Chantal M. Dolan

Design and baseline characteristics of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma

BACKGROUND Patients with severe and difficult-to-treat asthma represent a small percentage of asthma patients, yet they account for much of the morbidity, mortality, and cost of disease. The goal of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is to better understand the natural history of asthma in these patients. OBJECTIVE To describe the methods and baseline characteristics of the TENOR study cohort. METHODS The TENOR study is a 3-year, multicenter, observational study of patients with severe or difficult-to-treat asthma. From January through October 2001, more than 400 US pulmonologists and allergists enrolled patients. Patients 6 years or older who were considered to have severe or difficult-to-treat asthma by their physicians were eligible. Patients have been receiving care for 1 year or more, have a smoking history of 30 pack-years or less, and have current high medication or health care utilization in the past year. Data are collected semiannually. RESULTS A total of 4,756 patients enrolled and completed a baseline visit. Overall, 73% of the TENOR study patients are adults, 10% are adolescents, and 16% are children. According to physician evaluation, 48% of patients have severe asthma, 48% have moderate asthma, 3% have mild asthma, and 96% have difficult-to-treat asthma. Severe asthmatic patients have the highest health care utilization in the past 3 months (P < .001). CONCLUSIONS The TENOR study is the largest cohort of patients with severe or difficult-to-treat asthma. Although patients are equally divided into moderate or severe asthma categories, most are considered difficult-to-treat. The TENOR study highlights the lack of control in moderate-to-severe asthma and provides a unique opportunity to examine factors related to health outcomes in this understudied population.

Total serum IgE levels in a large cohort of patients with severe or difficult-to-treat asthma

BACKGROUND Limited data are available on levels of IgE in large cohorts of patients with severe or difficult-to-treat asthma. OBJECTIVE To examine IgE levels and disease in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS From January 2001 to October 2001, 4,923 patients were screened for inclusion in the study. Of these, 4,756 patients 6 years or older with severe or difficult-to-treat asthma were enrolled and completed a baseline study visit. Total serum IgE levels were measured at the baseline visit and are summarized by geometric means. RESULTS The mean total IgE level of the population is 106.6 IU/mL (95% confidence interval, 101.5-112.0 IU/mL). Children (6-12 years old) and adolescents (13-17 years old) have higher mean IgE levels than adults (> or =18 years old) (P < .001). Males have a higher mean IgE level than females (P < .001). IgE levels are higher among nonwhite patients than white patients (P < .001). Current smokers have higher IgE levels than past smokers or never smokers (P < .001). Among children, patients with severe asthma have a higher mean IgE level (280.2 IU/mL) than patients with moderate (145.8 IU/mL) or mild (137.8 IU/mL) asthma (P < .001). Among adults, patients with childhood-onset asthma have higher IgE levels (124.3 IU/mL [n = 1,348]) than patients with adult-onset asthma (65.7 IU/mL [n = 1,956]) (P < .001). CONCLUSION In patients with severe or difficult-to-treat asthma from the TENOR study, higher total IgE levels were observed in males, children, smokers, nonwhite racial/ethnic groups, and adults with childhood-onset disease. In addition, IgE levels are associated with asthma severity among younger patients.

Improved vision-related function after ranibizumab for macular edema after retinal vein occlusion: Results from the BRAVO and CRUISE trials

