the mean number administered was 11.1 inthe verteporfin group, 11.0 in the 0.3-mg group, and 11.2 inthe 0.5-mg group. Including the required administration on day0 and excluding month 12, active verteporfin therapy was administereda mean of 2.8 times in the verteporfin group, and sham verteporfinwas administered a mean of 1.7 times in each of the ranibizumabgroups.
Randomized treatment groups were balanced for demographic andbaseline ocular and morphologic characteristics (Table 1). Theindependent reading center subtyped the choroidal neovascularizationas predominantly classic in all patients during the expeditedscreening evaluation. Subsequent reevaluation confirmed theinitial classification in 96.9% of patients, and 3.1% were reclassified.In each group, the mean total lesion area was slightly lessthan 2 optic-disk areas (1 optic-disk area equals 2.54 mm2 onthe basis of 1 optic-disk diameter of 1.8 mm).
Table 1. Baseline Characteristics of the Patients.
Primary and Secondary End Points
All end points with respect to visual acuity in the study eyeat 12 months favored ranibizumab treatment over verteporfintherapy. With respect to the primary efficacy end point, 94.3%of patients in the 0.3-mg group and 96.4% in the 0.5-mg grouplost fewer than 15 letters from baseline visual acuity, as comparedwith 64.3% in the verteporfin group (P<0.001 for each comparison)(Figure 1A). In addition, the proportion of patients whose visualacuity improved from baseline by 15 or more letters was significantlygreater among those receiving ranibizumab treatment (35.7% inthe 0.3-mg group and 40.3% in the 0.5-mg group, as comparedwith 5.6% in the verteporfin group; P<0.001 for each comparison)(Figure 1B). Significantly greater proportions of ranibizumab-treatedpatients than patients in the verteporfin group had visual acuityof 20/40 or better (P<0.001 for the comparison of each ranibizumabgroup with the verteporfin group) (Figure 1C), and smaller proportionshad visual acuity of 20/200 or worse (P<0.001 for each comparison)(Figure 1D). A severe loss of visual acuity (defined as a decreaseof 30 letters or more) did not occur in any patient in the ranibizumabgroups but occurred in 13.3% of patients in the verteporfingroup (P<0.001 for each comparison) (Figure 1E). Althoughno patient had baseline visual acuity of 20/20 or better, at12 months 7.1% of the patients in the 0.3-mg group and 6.4%in the 0.5-mg group had visual acuity of 20/20 or better, ascompared with 0.7% of patients in the verteporfin group.
Figure 1. Visual Acuity Scores and Snellen Equivalents at 12 Months.
Panel A shows the percentage of patients who lost fewer than 15 letters (moderate loss) from baseline visual acuity at 12 months (the primary efficacy end point). Panel B shows the percentage of patients who gained 15 or more letters (moderate gain) from baseline at 12 months. Panels C and D show the percentage of patients with vision of the Snellen equivalent of 20/40 or better and of those with vision of 20/200 or worse, respectively, at both baseline and 12 months. (For the group that received 0.5 mg of ranibizumab, 139 patients were observed at baseline and 140 patients were observed at 12 months in Panels C and D.) Panel E shows the percentage of patients who lost 30 or more letters (severe loss) from baseline at 12 months. Treatment comparisons were based on the Cochran chi-square test stratified according to the visual-acuity score on day 0 (<45 letters vs. 45 letters). Confidence intervals, denoted by I bars, were based on the normal approximation and the simple (unstratified) estimates of the percentages and their standard errors. The last-observation-carried-forward method was used to impute missing data. All statistical tests were two-sided. P<0.001 for all comparisons of each dose of ranibizumab with verteporfin.
The tracking of mean changes in visual-acuity scores over timeshowed that the values in each of the ranibizumab groups weresignificantly superior to those in the verteporfin group ateach month during the first year (P<0.001) (Figure 2). Onaverage, visual acuity of ranibizumab-treated patients increasedby 5.9 letters in the 0.3-mg group and 8.4 letters in the 0.5-mggroup at 1 month after the first treatment and increased furtherover time to a gain of 8.5 letters in the 0.3-mg group and 11.3letters in the 0.5-mg group by 12 months. In contrast, the verteporfingroup had an average loss in visual acuity at each month afterthe first month, with a mean loss of 9.5 letters by 12 months.Results for all end points with respect to visual acuity at12 months were similar when the analyses used the observed datawith no imputation of missing values (data not shown).
