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Sporadic Visual Acuity Loss in the Comparison ofAge-RelatedMacularDegenerationTreatmentsTrials (CATT)

BENJAMIN J. KIM, GUI-SHUANG YING, JIAYAN HUANG, NICOLE E. LEVY, ANDMAUREEN G. MAGUIRE, ONBEHALF OF THE CATT RESEARCH GROUP

PURPOSE: To evaluate transient, large visual acuity(VA) decreases, termed sporadic vision loss, duringantivascular endothelial growth factor treatment forneovascular age-related macular degeneration (AMD). DESIGN: Cohort within a randomized clinical trial. METHODS: SETTING: Comparison of Age-RelatedMacular Degeneration Treatments Trials (CATT).STUDY POPULATION: Total of 1185 CATT patients. MAINOUTCOME MEASURES: Incidence of sporadic vision loss andodds ratio (OR) for association with patient and ocularfactors. Sporadic vision loss was a decline of 15 lettersfrom the previous visit, followed by a return at the nextvisit to no more than 5 letters worse than the visit beforethe VA loss. RESULTS: There were 143 sporadic vision loss eventsin 122 of 1185 patients (10.3%). Mean VA at 2 yearsfor those with and without sporadic vision loss was 58.5(w20/63) and 68.4 (w20/40) letters, respectively(P< .001). Among patients treated pro re nata, no injec-tion was given for 27.6% (27/98) of sporadic vision lossevents. Multivariate analysis demonstrated that baselinepredictors for sporadic vision loss included worse baselineVA (OR 2.92, 95% confidence interval [CI]:1.655.17for 20/200 compared with 20/40), scar (OR 2.21,95% CI:1.224.01), intraretinal foveal fluid on opticalcoherence tomography (OR 1.80, 95% CI:1.112.91),and medical history of anxiety (OR 1.90, 95%CI:1.123.24) and syncope (OR 2.75, 95% CI:1.455.22). Refraction decreased the likelihood of sporadicvision loss (OR 0.62, 95%CI: 0.420.91). CONCLUSIONS: Approximately 10% of CATTpatients had sporadic vision loss. Baseline predictorsincluded AMD-related factors and factors independentof AMD. These data are relevant for clinicians in prac-tice and those involved in clinical trials. (Am JOphthalmol 2014;158:128135. 2014 by ElsevierInc. All rights reserved.)

Supplemental Material available at AJO.com.Accepted for publication Apr 1, 2014.

From the Scheie Eye Institute, Perelman School of Medicine,University of Pennsylvania, Philadelphia, Pennsylvania.

Inquiries to Benjamin J. Kim, Scheie Eye Institute, 51 N 39th St,Philadelphia, PA 19104; e-mail: benjamin.kim@uphs.upenn.edu

128 2014 BY ELSEVIER INC.

VISUAL ACUITY (VA) HAS BEEN THE PRIMARY

outcome measure for every major clinical trial forneovascular age-related macular degeneration

(AMD).17 Previous studies have established that VAmeasurement administered under a standard protocolthat includes refraction provides a reliable outcomemeasure.8,9 Still, VA scores can be affected by multiplefactors, some of which have little to do with the conditionof the eye. Health issues that are not primarily ocular,such as depression and neurologic disease, can impactVA measurement or visual function.1017 In addition,clinicians occasionally see patients in follow-up who havea worse VA measurement without any change on clinicalexamination.As part of their analysis of vision loss during the Mini-

mally Classic/Occult Trial of the Anti-VEGF AntibodyRanibizumab in the Treatment of Neovascular AMD(MARINA) and Anti-VEGF Antibody for the Treatmentof Predominantly Classic Choroidal Neovascularizationin AMD (ANCHOR) trials, Wolf and associates identi-fied patients that had acute loss of >_15 letters within any1-month period.18 A total of 106 of 758 ranibizumab-treated patients (13.9%) experienced an acute loss of visionduring the first year, and several had more than 1 episode ofacute vision loss. Although they concluded that continuedtreatment was beneficial, there was no clear relationshipbetween patient characteristics and acute vision loss,including an analysis of study eye adverse events (AEs) orserious adverse events (SAEs). It is possible that other fac-tors in addition to progressive AMD disease were involvedin some of these acute vision loss events.Given that significant resources are devoted to studying a

treatments effects on VA inAMDpatients, we have soughtfurther understanding of factors that influence this outcomemeasurement. The Comparison of Age-Related MacularDegeneration Treatments Trials (CATT) was a 2-yearstudy that evaluated the efficacy of ranibizumab comparedwith bevacizumab, as well as monthly compared withas-needed treatments.6,19 The CATT database providesan unprecedented opportunity to investigate AMDpatients as it expands on MARINA and ANCHOR data,providing treatment regimen, drug, and optical coherencetomography (OCT) correlations. We previously reportedthe frequency of sustained VA loss and its associatedfactors within CATT.20 Here, we report similarly for spo-radic VA loss within CATT. Rather than studying patients

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ALL RIGHTS RESERVED.

