Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States.

BACKGROUND: In the United States, major depressive disorder (MDD) is one of the most prevalent mental health disorders. Treatment guidelines for MDD recommend pharmacologic and nonpharmacologic therapies tailored to the patient's disease severity, level of function, and comorbid health conditions. While previous studies examined real-world pharmacologic treatment patterns and costs among patients with MDD, few have examined the use of nonpharmacologic treatments and their association with health care resource utilization (HCRU) and cost. OBJECTIVE: To describe prevalence and associations between patient/provider characteristics and treatment modality and characterize HCRU and cost by treatment modality for patients with newly diagnosed MDD. METHODS: Commercially insured US patients, aged 18-62 years with newly diagnosed MDD between January 1, 2017, and September 30, 2019, were retrospectively identified from the Healthcare Integrated Research Database. Eligible patients were continuously enrolled in the health plan for 1 year before and 2 years after the first MDD diagnosis (index date). Those with co-occurring schizophrenia, bipolar disorder, postpartum depression, substance use disorder, and any prior MDD treatments were excluded. Treatment modalities assessed in the 2-year post-index period included antidepressant only (Rx-only), nonpharmacologic only (non-Rx-only), both antidepressant and nonpharmacologic (combination), and no treatment. HCRU and costs were assessed in the 2-year post-index period by treatment modality. Regression models identified associations between patient/provider characteristics and treatment modality, and the relationship between treatment modality and MDD severity changes. RESULTS: In total, 12,657 patients were included (mean age: 36 years; 60% female). During follow-up, 34% of patients received Rx-only, 25% received non-Rx-only, 28% received combination, and 13% received no treatment. MDD severity at diagnosis (26% mild, 54% moderate, 20% severe) was available for 51% of patients. Post-index inpatient hospitalizations were 11% for those with Rx-only, 10% for non-Rx-only, 16% for combination, and 29% for no treatment, whereas all-cause mean monthly total costs were $792, $633, $786, and $1,292, respectively. In multinomial logistic regression, age, sex, geographic region and urbanicity of patient residence, socioeconomic status, diagnosing provider specialty, and initial diagnosis location were significantly associated (P < 0.05) with treatment modality. In multivariable logistic regression, recipients of Rx-only (odds ratio = 2.03, P < 0.01) or combination (odds ratio = 3.26, P < 0.01) had higher odds of improving MDD severity than patients who received no treatment. CONCLUSIONS: In this real-world sample of commercially insured patients, we observed variations in outcomes by treatment modality and an association between treatment modality and disease severity. Further research is needed to explore the underlying causal relationships between treatment modality and patient outcomes. Study Registration: https://doi.org/10.17605/OSF.IO/YQ6B3 DISCLOSURES: Dr Grabner is an employee of Carelon Research, which received funding from the Innovation and Value Initiative for the conduct of the study on which this manuscript is based. Ms Pizzicato and Mr Yang were employees of Carelon Research at the time the study was conducted. Dr Grabner is a shareholder of Elevance Health. Drs Xie and Chapman are employees of the Innovation and Value Initiative.

Identification of inadequate responders to advanced therapy among commercially-insured adult patients with Crohn's disease and ulcerative colitis in the United States.

BACKGROUND: The purpose of this analysis was to assess the frequency of inadequate response over 1 year from advanced therapy initiation among patients with Crohn's disease (CD) or ulcerative colitis (UC) in the United States using a claims-based algorithm. Factors associated with inadequate response were also analyzed. METHODS: This study utilized claims data of adult patients from the HealthCore Integrated Research Database (HIRD®) from January 01, 2016 to August 31, 2019. Advanced therapies used in this study were tumor necrosis factor inhibitors (TNFi) and non-TNFi biologics. Inadequate response to an advanced therapy was identified using a claims-based algorithm. The inadequate response criteria included adherence, switching to/added a new treatment, addition of a new conventional synthetic immunomodulator or conventional disease-modifying drugs, increase in dose/frequency of advanced therapy initiation, and use of a new pain medication, or surgery. Factors influencing inadequate responders were assessed using multivariable logistic regression. RESULTS: A total of 2437 patients with CD and 1692 patients with UC were included in this analysis. In patients with CD (mean age: 41 years; female: 53%), 81% had initiated TNFi, and 62% had inadequate response. In patients with UC (mean age: 42 years; female: 48%), 78% had initiated a TNFi, and 63% had an inadequate response. In both patients with CD and UC, inadequate response was associated with low adherence (CD: 41%; UC: 42%). Inadequate responders were more likely to be prescribed a TNFi (for CD: odds ratio [OR] = 1.94; p < 0.001; for UC: OR = 2.76; p < 0.0001). CONCLUSION: More than 60% of patients with CD or UC had an inadequate response to their index advanced therapy within 1 year after initiation, mostly driven by low adherence. This modified claims-based algorithm for CD and UC appears useful to classify inadequate responders in health plan claims data.

Real-world treatment patterns and use of adjunctive pain and anti-inflammatory medications among patients with psoriatic arthritis treated with IL-17A inhibitors in the United States.

