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PURPOSE: To investigate whether a nonlinear association between central subfield thickness (CST) on spectral-domain OCT and concurrent visual acuity letter score (VALS) exists in eyes treated initially with aflibercept or bevacizumab for macular edema associated with central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2). DESIGN: Long-term follow-up after a randomized clinical trial from 64 centers in the United States. PARTICIPANTS: Participants were followed up to 60 months and treated at investigator discretion after completing the 12-month treatment protocol. METHODS: Two-segment linear regression models were compared with simple linear regression models of VALS on CST. Pearson correlation coefficients were calculated to assess strength of CST and VALS associations. MAIN OUTCOME MEASURES: Central subfield thickness was measured by OCT and VALS by the electronic Early Treatment Diabetic Retinopathy Study methodology. RESULTS: Estimated inflection points, reflecting turning points at which the CST and VALS association changes from positive to negative, calculated at 7 postbaseline visits, range from 217 to 256 µm. A strongly positive correlation exists to the left of each estimated inflection point, ranging from 0.29 (P < 0.01 at month 60) to 0.50 (P < 0.01 at month 12), and a strongly negative correlation exists to the right of each estimated inflection point, ranging from -0.43 (P < 0.01 at month 1) to -0.74 (P < 0.01 at month 24). Randomization statistical tests showed that 2-segment models are favored over 1-segment models for all postbaseline months (P < 0.001 for all tests performed). CONCLUSIONS: The relationship between CST and VALS in eyes with CRVO or HRVO after treatment with anti-vascular endothelial growth factor (VEGF) therapy is not simply linear. The usually modest correlations between OCT-measured CST and visual acuity belie strong left and right correlations present in 2-segment models. Post-treatment CST close to the estimated inflection points showed the best expected VALS. The SCORE2 participants with a post-treatment CST after treatment close to the estimated inflection points of 217 to 256 µm showed the best VALS. In patients treated with anti-VEGF for macular edema associated with CRVO or HRVO, a thinner retina is not always associated with better VALS. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Edema Macular , Oclusión de la Vena Retiniana , Humanos , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Inhibidores de la Angiogénesis/uso terapéutico , Inyecciones Intravítreas , Tomografía de Coherencia Óptica , Retina , Bevacizumab/uso terapéutico , Agudeza Visual , Valsartán/uso terapéuticoRESUMEN
PURPOSE: To evaluate macular thickness fluctuations and their association with visual acuity outcome in eyes with macular edema (ME) secondary to central (CRVO) or hemiretinal vein occlusion (HRVO) treated initially with intravitreal aflibercept or bevacizumab. METHODS: Post hoc analysis of 362 patients with ME secondary to CRVO or HRVO initially randomized to six monthly intravitreal injections of aflibercept or bevacizumab. Three spectral domain optical coherence tomography (SD-OCT) central subfield thickness (CST) fluctuation measures were investigated over Months 1-12: standard deviation (SD), number of turning points (T) for each participant, and a measure denoted as Zigzag reflecting the magnitude of alternating ups and downs in a participant's CST. Main outcome measure is Month 12 visual acuity letter score (VALS). RESULTS: More fluctuations occurred in eyes randomized to bevacizumab than aflibercept: SD (59.98 vs 32.12; p < 0.0001), T (4.03 vs 3.53; p = 0.02) and Zigzag (24.91 vs 11.60; p = 0.0003). Month 12 VALS is significantly lower for the 4th (highest) quartile of the CST fluctuation measure than for the 1st (lowest) quartile for both SD (mean difference in VALS of 7.87; 95% confidence interval: 3.03, 12.70) and Zigzag (mean difference in VALS of 5.11; 95% confidence interval: 0.29, 9.93). SD and Zigzag quartiles were no longer significantly different after Month 1 VALS was added to the regression analysis. CONCLUSIONS: Greater CST fluctuation as assessed by SD and Zigzag was negatively associated with Month 12 VALS. However, early post-treatment VALS is a stronger predictor of VALS outcomes than the CST fluctuation measures.
