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Improved Vision-Related Function After Ranibizumab vs Photodynamic TherapyA Randomized Clinical Trial
Neil M. Bressler, MD;
Tom S. Chang, MD;
Jennifer T. Fine, ScD;
Chantal M. Dolan, PhD;
James Ward, PhD; for the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) Research Group
Arch Ophthalmol. 2009;127(1):13-21.
ABSTRACT
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Objective To compare patient-reported visual function in those with neovascular age-related macular degeneration treated with ranibizumab or verteporfin photodynamic therapy (PDT).
Design Multicenter, double-masked, phase 3 trial (ANCHOR). Participants were randomized in a 1:1:1 ratio to receive 0.3 or 0.5 mg of intravitreal ranibizumab plus sham verteporfin or sham injections plus active verteporfin monthly. The National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) was administered at baseline and 1, 2, 3, 6, 9, 12, 18, and 24 months.
Main Outcome Measure Mean change from baseline in NEI VFQ-25 scores at 12 months.
Results At 12 months, patients treated with ranibizumab (0.3 mg [n = 137] or 0.5 mg [n = 139]) had mean improvements in NEI VFQ-25 composite scores of 5.9 (95% confidence interval [CI], 3.6 to 8.3) and 8.1 (95% CI, 5.3 to 10.8) points, respectively; patients treated with PDT (n = 142) had a mean improvement of 2.2 points (95% CI, –0.3 to 4.7; vs 0.5 mg of ranibizumab, P < .001; vs 0.3 mg of ranibizumab, P = .003). At each dose through 24 months, patients treated with ranibizumab were more likely to improve in most subscales, including the prespecified subscales (near activities, distance activities, and vision-specific dependency).
Conclusions Patients treated with ranibizumab were more likely to report clinically meaningful improvements in visual function through 24 months compared with those treated with verteporfin PDT.
Application to Clinical Practice Ranibizumab treatment in neovascular age-related macular degeneration can improve patient-reported visual function.
Trial Registration clinicaltrials.gov Identifier: NCT00061594
INTRODUCTION
Neovascular age-related macular degeneration (AMD) is the leading cause of blindness when left untreated in adults in the industrial world.1 It can affect central, high-acuity vision, compromising one's ability to perform basic activities of daily living, such as reading, writing, cooking, and driving,2 leading to a progressive loss of independence and decreased vision-related function. Clinical trials in AMD, such as those showing ranibizumab's effectiveness, typically use the percentage of patients who do not lose 15 or more letters in the treated eye as their primary outcome measure.3 Previously published studies have demonstrated that visual acuity is correlated with patient-reported vision-related function measured by the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25)4-5 but suggest that clinical and vision-related function assessments are not interchangeable for assessing patient outcomes6 and should be viewed as complementary. The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial recently showed that ranibizumab treatment of neovascular AMD with a minimally classic or occult lesion, without classic lesion composition on fluorescein angiography, and presumed recent disease progression resulted in clinically meaningful improvement in vision-related function more often than sham injections.7 The effects of ranibizumab on patient-reported vision-related function compared with an active treatment or across each subscale have not yet been reported.
Herein, we describe the results of the NEI VFQ-25 from the ANCHOR trial. This randomized clinical trial reported better visual acuity outcomes with ranibizumab than with verteporfin photodynamic therapy (PDT) (Visudyne; Novartis Pharmaceuticals, Basel, Switzerland) in patients with choroidal neovascularization with a predominantly classic lesion composition on fluorescein angiography, with or without recent disease progression.8 Patient-reported outcomes from this neovascular AMD clinical trial provide information about critical functional parameters that supplement traditional clinical measures of vision.9-10
METHODS
Institutional review board approval was obtained before patient enrollment began, and Health Insurance Portability and Accountability Act compliance was achieved at all 83 participating study sites. All patients provided signed consent for participation before enrollment and random treatment assignment.
