To describe risk factors for geographic atrophy (GA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
Cohort within a randomized clinical trial.
We analyzed 1024 CATT ...patients with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment.
Eyes were assigned to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a 2-year monthly or pro re nata (PRN) injection regimen, or monthly injections for 1 year and PRN for 1 year. Demographic, genetic, and baseline ocular characteristics and lesion features of CFP/FA and optical coherence tomography (OCT) were evaluated as risk factors for GA through 2 years of follow-up. Time-dependent Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs).
Development of GA.
By 2 years, GA developed in 187 of 1024 patients (18.3%). Baseline risk factors for GA development included baseline visual acuity (VA) ≤20/200 (aHR, 2.65; 95% confidence interval CI, 1.43-4.93), retinal angiomatous proliferation (RAP; aHR, 1.69; 95% CI, 1.16-2.47), GA in the fellow eye (aHR, 2.07; 95% CI, 1.40-3.08), and intraretinal fluid at the foveal center (aHR, 2.10; 95% CI, 1.34-3.31). Baseline factors associated with lower risk for GA development included blocked fluorescence (aHR, 0.49; 95% CI, 0.29-0.82), OCT measurements of subretinal fluid thickness of >25 μ (aHR, 0.52; 95% CI, 0.35-0.78), subretinal tissue complex thickness of >275 compared with ≤75 μ (aHR, 0.31; 95% CI, 0.19-0.50), and vitreomacular attachment (aHR, 0.55; 95% CI, 0.31-0.97). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06-1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17-2.16) than PRN dosing. There were no strong associations between development of GA and the presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3.
Approximately one fifth of CATT patients developed GA within 2 years of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor therapy may have a role in the development of GA.
To describe risk factors for scar in eyes treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD).
Prospective cohort study within a randomized clinical trial.
...Patients with no scar on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
Eyes were assigned to ranibizumab or bevacizumab treatment and to 1 of 3 dosing regimens for 2 years. Masked readers assessed CFP and FA. Baseline demographic characteristics, visual acuity, morphologic features on photography and optical coherence tomography (OCT), and genotypes associated with AMD risk were evaluated as risk factors using adjusted hazard ratios (aHRs) and associated 95% confidence intervals (CIs). Scars were classified as fibrotic with well-demarcated elevated mounds of yellowish white tissue or nonfibrotic with discrete flat areas of hyperpigmentation with varying amounts of central depigmentation.
Scar formation.
Scar developed in 480 of 1059 eyes (45.3%) by 2 years. Baseline characteristics associated with greater risk of scarring were predominantly classic choroidal neovascularization (CNV) (aHR, 3.1; CI, 2.4-3.9) versus occult CNV, blocked fluorescence (aHR, 1.4; CI, 1.1-1.8), foveal retinal thickness >212 μm (aHR, 2.4; CI, 1.7-3.6) versus <120 μm, foveal subretinal tissue complex thickness >275 μm (aHR, 2.4; CI, 1.7-3.6) versus ≤75 μm, foveal subretinal fluid (aHR, 1.5; CI, 1.1-2.0) versus no subretinal fluid, and subretinal hyperreflective material (SHRM) (aHR, 1.7; CI, 1.3-2.3) versus no SHRM. Eyes with elevation of the retinal pigment epithelium had lower risk (aHR, 0.6; CI, 0.5-0.8) versus no elevation. Drug, dosing regimen, and genotype had no statistically significant association with scarring. Fibrotic scars developed in 24.7% of eyes, and nonfibrotic scars developed in 20.6% of eyes. Baseline risk factors for the scar types were similar except that eyes with larger lesion size or visual acuity <20/40 were more likely to develop fibrotic scars.
Approximately half of eyes enrolled in CATT developed scar by 2 years. Eyes with classic neovascularization, a thicker retina, and more fluid or material under the foveal center of the retina are more likely to develop scar.
Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite ...the absence of similar supporting data.
In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart.
Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.
At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).
To describe outcomes 5 years after initiating treatment with bevacizumab or ranibizumab for neovascular age-related macular degeneration (AMD).
Cohort study.
Patients enrolled in the Comparison of ...AMD Treatments Trials.
Patients were assigned randomly to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After 2 years, patients were released from the clinical trial protocol. At 5 years, patients were recalled for examination.
Visual acuity (VA) and morphologic retinal features.
