The State of Use and Utility of Negative Controls in Pharmacoepidemiologic Studies.

Uses of real-world data in drug safety and effectiveness studies are often challenged by various sources of bias. We undertook a systematic search of the published literature through September 2020 to evaluate the state of use and utility of negative controls to address bias in pharmacoepidemiologic studies. Two reviewers independently evaluated study eligibility and abstracted data. Our search identified 184 eligible studies for inclusion. Cohort studies (115, 63%) and administrative data (114, 62%) were, respectively, the most common study design and data type used. Most studies used negative control outcomes (91, 50%), and for most studies the target source of bias was unmeasured confounding (93, 51%). We identified 4 utility domains of negative controls: 1) bias detection (149, 81%), 2) bias correction (16, 9%), 3) P-value calibration (8, 4%), and 4) performance assessment of different methods used in drug safety studies (31, 17%). The most popular methodologies used were the 95% confidence interval and P-value calibration. In addition, we identified 2 reference sets with structured steps to check the causality assumption of the negative control. While negative controls are powerful tools in bias detection, we found many studies lacked checking the underlying assumptions. This article is part of a Special Collection on Pharmacoepidemiology.

Real-world changes in costs over time among patients in the United States with hereditary angioedema on long-term prophylaxis with lanadelumab.

AIMS: Investigate trends in paid lanadelumab costs over time in a population of patients persistent for 18 months, and to understand overall hereditary angioedema (HAE) treatment cost trends, including costs of acute medication/short-term prophylaxis and supportive care. Lastly, we sought to describe the proportion of lanadelumab patients with evidence of down titration via changes in total paid amounts for lanadelumab in a fixed time period. METHODS: Patients were identified in the Merative MarketScan Databases who had ≥1 claim for lanadelumab during 1/1/2018-6/30/2022 (index), a ≤ 60-d gap in days of supply over 18 months, and were enrolled for ≥6 months pre-index and 18 months post-index. Lanadelumab and HAE-specific costs were assessed during follow-up months 0-6, 7-12, and 13-18. Down titration was defined as a ≥ 25% decrease in lanadelumab costs from months 0-6 to months 7-12 or 13-18. Outcomes were compared between time periods using paired t-tests and McNemar's test. RESULTS: Fifty-four lanadelumab users were included; 25 (46%) had evidence of down titration. Lanadelumab costs decreased from $316,724 to $269,861 to $246,919 in months 0-6, 7-12, and 13-18, respectively (p < .01); total HAE treatment costs decreased from $377,076 to $329,855 to $286,074 in months 0-6, 7-12, and 13-18, respectively (p < .01). LIMITATIONS: Persistence was determined via days of supply on medication claims; use of the medication was not confirmed. Down titration was based on costs; the lanadelumab regimen could not be assessed. Results may not be generalizable to uninsured patients or those without commercial or Medicare insurance. CONCLUSIONS: Patients on long-term prophylaxis with lanadelumab experienced a significant reduction (24%) in HAE treatment costs over 18 months, driven by lower costs of acute medications and lanadelumab down titration. Down titration among appropriate patients with controlled HAE may lead to substantial savings in healthcare costs.

Direct Medical Costs of COPD in the USA: An Analysis of the Medical Expenditure Panel Survey 2017-2018.

AIM: In this study, we aimed to provide a nationally representative estimate of the economic burden of chronic obstructive pulmonary disease (COPD) by examining direct medical costs among individuals aged 45 years and older in the USA. METHODS: Medical Expenditure Panel Survey (2017-2018) data were used to estimate the direct medical costs associated with COPD. All-cause (unadjusted) cost and COPD-specific (adjusted) cost were determined for the various service categories using a regression-based approach among patients with COPD. We developed a weighted two-part model and adjusted for various demographic, socioeconomic, and clinical characteristics. RESULTS: The study sample consisted of 23,590 patients, of which 1073 had COPD. Patients with COPD had a mean age of 67.4 years (standard error (SE): 0.41), and the total all-cause mean medical cost per patient per year (PPPY) was 2018 US $19,449 (SE: US $865), of which US $6145 (SE: US $295) was for prescription drugs. Using the regression approach, the mean total COPD-specific cost was US $4322 (SE: US $577) PPPY, with prescription drugs contributing US $1887 (SE: 216) PPPY. These results represented an annual total COPD-specific cost of US $24.0 billion, with prescription drugs contributing US $10.5 billion. The mean annual out-of-pocket spending accounted for 7.5% (mean: US $325) of the total COPD-specific cost; for COPD-specific prescription drug cost, 11.3% (mean: US $212) was out-of-pocket cost. CONCLUSION: COPD poses a significant economic burden on healthcare payers and patients 45 years of age and older in the USA. While prescription drugs accounted for almost half of the total cost, more than 10% of the prescription drug cost was out-of-pocket.