Figure 2. Mean (±SE) Changes in the Number of Letters Read as a Measure of Visual Acuity from Baseline through 12 Months.
P<0.001 for all monthly comparisons of each dose of ranibizumab with verteporfin. Pairwise analysis of variance adjusting for the visual-acuity score on day 0 (<45 letters vs. 45 letters) was used to analyze the mean change in visual acuity from baseline at each monthly assessment. The last-observation-carried-forward method was used to impute missing data. All statistical tests were two-sided.
Results for prespecified secondary end points related to themorphologic characteristics of lesions are summarized in Table 2.At 12 months, the area occupied by classic choroidal neovascularizationdecreased by a mean of 0.52 optic-disk area in the 0.3-mg groupand 0.67 optic-disk area in the 0.5-mg group, as compared witha mean increase of 0.54 optic-disk area in the verteporfin group(P<0.001 for each comparison). The area of leakage from choroidalneovascularization plus intense, progressive staining of theretinal pigment epithelium at 12 months decreased by a meanof 1.80 optic-disk areas in the 0.3-mg group and 2.05 optic-diskareas in the 0.5-mg group, as compared with a mean increaseof 0.32 optic-disk area in the verteporfin group (P<0.001for each comparison). Figure 3 shows a representative patientwith a reduction in the area of choroidal neovascularizationand leakage from baseline to 12 months.
Figure 3. Fundus Fluorescein Angiography in a 79-Year-Old Patient.
The patient presented with a best-corrected visual acuity of 20/100 and was randomly assigned to the group receiving 0.3 mg of ranibizumab. The early-phase angiogram shows a predominantly classic lesion (Panel A); intense leakage is visible in the late phase (Panel B). At 12 months, the patient's visual acuity had improved by 3 lines to 20/50. Repeated angiography shows involution of the classic choroidal neovascularization (Panel C) with a reduction in leakage in the late phase (Panel D).
The area occupied by choroidal neovascularization (classic andoccult, if present) increased by a mean of 1.63 optic-disk areasin the verteporfin group, as compared with small mean increasesof 0.20 optic-disk area in the 0.3-mg group and 0.22 optic-diskarea in the 0.5-mg group (P<0.001 for each comparison). Themean lesion area increased in the verteporfin group to 2.56optic-disk areas, as compared with small increases in the ranibizumabgroups of 0.36 optic-disk area in the 0.3-mg group and 0.28optic-disk area in the 0.5-mg group (P<0.001 for each comparison).
Adverse Events
Safety results are summarized in Table 3. Serious ocular adverseevents associated with treatment were uncommon. Endophthalmitis,classified as a condition treated with intravitreal or systemicantibiotics, was reported in one patient, who was in the 0.5-mggroup (0.7%). An additional patient in the 0.5-mg group (0.7%)had two events of intraocular inflammation that were classifiedby the investigator as serious uveitis. However, since one ofthe events was treated with systemic antibiotics (without obtainingocular culture specimens or treatment with intravitreal antibiotics),this patient was presumed to have had endophthalmitis, and wasso classified in Table 3. Rhegmatogenous retinal detachmentoccurred in one patient (0.7%) in the 0.3-mg group and one inthe verteporfin group, and vitreous hemorrhage occurred in onepatient (0.7%) in the 0.3-mg group.
Rates of adverse events of intraocular inflammation (pooledfor reported events of iritis, iridocyclitis, vitritis, uveitis,and anterior-chamber inflammation) were higher in both ranibizumabgroups (10.2% in the 0.3-mg group and 15.0% in the 0.5-mg group)than in the verteporfin group (2.8%). Rates of intraocular inflammation(regardless of cause) observed during slit-lamp examinationwere consistent with those reported as adverse events (12.4%in the 0.3-mg group and 17.1% in the 0.5-mg group, as comparedwith 3.5% in the verteporfin group). Most patients in all groupshad no observable inflammation during the study, and the proportionof inflammation events graded 2+ or higher among ranibizumab-treatedpatients was small: three patients in each dose group (2.2%in the 0.3-mg group and 2.1% in the 0.5-mg group).
