SCORE2 Report 24: Nonlinear Relationship of Retinal Thickness and Visual Acuity in Central Retinal and Hemiretinal Vein Occlusion.

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.

SCORE2 Report 17: Macular thickness fluctuations in anti-VEGF-treated patients with central or hemiretinal vein occlusion.

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.

Association between early and late response in eyes with central or hemiretinal vein occlusion treated with anti-VEGF agents : SCORE2 report 12: secondary analysis of the SCORE2 clinical trial.

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.

LONG-TERM PHYSICAL STABILITY, STERILITY, AND ANTI-VEGF BIOACTIVITY OF REPACKAGED BEVACIZUMAB IN 2-ML GLASS VIALS.

PURPOSE: Repackaged bevacizumab in single-dose, prefilled syringes for intravitreal injection is available, but with shelf life limited from 60 days to 90 days. For the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2), 2-mL sterile glass vials were used rather than prefilled syringes to provide a longer shelf life for study supplies. METHODS: Repackaged bevacizumab in glass vials was tested at release and, for 1 lot, after 1, 3, 6, and 12 months for physical stability, including concentration, purity and appearance, and for sterility and endotoxins. Vials from 2 lots were tested at release and after 20 months and 21 months, respectively. One lot was tested at 21 months for anti-VEGF bioactivity compared with a fresh supply of commercial bevacizumab. RESULTS: Repackaged bevacizumab in 2-mL glass vials continued to meet all quality release specifications and remain sterile for up to 21 months. In addition, no degradation in anti-VEGF bioactivity was observed at 21 months compared with a fresh bevacizumab control. CONCLUSION: Bevacizumab can be repackaged into small, single-dose glass vials for intravitreal injection and the qualities of the commercial product maintained, including anti-VEGF bioactivity, for up to 21 months in refrigerated storage. Consideration should be given to repackaging bevacizumab for ophthalmic use in small glass vials as opposed to plastic syringes.

Use of a prescription opioid registry to examine opioid misuse and overdose in an integrated health system.

Strategies are needed to identify at-risk patients for adverse events associated with prescription opioids. This study identified prescription opioid misuse in an integrated health system using electronic health record (EHR) data, and examined predictors of misuse and overdose. The sample included patients from an EHR-based registry of adults who used prescription opioids in 2011 in Kaiser Permanente Northern California, a large integrated health care system. We characterized time-at-risk for opioid misuse and overdose, and used Cox proportional hazard models to model predictors of these events from 2011 to 2014. Among 396,452 patients, 2.7% were identified with opioid misuse and 1044 had an overdose event. Older patients were less likely to meet misuse criteria or have an overdose. Whites were more likely to be identified with misuse, but not to have an overdose. Alcohol and drug disorders were related to higher risk of misuse and overdose, with the exception that marijuana disorder was not related to opioid misuse. Higher daily opioid dosages and benzodiazepine use increased the risk of both opioid misuse and overdose. We characterized several risk factors associated with misuse and overdose using EHR-based data, which can be leveraged relatively quickly to inform preventive strategies to address the opioid crisis.

SCORE2 Report 2: Study Design and Baseline Characteristics.

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.

Care cascade structural intervention versus standard of care in the diagnosis and treatment of HIV in China: a cluster-randomized controlled trial protocol.

BACKGROUND: The high rate of attrition along the care cascade of infection with human immunodeficiency virus (HIV) results in lost opportunities to provide timely antiretroviral therapy (ART) and to prevent unnecessarily high mortality. This study aims to assess the effectiveness of a structural intervention, the one-stop ("One4All") strategy that streamlines China's HIV care cascade with the intent to improve testing completeness, ART initiation, viral suppression, and mortality. METHOD: A two-arm, cluster-randomized controlled trial was implemented in twelve county hospitals in Guangxi China to test the effectiveness of the One4All strategy (intervention arm) compared to the current standard of care (SOC; control arm). The twelve study hospitals were selected for homogeneity and allocated one-to-one to the intervention and control arms. All patients screening HIV positive in study hospitals were enrolled. Target study enrollment was 180 participants per arm, 30 participants per hospital. Basic demographic information was collected as well as HIV risk behavior and route of infection. In intervention hospitals, patients then went on to receive point-of-care CD4 testing and in-parallel viral load (VL) testing whereas patients in control hospitals progressed through the usual SOC cascade. The primary outcome measure was testing completeness within 30 days of positive initial HIV screening result. Testing completeness was defined as receipt of all tests, test results, and post-test counseling. The secondary outcome measure was ART initiation (receipt of first ART prescriptions) within 90 days of positive initial HIV screening result. Tertiary outcome measures were viral suppression (≤200 copies/mL) and all-cause mortality at 12 months. DISCUSSION: We expect that this first-ever, cluster-randomized controlled trial of a bundle of interventions intended to streamline the HIV care cascade in China (the One4All strategy) will provide strong evidence for the benefit of accelerating diagnosis, thorough clinical assessment, and ART initiation via an optimized HIV care cascade. We furthermore anticipate that this evidence will be valuable to policymakers looking to elevate China's overall HIV/AIDS response to meet the UNAIDS 90-90-90 targets and the broader, global goal of eradication of the HIV/AIDS epidemic. TRIAL REGISTRATION: ClinicalTrials.gov # NCT02084316 . (Registered on March 7, 2014).

