Surgical Removal vs Observation for Subfoveal Choroidal Neovascularization,Either Associated With the Ocular Histoplasmosis Syndrome or Idiopathic: Title and subTitle BreakII. Quality-of-Life Findings From a Randomized Clinical Trial: SSTGroup H Trial: SST Report No. 10 FREE

Measurement of health-related quality of life has been advocated asan adjunct to clinical measurements in randomized treatment trials and otherstudy designs in which patient outcomes are assessed.^{1 - 3} Whenthe condition for which treatment is being evaluated is non–life threateningand when differences between treatments with respect to clinical outcomesmay be small, assessment of patients' perceptions of treatment benefitor harm is particularly important.⁴ However,patient perceptions of treatment effects may be informative whether similarto or different from clinical outcomes.

Since 1997, the Submacular Surgery Trials (SST) Research Group has beenconducting randomized trials of surgical removal of subfoveal choroidal neovascularlesions to evaluate the role of this procedure in the treatment of patientswith age-related macular degeneration and other ophthalmic conditions. Thefirst trial to be initiated was for patients who had subfoveal choroidal neovascularizationthat was either idiopathic or associated with the ocular histoplasmosis syndrome(SST Group H Trial). Data from uncontrolled case series and from a small pilotstudy suggested that such patients were those most likely to benefit fromsubmacular surgery. Because neovascular lesions of ocular histoplasmosis typicallyare diagnosed when patients are in midlife, these patients are at risk ofloss of employment in their usual occupations. Thus, many aspects of theirlives may be affected by their vision problems and by treatments that maybe administered.

Measurement of both vision-targeted and general health-related qualityof life was included in the design of the SST. These measures were consideredimportant because of the cost of surgery, inconvenience to patients treatedsurgically who were instructed to maintain a face-down position for 2 days(or longer) after surgery, and risk of postoperative complications that wereexpected to require further treatment. Furthermore, review of findings fromrandomized trials of other treatments for subfoveal choroidal neovascularizationsecondary to age-related macular degeneration⁵ suggestedthat differences between active interventions and observation with respectto visual acuity may be small. Thus, it was plausible that surgically treatedand observed patients would differ more on health-related quality-of-lifescales, particularly vision-targeted scales, than on visual acuity measurementsand other clinical outcomes.

The SST Research Group has published data regarding health-related qualityof life at the time patients enrolled in the SST Group H Trial.⁶ Scoreson a standard vision-targeted instrument were lower than expected based onthe visual acuity of the better eye when compared with published scores frompatients who had other ophthalmologic conditions. In particular, patientswho had bilateral choroidal neovascularization reported substantial loss ofvisual function on some scales even after accounting for differences in visualacuity of the better eye and other factors.⁶ Visualacuity and related findings from the SST Group H Trial have been reportedelsewhere.⁷ For the full group of patientsenrolled, visual acuity changes over time suggested a small benefit to surgery,but differences between the surgery and observation arms were largest duringthe first year after enrollment and declined over time. The prespecified subgroupof patients who had best-corrected visual acuity of the study eye worse than20/100 (20/125-20/800) at baseline had a large benefit from surgery, basedon stabilization or improvement of visual acuity, but patients who had a betterbaseline visual acuity (20/50-20/100) had no benefit.

The purpose of this report is to summarize health-related quality-of-lifefindings from the interviews conducted during the follow-up period with patientswho participated in the SST Group H Trial and to compare these findings betweenpatients in the randomly assigned treatment arms. Because of the marked differencein baseline scores observed between patients with unilateral and bilateralchoroidal neovascular lesions⁶ and becauseof the difference in visual acuity outcomes by baseline visual acuity,⁷ comparisons of findings by treatment arm within thesesubgroups of patients are of particular interest.

The members of an independent Data and Safety Monitoring Committee approvedthe design and methods proposed for the SST before enrollment of patientswas initiated in the SST Group H Trial in April 1997. Institutional reviewboards at all participating institutions reviewed and approved the study designand the consent forms to be used locally. All patients gave signed consentbefore enrollment and random treatment assignment.