Transient changes in intraocular pressure after injection werecommon in the ranibizumab-treated patients. The proportion ofpatients with a postinjection intraocular pressure of 30 mmHg or more was greater in both ranibizumab groups (8.8% in the0.3-mg group and 8.6% in the 0.5-mg group) than in the verteporfingroup (4.2%). However, very few patients had measurements of40 mm Hg or more (2.9% in each ranibizumab group vs. 0.7% inthe verteporfin group).
The ranibizumab groups had an increased frequency of cataractformation (10.9% in the 0.3-mg group and 12.9% in the 0.5-mggroup, as compared with 7.0% in the verteporfin group). Withthe exception of one severe cataract in the verteporfin group,all adverse events associated with cataracts were mild or moderate.A small number of patients had changes in lens status reportedduring the first treatment year. Of patients whose study eyewas phakic at baseline, five underwent cataract surgery duringthe 12 months of the study: four (5.3%) in the 0.3-mg groupand one (1.2%) in the 0.5-mg group, as compared with none inthe verteporfin group. Visual-acuity outcomes of these patientsat 12 months were not notably different from those of the respectivetreatment groups overall. No traumatic lens damage was reportedin the study eye of any patient during the first treatment year.
There was no overall imbalance among groups in the rates ofserious nonocular adverse events: 14.6% in the 0.3-mg groupand 20.0% in the 0.5-mg group, as compared with 19.6% in theverteporfin group. The numbers of deaths were similar acrossgroups: three patients (2.2%) in the 0.3-mg ranibizumab groupand two patients each (1.4%) in the 0.5-mg group and verteporfingroup. With respect to specific nonocular adverse events, therewere imbalances in back pain and nonocular hemorrhage (a combinationof serious and nonserious events). Back pain was less commonin the ranibizumab groups (3.6% in the 0.3-mg group and 1.4%in the 0.5-mg group) than in the verteporfin group (9.1%) andis a well-known potential adverse reaction to verteporfin infusion.18The incidence of nonocular hemorrhage, an adverse event thatpotentially reflects systemic VEGF inhibition,19 was higherin the ranibizumab groups (5.1% in the 0.3-mg group and 6.4%in the 0.5-mg group, as compared with 2.1% in the verteporfingroup). There was no increase in the ranibizumab groups in meansystolic or diastolic blood pressure or in the rates of hypertensionand proteinuria, other adverse events potentially reflectingsystemic VEGF inhibition.
Serious adverse events of arterial thromboembolism were evaluatedwith the use of the Antiplatelet Trialists' Collaboration (APTC)criteria, in which an event is defined as a nonfatal myocardialinfarction, nonfatal ischemic stroke, nonfatal hemorrhagic stroke,or death owing to vascular or unknown causes.20 Overall, APTC-classifiedarterial thromboembolic events occurred in three patients (2.2%)in the 0.3-mg group, six patients (4.3%) in the 0.5-mg group,and three patients (2.1%) in the verteporfin group (Table 3).One patient (0.7%) in each group had a nonfatal cerebrovascularevent. Nonfatal myocardial infarction occurred in one patient(0.7%) in the 0.3-mg group, three patients (2.1%) in the 0.5-mggroup, and in one patient (0.7%) in the verteporfin group. Noapparent relationship between the onset of those events andthe time of study treatment was observed; the differences werenot significant. One patient in the 0.3-mg group who began concomitanttreatment with the systemic anti-VEGF agent bevacizumab formetastatic cancer midway through the study and continued toreceive ranibizumab had an intestinal perforation, a known riskassociated with systemic bevacizumab therapy.19
We observed immunoreactivity to ranibizumab in a percentageof patients in all treatment groups (1.5% in the verteporfingroup, 3.2% in the 0.3-mg group, and 0.8% in the 0.5-mg group)before any exposure to ranibizumab. Monitoring of immunoreactivityduring the first treatment year revealed no increase from baselinein the number of patients testing positive in the verteporfingroup or the 0.3-mg group (1.6% in each group at 12 months),whereas the 0.5-mg group showed an increase to 3.9% of patientsat 12 months. Although the small number of patients with immunoreactivityprecludes drawing definitive conclusions, proportionately moreranibizumab-treated patients who were immunoreactive at anypoint had adverse events associated with intraocular inflammation(3 of 6 in the 0.3-mg group and 3 of 5 in the 0.5-mg group,as compared with 0 of 3 in the verteporfin group) than did patientswho were never immunoreactive (11 of 127 in the 0.3-mg groupand 17 of 129 in the 0.5-mg group, as compared with 3 of 129in the verteporfin group). The presence or absence of immunoreactivityappeared to be unrelated to end points associated with visualacuity or nonocular adverse events potentially related to immunoreactivity.