STUDY DESIGN AND PROTOCOL
Between June 2003 and September 2004, 423 patients with subfoveal choroidal neovascularization and a predominantly classic lesion composition on fluorescein angiography11-12 secondary to AMD were enrolled in the study. Baseline responses on the NEI VFQ-25 were obtained from 418 of the 423 patients. The eligibility requirements for patients and eyes, clinical evaluation procedures, and clinical data collection methods and schedules are described in detail elsewhere.8 Patients were randomized in a 1:1:1 ratio to receive monthly intravitreal injections of 0.3 mg or 0.5 mg of ranibizumab with sham PDT or monthly sham injections with active verteporfin PDT administered as often as every 3 months, based on the investigators' evaluation of angiography. Patients were to receive monthly injections for 2 years in the study eye. Only 1 eye per patient was chosen as the study eye, and only the study eye received ranibizumab with sham PDT or sham injection with active PDT. If both of a patient's eyes were eligible, the eye with the better visual acuity was selected for treatment unless, for medical reasons, the investigator deemed the eye with worse visual acuity more appropriate for the study. As 1 of the first 2 phase 3 studies evaluating ranibizumab for treatment of neovascular AMD, it was unknown when treatment effects on vision-related function might be observed. Thus, all patients were scheduled for follow-up interviews at 1, 2, 3, 6, 9, 12, 18, and 24 months after the initial interview and treatment, with best-corrected visual acuity measured at each monthly visit. Before study completion, the protocol was amended so that patients who had not yet completed their month 23 injection visit were offered the option to receive monthly injections of 0.3 mg of ranibizumab for the remainder of the treatment period.
NEI VFQ-25 METHODS
The interview instrument used was the NEI VFQ-25.13 It consisted of a 25-item base set of questions that measured different aspects of visual function and 6 additional items to enhance the reliability of the near and distance visual subscales.13-15 The NEI VFQ-25 scores were calculated using the developers' recommendations according to published guidelines.
Although no minimum important difference has been established for the NEI VFQ-25, several studies have suggested that a 10-point difference in NEI VFQ-25 scores is clinically important and correlates with a 15-letter change in visual acuity.6, 16-17 It has also been suggested that a 5-point change in NEI VFQ-25 scores is clinically important.17-18 In the current study, a 10-point change in the NEI VFQ-25 overall composite or subscale scores was considered a clinically meaningful change (though not necessarily the minimum clinically meaningful change) across the range of enrolling visual acuities. The NEI VFQ-25 interview was administered prior to visual acuity measurements at each follow-up visit by trained study-site personnel who were masked to treatment assignment.
STATISTICAL ANALYSIS
Mean change from baseline in NEI VFQ-25 scores was one of the secondary efficacy end points in ANCHOR. Three subscales—near activities, distance activities, and vision-specific dependency—were identified before analysis of the study as important to patients with AMD.6, 17 All efficacy analyses were performed on the intent-to-treat patient population, using the last-observation-carried-forward approach to impute missing scores unless otherwise indicated, with no adjustment for the 50 patients treated with PDT who switched to ranibizumab after 18 to 23 months following randomization. Patients with missing baseline scores were excluded from the analysis. Sensitivity analyses (data not shown) were performed on mean values based on observed data, with no imputation of missing data, and supported the primary conclusions.
The Pearson product moment correlation of baseline NEI VFQ-25 overall composite score and baseline visual acuity was calculated for the 417 patients with both measures available. Mean changes in NEI VFQ-25 scores from baseline to follow-up interviews were compared in the treatment groups using t tests from analysis of covariance models that were adjusted for baseline visual acuity ( 45 or <45 letter score), using the relevant baseline NEI VFQ-25 subscale score as covariates. Patients achieving a 10-point or greater gain (as well as a 10-point or greater loss) on the NEI VFQ-25 at 12 or 24 months were compared using descriptive statistics (percentages and corresponding 95% confidence intervals [CIs]) as well as Pearson  2 tests. Times to first gain of 10 or more points from baseline across 24 months were also descriptively compared with Kaplan-Meier time-to-event curves for the near activities, distance activities, and dependency subscales.