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Edema Macular , Oclusión de la Vena Retiniana , Inhibidores de la Angiogénesis , Bevacizumab , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Valsartán/uso terapéutico , Factores de Crecimiento Endotelial VascularRESUMEN
PURPOSE: To assess whether early visual acuity letter score change from baseline (ΔVALS) and early spectral domain optical coherence tomography (SD-OCT) measures of center point thickness (CPT) are associated with later ΔVALS in eyes with macular edema due to central or hemiretinal vein occlusion treated with intravitreal aflibercept or bevacizumab. METHODS: Secondary analysis of a randomized clinical trial of 362 participants. RESULTS: Considered separately at month 3, CPT (categorized as ≤ 300 µm, > 300 µm) and ΔVALS (categorized as < 5, 5-9, ≥ 10) are predictive of ΔVALS at month 6 (aflibercept: P = 0.02 for CPT and P < 0.0001 for ΔVALS; bevacizumab: P = 0.007 for CPT and P < 0.0001 for ΔVALS) and, except for CPT in the bevacizumab arm, also predictive of ΔVALS at month 12 (aflibercept: P = 0.03 for CPT and P < 0.0001 for ΔVALS; bevacizumab: P = 0.18 for CPT and P < 0.0001 for ΔVALS). Month 3 predictors are also associated with average ΔVALS from months 4 to 12 (CPT P = 0.01 in the aflibercept arm, P = 0.02 in the bevacizumab arm; ΔVALS > 10 versus < 5; P < 0.001 for both aflibercept and bevacizumab). When month 3 measures are considered jointly, ΔVALS effect remains significant for average ΔVALS from months 4 to 12 (aflibercept: P = 0.002; bevacizumab: P < 0.0001) but not CPT (aflibercept: P = 0.18; bevacizumab: P = 0.22). CONCLUSION: While both month 3 ΔVALS and CPT are predictive of ΔVALS after month 3 through month 12, early ΔVALS has a stronger relationship than CPT with later ΔVALS. SCORE2 registration number is NCT01969708.
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Inhibidores de la Angiogénesis , Oclusión de la Vena Retiniana , Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Humanos , Inyecciones Intravítreas , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Retina , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Tomografía de Coherencia ÓpticaRESUMEN
Increased risk of thromboembolism has been recognized in individuals with mosaic overgrowth disorders, Proteus syndrome (PS) and PIK3CA-related overgrowth spectrum (PROS), including Klippel-Trenaunay syndrome and CLOVES syndrome. PS and PROS have distinct, yet overlapping clinical findings and are caused by somatic pathogenic variants in the PI3K/AKT gene signaling pathway. PS is caused by a single somatic activating AKT1 c.49G > A p.E17K variant while PROS can be caused one of multiple variants in PIK3CA. The role of prothrombotic factors, endothelial cell adhesion molecules, and vascular malformations in both PS and PROS have not been previously investigated. A pilot study of prospective clinical and laboratory evaluations with the purposes of identifying potential risk factors for thrombosis was conducted. Doppler ultrasounds and magnetic resonance angiogram/ venography (MRA/MRV) scans identified vascular malformations in PS and PROS that were not appreciated on physical examination. Abnormal D-dimers (0.60-2.0 mcg/ml) occurred in half of individuals, many having vascular malformations, but no thromboses. Soluble vascular endothelial markers, including thrombomodulin, soluble vascular adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM), E-selectin, and P-selectin were significantly higher in PS and PROS compared to controls. However, no single attribute was identified that explained the risk of thrombosis. Predisposition to thrombosis is likely multifactorial with risk factors including chronic stasis within vascular malformations, stasis from impaired mobility (e.g., following surgery), decreased anticoagulant proteins, and effects of AKT1 and PIK3CA variants on vascular endothelium. Based on our findings, we propose clinical recommendations for surveillance of thrombosis in PS and PROS.
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Fosfatidilinositol 3-Quinasa Clase I/genética , Predisposición Genética a la Enfermedad , Trastornos del Crecimiento/genética , Síndrome de Proteo/genética , Trombosis/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Adulto JovenRESUMEN
PURPOSE: PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. METHODS: Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. RESULTS: Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. CONCLUSION: This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.
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Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Trastornos del Crecimiento/tratamiento farmacológico , Sirolimus/farmacología , Anomalías Múltiples/tratamiento farmacológico , Anomalías Múltiples/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Trastornos del Crecimiento/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Fosfatidilinositol 3-Quinasas/genética , Sirolimus/metabolismo , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
PURPOSE: Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients. METHODS: In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES). RESULTS: We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease. CONCLUSION: In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.Genet Med advance online publication 26 January 2017.
