Procedure for Organizing a Post-FDA-approval Evaluation of Antidepressants.

PURPOSE: The study reports the construction of a cohort used to study the effectiveness of antidepressants. METHODS: The cohort includes experiences of 3,678,082 patients with depression in the United States on antidepressants between January 1, 2001, and December 31, 2018. A total of 10,221,145 antidepressant treatment episodes were analyzed. Patients who had no utilization of health services for at least two years, or who had died, were excluded from the analysis. Follow-up was passive, automatic, and collated from fragmented clinical services of diverse providers. RESULTS: The average follow-up was 2.93 years, resulting in 15,096,055 person-years of data. The mean age of the cohort was 46.54 years (standard deviation of 17.48) at first prescription of antidepressant, which was also the enrollment event (16.92% were over 65 years), and most were female (69.36%). In 10,221,145 episodes, within the first 100 days of start of the episode, 4,729,372 (46.3%) continued their treatment, 1,306,338 (12.8%) switched to another medication, 3,586,156 (35.1%) discontinued their medication, and 599,279 (5.9%) augmented their treatment. CONCLUSIONS: We present a procedure for constructing a cohort using claims data. A surrogate measure for self-reported symptom remission based on the patterns of use of antidepressants has been proposed to address the absence of outcomes in claims. Future studies can use the procedures described here to organize studies of the comparative effectiveness of antidepressants.

Effectiveness of common antidepressants: a post market release study.

BACKGROUND: This study summarizes the experiences of patients, who have multiple comorbidities, with 15 mono-treated antidepressants. METHODS: This is a retrospective, observational, matched case control study. The cohort was organized using claims data available through OptumLabs for depressed patients treated with antidepressants between January 1, 2001 and December 31, 2018. The cohort included patients from all states within United States of America. The analysis focused on 3,678,082 patients with major depression who had 10,221,145 antidepressant treatments. Using the robust, and large predictors of remission, and propensity to prescribe an antidepressant, the study created 16,770 subgroups of patients. The study reports the remission rate for the antidepressants within the subgroups. The overall impact of antidepressant on remission was calculated as the common odds ratio across the strata. FINDINGS: The study accurately modelled clinicians' prescription patterns (cross-validated Area under the Receiver Operating Curve, AROC, of 82.0%, varied from 77% to 90%) and patients' remission (cross-validated AROC of 72.0%, varied from 69.5% to 78%). In different strata, contrary to published randomized studies, remission rates differed significantly and antidepressants were not equally effective. For example, in age and gender subgroups, the best antidepressant had an average remission rate of 50.78%, 1.5 times higher than the average antidepressant (30.30% remission rate) and 20 times higher than the worst antidepressant. The Breslow-Day chi-square test for homogeneity showed that across strata a homogenous common odds-ratio did not exist (alpha<0.0001). Therefore, the choice of the optimal antidepressant depended on the strata defined by the patient's medical history. INTERPRETATION: Study findings may not be appropriate for specific patients. To help clinicians assess the transferability of study findings to specific patient, the web site http://hi.gmu.edu/ad assesses the patient's medical history, finds similar cases in our data, and recommends an antidepressant based on the experience of remission in our data. Patients can share this site's recommendations with their clinicians, who can then assess the appropriateness of the recommendations. FUNDING: This project was funded by the Robert Wood Johnson foundation grant #76786. The development of related web site was supported by grant 247-02-20 from Virginia's Commonwealth Health Research Board.

Expenditures among young adults with acute lymphoblastic leukemia by site of care.