The study eye was defined as the better-seeing eye when the visual acuity letter score at baseline was higher than the visual acuity letter score for the nonstudy eye; the study eye was defined as the worse-seeing eye when the letter score at baseline was worse than the visual acuity letter score for the nonstudy eye. SAS software (SAS Inc, Cary, North Carolina) was used for data analyses.
RESULTS
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS
Baseline responses on the NEI VFQ-25 were obtained for 418 of the 423 patients enrolled in ANCHOR: 142 randomized to PDT, 137 to 0.3 mg of ranibizumab, and 139 to 0.5 mg of ranibizumab. The mean age at baseline was 77 years (range, 53-97 years). Relevant participant characteristics at baseline by treatment arm were well balanced (Table 1). More patients received treatment in their worse-seeing eye in each treatment arm: 68% in the PDT arm, 66% in the 0.3-mg ranibizumab arm, and 75% in the 0.5-mg ranibizumab arm. Of the enrolled patients, 42% in the PDT arm, 35% in the 0.3-mg ranibizumab arm, and 31% in the 0.5-mg ranibizumab arm had neovascular AMD in the fellow eye. The treatment groups also had a balanced distribution of visual acuity, whether or not their study eye was the better- or worse-seeing eye at baseline (Table 1). The baseline NEI VFQ-25 overall composite and subscale scores for the analysis population are presented in Table 2. The Pearson product moment correlation coefficient for baseline NEI VFQ-25 overall composite score and baseline visual acuity was r = 0.12 (n = 417, P = .01). For better-seeing eyes, the correlation was r = 0.36 (n = 126, P < .001).
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Table 1. Baseline Patient-Reported Vision-Related Outcomes and Visual Acuity Distribution
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Table 2. Baseline NEI VFQ-25 Scores in the ANCHOR Study
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INTERVIEW COMPLETION
Interview completion rates during follow-up in the 418 patients with an interview at baseline were 89% for the PDT group, 91% for the 0.3-mg ranibizumab group, and 92% for the 0.5-mg ranibizumab group at 12 months. These rates were 77%, 82%, and 82%, respectively, at 24 months.
NEI VFQ-25 SCORES DURING FOLLOW-UP
Overall Composite Score
The mean NEI VFQ-25 overall composite score improved in all 3 treatment arms by month 12, but only in the ranibizumab-treatment groups by month 24 (Table 3). In the PDT, 0.3-mg ranibizumab, and 0.5-mg ranibizumab treatment arms, respectively, 7, 10, and 11 of the subscale scores improved by month 12; and 5, 10, and 11 of the subscale scores improved by month 24. Furthermore, the patients treated with ranibizumab had mean changes that were higher from baseline in NEI VFQ-25 scores than those in patients receiving PDT and sham intravitreal injections through month 24 in most subscales (Table 3). For the analysis sample, the mean changes from baseline in the overall composite scores at 12 months of follow-up were 2.2 (95% CI, –0.3 to 4.7), 5.9 (95% CI, 3.6 to 8.3), and 8.1 (95% CI, 5.3 to 10.8) in the PDT, 0.3-mg ranibizumab, and 0.5-mg ranibizumab treatment arms, respectively (Table 3). At 24 months, the mean improvements from baseline in the overall composite scores were sustained in the 0.3-mg ranibizumab group (5.0; 95% CI, 2.2 to 7.8) and the 0.5-mg ranibizumab group (5.8; 95% CI, 2.6 to 9.0), but not in the PDT group (–0.3; 95% CI, –3.1 to 2.5). Similar patterns were observed in the 2 ranibizumab treatment arms throughout the study.
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Table 3. Change in NEI VFQ-25 Scores From Baseline to Months 12 and 24
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Subscale Scores
From baseline to months 12 and 24, the mean change in most subscale scores, including in the 3 prespecified NEI VFQ-25 subscale scores (near activities, distance activities, and vision-specific dependency), indicated improvement in the patients who were treated with either dose of ranibizumab (Table 3, Figure 1, and eFigure 1). The mean improvements and effectiveness of ranibizumab over PDT were sustained for 24 months.