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Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Cerebelo/anomalías , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/genética , Técnicas de Diagnóstico Molecular , Retina/anomalías , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Cerebelo/fisiopatología , Niño , Preescolar , Estudios de Cohortes , Coloboma/diagnóstico , Coloboma/genética , Anomalías del Ojo/fisiopatología , Femenino , Humanos , Lactante , Enfermedades Renales/diagnóstico , Enfermedades Renales/genética , Enfermedades Renales Quísticas/fisiopatología , Hepatopatías/diagnóstico , Hepatopatías/genética , Masculino , Sondas Moleculares , Estudios Prospectivos , Retina/fisiopatología , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/genética , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
PURPOSE: To describe the design and baseline characteristics of participants in the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2) and to compare with cohorts from other retinal vein occlusion trials. DESIGN: Phase III prospective, multicenter, randomized clinical trial designed to assess whether intravitreal bevacizumab is noninferior to intravitreal aflibercept for treatment of decreased vision attributable to macular edema associated with central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO). PARTICIPANTS: Total of 362 participants: 307 with CRVO and 55 with HRVO. METHODS: Demographic and study eye characteristics are summarized and compared between CRVO and HRVO study participants. MAIN OUTCOME MEASURES: Baseline ophthalmic characteristics, including visual acuity and retinal thickness, and medical history characteristics, including hypertension, diabetes mellitus, and coronary artery disease. RESULTS: The mean age of participants was 69 years, 76% of participants were white, and 90% were non-Hispanic. There was a racial disparity with respect to disease type, with 38% of HRVO patients being black compared with 11% of CRVO patients (P value adjusted for multiple testing = 0.0001). This is similar to findings from the previous SCORE Study. Comorbidities included hypertension (77%), diabetes mellitus (31%), and coronary artery disease (15%). At baseline, mean visual acuity letter score was 50 (20/100) (range, 19-73 [20/400 to 20/40]), mean optical coherence tomography (OCT)-measured central subfield thickness was 678 µm (range, 300-1203 µm), and mean number of months from diagnosis of macular edema to randomization was 6 (range, 0-104 months). One hundred twenty (33%) SCORE2 participants had been treated previously with anti-vascular endothelial growth factor (anti-VEGF) therapy, with these participants having baseline visual acuity letter score and OCT-measured central subfield thickness similar to those without prior anti-VEGF treatment, but longer mean duration of macular edema before randomization (18 months vs. 1 month for those without prior anti-VEGF treatment; P < 0.0001). CONCLUSIONS: The SCORE2 cohort is a heterogeneous population, including both CRVO and HRVO eyes and both treatment-naïve eyes and eyes treated previously with anti-VEGF, which will allow study results to have broad applicability to CRVO and HRVO patients receiving treatment for macular edema. Similarities of the baseline characteristics of the SCORE2 population to other CRVO trial cohorts will allow meaningful comparisons of outcome results across trials.
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Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Edema Macular/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Femenino , Angiografía con Fluoresceína , Humanos , Inyecciones Intravítreas , Edema Macular/etiología , Edema Macular/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/fisiopatología , Tomografía de Coherencia Óptica , Agudeza Visual/fisiologíaRESUMEN
IMPORTANCE: Studies have established the efficacy and safety of aflibercept for the treatment of macular edema due to central retinal vein occlusion. Bevacizumab is used off-label to treat this condition despite the absence of supporting data. OBJECTIVE: To investigate whether bevacizumab is noninferior to aflibercept for the treatment of macular edema secondary to central retinal or hemiretinal vein occlusion. DESIGN, SETTING, AND PARTICIPANTS: The SCORE2 randomized noninferiority clinical trial was conducted at 66 private practice or academic centers in the United States, and included 362 patients with macular edema due to central retinal or hemiretinal vein occlusion who were randomized 1:1 to receive aflibercept or bevacizumab. The first participant was randomized on September 17, 2014, and the last month 6 visit occurred on May 6, 2016. Analyses included data available as of December 30, 2016. INTERVENTIONS: Eyes were randomized to receive intravitreal injection of bevacizumab (1.25 mg; n = 182) or aflibercept (2.0 mg; n = 180) every 4 weeks through month 6. MAIN OUTCOMES AND MEASURES: The primary outcome was mean change in visual acuity (VA) letter score (VALS) from the randomization visit to the 6-month follow-up visit, based on the best-corrected electronic Early Treatment Diabetic Retinopathy Study VALS (scores range from 0-100; higher scores indicate better VA). The noninferiority margin was 5 letters, and statistical testing for noninferiority was based on a 1-sided 97.5% confidence interval. RESULTS: Among 362 randomized participants (mean [SD] age, 69 [12] years; 157 [43.4%] women; mean [SD] VALS at baseline, 50.3 [15.2] [approximate Snellen VA 20/100]), 348 (96.1%) completed the month 6 follow-up visit. At month 6, the mean VALS was 69.3 (a mean increase from baseline of 18.6) in the bevacizumab group and 69.3 (a mean increase from baseline of 18.9) in the aflibercept group (model-based estimate of between-group difference, -0.14; 97.5% CI, -3.07 to ∞; P = .001 for noninferiority), meeting criteria for noninferiority. Ocular adverse events in the aflibercept group included 4 participants with intraocular pressure (IOP) more than 10 mm Hg greater than baseline; ocular adverse events in the bevacizumab group included 1 participant with endophthalmitis (culture negative), 9 with IOP more than 10 mm Hg greater than baseline, 2 with IOP higher than 35 mm Hg, and 1 with angle-closure glaucoma not attributed to the study drug or procedure. CONCLUSIONS AND RELEVANCE: Among patients with macular edema due to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept with respect to visual acuity after 6 months of treatment.