Visual acuity was obtained for 647 of 914 (71%) living patients with average follow-up of 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments was 15.4. Most patients (60%) were treated 1 time or more with a drug other than their assigned drug. At the 5-year visit, 50% of eyes had VA of 20/40 or better and 20% had VA of 20/200 or worse. Mean change in VA was -3 letters from baseline and -11 letters from 2 years. Among 467 eyes with fluorescein angiography, mean total lesion area was 12.9 mm(2), a mean of 4.8 mm(2) larger than at 2 years. Geographic atrophy was present in 213 of 515 (41%) gradable eyes and was subfoveal in 85 eyes (17%). Among 555 eyes with spectral-domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub-retinal pigment epithelium). Mean foveal total thickness was 278 μm, a decrease of 182 μm from baseline and 20 μm from 2 years. The retina was abnormally thin (<120 μm) in 36% of eyes. Between 2 and 5 years, the group originally assigned to ranibizumab for 2 years lost more VA than the bevacizumab group (-4 letters; P = 0.008). Otherwise, there were no statistically significant differences in VA or morphologic outcomes between drug or regimen groups.
Vision gains during the first 2 years were not maintained at 5 years. However, 50% of eyes had VA of 20/40 or better, confirming anti-vascular endothelial growth factor therapy as a major long-term therapeutic advance for neovascular AMD.
To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.
...Multicenter, randomized clinical trial.
Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial.
At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.
Mean change in visual acuity.
Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval CI, -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF).
Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.
To assess the influence of drug; dosing regimen; and traditional, nontraditional, and genetic risk factors on the incidence of choroidal neovascularization (CNV) in the fellow eye of patients treated ...for CNV with ranibizumab or bevacizumab.
Cohort study of patients enrolled in a multicenter, randomized clinical trial.
Patients with no CNV in the fellow eye at the time of enrollment in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).
Eligibility criteria for the clinical trial required that study eyes have evidence on fluorescein angiography and optical coherence tomography of CNV secondary to age-related macular degeneration (AMD) and visual acuity between 20/25 and 20/320. Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different regimens for dosing over a 2-year period. The genotypes for 4 single nucleotide polymorphisms (SNPs) associated with risk of AMD were determined. Only patients without CNV in the fellow eye at baseline were considered at risk. The CATT ophthalmologists examined patients every 4 weeks through 2 years and recorded treatment for CNV in the fellow eye.
Development of CNV in the fellow eye.
Among 1185 CATT participants, 727 (61%) had no CNV in the fellow eye at enrollment. At 2 years, CNV had developed in 75 (20.6%) of 365 patients treated with ranibizumab and in 60 (16.6%) of 362 patients treated with bevacizumab (absolute difference, 4.0%; 95% confidence interval CI, -1.7% to 9.6%; P = 0.17). The risk ratio for pro re nata dosing relative to monthly dosing was 1.1 (95% CI, 0.8-1.6). Greater elevation of the retinal pigment epithelium and fluid in the foveal center of the study eye were associated with increased incidence of CNV in the fellow eye. Incidence was not associated with genotype on rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3; P>0.35).
Through 2 years, there was no statistically significant difference between ranibizumab and bevacizumab in incidence of CNV in the fellow eye. Genotype on 4 SNPs previously found to be associated with AMD did not affect the risk of CNV in the fellow eye among CATT patients.
Proprietary or commercial disclosure may be found after the references.
To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.
...Multicenter, randomized clinical trial.
Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial.
At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.
Mean change in visual acuity.
Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval CI, -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF).
Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.
Proprietary or commercial disclosure may be found after the references.
The aim of treatment for attention-deficit/hyperactivity disorder (ADHD) is to decrease symptoms, enhance functionality, and improve well-being for the child and his or her close contacts. However, ...the measurement of treatment response is often limited to measuring symptoms using behavior rating scales and checklists completed by teachers and parents. Because so much of the focus has been on symptom reduction, less is known about other possible health problems, which can be measured easily using health-related quality-of-life (HRQL) questionnaires, which are designed to gather information across a range of health domains. The aim of our study was to measure HRQL in a clinic-based sample of children who had a diagnosis of ADHD and consider the impact of 2 clinical factors, symptom severity and comorbidity, on HRQL. Our specific hypotheses were that parent-reported HRQL would be poorer in children with ADHD than in normative US and Australian pediatric samples, in children with increasing severity of ADHD symptoms, and in children who had diagnoses of comorbid psychiatric disorders.