BACKGROUND: Much of the current research on treatment patterns and use of adjunctive pain and anti-inflammatory medications among patients living with psoriatic arthritis (PsA) predates the approval and uptake of IL (interleukin)-17A inhibitors. OBJECTIVE: To compare real-world treatment patterns and use of adjunctive pain and antiinflammatory medications between patients with PsA initiating the IL-17A inhibitors, ixekizumab and secukinumab, in a US-managed care population. METHODS: We conducted a retrospective cohort study using the HealthCore Integrated Research Database. Patients with a PsA diagnosis who initiated ixekizumab or secukinumab treatment between December 1, 2017, and November 30, 2019, were identified. Two cohorts were created based on which of the 2 medications was initiated (index date), and patients with prior use of either drug were excluded, as were patients with ankylosing spondylitis. Patients had to be continuously enrolled in the health plan for 6 months prior to (baseline) and 12 months after the index date (post-index). Inverse probability of treatment weighting was used to minimize confounding from baseline demographic and clinical differences between cohorts. Treatment patterns (dosing, persistence, discontinuation, and switching) and use of adjunctive pain/anti-inflammatory medications were assessed and compared between weighted cohorts using chi-square and t-tests. RESULTS: In total, 407 patients were identified in the ixekizumab cohort (mean age 51.6 years; 54% female) and 1,508 patients were identified in the secukinumab cohort (mean age 50.1 years; 59% female). Prior to weighting, presence of a psoriasis diagnosis code (ixekizumab: 60% vs secukinumab: 45%; standardized difference [std diff] = -0.30), specialty of the index prescriber (std diff = 0.38), and mean number of prior advanced therapies (2.0 vs 1.5; std diff = -0.33) were different between cohorts. Cohorts were well balanced after weighting. The majority of secukinumab patients (71%) received an index dose of 300 mg. Rates of persistence (ixekizumab: 40% vs secukinumab: 43%; P = 0.411) and switching (25% vs 20%; P = 0.072) were not statistically different between cohorts. Use of new adjunctive pain and anti-inflammatory medications was not statistically different between cohorts either (ixekizumab: 63% vs secukinumab: 58%; P = 0.187). CONCLUSIONS: Real-world treatment patterns and use of adjunctive pain and anti-inflammatory medications were similar in patients with PsA initiating ixekizumab and secukinumab in this US-managed care population. Further research examining reasons for discontinuation, switching, and use of adjunctive medications may help inform treatment decisions for patients living with PsA. DISCLOSURES: Ms Pizzicato, Ms Ketkar, and Dr Grabner are employees of HealthCore, Inc, which received funding from Eli Lilly and Company for the conduct of the study on which this manuscript is based. Ms Pepe was an employee of HealthCore, Inc., during the time the study was conducted. Dr Grabner is a shareholder of Elevance Health (legacy Anthem, Inc.). Dr Vadhariya, Dr Birt, and Ms Bolce are employees of Eli Lilly and Company, the manufacturer of ixekizumab (Taltz). Dr Birt and Ms Bolce are shareholders of Eli Lilly and Company. Dr Walsh is a paid consultant to Eli Lilly and Company and Novartis, the manufacturers of ixekizumab (Taltz) and secukinumab (Cosentyx), respectively. Additionally, Dr Walsh is a paid consultant for Pfizer, Janssen, AbbVie, and UCB and has contracts with Pfizer, AbbVie, and Merck.

Complement activation products vs standard ANA testing: Treatment outcomes, diagnosis, and economic impact (CAPSTONE) in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex clinical diagnosis historically aided by imperfect biomarkers. The advent of a multianalyte assay panel incorporating innovative cell-bound complement activation markers necessitates a comparison of its clinical utility to conventional autoantibodies for the diagnosis and treatment of SLE. OBJECTIVES: To compare the likelihood of SLE diagnosis, SLE treatment initiation, and the downstream impact on health care utilization among patients tested with AVISE Lupus (AVISE) vs standard-of-care laboratory testing with the traditional antinuclear antibody (ANA) testing strategy cohort (tANA). METHODS: An observational retrospective cohort study was conducted using electronic health record (EHR) data from the Illumination Health registry, which integrates EHR records from more than 300 rheumatologists across the US. Health records from January 2016 to December 2020 and administrative claims with cost data for a subset of patients linkable to the HealthCore Integrated Research Database and Medicare data were analyzed. The AVISE and tANA test results were classified as positive, negative, or indeterminate, and outcomes were stratified based on test results. Two cohorts were established: AVISE testing strategy and the tANA approach. Analyses included test impact on SLE diagnosis, treatment initiation, patterns of repeat testing, and downstream health care utilization. Multivariable logistic regression was used to estimate odds ratios (ORs) comparing the likelihood of SLE medication initiation and SLE diagnosis between the AVISE and tANA cohorts. RESULTS: The main cohort included 21,827 AVISE testing episodes and 22,778 tANA testing episodes. A total of 2,437 (11.2%) patients tested positive by AVISE compared with 5,364 (23.6%) of tANA positive patients. Among patients with no baseline prescription for SLE medication(s), patients with a positive AVISE test result were more likely to initiate SLE medications compared with tANA positive patients (43% vs 32%; OR = 1.57; 95% CI = 1.41-1.76). The treatment effect was larger in patients new to the practice within the preceding year (55% vs 33%; adjusted OR = 2.77; 95% CI = 2.31-3.32). AVISE positive patients were more than 5-fold more likely to be diagnosed with SLE, as compared with the tANA patients (31% vs 8%; OR = 5.11; 95% CI = 4.43-5.89), and similar in the new patient cohort (30% vs 6%; OR = 6.34; 95% CI = 5.12-7.86). Linked EHR-Medicare data revealed a greater decrease in posttest vs pretest mean annualized outpatient laboratory testing in AVISE negative (-$985; P < 0.0001) vs tANA negative (-$356; P < 0.0001) patients. A similar analysis in the EHR-HealthCore linked data revealed similar numerical trends as the Medicare data for outpatient laboratory testing but did not reach significance (P > 0.05). Cost comparisons in the categories of hospitalization, emergency department, outpatient imaging, and pharmacy costs did not yield significant differences. CONCLUSIONS: The significantly greater likelihood of SLE diagnosis and SLE medication initiation in AVISE positive vs tANA positive patients is consistent with improved clinical actionability, potentially shortening time to diagnosis. AVISE negative patients experienced a greater decrease in outpatient laboratory testing posttest relative to tANA negative patients, supporting the improved negative predictive value of AVISE vs tANA. DISCLOSURES: Mr O'Malley and Dr Zack are employed by Exagen Inc. Drs Curtis and Xie, Ms Su, and Ms Clinton are affiliated with the University of Alabama at Birmingham. Mr Haechung and Dr Grabner are employees of HealthCore, Inc., which received funding from Bendcare (owner of the Illumination Health Registry) for the conduct of parts of the study on which this manuscript is based. Exagen Inc. provided funding to Bendcare for the conduct of the study. Dr Grabner is also a shareholder of Anthem, Inc.