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Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Edema Macular/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Agudeza Visual/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Bevacizumab/efectos adversos , Femenino , Fondo de Ojo , Humanos , Inyecciones Intravítreas , Edema Macular/etiología , Masculino , Persona de Mediana Edad , Uso Fuera de lo Indicado , Oclusión de la Vena Retiniana/complicaciones , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
IMPORTANCE: Substance use is a major driver of the HIV epidemic and is associated with poor HIV care outcomes. Patient navigation (care coordination with case management) and the use of financial incentives for achieving predetermined outcomes are interventions increasingly promoted to engage patients in substance use disorders treatment and HIV care, but there is little evidence for their efficacy in improving HIV-1 viral suppression rates. OBJECTIVE: To assess the effect of a structured patient navigation intervention with or without financial incentives to improve HIV-1 viral suppression rates among patients with elevated HIV-1 viral loads and substance use recruited as hospital inpatients. DESIGN, SETTING, AND PARTICIPANTS: From July 2012 through January 2014, 801 patients with HIV infection and substance use from 11 hospitals across the United States were randomly assigned to receive patient navigation alone (n = 266), patient navigation plus financial incentives (n = 271), or treatment as usual (n = 264). HIV-1 plasma viral load was measured at baseline and at 6 and 12 months. INTERVENTIONS: Patient navigation included up to 11 sessions of care coordination with case management and motivational interviewing techniques over 6 months. Financial incentives (up to $1160) were provided for achieving targeted behaviors aimed at reducing substance use, increasing engagement in HIV care, and improving HIV outcomes. Treatment as usual was the standard practice at each hospital for linking hospitalized patients to outpatient HIV care and substance use disorders treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was HIV viral suppression (≤200 copies/mL) relative to viral nonsuppression or death at the 12-month follow-up. RESULTS: Of 801 patients randomized, 261 (32.6%) were women (mean [SD] age, 44.6 years [10.0 years]). There were no differences in rates of HIV viral suppression versus nonsuppression or death among the 3 groups at 12 months. Eighty-five of 249 patients (34.1%) in the usual-treatment group experienced treatment success compared with 89 of 249 patients (35.7%) in the navigation-only group for a treatment difference of 1.6% (95% CI, -6.8% to 10.0%; P = .80) and compared with 98 of 254 patients (38.6%) in the navigation-plus-incentives group for a treatment difference of 4.5% (95% CI -4.0% to 12.8%; P = .68). The treatment difference between the navigation-only and the navigation-plus-incentives group was -2.8% (95% CI, -11.3% to 5.6%; P = .68). CONCLUSIONS AND RELEVANCE: Among hospitalized patients with HIV infection and substance use, patient navigation with or without financial incentives did not have a beneficial effect on HIV viral suppression relative to nonsuppression or death at 12 months vs treatment as usual. These findings do not support these interventions in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01612169.
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Manejo de Caso , Financiación Personal , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Navegación de Pacientes , Trastornos Relacionados con Sustancias/complicaciones , Adulto , Niño , Preescolar , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Humanos , Lactante , Pacientes Internos , Masculino , Persona de Mediana Edad , Motivación , Entrevista Motivacional , Resultado del Tratamiento , Carga ViralRESUMEN
PURPOSE: We quantify the association between visit adherence and visual acuity (VA) in retinal vein occlusions (CRVO). METHODS: The SCORE2 protocol included a visit every 4 weeks (every 28-35 days) during the first year. Visit adherence was measured as follows: number of missed visits, average and longest (avg and max days) visit interval, and average and longest (avg and max missed days) and unintended visit interval. Avg and max missed days were categorized as on time (0 days), late (>0-60 days), and very late (>60 days). The primary outcome was a change in the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity letter score (VALS) between baseline study visit and last attended visit during Year 1, using multivariate linear regression models controlling for numerous demographic and clinical factors. RESULTS: After adjustment, for each visit missed, patients lost 3.0 letters (95% CI: -6.2, 0.2) of vision (p = .07). On average, the 48 patients who missed at least 1 visit lost 9.4 letters (95% CI: -14.4, -4.3, p < .001) of vision after adjustment. Average days and maximal intervals between visits were not associated with changes in VALS (p > .22) for both comparisons. However, when a visit was missed, the average missed days between missed visits and the max missed interval were both associated with loss of VALS (both variables: 0 days missed as reference, late [1-60 days] -10.8 letters [95% CI: -16.9, -4.7], very late [>60 days] -7.3 letters [95% CI: -14.5, -0.2]; p = .003 for both). CONCLUSIONS: Visit adherence is associated with VALS outcomes in CRVO patients.