BACKGROUND: Individuals diagnosed with acute lymphoblastic leukemia (ALL) between the ages of 22 and 39 years experience worse outcomes than those diagnosed when they are 21 years old or younger. Treatment at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) mitigates these disparities but may be associated with higher expenditures. METHODS: Using deidentified administrative claims data (OptumLabs Data Warehouse), the cancer-related expenditures were examined among patients with ALL diagnosed between 2001 and 2014. Multivariable generalized linear model with log-link modeled average monthly health-plan-paid (HPP) expenditures and amount owed by the patient (out-of-pocket [OOP]). Cost ratios were used to calculate excess expenditures (CCC vs non-CCC). Incidence rate ratios (IRRs) compared CCC and non-CCC monthly visit rates. Models adjusted for sociodemographics, comorbidities, adverse events, and months enrolled. RESULTS: Clinical and sociodemographic characteristics were comparable between CCC (n = 160) and non-CCC (n = 139) patients. Higher monthly outpatient expenditures in CCC patients ($15,792 vs $6404; P < .001) were driven by outpatient hospital HPP expenditures. Monthly visit rates and per visit expenditures for nonchemotherapy visits (IRR = 1.6; P = .001; CCC = $8247, non-CCC = $1191) drove higher outpatient hospital expenditures among CCCs. Monthly OOP expenditures were higher at CCCs for outpatient care (P = .02). Inpatient HPP expenditures were significantly higher at CCCs ($25,918 vs $13,881; ꞵ = 0.9; P < .001) before accounting for adverse events but were no longer significant after adjusting for adverse events (ꞵ = 0.4; P = .1). Hospitalizations and length of stay were comparable. CONCLUSIONS: Young adults with ALL at CCCs have higher expenditures, likely reflecting differences in facility structure, billing practices, and comprehensive patient care. It would be reasonable to consider CCCs comparable to the oncology care model and incentivize the framework to achieve superior outcomes and long-term cost savings. LAY SUMMARY: Health care expenditures in young adults (aged 22-39 years) with acute lymphoblastic leukemia (ALL) are higher among patients at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) than those at non-CCCs. The CCC/non-CCC differences are significant among outpatient expenditures, which are driven by higher rates of outpatient hospital visits and outpatient hospital expenditures per visit at CCCs. Higher expenditures and visit rates of outpatient hospital visits among CCCs may also reflect how facility structure and billing patterns influence spending or comprehensive care. Young adults at CCCs face higher inpatient HPP expenditures; these are driven by serious adverse events.

Health Care Cost Associated With Contemporary Chronic Myelogenous Leukemia Therapy Compared With That of Other Hematologic Malignancies.

PURPOSE: Given the widespread introduction of tyrosine kinase inhibitors (TKIs), we evaluated the cost associated with chronic myelogenous leukemia (CML) care compared with the cost of care for patients with hematologic malignancies (HEM) and for patients without cancer (GEN), to aid with resource allocation and clinical decision making. METHODS: A retrospective cohort was constructed from the OptumLabs Data Warehouse using claims from 2000 to 2016. Eligible patients had ≥ 2 CML claims and were enrolled continuously for ≥ 6 months before diagnosis and ≥ 1 year afterward (n = 1,909). Patients with CML were frequency matched 4:1 with HEM and GEN cohorts and were observed through October 2017. We used generalized linear models to assess the variation in total mean annualized health care costs in the 3 cohorts and to examine the influence of factors associated with costs. RESULTS: Mean annualized costs for CML were $82,054 (ie, $25,471 [95% CI, $20,808 to $30,133] more than those for HEM and $74,993 [95% CI, $70,818 to $79,167] more than those for GEN); these differences were driven by pharmacy costs in the CML group. The cost of CML care exceeded that for HEM and GEN for all index years in this study and increased over each diagnostic interval until 2015, peaking at $91,990. The mean annual cost of all TKIs increased. Imatinib's mean annualized cost was $41,546 in the period 2000-2004 but increased to $105,069 in the period 2015-2017. In multivariable analysis, percent days on TKIs had the greatest influence on cost: ≥ 75% of the time versus none showed a difference in cost of $108,716 (95% CI, $99,193 to $118,239). CONCLUSION: Contemporary CML costs exceeded the cost of treatment of other hematologic malignancies. Cost was primarily driven by TKIs, whose cost continued to increase over time.

Adverse events among chronic myelogenous leukemia patients treated with tyrosine kinase inhibitors: a real-world analysis of health plan enrollees.