Identifying inadequate response among patients with ankylosing spondylitis and psoriatic arthritis prescribed advanced therapy in a real-world, commercially insured adult population in the USA.

OBJECTIVE: This study aimed to assess treatment patterns and frequency of inadequate response associated with advanced therapy initiation among patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in the USA. METHODS: Adult patients with AS or PsA who initiated advanced therapy were identified from the HealthCore Integrated Research Database®. Inadequate response to advanced therapies (tumour necrosis factor inhibitors [TNFi] and non-TNFi biologics) was identified using a claims-based algorithm. Factors influencing inadequate response were assessed using multivariable logistic regression. RESULTS: In total, 646 patients with AS, and 1433 patients with PsA were evaluated. Among patients with AS (mean age, 43 years; male, 58%), 93% patients initiated TNFi, and 69% of patients had inadequate response. In patients with PsA (mean age, 49 years; male, 47%), 67% initiated TNFi, and 77% had inadequate response. Low adherence was the main predictor of inadequate response in patients with AS (56%) and PsA (63%). Inadequate responders were more likely to be female (odds ratio [OR] 2.05 for AS and 1.37 for PsA). Prior exposure to TNFi was associated with 3.89- and 2.14-fold greater odds of inadequate response in both AS and PsA patients, respectively, while patients using methotrexate were less likely to have inadequate response (OR 0.48 for AS and 0.72 for PsA; all p < 0.05). CONCLUSIONS: Over 69% of patients with AS and 77% of patients with PsA had inadequate response to their index advanced therapy during 1 year after initiation. Health plan claims data appear useful to classify inadequate responders in AS and PsA. Key Points • Estimating inadequate response to advanced therapies and identifying factors associated with this outcome using claims data could improve treatment outcomes in AS and PsA. • In a sample of commercially insured US patients, over 69% of patients with AS and 77% of patients with PsA had inadequate response to their index advanced therapy during 1 year after initiation. Patient characteristics such as sex and prior therapy use were predictive of inadequate response to advanced therapies. • Health plan claims data appear useful to classify inadequate responders in AS and PsA and identify factors associated with this outcome.

Association of Dulaglutide Initiation Timing With Treatment Patterns and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus in the United States.

PURPOSE: To describe clinical characteristics and treatment outcomes for early or late initiation of dulaglutide therapy in patients with type 2 diabetes. METHODS: This retrospective, claims-based analysis evaluated adults with type 2 diabetes, ≥1 claim for dulaglutide 0.75 mg or 1.5 mg once-weekly injection (between November 2014 and August 2019), and no prior use of glucagon-like peptide 1 receptor agonists or insulin. Cohorts were defined based on the number of oral antidiabetic drug (OAD) classes used within the 24-month baseline period before dulaglutide therapy initiation: 1 OAD, 2 OADs, or ≥3 OADs. The number of OAD classes used before dulaglutide therapy initiation served as a proxy for timing of initiation, with a higher number of OAD classes indicating a longer duration of T2D. Baseline demographic and clinical characteristics were compared across each cohort. Six-month follow-up outcomes, including change in glycosylated hemoglobin (HbA1c) and treatment patterns, were descriptively assessed within each cohort. FINDINGS: The study population consisted of 18,121 patients across the 1 OAD (n = 4822), 2 OADs (n = 6293), and ≥3 OADs (n = 7006) cohorts. Mean age at baseline was 54.7 years. Males were more prevalent in the ≥3 OADs cohort. Most patients (67%-70%) initiated treatment with dulaglutide 0.75 mg. Dose escalation to 1.5 mg was uncommon (15%-20%) but trended higher in the ≥3 OAD cohort. Adherence to dulaglutide at 6-month follow-up (61%-67%) increased with higher baseline OAD use. The HbA1c assessment (n = 3178) included 761 patients in the 1 OAD cohort, 1088 patients in the 2 OADs cohort, and 1329 patients in the ≥3 OADs cohort. Baseline mean [SD] HbA1c level increased with number of OAD classes (1 OAD: 8.18% [1.80]; 2 OADs: 8.56% [1.66]; and ≥3 OADs: 8.73% [1.51]). Patients in the early dulaglutide therapy initiator group experienced larger reductions in HbA1c levels (1 OAD: -1.39%; 95% CI, -1.50 to -1.27; 2 OADs: -1.30%; 95% CI, -1.39 to -1.20; and ≥3 OADs: -1.01%; 95% CI, -1.09 to -0.93) versus the patients in the delayed initiator group. Patients in the early dulaglutide therapy initiator group also achieved HbA1c <7% at 6-month follow-up more frequently than those in the later initiator group (1 OAD: 68%; 2 OADs: 51%; and ≥3 OADs: 33%). IMPLICATIONS: Cohorts of dulaglutide therapy initiators, defined by prior OAD use as a proxy of timing of initiation, differed in their baseline characteristics and short-term follow-up outcomes. Earlier dulaglutide therapy initiation was associated with lower mean HbA1c levels and increased probability of achievement of HbA1c <7% during the 6-month follow-up period.