Onychoscopy of Nail Lesions in Dermatological Disorders: A Cross-Sectional Observational Study.

Background: Nail disorders account for about 10% of all dermatological conditions. Onychoscopy is useful not only for their diagnosis but also for assessing severity/progression and monitoring the response to therapy. Aims and Objectives: Describing dermoscopic features of nail disorders in patients reporting to the dermatology OPD of our tertiary care hospital and recording the sociodemographic profiles thereof. Materials and Methods: This cross-sectional observational study was carried out on 176 patients with effect from August 2019 to August 2021. Results: Males (99; 56.25%) outnumbered females (77; 43.75%); males: female: 1.28: 1; their mean age was 35.8 years. Fingernails were affected more oftener (84.09%) than toenails (38.64%). Onychomycosis, the commonest (58;32.95%) condition, revealed findings of aurora borealis pattern (75.86%), subungual hyperkeratosis (72.41%), and onycholysis with jagged edges and spikes (68.97%). The next frequent (32;18.18%) condition was nail psoriasis which revealed pits (81.25%); onycholysis (62.5%) and dilated globose nail fold vessels on capillaroscopy (25%). Limitations: The small sample size proved inadequate for the evaluation of statistical significance in the less common conditions and the correlation of disease severity of many. Ideally, confirmatory diagnostic tests should have been done in every patient, as indicated. The magnification of our dermoscopy was 10X; 20- and 40X permit better capillaroscopy. Conclusions: Onychocopy can minimize the need for biopsy by highlighting subtle changes and helps narrow down the differentials. It is potentially a diagnostic test of choice in younger children. Our study helped to grade the severity of connective tissue disorders and establish the benignity of melanonychia. Photographic documentation facilitates record-keeping.

Healthcare costs associated with comorbid cardiovascular and renal conditions among persons with diabetes, 2008-2019.

BACKGROUND: There is paucity of data examining healthcare costs among persons with comorbid diabetes and cardiorenal conditions. OBJECTIVE: To elucidate the longitudinal trends and quantify the incremental healthcare costs associated with the following cardiorenal conditions: atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and kidney disease, among persons with diabetes. METHODS: Medical Expenditure Panel Survey data (2008-2019) were used to identify adults with diabetes and comorbid cardiorenal conditions. Overall, medical and pharmaceutical costs were ascertained (in 2019 US dollars). Analyses were adjusted for 14 variables using a two-part regression model. RESULTS: Among 32,519 adults with diabetes, the mean (standard error [SE]) annual healthcare costs were $13,829 ($213), with medical and prescription components contributing $9301 ($172) and $4528 ($98), respectively. Overall healthcare costs rose by 26.8% from $12,791 (2008-2009) to $16,215 (2018-2019) over the study period, driven by 42.5% and 20.3% increase in pharmaceutical and medical spending, respectively. Similar trends were observed for subgroup of persons with cardiorenal conditions. Compared to their counterparts without cardiorenal conditions and prior to adjustment, persons with ASCVD, HF and kidney disease incurred healthcare costs that were approximately 2.2, 3.3, and 2.7 times greater. After adjustment, comorbid ASCVD, HF and kidney disease were associated with annual excess spending of $8651 (95% CI $7729-$9573), $9373 (95% CI $9010-$9736), and $9995 (95% CI $8781-$11,209), respectively. CONCLUSIONS: Study results are generalizable to non-institutionalized US persons. Healthcare costs associated with the management of diabetes are high-especially among those with comorbid cardiorenal conditions, and have risen in recent years.

Direct medical and indirect absenteeism costs among working adult ADHD patients in the United States.