Discussion
Our study demonstrated that ranibizumab prevents central visionloss and improves mean visual acuity at 1 year. In this study,monthly intravitreal injections of ranibizumab were superiorin efficacy to verteporfin therapy. Although our study was notdesigned to evaluate the superiority of one ranibizumab doseover the other, efficacy results suggest a dose–responseeffect.
Intravitreal injections of ranibizumab were associated witha low rate of serious ocular adverse events, including suchkey events as presumed endophthalmitis, severe intraocular inflammation,and retinal detachment (each of which was reported in less than1% of the pooled ranibizumab-treated patients and in less than0.1% of ranibizumab injections). The ocular safety profilesfor the three treatment groups revealed no overall imbalancein serious and nonserious adverse events, although there weretrends toward increased rates of intraocular inflammation (generallymild), cataract (consistently mild or moderate), and nonocularhemorrhage with ranibizumab. The rates of intraocular inflammationand cataract in the ranibizumab groups were similar to thosefor ranibizumab-treated patients in the MARINA study.14 However,the rates of these events in the verteporfin group in our studywere lower than the rates in the sham-injection group in theMARINA study.14
Regarding adverse events that potentially reflect systemic VEGFinhibition, no adverse events of proteinuria were reported andno imbalance in adverse events of hypertension or in blood-pressuremeasurements was noted in either our study or the MARINA study.In both studies, ranibizumab-treated patients had a higher percentageof nonocular hemorrhages than did patients who did not receiveranibizumab, and patients treated with a 0.5-mg dose had a higherrate of APTC-classified arterial thromboembolic events thandid those who received a 0.3-mg dose or verteporfin therapy(Table 3). Since our study was not designed to distinguish smalldifferences in rare adverse events among treatment groups, theclinical significance of these trends is unclear and requiresfurther attention. In the MARINA study, with 2 years of studytreatment, the rates of events classified as arterial thromboembolismaccording to APTC criteria were similar among the treatmentgroups.13 Follow-up is continuing through 2 years of treatmentin our study to identify these events. The clinical significanceof immunoreactivity to ranibizumab observed with the assay methodused in our study and in the MARINA study is also not clear.
In summary, the ANCHOR study showed that ranibizumab administeredmonthly by intravitreal injection was superior in efficacy tophotodynamic therapy with verteporfin in patients with subfoveal,predominantly classic choroidal neovascularization associatedwith age-related macular degeneration. The first-year resultsof our study and the 2-year results of the MARINA study, consideredtogether, demonstrate that ranibizumab was effective with anacceptable adverse-event profile in the treatment of all angiographicsubtypes of choroidal neovascularization associated with age-relatedmacular degeneration.
Supported by Genentech and Novartis Pharma.
Dr. Brown reports having received consulting fees from Genentech,Alcon, Eyetech, Novartis, and Allergan; lecture fees from Genentechand Eyetech; and grant support from Alcon, Acuity Pharmaceuticals,Allergan, Alimera, Eyetech, Pfizer, Novartis, Genentech, EliLilly, Oxigene, and the Diabetic Retinopathy Clinical Researchnetwork; and having an equity interest in Pfizer. Dr. Kaiserreports having received consulting fees from Genentech, Alcon,Allergan, and Novartis and having received lecture fees fromNovartis and Genentech. Dr. Michels reports having receivedconsulting fees from Genentech and Pfizer–(OSI) Eyetechand lecture fees from Pfizer–(OSI) Eyetech, Novartis,and Genentech. Dr. Soubrane reports having received consultingfees from Alcon, Allergan, Thea, Alimera, Pfizer–(OSI)Eyetech, and Novartis and lecture fees from Pfizer, Alcon, Thea,and Novartis. Dr. Heier reports having received consulting feesfrom Genentech, Eyetech, Oxigene, Novartis, Allergan, Genzyme,iScience, ISTA, Pfizer, Regeneron, Theragenics, VisionCare,and Jerini; lecture fees from Genentech, Eyetech, Jerini, andAllergan; and grant support from Genentech, Eyetech, Pfizer,and Eli Lilly Theragenics. Dr. Kim reports being a full-timeemployee of Genentech and having received stock options. Dr.Sy and Dr. Schneider report being full-time employees of Genentech,holding an equity interest in the company, and having receivedstock options. No other potential conflict of interest relevantto this article was reported.