Effect of Bevacizumab vs Aflibercept on Visual Acuity Among Patients With Macular Edema Due to Central Retinal Vein Occlusion: The SCORE2 Randomized Clinical Trial.

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.

Effect of Patient Navigation With or Without Financial Incentives on Viral Suppression Among Hospitalized Patients With HIV Infection and Substance Use: A Randomized Clinical Trial.

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.

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹8), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹°). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Visit Adherence and Visual Acuity in Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2).

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.

Month 60 Imaging Findings and Relationship to Treatment Outcomes Following Anti-VEGF Therapy for Macular Edema Due to Central or Hemi-Retinal Vein Occlusion.

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.

Association of Retinal Thickness at Month 1 Postrandomization With Later Thickness and Visual Acuity in Central Vein Occlusion.

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.

Individual-Level Risk Prediction of Return to Use During Opioid Use Disorder Treatment.

Importance: No existing model allows clinicians to predict whether patients might return to opioid use in the early stages of treatment for opioid use disorder. Objective: To develop an individual-level prediction tool for risk of return to use in opioid use disorder. Design, Setting, and Participants: This decision analytical model used predictive modeling with individual-level data harmonized in June 1, 2019, to October 1, 2022, from 3 multicenter, pragmatic, randomized clinical trials of at least 12 weeks' duration within the National Institute on Drug Abuse Clinical Trials Network (CTN) performed between 2006 and 2016. The clinical trials covered a variety of treatment settings, including federally licensed treatment sites, physician practices, and inpatient treatment facilities. All 3 trials enrolled adult participants older than 18 years, with broad pragmatic inclusion and few exclusion criteria except for major medical and unstable psychiatric comorbidities. Intervention: All participants received 1 of 3 medications for opioid use disorder: methadone, buprenorphine, or extended-release naltrexone. Main Outcomes and Measures: Predictive models were developed for return to use, which was defined as 4 consecutive weeks of urine drug screen (UDS) results either missing or positive for nonprescribed opioids by week 12 of treatment. Results: The overall sample included 2199 trial participants (mean [SD] age, 35.3 [10.7] years; 728 women [33.1%] and 1471 men [66.9%]). The final model based on 4 predictors at treatment entry (heroin use days, morphine- and cocaine-positive UDS results, and heroin injection in the past 30 days) yielded an area under the receiver operating characteristic curve (AUROC) of 0.67 (95% CI, 0.62-0.71). Adding UDS in the first 3 treatment weeks improved model performance (AUROC, 0.82; 95% CI, 0.78-0.85). A simplified score (CTN-0094 OUD Return-to-Use Risk Score) provided good clinical risk stratification wherein patients with weekly opioid-negative UDS results in the 3 weeks after treatment initiation had a 13% risk of return to use compared with 85% for those with 3 weeks of opioid-positive or missing UDS results (AUROC, 0.80; 95% CI, 0.76-0.84). Conclusions and Relevance: The prediction model described in this study may be a universal risk measure for return to opioid use by treatment week 3. Interventions to prevent return to regular use should focus on this critical early treatment period.

The national drug abuse treatment clinical trials network data share project: website design, usage, challenges, and future directions.

BACKGROUND: There are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the 'gold standard' for establishing treatment effectiveness, but clinical trial research is very costly, and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs. PURPOSE: We describe the goals, developments, and usage of the Data Share website (http://www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the United States, including lessons learned, limitations, and major revisions, and considerations for future directions to improve data sharing. METHODS: Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website. RESULTS: Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website. LIMITATIONS: Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses. CONCLUSIONS: The Data Share website offers researchers easy access to de-identified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website, ongoing collaborative efforts are needed to standardize the core measures used for data collection in the CTN studies with the goal to increase their comparability and to facilitate the ability to pool data files for cross-study analyses.

Score Study Report 12: Development of venous collaterals in the Score Study.

PURPOSE: To investigate the prevalence of venous collaterals after branch and central retinal vein occlusion, assess the association of venous collaterals with other clinical features (including visual acuity), and determine if treatment with intravitreal corticosteroids influences the development of new venous collaterals. METHODS: Review of data from two multicenter randomized clinical trials in the Standard of Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study. RESULTS: Statistically significant associations of venous collaterals and visual acuity at baseline or at follow-up were not found. Treatment with intravitreal triamcinolone acetonide did not appear to influence the development of venous collaterals. CONCLUSION: In contrast to some previous reports, development of venous collaterals did not demonstrate an independent association with visual acuity in eyes with branch retinal vein occlusion or central retinal vein occlusion in the SCORE Study. Intravitreal steroid effects do not appear to influence the development of venous collaterals.

SCORE2 Report 20: Relationship of Treatment Discontinuation With Visual Acuity and Central Subfield Thickness Outcomes.

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.

Cost-Utility Comparison of Bevacizumab and Aflibercept in the Treatment of Central or Hemiretinal Vein Occlusion in the SCORE2 Trial.

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 $18 127 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.

High Variation in Inner Retinal Reflectivity Predicts Poor Visual Outcome in Patients With Central Retinal Vein Occlusion: SCORE2 Report 21.

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.