Many of the methods used in the SST and in the SST Group H Trial havebeen published.^{6 - 7} The SST Manual of Procedures⁸ and the SST Forms Book⁹ are availableand provide detailed information regarding study design, methods, and policies.

The details of eligibility requirements for patients and eyes, clinicalevaluation procedures, and clinical data collection methods and schedulesare given elsewhere.⁷ Eligible patients were18 years or older and had new or recurrent subfoveal choroidal neovascularlesions with evidence of classic choroidal neovascularization on fluoresceinangiography and best-corrected visual acuity of 20/50 to 20/800, inclusive,in at least 1 eye (study eye). The visual acuity of the fellow (nonstudy)eye had to be light perception or better. Patients had to agree to completetelephone interviews administered prior to enrollment and at scheduled timesafter enrollment to be eligible for the randomized trial. Enrollment and randomtreatment assignment did not take place until the baseline interview was completedby telephone with an interviewer located at the SST Coordinating Center, Baltimore,Md.

Patients judged to be eligible by the examining ophthalmologist wereinvited to participate in the study. The consent and enrollment process aredescribed elsewhere.^{6 - 7} Randomizationwas stratified by enrolling clinical center only. The clinical center staffwere notified of the assigned treatment for the study eye, surgery or observation,by means of an automated message sent by telecopier on the day of enrollment.This notice was accompanied by a schedule of the target dates for future interviewsand examinations and the permissible intervals during which each one couldbe completed for the data to be accepted into the study database. The patientspecified on the telecopied notice whether future interviews should be initiatedby the interviewers or would be initiated by the patient. Whenever the interviewerswere asked to initiate the interview contact, the patient provided telephoneinformation, preferred days of the week, and times of day for future interviewsbefore the notice was telecopied back to the coordinating center.

The interview instruments selected for the SST were theNational EyeInstitute Visual Function Questionnaire(NEI-VFQ),^{10 - 12} the36-Item Short-Form Health Survey(SF-36),¹³ theHospital Anxiety and Depression Scale (HADS, 14 items),¹⁴ andthe 3-item SST Vision Preference Value Scale.¹⁵ TheNEI-VFQ was designed to be applicable to patients with a number of differentvision-limiting or vision-threatening conditions. Initially, the 25-item NEI-VFQwith selected supplemental questions added was used for the interviews. ByJanuary 1998, all 14 supplemental questions provided by the developers¹² had been incorporated into the interview. The itemsare scored to yield an overall score and scores on 11 subscales that addressdifferent aspects of visual function and a general health subscale. Overallscores on the NEI-VFQ and subscale scores have a range of 0 (worst score)to 100 (best score). The SF-36 measures general health status and health-relatedfunctioning. The SF-36 items are combined to create 8 subscales that can becombined further to create 2 summary scales.¹⁶ Thesummary scale developers calibrated scores on the physical and mental componentsummary scales to have means of 50 points and standard deviations of 10 pointsin the general US population.¹⁶ Higher scoreson SF-36 summary scales indicate better perceived health status. The HADSinstrument was included in the interview because of both anecdotal and publishedevidence of depression¹⁷ among patients withpoor vision and anxiety regarding future vision reported by patients who participatedin a pilot study conducted by the SST investigators. The HADS has been usedwith outpatients with many medical conditions.¹⁸ Scoreson the 2 HADS scales (anxiety and depression, 7 items each) range from 0 (bestscore) to 21 (worst score). The SST Vision Preference Value Scale was incorporatedinto the interview to permit assessment of the value patients placed on currentvision and health relative to perfect vision or complete blindness. Baselinefindings from the SST Vision Preference Value Scale have been reported elsewhere.¹⁵

All interviews were conducted from the Coordinating Center by trainedinterviewers who were masked to the study eye, the clinical trial, and thetreatment arm. However, patients occasionally revealed pertinent informationduring the course of the interviews despite instructions not to do so. Interviewersused a computer-assisted system that interacted with the primary study databaseto confirm study identifiers assigned to the patient so that the interviewdata could be integrated with the clinical data for each patient. Before eachinterview was concluded, scores for the HADS depression subscale were calculatedautomatically from the responses given by the patient. Whenever a patienthad a score that would result in classification as a “definite case”of depression, based on the recommendations of the HADS developers,¹⁴ the interviewer requested the patient's permissionto notify the SST ophthalmologist of the score so that an appropriate referralcould be considered.