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Edema Macular , Oclusión de la Vena Retiniana , Humanos , Oclusión de la Vena Retiniana/diagnóstico , Bevacizumab/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Inyecciones Intravítreas , Agudeza Visual , Tomografía de Coherencia Óptica , Valsartán/uso terapéutico , Resultado del Tratamiento , Ranibizumab/uso terapéuticoRESUMEN
PURPOSE: To evaluate imaging findings from SCORE2 participants through 60 months, to describe the degree of resolution or progression of these variables, and to correlate changes in these imaging findings to treatment outcomes such as visual acuity and the number of treatments administered. METHODS: SCORE2 participants were followed for up to 60 months. Visual acuity, injection frequency and imaging tests color fundus photography (CFP), optical coherence tomography (OCT), and ultra-widefield fluorescein angiography [UWFA]) were performed throughout this period. RESULTS: Less than 6% of eyes had subretinal fluid at month 60. Disorganization of the retinal inner layers (DRIL) was the most likely finding to persist, present in 96% of eyes at baseline and unchanged at 95% at month 60. For UWFA, at baseline, there was a mean of 5.0% non-perfusion area (95% CI: 3.3%-6.8%) in the NETWORC grid with little change to month 60. For the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, at baseline, there was a mean of 2.3% non-perfusion area (95% CI: 0.7%-3.9%) with little change to month 60. There was no correlation between any of the imaging variables at baseline and change in visual acuity to month 60 or in the number of injections following the variable treatment timeframe (month 12 to month 60). CONCLUSIONS: These analyses provide an anatomic explanation for persistent functional deficits many years following initial treatment. Clinical practice patterns should consider evaluation with these imaging tests to help explain persistent functional deficits in many eyes. Additionally, these 8 baseline imaging variables generally should not be relied on to predict visual acuity or intensity of treatment. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
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Edema Macular , Oclusión de la Vena Retiniana , Humanos , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Estudios Retrospectivos , Retina , Resultado del Tratamiento , Tomografía de Coherencia Óptica/métodos , Inyecciones Intravítreas , Inhibidores de la Angiogénesis/uso terapéutico , Angiografía con Fluoresceína/métodosRESUMEN
PURPOSE: To investigate the association of retinal thickness 1 month after the first study aflibercept or bevacizumab injection with later retinal thickness, visual acuity, and number of treatments in eyes enrolled in the Study of COmparative Treatments for REtinal Vein Occlusion 2. DESIGN: Cohort study using data from a randomized clinical trial. METHODS: Analysis included one eye from each of 350 participants through 2 years of follow-up. Main outcome measures were central subfield thickness (CST), best-corrected visual acuity letter score (VALS), and number of treatments for macular edema. Retinas were classified as thin (≤216 µm), medium (>216 and ≤300 µm), or thick (>300 µm) based on CST. RESULTS: At Month 1, 15% (51/350) of retinas were thin, 57% (199/350) were medium, and 29% (100/350) were thick. Of retinas that were thin at Month 1, 89% to 96% were thin during Months 2 to 12. Over all visits studied, the VALS of eyes with medium retinas at Month 1 was significantly greater than that of eyes with Month 1 thin retinas. During Months 6 to 12 (P < .001) and 12 to 24 (P < .001), the mean number of treatments was highest in eyes with thick retinas and lowest in eyes with thin retinas. Thin retinas had significantly more paracentral acute middle maculopathy and were more likely to have disorganization of the retinal inner layers inside the central subfield, and a history of anti-vascular endothelial growth factor treatment. CONCLUSIONS: Having a post-treatment thin retina can be as detrimental to visual acuity as a post-treatment thick retina.