We are indebted to the patients who participated in this study,their families, and the research teams at each site; to themembers of the data and safety monitoring committee: FrederickL. Ferris III, M.D. (chair), Susan B. Bressler, M.D., StuartL. Fine, M.D., and Marian Fisher, Ph.D.; to the members of theUniversity of Wisconsin Fundus Photograph Reading Center; tothe members of the data-coordinating center (Statistics Collaborative);to members of the Genentech Clinical Operations organizationfor their invaluable assistance in the conduct of this study;to Charles Semba, M.D., Naveed Shams, M.D., Ph.D., James F.Ward, Ph.D., Lisa Damico, Ph.D., and Steven Butler, Ph.D., ofGenentech for their critical comments and review throughoutthe design, conduct, and analysis of the study; and to staffmembers at Genentech for their assistance in the preparationof the manuscript.
* Principal investigators in the Anti-VEGF Antibody for the Treatmentof Predominantly Classic Choroidal Neovascularization in Age-RelatedMacular Degeneration (ANCHOR) Study Group are listed in theAppendix.
Source Information
From Vitreoretinal Consultants, Methodist Hospital, Houston (D.M.B.); the Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (P.K.K.); Retina Care Specialists, Palm Beach Gardens, FL (M.M.); the Clinique d'Ophtalmologie, University of Paris XII, Créteil, France (G.S.); Ophthalmic Consultants of Boston, Boston (J.S.H.); and Genentech, South San Francisco, CA (R.Y.K., J.P.S., S.S.).
Address reprint requests to Dr. Brown at Vitreoretinal Consultants, 6560 Fannin St., Suite 750, Houston, TX 77030, or at dmbmd{at}houstonretina.com.
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Appendix
The following principal investigators were members of the ANCHORStudy Group: T. Aaberg, Associated Retinal Consultants, GrandRapids, MI; P. Abraham, Black Hills Regional Eye Institute,Rapid City, SD; L. Akduman, Saint Louis University Eye Institute,St. Louis; D. Alfaro III, Retina Consultants of Charleston,Charleston, SC; A. Antoszyk, Southeast Clinical Research Associates,Charlotte, NC; J. Arnold, Marsden Eye Research, Parramatta,Australia; C. Awh, Retina Vitreous Associates, Nashville; P.Beer, New Lions Eye Institute, Slingerlands, NY; J. Belmont,Retina Diagnostic and Treatment, Philadelphia; B. Berger, RetinaResearch Center, Austin, TX; D. Berinstein, Retina Group ofWashington, Fairfax, VA; R. Bhisitkul, University of Californiaat San Francisco School of Medicine, San Francisco; D. Boyer,Retina–Vitreous Associates, Beverly Hills, CA; W. Bridges,Western Carolina Retinal Associates, Asheville, NC; H. Brooks,Jr., Southern Vitreoretinal Associates, Tallahassee, FL; D.Brown, Vitreoretinal Consultants, Houston; T. Ciulla, MidwestEye Institute, Indianapolis; W. Clark, Palmetto Retina Center,Columbia, SC; T. Connor, Medical College of Wisconsin, Milwaukee;S. Cousins, Bascom Palmer Eye Institute, Palm Beach Gardens,FL; F. Devin, Clinique Monticelli, Marseilles, France; W. Dunn,Florida Retina Institute, Daytona Beach; A. Eaton, Retina HealthCenter, Fort Myers, FL; S. Fekrat, Duke University Eye Center,Durham, NC; C. Foja, Universitätsklinikum Leipzig, Leipzig,Germany; B. Foster, New England Retina Consultants, West Springfield,MA; A. Gaudric, Hôpital Lariboisière, Paris; M.Gilles, Save Sight Institute, Sydney; D. Glaser, Retina Associatesof St. Louis, Florissant, MO; B. Godley, Retina Specialists,Desoto, TX; V. Gonzalez, Valley Retina Institute, McAllen, TX;R. Goodart, Rocky Mountain Retina Consultants, Salt Lake City;R. Guymer, University of Melbourne, Centre for Eye ResearchAustralia, East Melbourne, Australia; L. Halperin, Retina