With tyrosine kinase inhibitor (TKI) therapy, chronic myelogenous leukemia (CML) is now a chronic disease. CML patients treated with TKIs (n = 1200) were identified from the OptumLabs® Data Warehouse (de-identified claims and electronic health records) between 2000 and 2016 and compared with a non-cancer cohort (n = 7635). The 5-year cumulative incidence of all organ system outcomes was significantly greater for the TKI versus non-cancer group. In the first year, compared with imatinib, later generation TKIs were associated with primary infections (hazard ratios [HR] 1.43, 95% CI 1.02-2.00), circulatory events (HR 1.15, 95% CI 1.01-1.31), and skin issues (HR 1.43, 95% CI 1.13-1.80); musculoskeletal and nervous system/sensory issues were less common (HRs 0.83-0.84, p < 0.05). Increased risk of infections, cardiopulmonary and skin issues associated with later generation TKIs persisted in subsequent years. In this real-world population, TKI therapy was associated with a high burden of adverse events. Later generation TKIs may have greater toxicity than imatinib.

A cross-sectional survey of work and income loss consideration among patients with herpes zoster when completing a quality of life questionnaire.

BACKGROUND: Prior research suggests that many patients do not spontaneously include work/income loss when responding to utility assessments, although this remains unconfirmed in the US due to almost no published US-based studies to date, and has not been previously studied among patients with herpes zoster (HZ). The objective of this study was to examine whether patients with HZ consider work and income loss when completing a quality of life survey. METHODS: A cross-sectional survey was administered to 2000 US adult commercial health plan enrollees aged 50-64 years with ≥ 1 HZ medical claim during 2014. The survey collected information related to health status (EQ-5D), work productivity, and HZ severity and clinical features. RESULTS: Mean respondent age was 58.4 years [standard deviation (SD) 4.1] and 62.0% were female. About 3 in 4 (76.8%) patients (N = 772) were employed either full (69.9%) or part time (6.9%). Less than half (45%) spontaneously considered work/income loss when responding to EQ-5D, and mean EQ-5D scores for patients who considered work/income loss were lower than for patients who did not [0.56 (SD = 0.28) vs. 0.69 (SD = 0.24); p < 0.001]. Overall, 43% of patients reported at least one full day missed (mean = 9 full days) and 29% reported at least one partial day missed (mean = 6 partial days) during the most recent shingles episode. Patients who considered work loss were more likely to have missed full (76.4% vs 26.0%, p < 0.001) or partial (70.9% vs. 35.2%, p < 0.001) days. Patients with absenteeism were more likely to consider work/income loss when completing EQ-5D [odds ratio (OR) = 7.91, 95% confidence interval (CI) 5.01-12.31]. Odds of absenteeism/presenteeism increased significantly with increasing levels of HZ severity, and higher odds were associated with pain located on the face/scalp/neck/eye/ear (OR 1.90, 95% CI 1.06-3.40) and with pain lasting 12+ months (OR = 2.91, 95% CI 1.14-7.42). CONCLUSIONS: HZ has considerable impact on the work and productivity of adults aged 50-64 years old. However, many patients with HZ do not spontaneously consider work/income loss when completing a standardized quality of life questionnaire. Studies that use health state utilities in HZ based on EQ-5D may not fully reflect the societal costs of work loss.

Outcomes of tumor necrosis factor inhibitor cycling versus switching to a disease-modifying anti-rheumatic drug with a new mechanism of action among patients with rheumatoid arthritis.