PURPOSE To examine the impact of intravitreal ranibizumab on patient-reported visual function using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) through 6 months in patients with macular edema (ME) secondary to branch or central retinal vein occlusion (RVO). DESIGN Two multicenter, double-masked trials, which enrolled participants with ME secondary to branch or central RVO: the RanibizumaB for the Treatment of Macular Edema following BRAnch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) trial or the Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety (CRUISE) trial. PARTICIPANTS Three hundred ninety-seven BRAVO and 392 CRUISE patients. METHODS Patients were randomized 1:1:1 to monthly sham, 0.3-mg, or 0.5-mg injections of ranibizumab for 6 months. MAIN OUTCOME MEASURES Although visual acuity was the main outcome measure for the trials, mean change from baseline in NEI VFQ-25 scores at month 6 was a secondary outcome measure. RESULTS In BRAVO, among the 132, 134, and 131 patients randomized, respectively, to sham, 0.3 mg ranibizumab, or 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 121 (91.7%), 118 (88.1%), and 125 (95.4%) patients and 123 (93.2%), 128 (95.5%), and 125 (95.4%), respectively, had a 6-month follow-up visit. In CRUISE, among the 130, 132, and 130 patients randomized, respectively, to sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 117 (90.0%), 123 (93.2%), and 120 (92.3%) patients and 115 (88.5%), 129 (97.7%), and 119 (91.5%), respectively, had a 6-month follow-up visit. In both trials, patients treated with ranibizumab reported greater mean improvements in visual function, with substantial differences observed as early as month 1, including the NEI VFQ-25 composite score and near and distance activities subscales, compared with sham patients. P values for comparisons with sham for the composite score and these 2 subscales were <0.05. CONCLUSIONS These results from the BRAVO and CRUISE trials indicate that patients with ME from RVOs treated with monthly ranibizumab report greater improvements in vision-related function compared with sham-treated patients through 6 months, even when a majority of patients present with RVOs in the worse-seeing eye.

Vision-Related Function after Ranibizumab Treatment by Better- or Worse-Seeing Eye: Clinical Trial Results from MARINA and ANCHOR

OBJECTIVE To examine the effects of ranibizumab on the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) scores in neovascular age-related macular degeneration (AMD) according to whether the study eye was the better- or worse-seeing eye at baseline. DESIGN Within 2 randomized, double-masked clinical trials (MARINA and ANCHOR), the NEI VFQ-25 was administered at 0, 1, 2, 3, 6, 9, 12, 18, and 24 months. PARTICIPANTS We included 646 MARINA and 379 ANCHOR patients. INTERVENTION Patients were randomized 1:1:1 to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or control (sham injections for MARINA; photodynamic therapy [PDT] with verteporfin for ANCHOR). MAIN OUTCOME MEASURES Mean change from baseline in NEI VFQ-25 scores at 12 and 24 months. RESULTS Across all treatment arms, 21% to 38% of enrolled eyes were the better-seeing eye. At the 24-month follow-up visit, mean change in composite scores with ranibizumab seemed to be better than control for both better-seeing eyes (8.4 [95% confidence interval (CI), 5.2-11.6], 7.5 [95% CI, 3.7-11.4], and -9.4 [95% CI, -12.5 to -6.3] for the 0.3-mg, 0.5-mg, and sham groups, respectively) and worse-seeing eyes (1.7 [95% CI, -1.1 to 4.4], 1.7 [95% CI, -0.7 to 4.1], and -5.4 [95% CI, -7.9 to -2.8] for the 0.3-mg, 0.5-mg, and sham groups, respectively) in MARINA, as well as the better-seeing eye in ANCHOR (11.3 [95% CI, 5.3-17.3], 13.3 [95% CI, 7.7-19.0], and -2.7 [95% CI, -9.0 to 3.7] for the 0.3-mg, 0.5-mg, and PDT groups, respectively). When the worse-seeing eye was treated in ANCHOR, such differences could not be detected at 24 months (1.3 [95% CI, -1.7 to 4.2], 2.6 [95% CI, -1.1 to 6.3], and 0.1 [95% CI, -3.5 to 3.7] for the 0.3-mg, 0.5-mg, and PDT groups, respectively). CONCLUSIONS Analysis of patient perception of vision-related function in phase III trials evaluating ranibizumab for neovascular AMD demonstrates improved patient-reported outcomes regardless of whether the treated eye is the better- or worse-seeing eye at onset of treatment, and supports treatment of such lesions with ranibizumab, even those in the worse-seeing eye. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Prevalence of and Risk Factors for Diabetic Macular Edema in the United States

