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.

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.

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.

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.

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.

Month 60 Outcomes After Treatment Initiation With Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal or Hemiretinal Vein Occlusion.

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.

Baseline Characteristics and Outcomes After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema in Participants With Hemiretinal Vein Occlusion Compared With Participants With Central Retinal Vein Occlusion: Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) Report 18.

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.

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.

Intraocular Pressure-Related Events After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal Vein Occlusion or Hemiretinal Vein Occlusion: SCORE2 Report 16 on a Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are used to treat a variety of posterior segment conditions, including some associated with glaucoma, such as macular edema due to central retinal vein occlusion (CRVO). Therefore, information regarding intraocular pressure (IOP)-related events associated with anti-VEGF therapies is important to help balance the risks and benefits over the course of therapy. OBJECTIVE: To investigate IOP-related events among participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2). DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of a randomized clinical trial that included 312 participants with macular edema secondary to CRVO or hemiretinal vein occlusion (HRVO) who were not taking IOP-lowering medications at baseline. First randomization occurred on September 14, 2014, and contained data through data freeze on April 1, 2020. Analysis took place from April 2020 through December 2020. INTERVENTIONS: Study participants were initially randomized to 6 monthly intravitreal injections of aflibercept or bevacizumab. At month 6, protocol-defined good responders were rerandomized to continued monthly or treat-and-extend dosing of their originally assigned study drug, and protocol-defined poor or marginal responders were switched to alternative treatment. After month 12, participants were treated as per investigator discretion. MAIN OUTCOMES AND MEASURES: Three different outcomes: (1) IOP elevation more than 10 mm Hg from baseline, (2) IOP to a level higher than 35 mm Hg, and (3) IOP-lowering incisional or laser surgery. RESULTS: Of the 312 participants meeting inclusion criteria (138 [44.2%] were female; mean [SD] age, 67.8 [12.1] years), 25 (8.0%) had IOP elevation more than 10 mm Hg over baseline through month 60, and 5 (1.6%) had IOP higher than 35 mm Hg. The 60-month Kaplan-Meier cumulative incidence of IOP elevation more than 10 mm Hg over baseline was 0.13 (95% CI, 0.08-0.19), and the 60-month Kaplan-Meier cumulative incidence of IOP higher than 35 mm Hg was 0.02 (95% CI, 0.01-0.06), and did not differ among participants initially randomly assigned to receive aflibercept or bevacizumab. Three participants (1.0%) underwent IOP-lowering incisional surgery, and 3 participants (1.0%) underwent IOP-lowering glaucoma laser surgery. CONCLUSIONS AND RELEVANCE: Intravitreal anti-VEGF injections are used to treat some conditions associated with glaucoma, such as macular edema due to CRVO, and the rates of IOP-related events in this trial support monitoring IOP in eyes treated with anti-VEGF therapy for macular edema associated with CRVO or HRVO for up to 60 months. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01969708.

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.

SCORE2 Report 13: Intraretinal Hemorrhage Changes in Eyes With Central or Hemiretinal Vein Occlusion Managed With Aflibercept, Bevacizumab or Observation. Secondary Analysis of the SCORE and SCORE2 Clinical Trials.

PURPOSE: To investigate the relationship between intraretinal macular hemorrhage and visual acuity outcomes in eyes with central retinal vein occlusion or hemiretinal vein occlusion managed with aflibercept, bevacizumab, or observation. DESIGN: Retrospective analysis of data from 2 randomized clinical trials. METHODS: A total of 362 participants were randomized in the Study of Comparative Treatments for Retinal Vein Occlusion 2, and 88 participants randomized to observation in the Standard Care vs Corticosteroid in Retinal Vein Occlusion Study. Participants received monthly intravitreal aflibercept or bevacizumab through month 6 or observation through month 8. The main outcome was visual acuity letter score (VALS). RESULTS: Reduced area of hemorrhage by month 6 was observed in 70.7% (116 of 164) of aflibercept-treated eyes, 63.8% (104 of 163) of bevacizumab-treated eyes, and 42.2% (27 of 64) of observation eyes by month 8 (P < .01). Relative to eyes with hemorrhage during follow-up, aflibercept-treated eyes without hemorrhage at month 6 had a mean VALS improvement of 8.0 (99% confidence interval [CI]: 1.9, 14.2); bevacizumab-treated eyes without hemorrhage at month 6 had a mean VALS improvement of 3.2 (99% CI: -4.6, 11.0); and observation eyes without hemorrhage at month 8 had a mean VALS improvement of 13.5 (99% CI: 0.4, 26.5). At month 6, the presence of hemorrhage and the change in central subfield thickness (CST) were significantly associated with the change in VALS; however, CST was a more important predictor. CONCLUSION: Improvement in hemorrhage during follow-up was associated with visual acuity improvements and predicted visual acuity changes beyond what was explained by CST. These findings suggest that intraretinal macular hemorrhage is an important indicator of disease severity in retinal vein occlusion.