Cross-sectional survey was conducted in British Columbia, Canada. The sample included 165 respondents of 259 eligible children (63.7% response rate) who were referred to the ADHD Clinic in British Columbia between November 2001 and October 2002. Children who are seen in this clinic come from all parts of the province and are diverse in terms of socioeconomic status and case mix. ADHD was diagnosed in 131 children, 68.7% of whom had a comorbid psychiatric disorder. Some children had >1 comorbidity: 23 had 2, 5 had 3, and 1 had 4. Fifty-one children had a comorbid learning disorder (LD), 45 had oppositional defiant disorder or conduct disorder (ODD/CD), and 27 had some other comorbid diagnosis. The mean age of children was 10 years (standard deviation: 2.8). Boys composed 80.9% (N = 106) of the sample. We used the 50-item parent version of the Child Health Questionnaire to measure physical and psychosocial health. Physical domains include the following: physical functioning (PF), role/social limitations as a result of physical health (RP), bodily pain/discomfort (BP), and general health perception (GH). Psychosocial domains include the following: role/social limitations as a result of emotional-behavioral problems (REB), self-esteem (SE), mental health (MH), general behavior (BE), emotional impact on parent (PTE), and time impact on parents (PTT). A separate domain measures limitations in family activities (FA). There is also a single-item measure of family cohesion (FC). Individual scale scores and summary scores for physical (PhS) and psychosocial health (PsS) can be computed. Symptom severity data (parent and teacher) came from the Child/Adolescent Symptom Inventory 4. These checklists provide information on symptoms for the 3 ADHD subtypes (inattentive, hyperactive, and combined). Each child underwent a comprehensive psychiatric assessment by 1 of 4 child psychiatrists. Documentation included a full 5-axis Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis on the basis of a comprehensive assessment. Clinical information for each child was extracted from hospital notes.
Compared with both population samples, children with ADHD had comparable physical health but clinically important deficits in HRQL in all psychosocial domains, FA, FC, and PsS, with effect sizes as follows: FC = -0.66, SE = -0.90, MH = -0.97, PTT = -1.07, REB = -1.60, BE = -1.73, PTE = -1.87, FA = -1.95, and PsS = -1.98. Poorer HRQL for all domains of psychosocial health, FA, and PsS correlated significantly with more parent-reported inattentive, hyperactive, and combined symptoms of ADHD. Children with > or =2 comorbid disorders differed significantly from those with no comorbidity in most areas, including RP, GH, REB, BE, MH, SE, PTT, FA, and PsS, and from those with 1 comorbid disorder in 3 domains, including BE, MH, and FA and the PsS. The mean PsS score for children in the ODD/CD group (mean difference: -12.9; effect size = -1.11) and children in the other comorbidity group (-9.0; effect size = -.77) but not children in the LD group were significantly lower than children with no comorbid disorder. Predictors of physical health in a multiple regression model included child's gender (beta = .177) and number of comorbid conditions (beta = -.197). These 2 variables explained very little variation in the PhS. Predictors of psychosocial health included the number of comorbid conditions (beta = -.374) and parent-rated combined ADHD symptoms (beta = -.362). These 2 variables explained 31% of the variation in the PsS.
Our study shows that ADHD has a significant impact on multiple domains of HRQL in children and adolescents. In support of our hypotheses, compared with normative data, children with ADHD had more parent-reported problems in terms of emotional-behavioral role function, behavior, mental health, and self-esteem. In addition, the problems of children with ADHD had a significant impact on the parents' emotional health and parents' time to meet their own needs, and they interfered with family activities and family cohesion. The differences that we found represent clinically important differences in HRQL. Our study adds new information about the HRQL of children with ADHD in relation to symptom severity and comorbidity. Children with more symptoms of ADHD had worse psychosocial HRQL. Children with multiple comorbid disorders had poorer psychosocial HRQL across a range of domains compared with children with none and 1 comorbid disorder. In addition, compared with children with no comorbidity, psychosocial HRQL was significantly lower in children with ODD/CD and children in the other comorbidity group but not in children with an LD. The demonstration of a differential impact of ADHD on health and well-being in relation to symptom severity and comorbidity has important implications for policies around eligibility for special educational and other supportive services. Because the impact of ADHD is not uniform, decisions about needed supports should incorporate a broader range of relevant indicators of outcome, including HRQL. Although many studies focus on measuring symptoms using rating scales and checklists, in our study, using a multidimensional questionnaire, we were able to show that many areas of health are affected in children with ADHD. We therefore argue that research studies of children with ADHD should include measurement of these broader domains of family impact and child health.