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INTRODUCTION AND BACKGROUND: Buprenorphine, and extended-release naltrexone, are effective in decreasing opioid use, morbidity and mortality. The available evidence suggests that these medications should be used for long term treatment; however, patients often ask how long they need to be on medication, and whether it would be safe to discontinue. There are sparse data to guide us. The CTN-0100 trial will address this gap in our knowledge by studying participants who have decided to discontinue buprenorphine and extended-release naltrexone for OUD. RESEARCH DESIGN AND METHODS: The trial is a multicenter, randomized, non-blinded study. Participants are stable adult volunteers, on sublingual buprenorphine, extended-release buprenorphine, or extended-release naltrexone, expressing an interest in discontinuing medication. Participants on buprenorphine must be stable for at least 1 year and participants on extended-release naltrexone must be stable for at least 6 months. Participants are engaged in the study for up to 96 weeks, including a flexible taper period, and are then transitioned to follow-up within the trial. All participants are randomly assigned to the study Medical Management (MM) or to MM plus Connections (CHESS health) digital smartphone application aimed at recovery and abstinence (MMD). Sublingual Buprenorphine participants are also randomized (2 × 2 design) to a taper using either sublingual or extended-release buprenorphine. DISCUSSION/CONCLUSION: It is hoped that this trial will provide a rich source of data on management of patients discontinuing medication for opioid use disorder (MOUD) to inform future research and practice. The trial will shed light on which strategies are most likely to lead to long-term success (absence of relapse), and what participant characteristics distinguish those who can safely discontinue MOUD from those who remain at risk of relapse should they discontinue. CLINICALTRIALS: gov Identifier: NCT04464980.
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Buprenorfina , Preparaciones de Acción Retardada , Naltrexona , Trastornos Relacionados con Opioides , Humanos , Buprenorfina/administración & dosificación , Buprenorfina/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Naltrexona/administración & dosificación , Naltrexona/uso terapéutico , Adulto , Administración Sublingual , Masculino , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéutico , Femenino , Tratamiento de Sustitución de Opiáceos/métodos , Proyectos de Investigación , Privación de Tratamiento , Persona de Mediana EdadRESUMEN
PURPOSE: To investigate the relationship of anti-vascular endothelial growth factor (anti-VEGF) treatment discontinuation with baseline factors and outcomes in eyes treated initially with aflibercept or bevacizumab for macular edema from central or hemiretinal vein occlusion. DESIGN: Long-term follow-up after a randomized clinical trial from 64 US centers. METHODS: Analysis included 150 SCORE2 Month 60 completers classified into 3 groups: discontinued treatment early, treated intermittently, and treated continuously. Outcomes included visual acuity (VA) and central subfield thickness (CST). RESULTS: Patients who discontinued treatment early were younger (60.9 years, vs 66.7 and 70.5 for the treated intermittently and treated continuously groups; P = .001), and 17.4% were Black, compared to 19.5% and 4.7% for the treated intermittently and treated continuously groups (P = .006). At Month 60, the discontinued treatment early group had a higher proportion with complete resolution of macular edema (69.6%) than those treated intermittently (15.0%) and treated continuously (15.7%) (P < .001). Least-squares means analyses over follow-up demonstrated that the discontinued treatment early group had a lower mean CST (257 µm) than the treated intermittently (CST = 303 µm, P = .02) and treated continuously (CST = 300 µm, P = .01) groups. CONCLUSIONS: Compared to those treated continuously, those who discontinued treatment early were younger and more likely Black. The discontinued treatment early group had a higher proportion with complete resolution of macular edema at Month 60, and a lower mean CST over follow-up, but not better VA, than the treated continuously and treated intermittently groups. Results support the need for continued monitoring and individualized treatment for patients treated with anti-VEGF for macular edema from central or hemiretinal vein occlusion.
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Edema Macular , Oclusión de la Vena Retiniana , Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/inducido químicamente , Factor A de Crecimiento Endotelial Vascular , Tomografía de Coherencia Óptica , Inyecciones Intravítreas , Bevacizumab/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Oclusión de la Vena Retiniana/inducido químicamente , Agudeza VisualRESUMEN
PURPOSE: To determine whether macular infarction measured as hyper-reflectivity of the middle and inner retinal layers predicts long-term visual acuity outcomes in participants with central retinal vein occlusion (CRVO) or hemi-retinal vein occlusion (HRVO). DESIGN: Clinical cohort study using post hoc secondary analysis of phase 3 clinical trial data. METHODS: This post hoc secondary analysis of the phase 3 Study of COmparative Treatments for REtinal Vein Occlusions 2 (SCORE2) clinical trial included 310 of the 362 participants with macular edema secondary to CRVO/HRVO who were randomized to injections of aflibercept or bevacizumab. Month 01 (M01) optical coherence tomography (OCT) images were analyzed using the following grading scheme: no infarction (grade 0), only middle retinal infarction (grade 1), diffuse middle and patchy inner retinal infarction (grade 2), and diffuse middle and inner retinal infarction (grade 3). Visual acuity letter score (VALS), central subfield thickness (CST), and number of anti-vascular endothelial growth factor (anti-VEGF) injections were correlated with the infarction severity grade at month 01. RESULTS: More severe macular infarction, with both middle and inner retinal layer hyper-reflectivity (ie, grades 2 and 3), was associated with worse M00 VALS and was predictive of VALS at M01 to M60 (P < .001). More severe infarction was associated with greater CST at presentation; however, after the first anti-VEGF injection, CST decreased and was similar across all grades at all time points (P > .05) with similar number of injections. CONCLUSIONS: Participants with more severe macular infarction at M01, as graded with OCT, exhibited worse visual outcomes despite significantly improved macular edema from month 6 to 5 years. This suggests that macular infarction may drive visual acuity after retinal fluid is treated with anti-VEGF.