OBJECTIVE: This study investigated the direct medical and indirect (i.e. absenteeism) costs among working adults diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) in the United States. METHODS: This study utilized 2017-2018 Medical Expenditure Panel Survey data. Attribution and regression-based incremental cost approaches were utilized to estimate direct medical costs, i.e. prescription drug costs and total costs. The regression-based approach was utilized to estimate absenteeism cost. RESULTS: The study sample consisted of 32,222 observations (weighted: 187,207,896). Of these, 459 (weighted: 3,175,033) had ADHD. The mean annual per person ADHD-attributable prescription drug cost was 2018 US $1,248 (standard error (SE): 97) and the ADHD-attributable total cost was $2,031 (SE: 371). This contributed to a mean overall annual spending of $3.96 (SE: 0.42) billion on ADHD-attributable prescription drugs and $6.45 (SE: 1.26) billion on ADHD-attributable total direct medical costs among adult ADHD patients. Based on the regression-based approach, the mean annual incremental cost for ADHD was $1,641 (SE: 164) and $4,328 (SE: 862) per person for prescription medication costs and total costs, respectively. The mean indirect cost of ADHD was estimated at $512 (SE: 91) per year, per person among working adults with ADHD in the United States. CONCLUSIONS: There is a significant direct and indirect economic burden on working adults with ADHD. EXPERT OPINION: There is a significant economic burden of ADHD in terms of direct medical (including out-of-pocket) cost as well as indirect absenteeism cost. The per person annual costs estimated using a regression approach were approximately twice as much as the costs using the sum disease-specific approach, suggesting a potential role for 'spillover' costs among working adults with ADHD. Prescription drug costs were top-ranked contributors to the direct medical costs. As a group, working adults with ADHD are relatively understudied and more research is needed to better understand the burden of ADHD in this group.

Economic burden of comorbidities among COPD Patients hospitalized for acute exacerbations: an analysis of a commercially insured population.

INTRODUCTION: This study quantifies costs associated with comorbid conditions among adults diagnosed with chronic obstructive pulmonary disease (COPD) who experience acute exacerbations (AECOPD) needing inpatient hospitalization. METHODS: This retrospective cohort study used 2006-2015 IQVIA PharMetrics® Plus data, a health plan claims database. Patients aged 40-64 years, with AECOPD, defined as an inpatient hospitalization for a COPD-related diagnosis were included. The impact of comorbidities on AECOPD costs (costs of the COPD-related inpatient stay plus healthcare services used 30 days post-discharge) was determined using multivariable regression. The models adjusted for clinical complications, previous utilization, age, sex, region, year, length of hospitalization, and season of admission. RESULTS: Among these COPD patients, 89.5% had at least 1 comorbidity. The mean cost for AECOPD was 2015 US $19,687 (SD: 27,035, median: 11,539). Congestive heart failure, lipid disorders, cancer, and presence of any of the 10 most frequent comorbidities were associated with $1,921 (95% confidence interval (CI): 977-2,866), $1,619 (95% CI: 967-2,272), $8,347 (95% CI: 7,236-9,458), and $4,433 (95% CI: 3,598-5,268) higher costs, respectively than corresponding individuals without these comorbid conditions. Patients with depressive disorders were associated with $1,592 (95% CI: 828-2,355) lower costs compared to those without depressive disorders. CONCLUSION: COPD comorbidity imposes a significant economic burden on AECOPD.