IMPORTANCE Diabetic macular edema (DME) is a leading cause of vision loss in persons with diabetes mellitus. Although there are national estimates for the prevalence of diabetic retinopathy and its risk factors among persons with diabetes, to our knowledge, no comparable estimates are available for DME specifically. OBJECTIVES To estimate the prevalence of DME in the US population and to identify associated risk factors. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional analysis of 1038 participants aged 40 years or older with diabetes and valid fundus photographs in the 2005 to 2008 National Health and Nutrition Examination Survey. MAIN OUTCOMES AND MEASURES The overall prevalence of DME and its prevalence according to age, race/ethnicity, and sex. RESULTS Of the 1038 persons with diabetes analyzed for this study, 55 had DME, for an overall weighted prevalence of 3.8% (95% CI, 2.7%-4.9%) or approximately 746, 000 persons in the US 2010 population aged 40 years or older. We identified no differences in the prevalence of DME by age or sex. Multivariable logistic regression analysis showed that the odds of having DME were higher for non-Hispanic blacks than for non-Hispanic whites (odds ratio [OR], 2.64; 95% CI, 1.19-5.84; P = .02). Elevated levels of glycosylated hemoglobin A1c (OR, 1.47; 95% CI, 1.26-1.71 for each 1%; P < .001) and longer duration of diabetes (OR, 8.51; 95% CI, 3.70-19.54 for ≥ 10 vs <10 years; P < .001) were also associated with DME prevalence. CONCLUSIONS AND RELEVANCE These results suggest a greater burden of DME among non-Hispanic blacks, individuals with high levels of hemoglobin A1c, and those with longer duration of diabetes. Given recent treatment advances in reducing vision loss and preserving vision in persons with DME, it is imperative that all persons with diabetes receive early screening; this recommendation is even more important for those at higher risk for DME.

Improved Vision-Related Function After Ranibizumab vs Photodynamic Therapy: A Randomized Clinical Trial

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.

Responsiveness of NEI VFQ-25 to Changes in Visual Acuity in Neovascular AMD: Validation Studies from Two Phase 3 Clinical Trials

PURPOSE To examine the responsiveness of the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) by using data from the MARINA and ANCHOR trials in neovascular age-related macular degeneration (AMD) and to establish the change in the NEI VFQ-25 associated with a 15-letter change in best corrected visual acuity (BCVA). METHODS In MARINA, 716 patients were randomized to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections. In ANCHOR, 423 patients were randomized to monthly ranibizumab (0.3 or 0.5 mg) with sham photodynamic therapy (PDT) or sham ocular injections with verteporfin PDT. Patients had follow-up interviews and BCVA measurements over 24 months. Data were analyzed separately for MARINA and ANCHOR, and treatment groups were pooled within each trial. The clinically relevant difference in NEI VFQ-25 was estimated based on regression models of change from baseline to month 12 in BCVA. RESULTS Subgroups categorized by BCVA change (>or=15 letters gained, <15 letters lost or gained, or >or=15 letters lost) differed substantially in mean change in NEI VFQ-25 composite scores and three pre-specified subscale scores (near activities, distance activities, and vision-specific dependency) over 12 months. According to the regression models, the difference associated with a 15-letter change was 4 to 6 points for the composite score and the three pre-specified subscales. CONCLUSIONS These data support the use of the NEI VFQ-25 as a responsive and sensitive measure of vision-related function in neovascular AMD populations. Based on MARINA and ANCHOR data, a 4- to 6-point change in NEI VFQ-25 scores represents a clinically meaningful change corresponding to a 15-letter change in BCVA.

Validation of the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) in Age-Related Macular Degeneration

PURPOSE Patient-reported measures of visual function are increasingly incorporated into clinical trials of new treatments for age-related macular degeneration (AMD). Limited information is available regarding the associations between distance visual acuity (VA), reading speed, or contrast sensitivity and the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) subscales judged relevant to these measures. This studys objective was to evaluate such associations along with questions on restricted activity days. METHODS This cross-sectional study was conducted in patients with clinical diagnoses of neovascular AMD. Patient-reported outcome measures included the NEI VFQ-25 and restricted activity days. Clinical assessments included best-corrected visual acuity (BCVA), reading speed, and contrast sensitivity. The better-seeing eye was defined based on the BCVA of each patient. Psychometric properties of the NEI VFQ-25 were examined; analyses a priori focused on the Near Activities, Distance Activities, and Vision-Specific Dependency subscales. RESULTS The final study group included 92 participants (mean age, 78 years). Cronbachs α for the subscales ranged from 0.67 to 0.92. The NEI VFQ-25 overall composite, Near Activities, Distance Activities, and Vision-Specific Dependency scores were correlated with BCVA (r = -0.48 to -0.54, all P < 0.0001), reading speed (r = 0.43 to 0.56, all P < 0.0001), and contrast sensitivity (r = -0.39 to -0.46, all P < 0.001) of the better-seeing eye and with restricted activity days (r = -0.52 to -0.55, all P < 0.0001). CONCLUSIONS This study provides additional evidence supporting the validity of the NEI VFQ-25 in neovascular AMD patients by demonstrating correlations with a spectrum of vision measurements and a daily function measure.