Jet stream position explains regional anomalies in European beech forest productivity and tree growth.

The mechanistic pathways connecting ocean-atmosphere variability and terrestrial productivity are well-established theoretically, but remain challenging to quantify empirically. Such quantification will greatly improve the assessment and prediction of changes in terrestrial carbon sequestration in response to dynamically induced climatic extremes. The jet stream latitude (JSL) over the North Atlantic-European domain provides a synthetic and robust physical framework that integrates climate variability not accounted for by atmospheric circulation patterns alone. Surface climate impacts of north-south summer JSL displacements are not uniform across Europe, but rather create a northwestern-southeastern dipole in forest productivity and radial-growth anomalies. Summer JSL variability over the eastern North Atlantic-European domain (5-40E) exerts the strongest impact on European beech, inducing anomalies of up to 30% in modelled gross primary productivity and 50% in radial tree growth. The net effects of JSL movements on terrestrial carbon fluxes depend on forest density, carbon stocks, and productivity imbalances across biogeographic regions.

Metabolism is a major driver of hydrogen isotope fractionation recorded in tree-ring glucose of Pinus nigra.

Stable isotope abundances convey valuable information about plant physiological processes and underlying environmental controls. Central gaps in our mechanistic understanding of hydrogen isotope abundances impede their widespread application within the plant and biogeosciences. To address these gaps, we analysed intramolecular deuterium abundances in glucose of Pinus nigra extracted from an annually resolved tree-ring series (1961-1995). We found fractionation signals (i.e. temporal variability in deuterium abundance) at glucose H1 and H2 introduced by closely related metabolic processes. Regression analysis indicates that these signals (and thus metabolism) respond to drought and atmospheric CO2 concentration beyond a response change point. They explain ≈ 60% of the whole-molecule deuterium variability. Altered metabolism is associated with below-average yet not exceptionally low growth. We propose the signals are introduced at the leaf level by changes in sucrose-to-starch carbon partitioning and anaplerotic carbon flux into the Calvin-Benson cycle. In conclusion, metabolism can be the main driver of hydrogen isotope variation in plant glucose.

A Twelve-Hundred-Year Stable Oxygen Isotope Chronology Constructed Using Subfossil Wood from Schwarzensee Lake, Austrian Alps.

This study presents a new stable oxygen isotope chronology, covering the years 800-2000 AD, constructed using modern and subfossil wood derived from trees growing around Lake Schwarzensee in Austria. The climatic signal imparted in the chronology is conditioned mainly by the direct influence of environmental factors on the isotopic signature of source water, which in turn is regulated by evaporation and condensation mechanisms. The second driver of stable oxygen isotope is the physiological response of trees to changing weather conditions, most importantly rates of transpiration. The chronology of stable oxygen isotopes corresponds well with both temperature (r = 0.485; p < 0.05) and total precipitation (r = -0.548; p < 0.05) during the growing season (May-September). This mixed signal results from the fact that the relationship between the content of stable oxygen isotopes and the influence of climate is multifactorial. Moreover, the effect exerted by meteorological conditions on stable isotope ratio changes over time. This is most probably linked to interannual variation in climatic and environmental factors.

Comparative Effectiveness of Persistent Use of a Name-Brand Levothyroxine (Synthroid®) vs. Persistent Use of Generic Levothyroxine on TSH Goal Achievement: A Retrospective Study Among Patients with Hypothyroidism in a Managed Care Setting.

INTRODUCTION: Levothyroxine monotherapy (Synthroid® or multiple generic levothyroxine [GL] formulations) is standard treatment for hypothyroidism. Our objective was to compare effectiveness (as measured by achievement of thyroid-stimulating hormone [TSH] levels) and economic outcomes of Synthroid vs. any one of multiple GLs in patients with hypothyroidism. METHODS: Data for this retrospective cohort study were obtained from the HealthCore Integrated Research Database®. All study patients had ≥ 2 claims between 1 January 2006 and 31 December 2017 with ICD-9/10-CM diagnosis codes for hypothyroidism; were persistent users of Synthroid vs. any GL; and had ≥ 1 TSH laboratory result during 12-month follow-up. Patients were divided into one of two cohorts based on index medication and were 1:1 matched using propensity scores. The primary outcome was the proportion of patients with last TSH laboratory result during follow-up within the reference range (0.3-4.12 mIU/L). Secondary outcomes included all-cause and hypothyroidism-related healthcare resource utilization (HCRU) and costs. RESULTS: After propensity score matching, the Synthroid and GL cohorts each contained 18,382 patients. At follow-up, significantly more patients receiving Synthroid were in the TSH reference range vs. GL (78.5% vs. 77.2%, respectively, p = 0.002). HCRU and costs were broadly similar between the cohorts in terms of all-cause inpatient hospitalizations, emergency department visits, outpatient services, and pharmacy fills. Irrespective of index medication, patients with TSH within the reference range had significantly lower hypothyroidism-related medical and total costs compared to those outside the range. CONCLUSIONS: This real-world data study showed Synthroid was associated with better TSH target achievement vs. GL in a US managed care population. Achieving TSH goals may provide substantial economic value by reducing hypothyroidism-related HCRU and costs.