Delta:1_given nameDelta:1_surnameDelta:1_given nameDelta:1_surnameDelta:1_given namehttp://AJO.commailto:benjamin.kim@uphs.upenn.eduhttp://dx.doi.org/10.1016/j.ajo.2014.04.004

with only an acute loss of >_15 letters, we were interested inpatients who had a decline of >_15 letters from the previousvisit, followed by a return of vision at the next visit.Although changes of 5 and occasionally 10 letters arewithin test-retest variability,9 little is known about thecauses of transient VA losses of >_15 letters for AMDpatients.

METHODS

THIS STUDY WAS A SECONDARY ANALYSIS OF A COHORT

within a randomized clinical trial (CATT). PreviousCATT reports provide a detailed summary of the CATTstudy design.6,19 CATT is registered with http://www.clinicaltrials.gov (NCT00593450). Design features relevantto this report are described here.

STUDY PATIENTS: Study patients provided writteninformed consent to participate in CATT. The Institu-tional Review Board of each study site prospectivelyapproved the CATT study protocol, and the study is inaccordance with the Health Insurance Portability andAccountability Act regulations. The inclusion criteriawere age >_50 years, untreated choroidal neovascularization(CNV) from AMD in the study eye, VA of 20/2520/320,and neovascularization or its sequelae at the foveal center.Baseline medical history was obtained from all patients.

Patientswere randomized at study entry to 1 of 4 treatmentarms: ranibizumabmonthly, bevacizumabmonthly, ranibizu-mab pro re nata (PRN), and bevacizumab PRN. At 1 year,study patients in the monthly groups were randomized again1:1 to continuedmonthly treatment or PRN treatment. PRNtreatment was given when there were signs of active neovas-cularization, defined as fluid onOCT,hemorrhage, decreasedVA compared with the prior visit, or leakage or increasedlesion size on fluorescein angiography.

All patients had monthly VA measurements using anelectronic VA testing system by certified VA examinerswho were masked to the patients treatment assignment.9

Protocol refraction before measurement of VA wasrequired at baseline and at weeks 4, 12, 24, 36, 52, 64,76, 88, and 104. For efficiency, refractions were notroutinely performed at every visit.

IMAGING PROCEDURES: Stereoscopic color fundusphotography and fluorescein angiography were per-formed by certified photographers at baseline, 52 weeks,and 104 weeks. Stratus (version 4.0 or higher) time-domain OCT systems (Carl Zeiss Meditec, Dublin, Cali-fornia, USA) were used for first-year visits and mostsecond-year visits. Spectral-domain OCT images wereobtained for 23% of second-year visits. OCT imageswere obtained monthly in the PRN arms. Certified tech-nicians masked to the patients treatment assignment

VOL. 158, NO. 1 SPORADIC VISION LOSS I

followed standardized procedures and performed OCTimaging with macular thickness maps and fast macularthickness maps. OCT scans were independently analyzedby 2 certified OCT readers at the CATT OCT ReadingCenter, and photographs were analyzed by 2 certifiedreaders at the CATT Photography Reading Center.Details about image acquisition and analysis by thereading centers are previously described.2123

DATA ANALYSIS: Sporadic vision loss required VA datafrom 3 consecutive visits (ie, VA1, VA2, and VA3). Spo-radic vision loss was defined as a decline of >_15 lettersfrom the previous visit (ie, VA1 VA2 >_ 15 letters),followed by a return at the next visit to no more than 5 let-ters worse than the visit before the VA loss (ie, VA3 VA1 >_ 5 letters). Five letters was chosen for the latterpart of this definition since 89% of test-retest electronicVAmeasurements reportedly are within 5 letters.9 Sporadicvision loss of 30 letters was defined as a decline of >_30 lettersfrom the previous visit, followed by a return at the next visitto no more than 5 letters worse than the visit before theVA loss.The incidence of sporadic vision loss loss was calculated

as the proportion of eyes with sporadic vision loss within 2years among all CATT patients. Mean VA during the studywas compared between eyes with sporadic vision loss andall other study eyes. VA, fundus photograph features, andOCT features were compared at 2 years between eyeswith and without sporadic vision loss. As noted, the2-group t test or the paired t test was used for comparisonof means. Fisher exact test or McNemar test was used forcomparison of proportions.For the 27 events of sporadic vision loss that did not

coincide with an injection, investigators for these eventswere queried about the possible cause of vision loss,whether new hemorrhage at the macula was present, andwhy no injection was given.For the evaluation of baseline medical history associations

with sporadic vision loss, we focused on neurologic and psy-chological histories because of their potential effects on visualf