Prevalence of obesity among U.S. population with substance dependence.

AIM: To investigate associations between substance dependence and obesity. METHODS: Obesity (body mass index ≥ 30 kg/m2) status and the status of dependence on heroin, stimulant, marijuana, nicotine and alcohol (past-month status for nicotine and past-year status for all others) were identified from the U.S. National Survey on Drug Use and Health (NSDUH, 2015-2017) datasets. SAS Surveylogistic regression was used to estimate adjusted odds ratio (AOR) for the association between each substance dependence and obesity, adjusting for potentially confounding effects of sociodemographic factors and health condition. RESULTS: It was estimated that 10.6 % of noninstitutional U.S. residents aged 12 years or older were nicotine-dependent, 3.0 % alcohol-dependent, 1.0 % marijuana-dependent, 0.6 % stimulant-dependent, and 0.2 % heroin-dependent. Heroin-dependent individuals had 59 % lower odds of obesity relative to their non-dependent counterparts (AOR = 0.41; 95 % CI: 0.28-0.60; p < 0.0001). Lower odds of obesity were also noted for marijuana-dependent (AOR = 0.64; 95 % CI: 0.56-0.73; p < 0.0001), nicotine-dependent (AOR = 0.68; 95 % CI: 0.64-0.72; p < 0.0001) and alcohol-dependent (AOR = 0.77, 95 % CI: 0.69-0.84; p < 0.0001) individuals, but not statistically significant for stimulant-dependent individuals (AOR = 0.84; 95 % CI: 0.68-1.02; p = 0.0825). CONCLUSIONS: Heroin, marijuana, nicotine and alcohol dependence were associated with lower odds of obesity than their non-dependence counterparts. Main findings based on 2015-2017 NSDUH are consistent with findings from our prior report based on clinical trials data from National Institute on Drug Abuse Clinical Trials Network, and other epidemiological evidence in the literature. These findings can alert substance abuse treatment professionals to monitor weight change, especially among weight-concerned substance abusers.

Month 24 Outcomes After Treatment Initiation With Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal or Hemiretinal Vein Occlusion: SCORE2 Report 10: A Secondary Analysis of the SCORE2 Randomized Clinical Trial.

Importance: Two-year outcomes are reported comparing eyes originally assigned to aflibercept or bevacizumab to assess the need for continued anti-vascular endothelial growth factor (VEGF) therapy for macular edema due to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) from participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial. Objective: To investigate outcomes 1 year after cessation of the SCORE2 treatment schedule. Design, Setting, and Participants: In this secondary analysis of the SCORE2 randomized clinical trial, follow-up included 117 participants originally randomized to aflibercept and 119 participants originally randomized to bevacizumab between September 17, 2014, and November 18, 2015. Data for the analyses were frozen on September 13, 2018. Interventions: SCORE2 participants completed the treatment protocol at month 12, were subsequently treated at investigator discretion, and underwent assessment at month 24. Main Outcomes and Measures: Visual acuity letter score (VALS) and central subfield thickness (CST) on spectral-domain optical coherence tomography. Results: Among 362 participants randomized to aflibercept or bevacizumab, 65.2% (236 of 362) completed a protocol visit at month 24 (mean [SD] age, 68.5 (12.0) years; 53.8% male). The mean (SD) VALS improved from baseline to 12 months by 21.6 (14.5) in the aflibercept group compared with 21.9 (16.6) in the bevacizumab group (difference, -0.3; 99% CI, -5.6 to 4.9), then worsened from those values by a mean (SD) VALS of 7.6 (17.5) in the aflibercept group and 7.5 (14.5) in the bevacizumab group (difference, -0.1; 99% CI, -5.6 to 5.3) at month 24. The mean (SD) CST improved from baseline to 12 months by 394 (231) µm in the aflibercept group compared with 420 (274) µm in the bevacizumab group (difference, 26 µm; 99% CI, -62 to 114 µm), then worsened from those values by a mean (SD) of 58 (192) µm in the aflibercept group compared with 48 (186) µm in the bevacizumab group (difference, 10 µm; 99% CI, -58 to 78 µm) at month 24. Conclusions and Relevance: No differences in VALS or CST outcomes at month 24 were identified when participants originally assigned to aflibercept were compared with those assigned to bevacizumab. Caution in interpretation is needed because of loss to follow-up. In both groups, VALS and CST improved through month 12 and then worsened somewhat during the second year, when treatment was at investigator discretion. This analysis suggests that CRVO and HRVO warrant close monitoring and treatment as needed over at least 2 years to optimize outcomes in eyes treated with anti-VEGF therapy. Trial Registration: ClinicalTrials.gov identifier: 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.