All patients were scheduled for follow-up interviews at 6, 12, and 24months after enrollment. Patients who enrolled by September 30, 2000, werescheduled for a 36-month interview and those who enrolled by September 30,1999, also were scheduled for a 48-month interview. The last study interviewsfor all patients who had not completed a 48-month interview already were conductedduring the final year of patient follow-up that began on October 1, 2002.

Clinical data collection at baseline and during follow-up is describedelsewhere.⁷ Baseline data collection includedmeasurement of the best-corrected visual acuity, reading speed, and contrastthreshold of each eye according to standard protocols. Baseline stereoscopiccolor photographs of the macula and optic disc of each eye and a film-basedfluorescein angiogram were taken and forwarded to the SST Photograph ReadingCenter, Baltimore, Md, for interpretation and documentation of characteristicsof the eyes and subfoveal lesions.

Best-corrected visual acuity measurements made before enrollment wereused to subgroup patients by the visual acuity of the study eye (20/50-20/100vs 20/125-20/800), a grouping of interest specified during trial planning.Patients were classified as having bilateral or unilateral neovascular diseaseprimarily on the basis of masked central interpretations of baseline photographs.⁶

An initial training session for interviewers was conducted by the chairof the SST Patient-Centered Outcomes Subcommittee before the trial began;additional training was provided during interviewer workshops held at leastonce each year. The goal of training was to standardize administration ofthe interview and interactions with trial patients. The interviewers met periodicallyduring the first years of the trial to reach agreement on issues of interviewadministration and interactions with patients and to recommend improvementsin the computer-assisted system. The SST Patient-Centered Outcomes Committeemet twice yearly to review data regarding interview administration, to reviewpreliminary data (combined across treatment arms), and to make recommendationsregarding methodology.

In the SST Group H Trial, visual acuity was the primary clinical measurementof interest for comparison of the treatment arms. In particular, change inbest-corrected visual acuity from baseline to the 24-month examination wasthe basis for calculating the target sample size.⁷ Inthe original study design of the parallel evaluation of quality of life, whichwas developed before the NEI-VFQ was published, 24-month change in scoreson the SF-36 interview was designated the most important secondary outcomefor assessing the effect of surgery. Subsequently, the NEI-VFQ interview wasgiven greater weight based on experience with the interview instruments andthe perception that it had greater relevance to the problems experienced bystudy patients and would be more responsive to changes in vision over time.The target sample size of 240 patients was calculated on the basis of theprimary clinical outcome of interest to provide 218 patients with visual acuitymeasured at the 24-month examination.^{7 - 8} Itwas estimated that this sample size would permit detection of 4-point differencesbetween treatment arms in the physical component summary and mental componentsummary scales of the SF-36.¹⁶ Informationprovided by the developers of the NEI-VFQ indicated that this sample sizewould permit detection of 10-point or greater differences in scores betweentreatment arms for most NEI-VFQ scales.¹² However,our purpose, and the focus of analyses, is description of findings from thequality-of-life interviews rather than hypothesis testing.

Responsibility for monitoring accumulating data regarding safety andeffectiveness of surgery was entrusted to the Data and Safety Monitoring Committeeappointed in 1996. However, monitoring focused on clinical outcomes ratherthan on quality-of-life outcomes. Key recommendations are summarized elsewhere.⁷

Owing to funding constraints and other considerations,⁷ accrualhalted on September 30, 2001, and scheduled patient follow-up ended on September30, 2003. Thus, all patients were eligible for interviews 24 months afterenrollment, but only patients who enrolled by September 2000 were eligiblefor 36-month interviews and only those who enrolled by September 1999 wereeligible for 48-month interviews.