OBJECTIVES: To examine treatment patterns, treatment effectiveness, and treatment costs for 1 year after patients with rheumatoid arthritis switched from a tumor necrosis factor inhibitor (TNFi) (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab), either cycling to another TNFi ("TNFi cyclers") or switching to a new mechanism of action (abatacept, tocilizumab, or tofacitinib) ("new MOA switchers"). METHODS: This retrospective cohort study used administrative claims data for a national insurer. Treatment persistence (without switching again, restarting, or discontinuing), treatment effectiveness (defined below), and costs were assessed for the 12-month post-switch period. Patients were "effectively treated" if they satisfied all six criteria for a treatment effectiveness algorithm (high adherence, no dose increase, no new conventional synthetic disease-modifying anti-rheumatic drug, no subsequent switch in therapy, no new/increased oral glucocorticoids, and <2 glucocorticoid injections). Multivariable logistic models were used to adjust for baseline factors. RESULTS: The database included 581 new MOA switchers and 935 TNFi cyclers. New MOA switchers were 39% more likely than TNFi cyclers to persist after the switch (odds ratio [OR] = 1.39; 95% confidence interval [CI] = 1.12-1.74; p = .003) and 36% less likely to switch therapy again (OR = 0.64; 95% CI = 0.51-0.81; p < .001). New MOA switchers were 43% more likely than TNFi cyclers to be effectively treated (OR = 1.43; 95% CI = 1.11-1.85; p = .006). New MOA switchers had 16% lower drug costs than TNFi cyclers (cost ratio = 0.84; 95% CI = 0.79-0.88; p < .001) and 11% lower total costs of rheumatoid arthritis-related medical care (cost ratio = 0.89; 95% CI = 0.84-0.94; p < .001). LIMITATIONS: Claims payments may not reflect rebates or other cost offsets. Medical and pharmacy claims do not include clinical end-points or reasons that lead to new MOA switching vs TNFi cycling. CONCLUSIONS: These results support switching to a new MOA after a patient fails treatment with a TNFi, which is consistent with recent guidelines for the pharmacologic management of established rheumatoid arthritis.

Incidence and Burden of Pertussis Among Infants Less Than 1 Year of Age.

BACKGROUND: Infant-specific pertussis data, especially among neonates, are limited and variable. This study (NCT01890850) provides overall and age-specific pertussis incidence and associated health care utilization and costs among commercially insured infants in the US. METHODS: Nearly 1.2 million infants born from 2005 to 2010 with commercial health plan coverage were followed during their first 12 months of life. Pertussis cases were identified from medical claims (International Classification of Diseases, 9th revision, Clinical Modification code: 033.0, 033.9, 484.3), and incidence rates were calculated. Each pertussis case was then matched to 10 comparators, so pertussis-related health care utilization and costs before and after the index date could be assessed. RESULTS: The overall pertussis incidence rate among infants <12 months of age was 117.7/100,000 person-years; infants 3 months of age had the highest incidence rate (247.7/100,000 person-years). Infants diagnosed with pertussis were significantly more likely to have prior diagnoses of upper respiratory infection, cough and wheezing-related illnesses than comparators (P < 0.001). Pertussis cases were more likely to be hospitalized within 14 days after the index date (31.8% vs. 0.5%; P < 0.001) and their adjusted health care costs during follow-up were 2.82 times higher than comparators (P < 0.001; 95% confidence interval: 2.08-3.81). The incremental cost of pertussis during the 12-month follow-up period averaged $8271 (P < 0.001). The average incremental cost varied substantially by age, ranging from $18,781 (P < 0.001) to $3772 (P = 0.02) among infants 1 month and 7-12 months of age, respectively. CONCLUSIONS: The health burden of pertussis, particularly in the youngest infants, remains substantial, highlighting the need to intensify efforts to protect this most vulnerable population.

Costs and mortality of recurrent versus de novo hormone receptor-positive/HER2(-) metastatic breast cancer.

AIM: To examine cost and mortality differences in postmenopausal women with HR(+)/HER2(-) advanced breast cancer. METHODS: Using claims data (2007-2013), women with newly diagnosed (de novo) stage IV, or early- or late-recurring metastatic breast cancer were identified. RESULTS: Compared with de novo (n = 121) and late-recurrent (n = 106), early-recurrent (n = 172) patients had significantly higher costs in total and for anticancer systemic agents. Adjusted per patient per month costs for early-recurrent patients were US$13,404, versus US$9955 (de novo) and US$9721 (late-recurrent; p = 0.02). Early-recurrent patients' risk of death was twice that of de novo patients (p = 0.02). CONCLUSION: Compared with new diagnosis or late recurrence, early recurrence of HR+/HER2- metastatic breast cancer was associated with higher mortality and healthcare costs.