Month 12 Outcomes After Treatment Change at Month 6 Among Poor Responders to Aflibercept or Bevacizumab in Eyes With Macular Edema Secondary to Central or Hemiretinal Vein Occlusion: A Secondary Analysis of the SCORE2 Study.

Importance: Information is needed to assess switching treatment in eyes with a poor response to 6 months of monthly administration of aflibercept or bevacizumab for macular edema from central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO). Objective: To investigate visual acuity letter score (VALS) and central subfield thickness (CST) changes from month 6 to 12 among eyes with a poor response at month 6 to monthly dosing of aflibercept or bevacizumab in the Study of Comparative Treatments for Retinal Vein Occlusion 2. Design, Setting, and Participants: This secondary analysis of the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) was conducted at 66 private practice or academic centers in the United States. Participants included 49 patients (1 eye from each patient evaluated) with CRVO- or HRVO-associated macular edema and a protocol-defined poor response to aflibercept or bevacizumab treatment at month 6. The first month 6 visit occurred on September 8, 2015, and the last month 12 visit occurred on October 24, 2016. Interventions: Treatment in eyes receiving monthly aflibercept was switched to a dexamethasone implant at month 6 and, if needed, at months 9, 10, or 11. Treatment in eyes receiving monthly bevacizumab was switched to aflibercept at months 6, 7, and 8, and then to a treat-and-extend aflibercept regimen until month 12. Main Outcomes and Measures: Change from month 6 to 12 in VALS and CST. Results: Of the 49 participants at month 6, aflibercept treatment had failed in 14 (6 [43%] women; mean [SD] age, 70.4 [13.0] years). Bevacizumab treatment had failed in 35 patients (16 [46%] women; mean age, 70.0 [13.2] years). In 14 eyes with treatment switched from aflibercept to dexamethasone, the estimated mean change from month 6 to 12 in VALS was 2.63 (95% CI, -3.29 to 8.56; P = .37) and 46.0 µm (95% CI, -80.9 to 172.9 µm; P = .46) for CST. In 35 eyes with treatment switched from bevacizumab to aflibercept, the estimated mean change from month 6 to 12 in VALS was 10.27 (95% CI, 6.05-14.49; P < .001) and -125.4 µm (95% CI, -180.9 to -69.9 µm; P < .001) for CST. Conclusions and Relevance: Eyes treated with aflibercept after a poor response to bevacizumab had improvement in VALS and CST. Few eyes had a poor response to aflibercept, and therefore, few eyes were switched to dexamethasone. Caution is warranted in interpreting these results owing to the small number of eyes and lack of comparison groups. These factors preclude definitive assessment of whether the switching strategy is superior to maintaining treatment.

Comparison of Monthly vs Treat-and-Extend Regimens for Individuals With Macular Edema Who Respond Well to Anti-Vascular Endothelial Growth Factor Medications: Secondary Outcomes From the SCORE2 Randomized Clinical Trial.