Treatment Experiences with CDK4&6 Inhibitors Among Women with Metastatic Breast Cancer: A Qualitative Study.

PURPOSE: To describe patients' perspectives on the use of and potential challenges and barriers with adherence/persistence to cyclin-dependent kinase 4 and 6 inhibitors (CDK4&6i's) to treat metastatic breast cancer (MBC). METHODS: This qualitative study consisted of 60-minute semi-structured telephone interviews with patients with MBC in the US who were either current or recent CDK4&6i users, identified from administrative claims of survey-eligible commercial and Medicare Advantage patients in the HealthCore Integrated Research Database between November 1, 2018 and November 1, 2019. Patients were recruited by email and/or mailed letter. The 60-minute telephone interviews were conducted by a trained facilitator using a study-developed interview discussion guide that included topics impacting treatment choice and adherence/persistence. Interviews were audio-recorded, transcribed, and thematically analyzed. RESULTS: All 462 eligible patients were sent a recruitment email and/or letter to which 36 patients responded, consented to participate, and met study inclusion criteria; 25 patients scheduled interviews, and 24 completed them. Study participants were predominately white, non-Hispanic (96%) with a mean age of 59.5 years. Participants reported a largely positive experience and mentioned very few adherence/persistence issues. They further reported appreciating the ease and convenience of oral oncolytics, coped with side effects, had strong medical and social support, and experienced few cost issues. CONCLUSION: The few adherence/persistence issues reported by participants contrasts with other findings of suboptimal oral oncolytic use. Interview themes indicated several factors that likely contributed to the lack of adherence/persistence issues: trusted relationship with oncologist, belief in importance of medication, positive medication views, strong medical and social support, and minimal personal drug cost. Future research should focus on whether and how much these factors impact adherence/persistence in more diverse populations. If adherence/persistence issues are identified in these populations, then it would be appropriate to study the development of interventions that target factors associated with better adherence/persistence.

Cost-Effectiveness of a Proteomic Test for Preterm Birth Prediction.

BACKGROUND: Preterm birth (PTB) carries increased risk of short- and long-term health problems as well as higher healthcare costs. Current strategies using clinically accepted maternal risk factors (prior PTB, short cervix) can only identify a minority of singleton PTBs. OBJECTIVE: We modeled the cost-effectiveness of a risk-screening-and-treat strategy versus usual care for commercially insured pregnant US women without clinically accepted PTB risk factors. The risk-screening-and-treat strategy included use of a novel PTB prognostic blood test (PreTRM®) in the 19th-20th week of pregnancy, followed by treatment with a combined regimen of multi-component high-intensity-case-management and pharmacologic interventions for the remainder of the pregnancy for women assessed as higher-risk by the test, and usual care in women without higher risk. METHODS: We built a cost-effectiveness model using a combined decision-tree/Markov approach and a US payer perspective. We modeled 1-week cycles of pregnancy from week 19 to birth (preterm or term) and assessed costs throughout the pregnancy, and further to 12-months post-delivery in mothers and 30-months in infants. PTB rates and costs were based on >40,000 mothers and infants from the HealthCore Integrated Research Database® with birth events in 2016. Estimates of test performance, treatment effectiveness, and other model inputs were derived from published literature. RESULTS: In the base case, the risk-screening-and-treat strategy dominated usual care with an estimated 870 fewer PTBs (20% reduction) and $54 million less in total cost ($863 net savings per pregnant woman). Reductions were projected for neonatal intensive care admissions (10%), overall length-of-stay (7%), and births <32 weeks (33%). Treatment effectiveness had the strongest influence on cost-effectiveness estimates. The risk-screening-and-treat strategy remained dominant in the majority of probabilistic sensitivity analysis simulations and model scenarios. CONCLUSION: Use of a novel prognostic test during pregnancy to identify women at risk of PTB combined with evidence-based treatment is estimated to reduce total costs while preventing PTBs and their consequences.

Prevalence of Renal Impairment in a US Commercially Insured Rheumatoid Arthritis Population: A Retrospective Analysis.