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Figure 1. Mean change from baseline through 24 months in National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) subscale scores by treatment group. Vertical lines represent ±1 standard error. The number of patients in the photodynamic therapy (PDT) and 0.3-mg and 0.5-mg ranibizumab groups were 142, 137, and 139, respectively, for all subscales, except the driving subscale (n = 120, n = 117, and n = 127, respectively). For a comparison of ranibizumab-dose groups with PDT at 12 and 24 months, see P values in eTable 1).
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Dichotomous Outcomes of Clinical Relevance
The NEI VFQ-25 overall composite and most subscale scores at 12 and 24 months in each ranibizumab arm were more likely to improve by at least 10 points and less likely to decrease by at least 10 points compared with scores in the PDT arm (Figure 2 and eFigure 2). An exploratory Kaplan-Meier analysis of patients by the first time to improvement of 10 or more points by treatment arm was evaluated among the 3 prespecified subscales. Such improvements could be seen by month 1 in any of the treatment arms, but the cumulative percentage of overall scores and scores from the 3 subscales that improved by 10 or more points was generally greater for patients treated with ranibizumab than for those treated with PDT (Figure 3). The cumulative percentage of patients treated with ranibizumab with these improvements was up to twice as high as that of patients treated with PDT. In all 3 treatment arms, the increase in the cumulative percentage between 3 and 6 months indicates that not all patients who improve by 10 or more points will do so within 3 months. Even after 6 months, additional patients achieved this outcome for the first time in the overall score and the distance activities and near activities subscales. Most of the patients treated with ranibizumab or PDT who achieved a clinically meaningful improvement of 10 or more points maintained this outcome at 12 and 24 months, as shown by the percentage with these outcomes at these times (Figure 2).
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Figure 2. Percentage of patients with improvement of 10 or more points or loss of 10 or more points from baseline to 12 or 24 months in National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) subscale scores by treatment group. The number of patients in the photodynamic therapy (PDT) and 0.3-mg and 0.5-mg ranibizumab groups were 142, 137, and 139, respectively, for all subscales, except the driving subscale (n = 120, n = 117, and n = 127, respectively). For a comparison of ranibizumab-dose groups with PDT at 12 and 24 months, see P values in eTable 2.
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Figure 3. Time to first gain of 10 or more points on the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) from baseline to the next qualifying visit or last qualifying visit across 24 months (Kaplan-Meier estimates) by treatment group. PDT indicates photodynamic therapy.
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COMMENT
The ANCHOR trial demonstrated improvement in patient-reported vision-related function more often with the use of ranibizumab than with another active treatment for neovascular AMD (PDT with verteporfin) for the overall composite score and across most subscale scores. These results are consistent with the MARINA trial,7 which compared ranibizumab treatment with a sham injection. After 12 months of treatment, patients in the ranibizumab arm not only had greater mean changes from baseline in overall and most subscale NEI VFQ-25 scores than those in the PDT arm, but they also had greater mean changes in scores than patients who underwent submacular surgery,6, 19 macular translocation,20 and treatment with pegaptanib.21 Direct comparisons with treatments from different trials and cohorts must be made with caution. Visual acuity values are moderately (not perfectly) correlated with NEI VFQ-25 scores4, 13, 22; thus, the NEI VFQ-25 results from the ANCHOR trial likely represent benefits (including for mental health, whose subscale showed the greatest improvement from baseline) of ranibizumab not captured by visual acuity results.
The MARINA trial previously reported comparable clinically relevant improvements in patient-reported vision-related function with ranibizumab treatment compared with sham injection for the overall and 3 prespecified subscale scores (10-point change from baseline).7 The ANCHOR trial independently corroborates clinically relevant changes from baseline in a large number of patients treated with ranibizumab not only for these prespecified subscales, but also across most of the subscales. Data across all other subscales in the MARINA trial are currently being analyzed. The changes in ANCHOR were detected as early as 2 months after treatment initiation (PDT or ranibizumab), and most patients with clinically relevant improvements achieved them during the first 6 months. More patients treated with ranibizumab experienced these improvements than those treated with PDT at most points. These gains were maintained in most patients at 12 and 24 months.