The NEI-VFQ, SF-36, and HADS scores were calculated using the recommendationsof the developers, except that a scale score was not calculated in the fewinstances in which half the items that make up a scale had not been answered.For the NEI-VFQ driving scale, patients who responded that they had stoppeddriving because of vision (26 patients at baseline; 30 patients at the 24-monthinterview) were given a score of 0. The HADS developers proposed scores toclassify patients for anxiety and depression: 0 to 7, noncases; 8 to 10, doubtful(unlikely) cases; 11 or greater, definite cases.

Because most patients who participated in this clinical trial had baselineNEI-VFQ scores at or near the ceiling on the color vision, peripheral vision,and ocular pain subscales⁶ and because thesubfoveal neovascular lesions in study eyes were relatively small, the visualacuity of the study eyes was relatively good and the visual acuity of thefellow eyes of most patients was excellent at baseline,⁷ thesesubscales were judged to be of less importance than others for comparisonof treatment arms during follow-up. Furthermore, these are 1- or 2-item scalesthat yield scores that have categorical distributions. They have been retainedin calculations of overall NEI-VFQ scores but have not been presented separatelyin this analysis of follow-up findings.

Distributions of baseline interview scores were summarized for displaypurposes using exploratory data analysis methods.¹⁹ Becauseof the highly skewed nature of the distributions of scores on most NEI-VFQscales, medians and interquartile ranges or 95% confidence intervals (CIs)on the medians have been used to describe the distributions. For the samereason, distributions of scores were compared between treatment arms usingthe Wilcoxon rank sum test.²⁰ Although notall patients completed all scheduled interviews, median scores from cross-sectionaldistributions at each interview time have been connected by lines for displaypurposes. Changes in scores from baseline to follow-up interviews, which tendedto be distributed normally or approximately so, were compared using t tests for means; mean changes in scores also have beenconnected by lines for display purposes. For comparisons of findings betweentreatment arms for the full group of patients, P≤.01was deemed “statistically significant.” Otherwise, P values were not adjusted for multiple comparisons. Within subgroupsof patients defined by baseline ophthalmic status, P≤.10also has been noted.

Continuous-time mixed linear marginal models were used to adjust forpotentially important covariates to estimate the overall effect of surgeryon NEI-VFQ scores. In addition to treatment arm and interview times, baselinescores and health status, as measured by the SF-36 physical component summaryscale, were included as covariates.

Data from all interviews completed by September 30, 2003, were analyzed.Data from each patient were analyzed with the treatment arm to which he orshe was assigned randomly at the time of enrollment (“intent-to-treat”analysis approach). All data displays use responses from completed interviewsonly; no attempt was made to impute scores for missed interviews. Data analysiswas performed using SAS software (SAS Inc, Cary, NC) and custom-written programs.

When accrual ended on September 30, 2001, two hundred twenty-five patientshad enrolled; 112 patients had been assigned to the surgery arm and 113 patientsto the observation arm. Ocular histoplasmosis was judged by personnel at theSST Photograph Reading Center to be the underlying cause of the choroidalneovascular lesion for 192 (85%) of the enrollees. Based on central reviewof baseline photographs and clinical data, 58 patients (30 [27%] in the observationarm and 28 [25%] in the surgery arm) had neovascular lesions in both eyesand were classified for analysis purposes as bilateral cases. Examples ofneovascular lesions observed in fellow eyes have been published elsewhere.⁶ All other patients were classified as unilateral cases.No consideration was given to other causes of vision loss in fellow eyes whenclassifying patients as unilateral or bilateral cases. Except for 1 patientwho refused surgery after enrollment, all patients had the assigned treatment,that is, submacular surgery or observation (no treatment).

Sociodemographic characteristics and visual status of patients at baselineare summarized in Table 1 and Table 2 by neovascular status within treatmentarms. The treatment arms were well balanced, both overall and within subgroupsof unilateral and bilateral patients, for all characteristics examined. Exceptfor 5 study eyes in the observation arm, all study eyes were phakic at baseline.Patients with bilateral choroidal neovascularization were older, less oftenemployed, and more often hypertensive. As expected, the fellow eye was thebetter-seeing eye among unilateral cases; among bilateral cases, the better-seeingeye was the study eye in almost half the patients (Table 2). Most bilateral cases had deficits in visual acuity, contrastthreshold, and reading speed in both eyes, as expected.