Trends in Medicaid spending on inhalers in the United States, 2012-2018.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma are common respiratory diseases that impose a significant economic burden on Medicaid. Inhalers are the mainstay treatment for relieving symptoms and improving outcomes for COPD and asthma patients. OBJECTIVE: To describe the total spending and trends of Medicaid expenditures on inhalers between 2012 and 2018 in the United States. METHODS: We analyzed the deidentified data from the Medicaid Drug Spending Dashboard and utilization datasets from 2012 to 2018. We identified 9 classes of inhalers and described the Medicaid total spending on and relative annual changes for those inhalers. We also described the spending on available generic inhalers and compared the Medicaid spending by manufacturers during this time frame. RESULTS: Medicaid spent $26.2 billion on inhalers from 2012 to 2018. This spending increased by $2.5 billion (120%) over this time frame. During this specified period, the highest Medicaid spending was on the group of inhaled corticosteroid (ICS)-containing inhalers ($14.9 billion). Within this group, the inhaler class of ICS/long-acting beta-2 adrenoceptor agonists contributed to the highest Medicaid spending (53%), with a growth of 607% between 2012 and 2018. Of the $26.2 billion that Medicaid spent on inhalers, $35.5 million (less than 0.01%) was spent on 2 generic inhalers: fluticasone propionate with salmeterol and levalbuterol tartrate hydrofluoroalkane. CONCLUSIONS: Between 2012 and 2018, on average, $3.5 billion per year was spent by Medicaid on inhalers. Decreasing the price of inhalers by introducing more generic inhalers in the market can potentially reduce the cost burden on Medicaid. DISCLOSURES: This study was funded by the American Foundation for Pharmaceutical Education (AFPE). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflicts of interest.

Association between lung function and future risks of diabetes, asthma, myocardial infarction, hypertension and all-cause mortality.

BACKGROUND: While forced expiratory volume in 1 s (FEV1) is a hallmark of disease progression in chronic obstructive lung diseases, little is known about the relationship between baseline FEV1 and future risks of other medical conditions. OBJECTIVE: The aim of this study was to investigate the association between baseline FEV1 and future risks of diabetes, asthma, myocardial infarction, hypertension and all-cause mortality. METHODS: We used data from the National Health and Nutrition Examination Survey and its Epidemiological Follow-Up Study. Our data provided longitudinal follow-up of the original cohort for up to 12 years. We used two competing risks approaches, the cause-specific hazard model and the Fine-Gray sub-distribution hazard model, to measure the associations between baseline FEV1 and future risks of the outcomes of interest. All models were adjusted for major confounding factors. RESULTS: The final sample included 3020 participants (mean±sd baseline age 44.64±13.44 years). In the cause-specific hazard model, for every per cent increase in the baseline per cent predicted FEV1, the hazard of the event reduced by 2.5% (HR 0.975; 95% CI 0.958-0.994) for diabetes, 4.3% (HR 0.957; 95% CI 0.932-0.983) for asthma and 1.8% (HR 0.982; 95% CI 0.971-0.992) for all-cause mortality. There was no statistically significant association between baseline per cent predicted FEV1 and future risks of myocardial infarction (HR 0.987; 95% CI 0.970-1.004) and hypertension (HR 0.998; 95% CI 0.992-1.005). Consistent results were observed for the Fine-Gray sub-distribution hazard model. CONCLUSION: Our data suggest that lower per cent predicted FEV1 values at baseline were significantly associated with higher future risks of diabetes, asthma and all-cause mortality.

Quantifying heterogeneity of physical and mental health-related quality of life in chronic obstructive pulmonary disease patients in the United States.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogenous condition. This study aims to quantify the heterogeneity of Health-related Quality of Life (HRQoL), and identify subgroups with the lowest HRQoL, in COPD patients in the United States (US). Methods Data from 2008-2015 Medical Expenditure Panel Survey were used to examine the heterogeneity of HRQoL between different COPD subgroups using mixed-effects modeling and G-computation. The Physical Composite Summary (PCS) and Mental Composite Summary (MCS) scores from the Short-Form-12 questionnaire were utilized. We also compared the heterogeneity of HRQoL in our COPD cohort against that in a matched non-COPD cohort. Results The final sample consisted of 1,866 (weighted = 19,952,143) COPD patients with a mean age of 63.2 years (Standard error (SE):0.38), mean MCS score of 46.84 (SE:0.35), and mean PCS score of 35.65 (SE:0.32). The adjusted MCS and PCS scores ranged from 36.19 to 53.06, and from 25.52 to 48.27, respectively, for COPD subgroups. COPD patients had statistically significantly lower MCS and PCS scores by 4.61, and 5.86 points, respectively, compared to the matched non-COPD cohort, and MCS scores showed a wider variability in the COPD cohort. Conclusion Our study quantifies substantial heterogeneity of HRQoL in COPD in the US and provides evidence for prioritizing COPD subgroups with the lowest HRQoL for targeted interventions.