Importance: Comparisons of monthly vs treat-and-extend anti-vascular endothelial growth factor (anti-VEGF) regimens for macular edema from central retinal vein occlusion or hemiretinal vein occlusion is needed. Objective: To compare visual acuity letter score and central subfield thickness outcomes of participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial who then received either monthly injections or treat-and-extend (TAE) regimens of aflibercept or bevacizumab after a good response at month 6. Design, Setting, and Participants: This randomized clinical trial enrolled participants from 66 private practice or academic centers in the United States. All participants had macular edema associated with central retinal vein occlusion or hemiretinal vein occlusion, had enrolled in the SCORE2 trial, and had a protocol-defined good response to monthly injections in the first 6 months of the trial. Participants initially assigned to receive monthly aflibercept were randomized to aflibercept on a monthly or TAE schedule, and participants initially assigned to receive monthly injections of bevacizumab were randomized to receive bevacizumab on a monthly or TAE schedule. The first participant was randomized in the SCORE2 trial on September 17, 2014, and the last month 12 visit occurred on October 24, 2016. Main Outcomes and Measures: Change from month 6 to month 12 in best-corrected electronic visual acuity letter score (per the Early Treatment Diabetic Retinopathy Study). Results: The 293 participants had a mean (SD) age of 68.9 (11.9) years; 127 (43.3%) were female. Of these, 79 were randomized to aflibercept on a monthly schedule, 80 to aflibercept on a TAE schedule, 67 to monthly bevacizumab, and 67 to bevacizumab on a TAE schedule. Mean treatment group difference (the change in visual acuity letter score in the monthly group minus the change in the TAE group) from month 6 to month 12 was 1.88 (97.5% CI, -1.07 to 4.83; P = .15) for aflibercept and 1.98 (97.5% CI, -1.08 to 5.03; P = .15) for bevacizumab. In the aflibercept arm, the mean number of injections between months 6 and 11 was 5.8 in the monthly injection group (95% CI, 5.6 to 5.9) and 3.8 in the TAE group (95% CI, 3.5 to 4.1; P < .001); in the bevacizumab arm, the mean number of injections was 5.8 (95% CI, 5.6 to 5.9) in the monthly group and 4.5 in the TAE group (95% CI, 4.2 to 4.8; P < .001). Conclusions and Relevance: One to 2 fewer injections of aflibercept or bevacizumab were given to the TAE groups than the monthly groups in months 6 to 12 for macular edema associated with central retinal or hemiretinal vein occlusion. Because of wide confidence intervals on the differences between the groups, caution is warranted before concluding that the regimens are associated with similar vision outcomes. Trial Registration: www.clinicaltrials.gov identifier: NCT01969708.

SCORE2 Report 5: Vision-Related Function in Patients With Macular Edema Secondary to Central Retinal or Hemiretinal Vein Occlusion.

PURPOSE: To describe baseline vision-related function, measured with the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), in patients with macular edema secondary to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) in the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2); evaluate the baseline relationship between NEI VFQ-25 scores with visual acuity letter score (VALS) and central retinal thickness; and compare baseline NEI VFQ-25 scores in SCORE2 participants with those in normal-vision reference populations and patients in other retinal vein occlusion trials. DESIGN: Multicenter, noninferiority randomized controlled trial. METHODS: SCORE2 was designed to assess whether intravitreal bevacizumab is noninferior to intravitreal aflibercept for treatment of decreased vision attributable to macular edema owing to CRVO or HRVO. SCORE2 enrolled 362 participants, including 305 with CRVO and 57 with HRVO. Analyses were of cross-sectional baseline data. The main outcome measures were baseline NEI VFQ-25 composite and subscale scores. RESULTS: SCORE2 participants' baseline NEI VFQ-25 composite and subscale scores are significantly lower compared with 3 normal-vision reference populations (P < .01; except for ocular pain score) and similar to patients in other retinal vein occlusion clinical trials. Baseline VALS in the better eye was correlated with baseline NEI VFQ-25 composite and subscale scores of general vision, near activities, role difficulties, dependency, and color vision, with correlations ranging from 0.19 to 0.26 (P < .05 for each score). CONCLUSIONS: CRVO and HRVO patients in SCORE2 had significantly worse baseline patient-reported vision-related function than normal vision populations, despite the disease being primarily unilateral with typically excellent vision in the fellow eye.

DSM-5 substance use disorders among adult primary care patients: Results from a multisite study.