Distributions of baseline scores from the NEI-VFQ are shown in Figure 1 overall (top, left) and for each scaleseparately and by treatment arm for all patients and for unilateral and bilateralcases separately. Baseline scores on most NEI-VFQ scales differed betweenpatients with unilateral and bilateral choroidal neovascularization. However,treatment arms were well balanced on interview scores at baseline among allpatients and within subgroups of bilateral and unilateral cases. None of thecomparisons of baseline scores suggested any clinically or statistically meaningfuldifference between treatment arms (P>.05, Wilcoxonrank sum tests).

A total of 989 follow-up interviews were expected based on vital statusand date of enrollment. Of 493 follow-up interviews expected for patientsin the observation arm, 421 (85%) were completed. Patients in the surgeryarm completed 443 (89%) of 496 interviews expected. Bilateral cases had somewhatbetter interview completion rates (91% overall) than unilateral cases (86%overall) in both treatment arms. Of 18 patients (16%) in the observation armand 15 patients (13%) in the surgery arm who missed the 24-month interview,9 patients in each arm completed either a 36-month or 48-month interview.

At baseline, 106 (94%) of 113 patients in the observation arm and 110(98%) of 112 patients in the surgery arm answered all of the questions. Forthe 24-month interviews, 92 (99%) of 93 patients in the observation arm and96 (99%) of 97 patients in the surgery arm answered all of the questions.

Baseline interviews were conducted by 9 different interviewers; 3 interviewersconducted 176 (78%) of the baseline interviews with the 225 enrollees. Twointerviewers administered 713 (83%) of the 864 follow-up interviews.

Median overall NEI-VFQ scores increased in both treatment arms fromthe baseline interview to the 6-month interview, from 77 to 81 among patientsin the observation arm, and from 74 to 81 among patients in the surgery arm(Figure 2). At the 24-month interview,median overall scores were 85 (95% CI, 80-88) and 86 (95% CI, 83-87) in theobservation and surgery arms, respectively. Distributions of scores in the2 treatment arms were similar at all interview times.

At the 24-month interview, only 25 patients (15 [16%] in the observationarm and 10 [10%] in the surgery arm) had NEI-VFQ overall scores that were5 points or more worse than at baseline. Of the other 166 patients, 13 (14%)in the observation arm and 26 (27%) in the surgery arm had 24-month scoresthat were 15 points or more better than at baseline. Mean changes in scoresfrom baseline, differences in changes between treatment arms, and 95% CIsare summarized in Table 3. Mean changeswere positive (mean scores improved from baseline) in both treatment armsat all times with only 2 exceptions (dependency subscale in the observationarm at 12 and 36 months). The mean difference in 24-month changes in overallscores was 4 (95% CI, 1-8), favoring surgery (P = .01, t test). For individual subscales, the differences in mean24-month changes ranged from 3 (social functioning) to 9 (role difficulties).The mean difference in changes for both the role difficulties subscale andthe dependency subscale met our criterion for statistical significance.

Adjustment for interview times, baseline score, and SF-36 physical componentsummary score at each interview using mixed linear models provided marginalestimates of the overall difference between treatment arms in changes in NEI-VFQscores from baseline. The estimated change from baseline in the overall scorewas 3.5 points larger in the surgery arm than in the observation arm (P = .005). Estimated differences favored surgeryover observation (P<.01) for 5 of the 8 subscalesof interest in this analysis: near activities (4.9 points), distance activities(4.3 points), role difficulties (5.0 points), dependency (6.8 points), andsocial functioning (3.6 points).