Application of the new GOLD COPD staging system to a US primary care cohort, with comparison to physician and patient impressions of severity.

BACKGROUND: In 2011, the traditional Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD spirometry-based severity classification system was revised to also include exacerbation history and COPD Assessment Test (CAT) and modified Medical Research Council Dyspnea Scale (mMRC) scores. This study examined how COPD patients treated in primary care are reclassified by the new GOLD system compared to the traditional system, and each system's level of agreement with patient's or physician's severity assessments. METHODS: In this US multicenter cross-sectional study, COPD patients were recruited by 83 primary care practitioners (PCPs) to complete spirometry testing and a survey. Patients were classified by the traditional spirometry-based system (stages 1-4) and under the new system (grades A, B, C, D) using spirometry, exacerbation history, mMRC, and/or CAT results. Concordance between physician and patient-reported severity, spirometry stage, and ABCD grade based on either mMRC or CAT scores was examined. RESULTS: Data from 445 patients with spirometry-confirmed COPD were used. As compared to the traditional system, the GOLD mMRC system reclassifies 47% of patients, and GOLD CAT system reclassifies 41%, but the distributions are very different. The GOLD mMRC system resulted in relatively equal distributions by ABCD grade (33%, 22%, 19%, 26%, respectively), but the GOLD CAT system put most into either B or D groups (9%, 45%, 4%, and 42%). The addition of exacerbation history reclassified only 19 additional patients. Agreement between PCPs' severity rating or their patients' self-assessment and the new ABCD grade was very poor (κ=0.17 or less). CONCLUSION: As compared to the traditional system, the GOLD 2011 multidimensional system reclassified nearly half of patients, but how they were reclassified varied greatly by whether the mMRC or CAT questionnaire was chosen. Either way, the new system had little correlation with the PCPs or their patients' impressions about the COPD severity.

Comparative effectiveness of colony-stimulating factors in febrile neutropenia prophylaxis: how results are affected by research design.

AIMS: To examine the impact of research design on results in two published comparative effectiveness studies. METHODS: Guidelines for comparative effectiveness research have recommended incorporating disease process in study design. Based on the recommendations, we develop a checklist of considerations and apply the checklist in review of two published studies on comparative effectiveness of colony-stimulating factors. Both studies used similar administrative claims data, but different methods, which resulted in directionally different estimates. RESULTS: Major design differences between the two studies include: whether the timing of intervention in disease process was identified and whether study cohort and outcome assessment period were defined based on this temporal relationship. CONCLUSION: Disease process and timing of intervention should be incorporated into the design of comparative effectiveness studies.

Service setting impact on costs for bevacizumab-treated oncology patients.

OBJECTIVES: To investigate treatment patterns and healthcare costs of patients with metastatic colorectal cancer (mCRC) or lung cancer (LC) who were treated with bevacizumab in a physician office (OFF) setting versus a hospital outpatient (HOP) setting. STUDY DESIGN: Retrospective analysis of claims from a national US health plan. METHODS: mCRC and LC patients initiating treatment with bevacizumab (index date) between January 1, 2006, and July 31, 2012, were identified. Patients were aged ≥18 years with ≥6-month pre- (baseline) and ≥6-month post index (follow-up) data, retaining patients who died with <6 months of follow-up. Differences by site of service were analyzed by χ2 and t test (bevacizumab administrations, dose) and general linear model adjusted for demographic and clinical characteristics (all-cause healthcare costs). RESULTS: A total of 1687 mCRC (OFF: 1292; HOP: 395) and 1232 LC patients (OFF: 983; HOP: 249) were identified. Mean age was 61.3 years, 56.3% were male, and 78% were treated in OFF. Treatment in OFF declined from 2006 (84% of patients) to 2012 (61%). For OFF versus HOP, mean length of treatment (208.3 vs 191.0 days; P=.007), number of bevacizumab administrations per month (1.4 vs 1.1; P<.001), and mean weekly dose (eg, for 2012, 4.34 vs 3.11 mg/kg, P<.05) were higher in OFF. Adjusted monthly HOP costs (vs OFF) were higher by 37.8% for mCRC patients (cost ratio=1.378; 95% CI, 1.282-1.482) and 31.1% for LC patients (cost ratio=1.311; 95% CI, 1.204-1.427) CONCLUSIONS: Despite fewer administrations and lower weekly dose of bevacizumab in HOP, adjusted total costs were 31% to 38% higher for mCRC and LC patients treated in the HOP setting.