BACKGROUND: There are limited data about the extent of DSM-5 substance use disorders (SUDs) among primary care patients. METHODS: This study analyzed data from a multisite validation study of a substance use screening instrument conducted in a diverse sample of 2000 adults aged ≥18 years recruited from five primary care practices in four states. Prevalence and correlates of 12-month DSM-5 SUDs were examined. RESULTS: Overall, 75.5% of the sample used any substance, including alcohol (62.0%), tobacco (44.1%), or illicit drugs/nonmedical medications (27.9%) in the past 12 months (marijuana 20.8%, cocaine 7.3%, opioids 4.8%, sedatives 4.1%, heroin 3.9%). The prevalence of any 12-month SUD was 36.0% (mild disorder 14.2%, moderate/severe disorder 21.8%): tobacco 25.3% (mild 11.5%, moderate/severe 13.8%); alcohol 13.9% (mild 6.9%, moderate/severe 7.0%); and any illicit/nonmedical drug 14.0% (mild 4.0%, moderate/severe 10.0%). Among past 12-month users, a high proportion of tobacco or drug users met criteria for a disorder: tobacco use disorder 57.4% (26.1% mild, 31.3% moderate/severe) and any drug use disorder 50.2% (14.3% mild, 35.8% moderate/severe); a lower proportion of alcohol users (22.4%) met criteria for alcohol use disorder (11.1% mild, 11.3% moderate/severe). Over 80% of adults with opioid/heroin use disorder met criteria for a moderate/severe disorder. Younger ages, male sex, and low education were associated with increased odds of having SUD. CONCLUSION: These findings reveal the high prevalence of SUDs in primary care and underscore the need to identify and address them.

Baseline Factors Associated With 6-Month Visual Acuity and Retinal Thickness Outcomes in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion or Hemiretinal Vein Occlusion: SCORE2 Study Report 4.

Importance: Macular edema (ME) is the leading cause of decreased visual acuity (VA) associated with retinal vein occlusion (RVO). Identifying factors associated with better outcomes in RVO eyes treated with anti-vascular endothelial growth factor (VEGF) therapy may provide information useful in counseling patients. Objective: To investigate baseline characteristics associated with 6-month VA and central subfield thickness (CST) outcomes in participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2). Design, Setting, and Participants: A total of 362 patients with central RVO or hemi-RVO were enrolled between September 17, 2014, and November 18, 2015, and randomized 1:1 in a masked fashion to receive bevacizumab or aflibercept. At month 6, 348 participants (96%) had VA outcomes measured and 335 participants (93%) had spectral domain optical coherence tomography outcomes measured. The current data analysis was conducted from February 27, 2017, to April 7, 2017. Interventions: Eyes were randomly assigned to receive an intravitreal injection of bevacizumab, 1.25 mg, or aflibercept, 2.0 mg, at baseline and every 4 weeks, with the primary outcome measured at 6 months. Main Outcomes and Measures: Change from baseline in VA letter score (VALS), VALS gain of 15 or more, change from baseline in CST, CST less than 300 µm, and resolution of ME. Baseline factors associated with 6-month outcome at the 0.05 level in univariate regressions were included in multivariate regressions, with those significant after multiplicity control by the Hochberg method reported. Results: The mean (SD) age of patients was 69 (12) years, and 43% were women. Younger patient age (odds ratio [OR], 0.95 per year of age; 95% CI, 0.93-0.98; P = .007) and lower baseline VALS (OR, 0.96 per letter; 95% CI, 0.94-0.98; P < .001) were associated with a 6-month VALS gain of 15 or greater. Compared with bevacizumab, aflibercept treatment was associated with a higher odds of ME resolution (OR, 3.59; 95% CI, 2.22-5.80; P < .001) and CST less than 300 µm (OR, 5.30; 95% CI, 2.40-11.67; P = .001), but not with a better VA outcome. Macular edema was less likely to resolve in eyes that received anti-VEGF treatment prior to study participation (OR, 0.33; 95% CI, 0.17-0.64; P = .03). Conclusions and Relevance: In eyes treated with bevacizumab or aflibercept, younger age and worse baseline VALS were associated with better 6-month VA outcomes. Aflibercept treatment was associated with more favorable spectral domain optical coherence tomography outcomes but not VA outcomes. These findings may be useful in assessing expected response at month 6 after monthly injection of anti-VEGF agents for treating ME due to CRVO and HRVO. Trial Registration: clinicaltrials.gov Identifier: NCT01969708.