Distributions of NEI-VFQ overall scores and changes in scores from baselinealso were compared between treatment arms within the subgroups of 167 unilateralcases and 58 bilateral cases. Median overall scores are displayed in Figure 3. As indicated by separation of the 95%CIs on the median overall scores from the 24-month interviews, median scoresfor unilateral cases remained at levels substantially better than those ofbilateral cases in both treatment arms during follow-up. Median scores onfollow-up interviews were slightly higher than on baseline interviews amongunilateral cases in both treatment arms. Among bilateral cases, median overallscores in the surgery arm were somewhat higher than in the observation armthrough the 24-month interview, with median overall NEI-VFQ scores from the24-month interview of 69 and 51 for the surgery and observation arms, respectively(P = .08, Wilcoxon rank sum test). Forunilateral and bilateral cases, the median scores for most subscales (datanot shown) followed the same pattern as the median overall scores displayedin Figure 3, with separation of scoresof unilateral and bilateral cases, higher (better) median scores during follow-upthan at baseline, and more variability over time among scores for bilateralcases.

Changes in overall NEI-VFQ scores from baseline to follow-up interviewsare shown in Figure 4. Among unilateralcases (Figure 4A), median scores inboth treatment arms increased from baseline, by 3 to 5 points in the observationarm and by 5 to 8 points in the surgery arm. Mean changes among unilateralcases differed between treatment arms only at the 12-month interview (P = .02, t test). Forbilateral cases, the differences in mean changes between the observation andsurgery arms were larger than for unilateral cases through the 24-month interviews(Figure 4B). Mean change in overallNEI-VFQ scores from baseline remained close to no change through the 36-monthinterview for bilateral cases in the observation arm but ranged from 4 to9 points in the surgery arm. The 24-month interviews yielded the largest difference(9 points, 95% CI, 1-17) between the surgery arm and observation arm (P = .03, t test) forbilateral cases.

Mean changes in NEI-VFQ subscale scores from baseline are displayedby treatment arm for unilateral and bilateral cases in Figure 5. For most scales, the patterns are similar to those seenfor changes in overall scores in Figure 4.The largest differences between treatment arms for 24-month changes amongunilateral cases were in the role difficulties and dependency subscales (6points each). Among bilateral cases the largest differences (12-16 points)between treatment arms were observed at the 24-month interviews for the nearactivities, distance activities, role difficulties, and mental health subscales(P≤.05, t tests). Amongbilateral cases, score changes to the 36- and 48-month interviews (when fewerpatients were eligible for interviews) were similar in the 2 treatment armson most scales. Changes from baseline to the 24-month interview are summarizedin Table 4 for unilateral cases andbilateral cases.

As noted earlier, changes in visual acuity favored the surgery arm inthe predefined subgroup of eyes with a best-corrected baseline visual acuityof 20/125 to 20/800 but did not differ between treatment arms in the subgroupof study eyes with a baseline visual acuity 20/50 to 20/100.⁷ Inboth subgroups, the 4-point difference in 24-month changes in overall scores(Table 5) was similar to the changefor the full group of patients (Table 3).Among the smaller subgroup of patients who had visual acuity of the studyeye worse than 20/100 at baseline, differences in 24-month changes are positiveoverall and for each subscale except driving, suggesting somewhat more improvementfrom baseline among patients in the surgery arm than in the observation arm.However, all CIs include 0, except for the general vision subscale, indicatingthat there may be no meaningful difference between treatment arms. The differencebetween treatment arms for the general vision subscale met our criterion forstatistical significance (P = .01, t test). In the larger subgroup of patients whose studyeyes had a baseline visual acuity of 20/50 to 20/100, inclusive, 24-monthchanges in the overall NEI-VFQ scores and scores on 4 subscales favored surgery(P<.05, t tests). Thesmall number of bilateral cases limited investigation of the combined effectsof bilateral choroidal neovascularization and baseline visual acuity of thestudy eye.

The mean SF-36 summary scale scores and standard deviations for thebaseline and 24-month interviews are given in Table 6 by treatment arm for all patients and separately for unilateralcases and bilateral cases. Scores were similar in the 2 treatment arms atboth time points. Mean scores for the physical component summary changed littleduring the 24-month period; in contrast, scores for the mental component summaryincreased (improved) during the same period, both overall and within subgroupsof unilateral cases and bilateral cases, in both treatment arms. The meandifference in changes in the physical component summary scores for patientsin the surgery arm vs patients in the observation arm was −0.4 (95%CI, −2.7 to +2.0). The mean difference in changes in the mental componentsummary scores was 1.0 (95% CI, −2.2 to +4.1). Neither the 24-monthdistributions of scores nor changes in scores differed between treatment arms(P>.40, Wilcoxon rank sum tests).