INTRODUCTION: Global prevalence estimates for chronic kidney disease (CKD) in rheumatoid arthritis (RA) vary. This study assessed real-world prevalence estimates of renal impairment, based on estimated glomerular filtration rate (eGFR), among commercially insured patients with RA in the United States (US). METHODS: In this retrospective cohort study, we used administrative claims data from the HealthCore Integrated Research Database (HIRD®) between January 2013 and December 2018. Adult patients with ≥ 2 claims for RA and ≥ 2 serum creatinine (SCr) measurements ≥ 90 days apart on or after the index date were included. eGFR was calculated per the Modification of Diet in Renal Disease equation. Prevalence of eGFR-based renal impairment was estimated for the overall RA population and for two subgroups: patients on advanced therapies (biologic disease-modifying antirheumatic drugs/tofacitinib) and patients stratified based on health plan types. RESULTS: Among 128,062 patients with ≥ 2 RA claims, 42,173 had qualifying SCr measurements, 16,197 were on advanced RA therapies, and 4911 had Medicare Advantage or Supplemental plus Part D coverage. For the overall population and the subgroup on advanced therapies, mild renal impairment was observed in 52% and 51%, moderate renal impairment in 9% and 7%, and severe renal impairment in 0.5% and 0.3% of patients, respectively. Moderate and severe renal impairment was more prevalent in the Medicare Advantage/Supplemental plus Part D population compared to the commercial coverage population. CONCLUSIONS: Approximately 7-10% of commercially insured adult patients in the US with RA had moderate or severe renal impairment. Assessment of renal function is an important consideration for safe treatment.

Evolvability of Drought Response in Four Native and Non-native Conifers: Opportunities for Forest and Genetic Resource Management in Europe.

Intraspecific genetic variation in drought response is expected to play an important role in determining the persistence of tree populations in global change as it (1) allows for spontaneous selection and local adaptation of tree populations, (2) supports assisted seed transfer of less-drought-sensitive provenance, and (3) enables the integration of drought-sensitivity traits into tree breeding. Estimating the potential of such adaptation options requires quantitative genetic knowledge of drought sensitivity across significant parts of species distributions and a comparative assessment of genetic variation within economically and ecologically important tree species. We quantified genetic variation within and among populations of four conifers growing within common garden experiments in the drought-prone eastern Austria. This region experienced three strong drought periods between 1980 and 2010 that resulted in significant reductions in radial growth. Among the four tested species, Douglas-fir revealed the highest resistance during drought and silver fir the best recovery after drought, while European larch and Norway spruce showed the lowest resistance. High genetic variation among populations and phenotypic stability across all three drought events was found for Norway spruce and silver fir, but not for the other species. Heritability and evolvability of drought traits, both approximated via genetic repeatability, revealed strong differences among populations of all four species. Repeatability and evolvability for resistance were highest in Norway spruce and, for recovery, highest in European larch. Our comparison indicates that the mean drought sensitivity of a species is not related to the intraspecific genetic variation in drought response. Thus, also highly drought-sensitive species, such as Norway spruce and European larch, harbor significant genetic variation in drought response within and among populations to justify targeted tree breeding, assisted gene flow, and supportive forest management to foster local adaptations to future conditions.

Looking for the needle in a downsized haystack: Whole-exome sequencing unravels genomic signals of climatic adaptation in Douglas-fir (Pseudotsuga menziesii).

Conifers often occur along steep gradients of diverse climates throughout their natural ranges, which is expected to result in spatially varying selection to local climate conditions. However, signals of climatic adaptation can often be confounded, because unraveled clines covary with signals caused by neutral evolutionary processes such as gene flow and genetic drift. Consequently, our understanding of how selection and gene flow have shaped phenotypic and genotypic differentiation in trees is still limited.A 40-year-old common garden experiment comprising 16 Douglas-fir (Pseudotsuga menziesii) provenances from a north-to-south gradient of approx. 1,000 km was analyzed, and genomic information was obtained from exome capture, which resulted in an initial genomic dataset of >90,000 single nucleotide polymorphisms. We used a restrictive and conservative filtering approach, which permitted us to include only SNPs and individuals in environmental association analysis (EAA) that were free of potentially confounding effects (LD, relatedness among trees, heterozygosity deficiency, and deviations from Hardy-Weinberg proportions). We used four conceptually different genome scan methods based on FST outlier detection and gene-environment association in order to disentangle truly adaptive SNPs from neutral SNPs.We found that a relatively small proportion of the exome showed a truly adaptive signal (0.01%-0.17%) when population substructuring and multiple testing was accounted for. Nevertheless, the unraveled SNP candidates showed significant relationships with climate at provenance origins, which strongly suggests that they have featured adaptation in Douglas-fir along a climatic gradient. Two SNPs were independently found by three of the employed algorithms, and one of them is in close proximity to an annotated gene involved in circadian clock control and photoperiodism as was similarly found in Populus balsamifera. Synthesis. We conclude that despite neutral evolutionary processes, phenotypic and genomic signals of adaptation to climate are responsible for differentiation, which in particular explain disparity between the well-known coastal and interior varieties of Douglas-fir.

Data Integration to Improve Real-world Health Outcomes Research for Non-Small Cell Lung Cancer in the United States: Descriptive and Qualitative Exploration.