In 5 of the remaining 9 NEI VFQ-25 subscales not specified as secondary end points (driving, role difficulties, mental health, social functioning, and general vision), patients treated with 0.5 mg or 0.3 mg of ranibizumab reported at least a 5-point benefit in mean change from baseline score at 12 and 24 months compared with patients treated with PDT. The mental health subscale demonstrated the greatest benefit, the magnitude of which was comparable with that observed in other studies evaluating interventions for AMD.23-24 Although color vision did not meet this 5-point threshold, other studies17, 20 have also suggested that patient-reported perception of visual function with respect to color vision measured as a subscale of the NEI VFQ-25 is not affected greatly by neovascular AMD. Patients treated with ranibizumab and PDT did not experience a difference of at least 5 points in the ocular pain, peripheral vision, or general health subscale scores, a finding that could be expected, as AMD is a painless disease that does not directly affect general health or peripheral vision. Results in these other subscales provide additional support regarding the validity of the treatment effect of ranibizumab on patient-reported vision-related function in those participating in the ANCHOR study and provide independent support of similar findings noted after ranibizumab treatments in the MARINA study.7
In the ANCHOR trial, patients treated with ranibizumab reported greater mean improvements in self-reported vision-specific outcomes than those treated with another active treatment, verteporfin PDT, demonstrating that not all of the improvement in visual function after ranibizumab treatment could be ascribed to a placebo effect. Previous randomized, controlled studies on patient-reported vision-related improvements in neovascular AMD have compared treatment with sham or no treatment, raising the possibility that some or all of the observed improvement could be related to the perception of an intervention rather than to a benefit intrinsic to the treatment. For example, in the National Institutes of Health–sponsored Submacular Surgery Trials, patients assigned to surgery for subfoveal choroidal neovascularization secondary to AMD maintained stable median NEI VFQ-25 scores relative to baseline after 24 months of follow-up (median gain of 1 point).6 Although this was a small improvement compared with the observation arm, which lost a median of 3 points, only the mental health subscale showed any substantial improvement from baseline at 24 months in the surgery arm. This raised the possibility that the improvement was due to an intervention, not specific to the surgical intervention. In previous patient-reported vision-related quality of life outcomes following pharmacologic treatment for choroidal neovascularization in AMD, improvements from baseline in the NEI VFQ-25 overall composite and most subscale scores6-7,19 were always compared with sham treatment.
Our study has several major strengths that minimize bias in the results reported. First, both patients and study personnel who administered the NEI VFQ-25 interviews were masked to treatment assignment. Masking is particularly important in research in which a patient's subjective assessment of function is measured, because his or her desire for treatment benefit, coupled with a physician's or surgeon's enthusiasm for a specific treatment, may bias self-reported vision-related scores in unmasked studies or studies in which not all treatment arms have an active treatment. Second, the randomization of a relatively large number of participants to the PDT arm in our study should eliminate most other potentially confounding variables, such as systemic health, adjustment to vision loss, and other unpredictable psychosocial factors. Finally, our relatively large study cohort provided sufficient statistical power to detect treatment differences of 10 or more points but not of 5 points or less.
Patient-reported vision-related outcomes are designed to measure visual function, which is a binocular phenomenon. In prior studies, correlation analysis determined that patient-reported vision-related function results depend more on changes in visual acuity of the better-seeing eye,25 a situation in which one might expect that a treatment that can improve visual acuity would more profoundly affect NEI VFQ-25 scores. In the ANCHOR trial, only 1 eye of any participant was treated. Future analyses that will examine the impact of ranibizumab treatment on vision-related function according to whether the study eye was the better- or worse-seeing eye at the time of randomization are under way.