At the time of enrollment, 10 patients (9%) in the observation arm and7 (6%) in the surgery arm were classified by the HADS criteria as definitecases of depression. Based on the 24-month interview, 3 patients (3%) in theobservation arm and 2 (2%) in the surgery arm among those interviewed wereso classified. Baseline prevalence of definite anxiety was higher than depression:20 patients (18%) in the observation arm and 15 (13%) in the surgery arm.Based on the 24-month interview, only 6 patients (6%) in each treatment armwere classified as definite cases of anxiety using the HADS criteria. Thus,treatment arms did not differ with respect to HADS classification as definitecases of either depression or anxiety.

During follow-up in the SST Group H Trial, patients in the surgery armreported somewhat better vision-targeted quality of life than patients inthe observation arm, as indicated by changes in scores on follow-up interviewscompared with baseline. Median scores from follow-up interviews tended toremain near baseline levels or to improve in both treatment arms (Figure 2). Improvements from baseline scoreswere larger in the surgery arm (Table 3),with the largest effect of surgery noted at 12 months. The modest differencein unadjusted and adjusted 24-month changes in overall NEI-VFQ scores favoringthe surgery arm parallels the difference of 1.2 lines (6 letters) in meanchange in visual acuity from baseline to the 24-month examination in studyeyes among SST Group H Trial patients reported elsewhere.⁷ Similarly,the difference in change scores on the near activities subscale (Table 3) may reflect the larger proportion ofstudy eyes in the surgery arm than in the observation arm that had fasterreading speeds at 24 months than at baseline.⁷

Most patients who participated in this clinical trial were of workingage and employed at baseline (Table 1).Thus, differences favoring surgery for bilateral cases merit considerationwhen treatment options for subfoveal choroidal neovascularization in the secondeye of a patient with the ocular histoplasmosis syndrome are presented. Bilateralcases were expected to demonstrate more marked effects of surgery, whetherpositive or negative. Some of the differences observed among bilateral casesthat favored surgery were quite large at 6 months through 24 months afterenrollment (Figure 5). When mean changesfrom baseline scores were considered (Table 4), differences of 10 points or larger were observed for bilateralcases for at least 2 years on several NEI-VFQ scales. An earlier investigation²¹ suggested that differences of this size may reflectan appreciable difference in the aspects of visual function captured by thesescales. The findings favoring surgery among both unilateral cases and bilateralcases on the role difficulties and dependency subscales (Table 4) may be particularly important to patients of working age.

The target sample size for the SST Group H Trial was projected basedon visual acuity outcomes of interest and not quality-of-life outcomes. Nevertheless,the power of the trial was sufficient to detect differences between treatmentarms for NEI-VFQ scores (Table 3). Furthermore,despite a smaller number of bilateral than unilateral cases enrolled (58 and167 patients, respectively), this number was sufficient to document poorerscores among bilateral cases than among unilateral cases at baseline (Figure 1) and during follow-up (Figure 3).

The largest improvements in visual acuity after surgery were observedduring the first year of clinical follow-up⁷ whilethe largest improvements in NEI-VFQ scores were observed at the 24-month interviews(Table 3). Although this comparisonand the decline in scores after the 24-month interview suggest a lag in thepatient's perception of the effects of worsening visual acuity when thechange is relatively slow, the difference could be due to chance or to factorsnot yet identified. Further exploration of the independent and joint effectsof visual acuity and changes from baseline over time, bilateral choroidalneovascularization, usual occupation, and other factors will be required tounderstand the net effect on vision-targeted quality of life as measured bythe NEI-VFQ.