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Edema Macular , Oclusión de la Vena Retiniana , Humanos , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Inhibidores de la Angiogénesis/uso terapéutico , Tomografía de Coherencia Óptica , Estudios de Cohortes , Inyecciones Intravítreas , Bevacizumab/uso terapéutico , Valsartán/uso terapéutico , Resultado del TratamientoRESUMEN
Importance: Retinal vein occlusion is the second most common retinal vascular disease. Bevacizumab was demonstrated in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) to be noninferior to aflibercept with respect to visual acuity in study participants with macular edema due to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) following 6 months of therapy. In this study, the cost-utility of bevacizumab vs aflibercept for treatment of CRVO is evaluated. Objective: To investigate the relative cost-effectiveness of bevacizumab vs aflibercept for treatment of macular edema associated with CRVO or HRVO. Design, Setting, and Participants: This economic evaluation study used a microsimulation cohort of patients with clinical and demographic characteristics similar to those of SCORE2 participants and a Markov process. Parameters were estimated and validated using a split-sample approach of the SCORE2 population. The simulated cohort included 5000 patients who were evaluated 100 times, each with a different set of characteristics randomly selected based on the SCORE2 trial. SCORE2 data were collected from September 2014 October 2019, and data were analyzed from October 2019 to July 2021. Interventions: Bevacizumab (followed by aflibercept among patients with a protocol-defined poor or marginal response to bevacizumab at month 6) vs aflibercept (followed by a dexamethasone implant among patients with a protocol-defined poor or marginal response to aflibercept at month 6). Main Outcomes and Measures: Incremental cost-utility ratio. Results: The simulation demonstrated that patients treated with aflibercept will have an expected cost $18â¯127 greater than those treated with bevacizumab in the year following initiation. When coupled with the lack of clinical superiority over bevacizumab (ie, patients treated with bevacizumab had a gain over aflibercept in visual acuity letter score of 4 in the treated eye and 2 in the fellow eye), these results demonstrate that first-line treatment with bevacizumab dominated aflibercept in the simulated cohort of SCORE2 participants. At current price levels, aflibercept would be considered the preferred cost-effective option only if treatment restored the patient to nearly perfect health. Conclusions and Relevance: While there will be some patients with CRVO-associated or HRVO-associated macular edema who will benefit from first-line treatment with aflibercept rather than bevacizumab, given the minimal differences in visual acuity outcomes and large cost differences for bevacizumab vs aflibercept, first-line treatment with bevacizumab is cost-effective for this condition.
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Edema Macular , Oclusión de la Vena Retiniana , Humanos , Bevacizumab/uso terapéutico , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Edema Macular/etiología , Edema Macular/complicaciones , Inhibidores de la Angiogénesis/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Inyecciones IntravítreasRESUMEN
Purpose: To assess the association of a novel spectral domain optical coherence tomography biomarker with 6-month visual acuity in in the Study of COmparative Treatments for REtinal Vein Occlusion 2. Methods: Spectral domain optical coherence tomography volume scans were evaluated for inner retinal hyperreflectivity, quantified by optical intensity ratio (OIR) and OIR variation. Baseline visual acuity letter score (VALS), baseline OCT biomarkers, and month 1 OIR were correlated with VALS at month 6. Regression trees, a machine learning technique yielding readily interpretable models, were used to assess for variable interaction. Results: Only baseline VALS correlated positively with month 6 VALS in multivariate regression. Regression trees detected a novel functional and anatomical interaction in a subgroup. Among patients with a baseline VALS worse than 43, those with an OIR variation at month 1 of more than 0.09 had a mean of 13 fewer letters of vision at 6 months compared with patients with an OIR variation of 0.09 or less. Conclusions: Baseline VALS was the strongest predictor of month 6 VALS. Regression tree analysis detected an interaction effect, in which higher OIR variation at month 1 predicted worse 6-month VALS in patients with low VALS at baseline. OIR variation may serve as a predictor for poor visual outcome despite treatment of macular edema secondary to retinal vein occlusion in patients with poor vision at baseline. Translational Relevance: Pixel heterogeneity in three-dimensional OCT data may serve as measure of disruption of the retinal laminations, and this factor may carry visually prognostic value.