Limitations of our study are in general consistent with those associated with understanding treatment effect in controlled trials vs actual clinical practice. It may be difficult to generalize these results to the entire neovascular AMD population meeting the criteria of the ANCHOR study, as the patients in this study were mostly white and were participating in a clinical trial with regular follow-up planned for at least 2 years. These study participants may be healthier and better able to cope with the visual disabilities that accompany neovascular AMD than the general AMD population. Also, these results apply to a neovascular AMD population with visual acuity within a specific range and with a specific fluorescein angiographic lesion composition (ie, predominantly classic). Moreover, there may be variations in patient responses when collected from many interviewers. However, randomization should decrease the impact of variability among interviewers.
In summary, we describe clinically relevant improvement in patient-reported vision-related function, comparing the use of ranibizumab with another active treatment, verteporfin PDT. These results were consistently observed in NEI VFQ-25 overall composite and most subscale scores, including in prespecified subscales of interest (near activities, distance activities, and dependency), were noted as early as 1 month after treatment initiation in some patients, and were maintained through 2 years of treatment. Very large differences were seen within the mental health subscale scores, in which 50% to 60% of treated patients improved by 10 or more points. The NEI VFQ-25 data from the ANCHOR trial capture patient-reported outcomes that represent the real-life challenges of neovascular AMD and show that, on average, treatment with ranibizumab compared with PDT improves patients' ability to function on a daily basis.
AUTHOR INFORMATION
Correspondence: Neil M. Bressler, MD, Department of Ophthalmology, Retina Division, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 550 North Broadway, Ste 115, Baltimore, MD 21205-2002 (nmboffice{at}jhmi.edu).
Submitted for Publication: March 10, 2008; final revision received July 27, 2008; accepted August 18, 2008.
Financial Disclosure: This study was supported by Genentech Inc and Novartis Pharma AG. Dr Bressler's employer, the Johns Hopkins University (JHU), but not Dr Bressler, receives funding as principal investigator from Allergan, Bausch & Lomb, Carl Zeiss Meditec, Genentech, Jerini, Notal Vision, Novartis, Othera, QLT, Regeneron, and Steba Pharmaceuticals for sponsored projects by the Department of Ophthalmology for Dr Bressler's efforts. Dr Bressler receives salary support for these sponsored projects; the terms of these projects are negotiated and administered by JHU's Office of Research Administration. Under JHU's policy, support for the costs of research, administered by the institution, does not constitute a conflict of interest. In addition, Dr Bressler's spouse is a paid consultant for Notal Vision and Oxigene. The terms of these arrangements are being managed by JHU in accordance with its conflict of interest policies. Dr Chang receives funding from Genentech for clinical and scientific consultation. Dr Fine is a Genentech employee. Drs Dolan and Ward are paid consultants for Genentech. The design and conduct of the study as well as the data collection, management, and analysis were supported by Genentech Inc and Novartis Pharma AG. Medical writing assistance for this manuscript was provided by Genentech Inc.
Disclaimer: The design of the ANCHOR study was in part similar to the design of the MARINA trial. As such, similar wording from parts of a report written by the authors on the MARINA trial, in which the copyright was transferred to the American Medical Association, were used for this report with permission of the American Medical Association when it was judged to be the best wording. Since the MARINA and ANCHOR studies are totally independent trials with many differences, the use of similar wording is not judged to represent duplicate publication as defined by medical editors.
Additional Contribution: Pamela Wong, MPH, provided statistical support.
Author Affiliations: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland (Dr Bressler); Retina Institute of California, Pasadena (Dr Chang); and Genentech Inc, South San Francisco, California (Drs Fine, Dolan, and Ward).
Group Information: A list of the ANCHOR Research Group members who contributed data for the patients enrolled in this clinical trial was published in N Engl J Med. 2006;355(14):1432-1444.
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Responsiveness of NEI VFQ-25 to Changes in Visual Acuity in Neovascular AMD: Validation Studies from Two Phase 3 Clinical Trials
Suner et al.
IOVS 2009;50:3629-3635.
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