VitreousConsultants, Fort Lauderdale, FL; J. Heier, Ophthalmic Consultantsof Boston, Boston; F. Holz, Universitätsklinikum Bonn,Bonn, Germany; B. Hubbard, Emory University, Atlanta; H. Hudson,Retina Centers, Tucson, AZ; D. Ie, Delaware Valley Retina Associates,Lawrenceville, NJ; M. Johnson, University of Michigan, Ann Arbor;A. Joussen, Universitätsklinikum Köln, Cologne, Germany;P. Kaiser, Cleveland Clinic Foundation, Cole Eye Institute,Cleveland; B. Kuppermann, University of California at Irvine,Irvine; M. Lomeo, Midwest Retina, Columbus, OH; C. MacDonald,University of Texas Health Science Center, San Antonio; D. Marcus,Southeast Retina Center, Augusta, GA; A. Martidis, Retina Diagnosticand Treatment, Philadelphia; J. Martinez, Austin Retina Associates,Austin, TX; D. Maxwell, Jr., Retinal Associates of Oklahoma,Oklahoma City; T. McMillan, Southeastern Retina Associates,Knoxville, TN; M. Michels, Palm Beach Gardens, FL; D. Miller,Retina Associates of Cleveland, Beachwood, OH; P. Michell, WestmeadHospital, Westmead, Australia; I. Orgel, Retina Vitreous Associates,Toledo, OH; R. Park, University of Arizona, Tucson; M. Paul,Danbury Eye Physicians and Surgeons, Danbury, CT; P. Pavan,University of South Florida, Tampa; M. Petersen, CincinnatiEye Institute, Cincinnati; J. Prensky, Pennsylvania Retina Specialists,Camp Hill, PA; P. Raskauskas, Retina Consultants of SouthwestFlorida, Fort Myers; E. Reichel, New England Eye Center, Boston;D. Reid, Retina Associates, Annapolis, MD; P. Richmond, CentralFlorida Retina, Orlando; W. Rodden, Retina and Vitreous Centerof Southern Oregon, Ashland, OR; P. Rosenfeld, Bascom PalmerEye Institute, Miami; P. Runge, Ophthalmic Consultants, Sarasota,FL; S. Sadda, Doheny Eye Institute, Los Angeles; S. Sanislo,California Vitreoretinal Research Center, Menlo Park; S. Schwartz,Bascom Palmer Eye Institute, Palm Beach Gardens, FL; A. Seres,Semmelweis University, Budapest, Hungary; M. Singer, MedicalCenter Ophthalmology Associates, San Antonio, TX; G. Soubrane,Clinique d'Ophtalmologie, University of Paris XII, Créteil,France; P. Soucek, University Hospital Vinohrady, Prague, CzechRepublic; W. Stern, Northern California Retina-Vitreous Associates,Mountain View; G. Stoller, Ophthalmic Consultants of Long Island,Rockville Centre, NY; J. Thompson, Retina Specialists, Towson,MD; D. Tom, New England Retina Associates, Hamden, CT; R. Torti,Retina Specialists, Desoto, TX; M. Trese, Associated RetinalConsultants, Royal Oak, MI; E. van Kuijk, University of TexasMedical Branch, Galveston; T. Verstaeten, Allegheny GeneralHospital, Pittsburgh; K. Warren, University of Kansas MedicalCenter, Kansas City; H. Weiss, Retina Consultants of Michigan,Southfield; J. Weiss, Retina Associates of South Florida, Margate,FL; C. Wells, Vitreoretinal Associates, Seattle; S. Wolf, UniversitätsklinikumLeipzig, Leipzig, Germany; and K. Zhang, John Moran Eye Center,University of Utah, Salt Lake City.
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45 letters, with a score of 45 letters as the approximate Snellen equivalent of 20/125 vision). In the group that received photodynamic therapy with verteporfin, intravenous administration of verteporfin (Visudyne, Novartis Pharmaceuticals) was followed by laser irradiation of the macula, according to instructions provided in the product package insert (www.visudyne.com). In the ranibizumab groups, sham verteporfin therapy was achieved by an intravenous infusion of saline rather than verteporfin, followed by laser irradiation of the macula identical to that in the active verteporfin-therapy group. 
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