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Oclusión de la Vena Retiniana , Humanos , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico por imagen , Oclusión de la Vena Retiniana/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Inyecciones Intravítreas , Retina/diagnóstico por imagen , Valsartán/uso terapéuticoRESUMEN
PURPOSE: To investigate 5-year outcomes in eyes initially treated with aflibercept or bevacizumab for macular edema due to central retinal or hemiretinal vein occlusion. METHODS: Long-term follow-up (LTF) after a randomized clinical trial from 64 centers in the United States. Participants were followed up to 60 months and treated at investigator discretion after completing the 12-month treatment protocol. Main outcomes were visual acuity letter score (VALS) and central subfield thickness (CST) on optical coherence tomography. RESULTS: Seventy-five percent (248/330) of eligible participants completed at least 1 visit between months 24 and 60, and 45% completed the month 60 visit. Among participants completing month 60, overall mean VALS improvement over baseline was 13.5 (95% CI: 9.6, 17.5), less than the mean improvement of 20.6 (95% CI: 18.7, 22.4) observed at month 12, with no significant differences between originally assigned study groups. Further, 66% (99/150) had at least 1 treatment between months 48 and 60 with a mean (SD) of 3.41 (3.69) treatments over this period. Mean CST was 671 µm at baseline and 261 µm (95% CI: 241.2, 280.9) at month 60. CONCLUSIONS: Although VALS improved substantially when patients were treated per protocol through month 12, improvement lessened when treatment was at investigator discretion and fewer treatments were received although VALS remained markedly improved over baseline through year 5. Most patients continued to receive treatment in year 5. This suggests that continued monitoring and, if warranted, treatment with anti-VEGF therapy benefits patients with macular edema associated with central retinal or hemiretinal vein occlusion. Publication of this article is sponsored by the American Ophthalmological Society.
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Edema Macular , Oclusión de la Vena Retiniana , Inhibidores de la Angiogénesis , Bevacizumab/uso terapéutico , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Proteínas Recombinantes de Fusión , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Importance: Intravitreal anti-vascular endothelial growth factor (VEGF) injections are commonly used to treat eyes with macular edema secondary to hemiretinal vein occlusion (HRVO) or central retinal vein occlusion (CRVO). Information on whether differences exist in outcomes after anti-VEGF therapy can help guide treatment for each of the different disease types. Objective: To compare baseline characteristics, treatment burden, and outcomes of macular edema treatment in participants with HRVO with those of participants with CRVO. Design, Setting, and Participants: This post hoc outcome analysis from the Study of Comparative Treatments for Retinal Vein Occlusion 2 randomized clinical trial included 362 participants with macular edema caused by HRVO or CRVO treated at 66 US sites. Randomization began in September 2014, and the last month 24 follow-up visit occurred in February 2018. Data were analyzed from April 2020 to May 2021. Interventions: Eyes were initially randomized to 6 monthly intravitreal injections of aflibercept or bevacizumab and were treated according to protocol between months 6 to 12 depending on 6-month outcome. After month 12, patients were treated per investigator discretion and observed through month 60. Main Outcomes and Measures: Mean visual acuity letter score (VALS). Results: Of 362 included patients, 157 (43.4%) were female, and the mean (SD) age was 68.9 (12.0) years. Outcome data were analyzed up to month 24 owing to substantial missing data at later visits. A significantly greater proportion of participants with HRVO than those with CRVO were Black (37% vs 11%). Treatment rates between months 12 to 23 were 0.36 (95% CI, 0.32-0.40) injections per month for patients with CRVO and 0.28 (95% CI, 0.19-0.36) for patients with HRVO (P = .11). The mean VALS from months 1 to 24 of an HRVO study eye exceeded that of a CRVO study eye by 5.5 (95% CI, 1.5-9.5; P = .01), consistent with the magnitude of the VALS difference between eyes with CRVO and HRVO at baseline. Eyes with CRVO presented at baseline with more macular edema than eyes with HRVO (difference in central subfield thickness [CST], 86 µm; 95% CI, 48-124; P < .001), with no difference in CST between the groups throughout months 1 to 24. Conclusions and Relevance: Black race was more prevalent among participants with HRVO than CRVO, and no differences were observed in the frequency of treatments for macular edema between eyes with CRVO and HRVO. Although eyes with CRVO presented with worse visual acuity and more macular edema on average than did eyes with HRVO, the magnitude of VALS improvement, central retinal thickness in response to anti-VEGF therapy, and treatment burden were similar between the groups.