Relationship between physician specialty and allopurinol prescribing patterns: a study of patients with gout in managed care settings.

OBJECTIVE: Allopurinol is used to lower serum uric acid (sUA) levels in gout patients. The objective of this study was to investigate the influence of physician specialty on allopurinol treatment patterns and sUA control. DESIGN AND METHODS: This was a retrospective study using claims from a managed care database of US health plan enrollees. Gout patients at least 18 years of age who received allopurinol were identified from the database between January 1, 2002 and April 30, 2007. The index date was defined as the date of the earliest allopurinol claim, and patients were required to have health plan enrollment for at least 365 days prior to and following the index date for inclusion. Physician specialty was determined using the index allopurinol claim. Dosage of allopurinol prescription(s) and number of gout flares were determined from claims data. sUA measurements were used to assess goal attainment over a period of at least one year following the index allopurinol prescription. RESULTS: There were 3363 patients with gout of whom 69.9% received an index allopurinol prescription from a generalist/internist, 5.7% from a rheumatologist, 2.6% from a nephrologist, and 21.8% from a physician with other specialty. Of patients receiving their index prescription from a nephrologist, 38.7% reached the sUA goal of <6 mg/dL (357 µmol/L), as compared to patients prescribed by a rheumatologist, generalist/internist, or other physician (35.4%, 31.4%, and 39.4%, respectively; P = 0.015). When controlling for patient characteristics, multivariate analysis did not reveal statistically significant different odds of sUA goal attainment based on prescribing physician specialty, though separate analyses indicated that patients prescribed by a nephrologist had fewer gout flares. Change in allopurinol dosage from initial to final dose was more frequent among patients prescribed by rheumatologists and nephrologists. CONCLUSION: There is significant heterogeneity in the specialists' management of sUA levels in patients with gout, possibly reflecting differences in case mix and treatment approaches. Limitations related to the use of claims data, such as inability to observe medications filled over-the-counter, should be considered when interpreting study results.

Clostridium difficile-associated disease in patients in a small rural hospital.

OBJECTIVE: To determine the risk factors for Clostridium difficile-associated disease (CDAD) in a 25-bed rural hospital and to compare antimicrobial use ratios at the study hospital with those at a large academic medical center. DESIGN: Case-control study. SETTING: A 25-bed rural hospital in Iowa during the period from August 2002 through January 2005. PATIENTS: A total of 17 case patients with CDAD and 34 control patients matched for age (ie, within 10 years of the case patient's age), sex, and admission date (ie, within 2 weeks of the case patient's admission date). METHODS: Retrospective medical record review was performed to obtain data on antimicrobial exposures during the 6 weeks before hospital admission for both case and control patients. Exact conditional logistic regression was used for univariable and multivariable analyses. Antimicrobial use ratios were calculated to compare the rates of antimicrobial use for case and control patients at the study hospital with the rates for patients evaluated in a study of CDAD at a nearly 700-bed teaching hospital. RESULTS: Case patients had a larger cumulative number of days of antimicrobial use (P=.004), and they received a larger total number of antimicrobial agents during hospitalization (P=.001). Antimicrobial use ratios were higher for both case and control patients at the smaller hospital, compared with the larger hospital. CONCLUSIONS: CDAD at a small rural hospital was not associated with exposure to the antimicrobial classes that are typically associated with CDAD, but was instead related to the total number of antimicrobials used to treat patients. The rate of antimicrobial use for case and control patients was about 40% higher at the small rural hospital, compared with the corresponding rates at a large academic medical center.