Several theories have been proposed to explain why scores on most NEI-VFQscales improved for most patients in both treatment arms. Patients may haveadapted to their vision problems or acquired coping skills. Participationin a multicenter clinical trial, in which both eyes were monitored, may havehad a positive effect on patients' perceptions of care received or mayhave had an altruistic appeal. However, a similar effect on vision-targetedquality of life was not observed in the SST Group B Trial²² orSST Group N Trial.²³ Scores may have improvedas patients gained familiarity with the interview or with the interviewers,possibly prompting a desire to please. Initially patients may have fearedfurther large losses of visual acuity in the study eye or fellow eye; withmean 2-year visual acuity losses of 2 lines in study eyes in the observationarm, 1 line in study eyes in the surgery arm, and no loss in the fellow eyesof patients in either treatment arm, patients may have been reassured regardingthe rate of future visual acuity loss. Finally, patients may have respondedpositively to the attention to their concerns, expressed by the clinical staffand implied by inclusion of the health-related quality-of-life interview aspart of data collection for this trial, or may have had a greater awarenessof being part of the research team. If this explanation were correct, thesame phenomenon should have been observed in the other SST clinical trials.^{22 - 23} These and other factors that mayhave contributed to improved scores require further investigation and arebeyond the scope of this report.

Although the SF-36 has been used widely, either alone or, as in theSST Group H Trial, together with a condition-targeted instrument, it has notproven to be sensitive to changes in vision in patients with subfoveal choroidalneovascularization.²⁴ Thus, this instrumentdoes not appear to be useful as an outcome measure in clinical trials in ophthalmologyin which vision is affected by the condition studied. However, the SF-36 hasbeen shown to be useful as a surrogate for other health conditions when adjustmentof NEI-VFQ scores for such conditions is desired in either cross-sectionalor prospective studies.²⁵

As the first study of vision-targeted and general health-related qualityof life among patients with choroidal neovascularization in the ocular histoplasmosissyndrome or idiopathic choroidal neovascularization, the SST Group H Trialhas quantified the effect of both unilateral and bilateral choroidal neovascularization⁶ and provided data regarding changes over time in awell-characterized subset of patients. The database on which these findingsare based was quite good, with high rates of completion of expected interviewsin both treatment arms and few missing responses. Findings for patients inthe observation arm may be particularly useful when designing future evaluationsof treatments for similar ophthalmic conditions. As demonstrated by the SSTGroup H Trial, findings from quality-of-life assessment may support recommendationsbased on clinical findings but also may prompt further investigation of factorsthat contribute to the clinical outcomes and effects on the patient. In conclusion,ophthalmologists and patients similar to those who participated in the SSTGroup H Trial should consider the potential effects of submacular surgeryon specific aspects of vision-targeted quality of life as well as on ophthalmicoutcomes when considering treatment options.

Correspondence: Barbara S. Hawkins, PhD,SST Coordinating Center, 550 N Broadway, Ninth Floor Baltimore, MD 21205-2010(bhawkins@jhmi.edu).

Submitted for Publication: May 20, 2004; finalrevision received August 3, 2004; accepted August 3, 2004.

Writing Committee for SST Group H Trial Report No.10: Barbara S. Hawkins, PhD; Päivi H. Miskala, PhD; Eric B. Bass,MD, MPH; Neil M. Bressler, MD; Ashley L. Childs, MS; Carol M. Mangione, MD,MSPH; Marta J. Marsh, MS.

Documentation of approval of the manuscript submitted for publicationby the members of the SST Research Group is on file at the SST CoordinatingCenter, Baltimore, Md.

Financial Disclosure: Dr Bressler’s employer,The Johns Hopkins University, receives funding from Novartis Pharma AG, Basel,Switzerland; QLT, Inc, Vancouver, British Columbia; and Genentech, South SanFrancisco, Calif, for consulting services and research efforts by Dr Bressler.The terms of these arrangements are managed by The Johns Hopkins Universityaccording to its conflict-of-interest policies.

Funding/Support: The SST is sponsored by theNational Eye Institute, National Institutes of Health, US Department of Healthand Human Services, Bethesda, Md, through cooperative agreements U10 EY11547,EY11557, and EY11558 with The Johns Hopkins University. Participating clinicalcenters were supported by contracts with The Johns Hopkins University. DrMangione's participation as chair of the SST Patient-Centered OutcomesSubcommittee is supported by contract between the David Geffen School of Medicine,University of California, Los Angeles, and The Johns Hopkins University.