Underuse of the Health Care System by Persons With Diabetes Mellitus and Diabetic Macular Edema in the United States

IMPORTANCE Thickening of the center of the retina, diabetic macular edema (DME), is the most common cause of visual loss due to diabetes mellitus. Treatment of DME has improved dramatically, and the prompt diagnosis of DME and referral of these patients have become more critical. Nonetheless, awareness of and care for DME in the US population is uncharacterized. OBJECTIVE To characterize eye care and awareness of eye disease among persons with DME in the general US population. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional analysis of data from participants in the 2005 to 2008 National Health and Nutrition Examination Survey 40 years or older with diabetes mellitus and fundus photographs. MAIN OUTCOMES AND MEASURES Among persons with DME, (1) awareness that diabetes has affected their eyes; (2) report on the last time they visited a diabetes specialist; (3) report on their last eye examination with pupil dilation; and (4) prevalence of visual impairment. RESULTS In 2010, only 44.7% (95% CI, 27.0%-62.4%) of US adults 40 years or older with DME reported being told by a physician that diabetes had affected their eyes or that they had retinopathy; 46.7% (95% CI, 27.5%-66.0%), that they had visited a diabetes nurse educator, dietician, or nutritionist for their diabetes mellitus more than 1 year ago or never; and 59.7% (95% CI, 43.5%-75.9%), that they had received an eye examination with pupil dilation in the last year. Among persons with DME, 28.7% (95% CI, 12.7%-44.7%) were visually impaired (defined as visual acuity worse than 20/40 in the eye with DME) based on visual acuity at the initial examination and 16.0% (95% CI, 2.5%-29.4%) based on best-corrected visual acuity. CONCLUSIONS AND RELEVANCE Many persons with diabetes mellitus in the United States are not getting care that can prevent visual impairment and blindness. Strategies to increase awareness are warranted, especially given the recent availability of improved therapies for DME.

Estimated Cases of Blindness and Visual Impairment from Neovascular Age-Related Macular Degeneration Avoided in Australia by Ranibizumab Treatment

Intravitreal injections of anti-vascular endothelial growth factor agents, such as ranibizumab, have significantly improved the management of neovascular age-related macular degeneration. This study used patient-level simulation modelling to estimate the number of individuals in Australia who would have been likely to avoid legal blindness or visual impairment due to neovascular age-related macular degeneration over a 2-year period as a result of intravitreal ranibizumab injections. The modelling approach used existing data for the incidence of neovascular age-related macular degeneration in Australia and outcomes from ranibizumab trials. Blindness and visual impairment were defined as visual acuity in the better-seeing eye of worse than 6/60 or 6/12, respectively. In 2010, 14 634 individuals in Australia were estimated to develop neovascular age-related macular degeneration who would be eligible for ranibizumab therapy. Without treatment, 2246 individuals would become legally blind over 2 years. Monthly 0.5 mg intravitreal ranibizumab would reduce incident blindness by 72% (95% simulation interval, 70–74%). Ranibizumab given as needed would reduce incident blindness by 68% (64–71%). Without treatment, 4846 individuals would become visually impaired over 2 years; this proportion would be reduced by 37% (34–39%) with monthly intravitreal ranibizumab, and by 28% (23–33%) with ranibizumab given as needed. These data suggest that intravitreal injections of ranibizumab, given either monthly or as needed, can substantially lower the number of cases of blindness and visual impairment over 2 years after the diagnosis of neovascular age-related macular degeneration.