BACKGROUND: The integration of data from disparate sources could help alleviate data insufficiency in real-world studies and compensate for the inadequacies of single data sources and short-duration, small sample size studies while improving the utility of data for research. OBJECTIVE: This study aims to describe and evaluate a process of integrating data from several complementary sources to conduct health outcomes research in patients with non-small cell lung cancer (NSCLC). The integrated data set is also used to describe patient demographics, clinical characteristics, treatment patterns, and mortality rates. METHODS: This retrospective cohort study integrated data from 4 sources: administrative claims from the HealthCore Integrated Research Database, clinical data from a Cancer Care Quality Program (CCQP), clinical data from abstracted medical records (MRs), and mortality data from the US Social Security Administration. Patients with lung cancer who initiated second-line (2L) therapy between November 01, 2015, and April 13, 2018, were identified in the claims and CCQP data. Eligible patients were 18 years or older and received atezolizumab, docetaxel, erlotinib, nivolumab, pembrolizumab, pemetrexed, or ramucirumab in the 2L setting. The main analysis cohort included patients with claims data and data from at least one additional data source (CCQP or MR). Patients without integrated data (claims only) were reported separately. Descriptive and univariate statistics were reported. RESULTS: Data integration resulted in a main analysis cohort of 2195 patients with NSCLC; 2106 patients had CCQP and 407 patients had MR data. The claims-only cohort included 931 eligible patients. For the main analysis cohort, the mean age was 62.1 (SD 9.27) years, 48.56% (1066/2195) were female, the median length of follow-up was 6.8 months, and for 37.77% (829/2195), death was observed. For the claims-only cohort, the mean age was 66.6 (SD 12.69) years, 52.1% (485/931) were female, the median length of follow-up was 8.6 months, and for 29.3% (273/931), death was observed. The most frequent 2L treatment was immunotherapy (1094/2195, 49.84%), followed by platinum-based regimens (472/2195, 21.50%) and single-agent chemotherapy (441/2195, 20.09%); mean duration of 2L therapy was 5.6 (SD 4.9, median 4) months. We describe challenges and learnings from the data integration process, and the benefits of the integrated data set, which includes a richer set of clinical and outcome data to supplement the utilization metrics available in administrative claims. CONCLUSIONS: The management of patients with NSCLC requires care from a multidisciplinary team, leading to a lack of a single aggregated data source in real-world settings. The availability of integrated clinical data from MRs, health plan claims, and other sources of clinical care may improve the ability to assess emerging treatments.

Economic burden of acute steroid-refractory graft-versus-host disease in commercially insured pediatric patients.

BACKGROUND: Acute graft-versus-host disease (aGVHD), a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT), often occurs within 100 days of HSCT. While steroids are typically used as first-line treatment, there is no consensus on second-line steroid-refractory (SR) treatments. SR aGVHD is associated with significantly worse pediatric health outcomes, but less is known about its economic impact. OBJECTIVE: To evaluate the economic burden of SR pediatric aGVHD in a commercially insured US patient population. METHODS: Retrospective analyses were conducted using medical and pharmacy claims data from the HealthCore Integrated Research Database (study period January 1, 2006-May 31, 2019). Included patients had at least 1 claim for allogeneic HSCT (earliest HSCT claim set as index date), no claims for autologous HSCT, and no pre-index GVHD. Patients were aged less than 18 years with no minimum pre- or post-index continuous enrollment. The GVHD cohort included patients with at least 1 claim for aGVHD over 100 days from index with at least 1 claim for any steroid and at least 1 claim for second-line therapy, both on or after the date of the first aGVHD claim. Patients post-HSCT with no GVHD claims over follow-up formed the comparison cohort. Health care resource utilization and costs over 12 months from the index date were calculated and compared between cohorts using parametric testing. RESULTS: 38 patients with SR aGVHD and 184 controls were included. Mean age and sex were similar for aGVHD (8.6 years, 50% female) and control (8.2 years, 45% female). During the 12-month post-index follow-up, SR aGVHD patients had higher rates of complications vs controls (* for P < 0.05): anemia (79% vs 68%), drug-induced anemia* (53% vs 34%), neutropenia (63% vs 53%), thrombocytopenia (58% vs 42%), gastrointestinal complications* (95% vs 65%), and infections* (95% vs 79%). Mean inpatient length of stay was longer by 31.6 days (P < 0.01) with a total average of 96.0 days for those with SR aGVHD vs 64.3 days for the controls. More SR aGVHD patients required inpatient total parenteral nutrition (71% vs 58%), readmission within 12 months of discharge from index hospitalization* (89% vs 60%), ER visits (34% vs 24%), and outpatient visits (100% vs 86%). Total 12-month mean medical costs were higher in aGVHD patients: $1,212,944 vs $673,491 (P < 0.001), mostly because of complication-related costs: $868,966 vs $396,757 (P < 0.001). Among patients with SR aGVHD, mean total costs were higher by about $1.8 million ($2,609,445 vs $812,385; P = 0.014) for those who died compared with those who were alive within 12 months. CONCLUSIONS: SR aGVHD in pediatric patients following HSCT is associated with incremental 12-month medical costs of greater than $500,000, driven largely by complications. DISCLOSURES: This research was sponsored by Mesoblast, Inc. Grabner is an employee of HealthCore, Inc., which acted as consultants to Mesoblast, Inc., during the conduct of this research. Strati is an employee of Mesoblast, Inc. Sandman and Forsythe are employees of Purple Squirrel Economics, which acted as consultants to Mesoblast, Inc., during the conduct of this research. This work was presented at the AMCP Annual Meeting online in April 2020 and was an encore presentation at AMCP Nexus 2020 Virtual in October 2020.

Adherence and persistence among patients with type 2 diabetes initiating dulaglutide compared with semaglutide and exenatide BCise: 6-month follow-up from US real-world data.