Reliability and Validity of the Short-Form 12 Item Version 2 (SF-12v2) Health-Related Quality of Life Survey and Disutilities Associated with Relevant Conditions in the U.S. Older Adult Population.

This study aimed to validate the Short-Form 12-Item Survey-version 2 (SF-12v2) in an older (≥65 years old) US population as well as estimate disutilities associated with relevant conditions, using data from the Medical Expenditure Panel Survey longitudinal panel (2014-2015). The physical component summary (PCS) and mental component summary (MCS) scores were examined for reliability (internal consistency, test-retest), construct validity (convergent and discriminant, structural), and criterion validity (concurrent and predictive). The study sample consisted of 1040 older adults with a mean age of 74.09 years (standard deviation: 6.19) PCS and MCS demonstrated high internal consistency (Cronbach's alpha-PCS: 0.87, MCS: 0.86) and good and moderate test-retest validity, respectively (intraclass correlation coefficient: PCS:0.79, MCS:0.59)). The questionnaire demonstrated sufficient convergent and discriminant ability. Confirmatory factor analysis showed adequate fit with the theoretical model and structural validity (goodness of fit = 0.9588). Concurrent criterion validity and predictive criterion validity were demonstrated. Activity limitations, functional limitations, arthritis, coronary heart disease, diabetes, myocardial infarction, stroke, angina, and high blood pressure were associated with disutilities of 0.18, 0.15, 0.06, 0.07, 0.07, 0.06, 0.09, 0.06, and 0.08, respectively, and demonstrated the responsiveness of the instrument to these conditions. The SF-12v2 is a valid and reliable instrument in an older US population.

Examining factors associated with adherence to hormonal therapy in breast cancer patients.

BACKGROUD: Breast cancer is a rampant disease and is highly prevalent among women in the United States. Two out of three breast cancers are hormone receptor positive and hormonal therapies (Tamoxifen and Aromatase Inhibitors) are used to treat this type of breast cancer. However, adherence to these efficacious therapies is relatively low. PURPOSE: The aim of this study was to identify factors that are associated with adherence to hormonal therapy among breast cancer patients, and the extent to which they influence adherence, by looking at data from a nationally representative database. METHODS: A retrospective cross-sectional study was conducted using Medical Expenditure Panel Survey (MEPS) for 2011-2015. Individuals ≥18 years diagnosed with breast cancer utilizing Tamoxifen and Aromatase inhibitors were identified. The Proportion of Days Covered (PDC) adherence measure was used to classify individuals as adherent (PDC≥80%) or non-adherent (PDC<80%). Multivariable logistic regression was used to determine factors associated with adherence to hormonal therapy. RESULTS: Out of the 354 breast cancer respondents utilizing hormonal therapy, 194 (54.8%) were adherent and 160 (45.20%) were non-adherent. From 2011 through 2015, an increase in the usage of hormonal therapy was observed. Individuals having at least a high school diploma or General Equivalency Diploma (GED) had 2.795 (1.081, 6.941) times the odds of being adherent when compared to those who did not have a high school diploma or GED. Race, insurance status, marital status, poverty level, class of drug (aromatase inhibitor/tamoxifen), age, comorbidities, out-of-pocket costs and region were not significantly associated with adherence to hormonal therapy among breast cancer patients. CONCLUSIONS: This study found an association between an individual's level of education and adherence to hormonal therapy among breast cancer patients. These results can be used to help optimize allocation of resources to promote knowledge designed to increase the adherence of breast cancer patients to hormonal therapy.

Disparities in prescription of opioids among prostate cancer patients of various racial groups.

Aim: To examine disparities in opioid prescription between different races of prostate cancer patients. Materials & methods: We used the Medical Expenditure Panel Survey data (2013-2015) and developed a model based on covariates that may affect opioid prescription and based on this model, we carried out logistic regression, where our outcome of interest was prescription of at least one opioid among prostate cancer patients. Results: Compared with non-Hispanic whites, Hispanics had 0.490 (0.214-1.123), non-Hispanics blacks had 0.745 (0.429-1.293) and other ethnic groups had 2.550 (0.947-6.863) times the odds of receiving opioids than non-Hispanic whites. These differences were not statistically significant. Conclusion: There were no differences between races in terms of opioid prescription for patients with prostate cancer.