AIM: To compare 6-month adherence, persistence and treatment patterns among patients initiating once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs), dulaglutide versus semaglutide, and dulaglutide versus exenatide BCise, using claims from the HealthCore Integrated Research Database. MATERIALS AND METHODS: Patients aged ≥18 years, with type 2 diabetes, ≥1 claim for dulaglutide, semaglutide or exenatide BCise during the index period February 2018 to December 2018 (index date = earliest GLP-1RA fill date), no claim for GLP-1RAs in the 6-month pre-index period, and continuous enrolment 6 months pre- and post-index were included. Dulaglutide users were propensity-matched 1:1 to semaglutide users (3852 pairs) or exenatide BCise users (1879 pairs). The proportions of adherent (proportion of days covered ≥80%) patients were compared using chi-squared tests. Persistence, measured as days to discontinuation, was analysed using a Cox regression model. RESULTS: Matched cohorts (dulaglutide:semaglutide and dulagutide:exenatide BCise) were balanced in baseline characteristics and the mean age was 54 and 55 years, respectively, with approximately 51% and 49% women, respectively. At 6 months, significantly more dulaglutide users were adherent than semaglutide (59.7% vs. 42.7%; P <0.0001) or exenatide BCise users (58.1% vs. 40.3%; P <0.0001). Cox regression showed that dulaglutide users were less likely to discontinue therapy than semaglutide (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.66, 0.76) or exenatide BCise users (HR 0.59, 95% CI 0.53, 0.65; P <0.0001, both). CONCLUSION: At 6-month follow-up, a higher proportion of patients initiating dulaglutide were adherent to and persistent with their treatment, compared to matched patients initiating either semaglutide or exenatide BCise.

Dulaglutide Shows Sustained Reduction in Glycosylated Hemoglobin Values: 2-Year US Real-world Study Results.

PURPOSE: Due to the chronic and progressive nature of type 2 diabetes mellitus (T2DM), it is important to understand the long-term outcomes associated with antihyperglycemic medications. There are currently few long-term studies evaluating the real-world effectiveness of dulaglutide, a glucagon-like peptide-1 receptor agonist. The primary objective of this retrospective observational study was to evaluate glycemic control over a 24-month follow-up period among dulaglutide initiators with continuous treatment. The study used US claims data from the HealthCore Integrated Research Database between May 2014 and May 2019. METHODS: Patients were included if they were ≥18 years old with T2DM and had ≥1 pharmacy claim for dulaglutide during the index period between November 2014 and May 2017 (with index date = set as the earliest dulaglutide fill during index period), continuous enrollment in the 6 months' preindex and 24 months' postindex, ≥1 claim for dulaglutide or ≥60 days' supply in every quarter during the 24-month follow-up period, and ≥1 glycosylated hemoglobin (HbA1c) result at both baseline and 24 months. FINDINGS: At baseline, 872 patients (47.5% female) had a mean (SD) age of 54.5 (8.2) years and an HbA1c value of 8.68% (1.8%) (71.36 [19.7] mmol/mol). More than two thirds were being treated for dyslipidemia, hypertension, or cardiovascular disease. A significant HbA1c reduction was observed from baseline to 24 months (-1.3% [-14.2 mmol/mol]; P < 0.0001) for dulaglutide initiators with continuous treatment. A significant reduction in HbA1c level was also observed for all prespecified subgroups (age, index dulaglutide dose [0.75 mg or 1.5 mg], insulin use, sodium-glucose co-transporter 2 inhibitor use, and dipeptidyl peptidase-4 inhibitor use; all, P < 0.0001). Forty-three percent of patients achieved an HbA1c value < 7% (53 mmol/mol), and 73% achieved an HbA1c value < 8% (64 mmol/mol) at 24 months. Most (520 [59.6%]) patients were initiated on dulaglutide 0.75 mg. Of these patients, 70% increased to dulaglutide 1.5 mg during follow-up. The mean time to first dose change was 242 (196) days for 0.75 mg-1.5 mg and 225 (160) days for 1.5 mg-0.75 mg. Antihyperglycemic medication use preindex/postindex included: insulin, 28%/35%; dipeptidyl peptidase-4 inhibitors, 37%/20%; and sodium-glucose co-transporter 2 inhibitors, 29%/44%. IMPLICATIONS: In this real-world study among dulaglutide initiators with continuous treatment, a clinically significant reduction in HbA1c value was seen at the 3-month assessment and persisted for up to 24 months. These data support the use of dulaglutide as an effective long-term treatment for T2DM in clinical practice.

Reliability of Conclusions from Early Analyses of Real-World Data for Newly Approved Drugs in Advanced Gastric Cancer in the United States.

BACKGROUND: As real-world data resources expand and improve, there will increasingly be opportunities to study the effectiveness of interventions. There is a need to ensure that study designs explore potential sources of bias and either acknowledge or mitigate them, in order to improve the accuracy of findings. The objective of this study was to understand newly approved drug utilization patterns in real-world clinical settings over time. METHODS: This retrospective study included three sources of real-world data (claims, electronic health records, and recoded data from a quality care program) collected from patients diagnosed with gastric cancer who initiated therapy with either trastuzumab or ramucirumab. Linear regression was used to investigate trends in the use of these drugs for the care of patients with gastric cancer over time from Food and Drug Administration (FDA) approval. RESULTS: Eligible patients (n=1700) had consistent demographic and clinical characteristics over time. After regulatory approval, trastuzumab was used in later lines of therapy and then shifted to earlier lines (p=0.002), while ramucirumab utilization remained consistent over time after FDA approval (p=0.49). Ramucirumab augmentation, defined as the addition of the drug after initiation of a line of therapy, decreased over time (p=0.03), and trastuzumab augmentation remained consistent over time (p=0.58). CONCLUSION: Since treatment effectiveness may change across lines of treatment, bias may arise if there are changes in the use of the drug (such as line migration) during the time period of analysis using real-world data.