Joshua D. Brown

Rural and Appalachian Disparities in Neonatal Abstinence Syndrome Incidence and Access to Opioid Abuse Treatment

OBJECTIVE Incidence of neonatal abstinence syndrome (NAS) is increasing due to the rise in opioid use. Rural states like Kentucky have been disproportionally impacted by opioid abuse, and this study determines NAS burden nationally and in Kentucky while quantifying differences in access to care between Appalachian and non-Appalachian counties. METHODS NAS rates were calculated using National (2013) and Kentucky (2008-2014) National Inpatient Sample discharge data. Births were identified using International Classification of Diseases v9 code 779.5 and live birth codes V30.x-V38.x. Counties were classified as rural, micropolitan, or metropolitan using census data. Proximity analysis was conducted via mapping from ZIP code centroid to nearest opioid treatment facility. Distance to treatment facilities was calculated and then compared using nonparametric testing for counties by rural and Appalachian status. RESULTS NAS cases tripled from 2008 to 2014 in Kentucky counties, with a 2013 NAS rate more than double the national NAS rate. Rural and Appalachian counties experienced an NAS increase per 1,000 births that was 2-2.5 times higher than urban/non-Appalachian counties, with a greater number of NAS births overall in Appalachian counties. All opioid treatment facility types were further from rural patients than micropolitan/metropolitan patients (P < .001), as well as further for Appalachians versus non-Appalachians (P < .001, all facility types). CONCLUSIONS NAS burden disparately affects rural and Appalachian Kentucky counties, while treatment options are disproportionately further away for these residents. Policy efforts to increase NAS prevention and encourage opioid abuse treatment uptake in pregnant women should address rural and Appalachian disparities.

Hospital Variation and Patient Characteristics Associated With Vena Cava Filter Utilization.

Introduction: There is a wide variation in the use of vena cava filter (VCF). Objective: This study assessed the hospital and patient characteristics associated with VCF use in deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods: Inpatient discharge data from all acute care hospitals with DVT/PE during 2008–2014 in Kentucky were used. Hierarchical logistic regression models were used to evaluate the relationships of study variables with VCF use. Results: During the study period, 81,922 discharges for DVT/PE were observed and 10.5% of these received a VCF. This included 12,083 cases of PE+DVT, 18,571 cases of PE only, and 51,268 cases of DVT only. VCF use among these groups was 22.7%, 6.0%, and 7.8%, respectively. In adjusted analyses, VCF use was associated with increasing age, indicating that those over age 65 were twice as likely to receive a filter compared with the reference (21–25 y old) group. Significant comorbidities associated with VCF use included cancer, liver disease, cerebrovascular disease, atrial fibrillation, anemia, and concurrent bleeding. Lower extremity, proximal DVTs, and patients receiving thrombolytic therapy or embolectomy, those having surgery, and those who were unstable or had trauma, were also more likely to receive a filter. Among cancer types, brain and metastatic tumors were significantly associated with VCF use. Between-hospital variation after controlling for all covariates was 7.1%. Conclusions: There was high variation in the use of VCFs. Several high-risk subgroups were more likely to use VCFs including older adults and those with cancer and concurrent bleeding.

Vena Cava Filter Retrieval Rates and Factors Associated With Retrieval in a Large US Cohort

Background Retrieval of vena cava filters (VCFs) is important for safety as complications increase with longer dwell times. This study assessed VCF retrieval rates and factors associated with retrieval in a national cohort. Methods and Results VCFs were identified by procedural codes from an administrative claims database. Patients were identified who had a VCF placement during a hospitalization from a national commercial administrative claims database. Indications for VCF placement were identified as pulmonary embolism with or without deep vein thrombosis, deep vein thrombosis only, or prophylactic. Patient demographic and clinical characteristics were included in proportional hazard regression models to find associations with early (90‐day) and 1‐year VCF retrieval. Initiation of anticoagulation and the correlation between time‐to‐retrieval and time‐to‐initiation of anticoagulation were observed. Of 54 766 patients receiving a VCF, 36.9% had pulmonary embolism, 43.9% had deep vein thrombosis only, and 19.2% had no apparent venous thromboembolism present. Over the 1 year of follow‐up, the cumulative incidence of VCF retrieval was 18.4%. Retrieval increased over time from a low of 14.0% in 2010 up to ≈24% in 2014. In adjusted time‐to‐event models, increasing age, differing regions, and some comorbidities were associated with poorer retrieval rates. Initiation of anticoagulation was poorly correlated with retrieval, with anticoagulation preceding retrieval by a median of 51 days while those without retrieval had a median of 278 days of exposure to anticoagulation. Conclusions VCF retrieval increased over the study period but remained suboptimal and was weakly correlated with anticoagulation initiation.

Low-Cost Generic Program Use by Medicare Beneficiaries: Implications for Medication Exposure Misclassification in Administrative Claims Data

BACKGROUND Administrative claims data are used for a wide variety of research and quality assurance purposes; however, they are prone to medication exposure misclassification if medications are purchased without using an insurance benefit. Low-cost generic drug programs (LCGPs) offered at major chain pharmacies are a relatively new and sparsely investigated source of exposure misclassification. LCGP medications are often purchased out of pocket; thus, a pharmacy claim may never be submitted, and the exposure may go unobserved in claims data. As heavy users of medications, Medicare beneficiaries have much to gain from the affordable medications offered through LCGPs. This use may put them at increased risk of exposure misclassification in claims data. Many high-risk medications (HRMs) and medications tracked for adherence and utilization quality metrics are available through LCGPs, and exposure misclassification of these medications may impact the quality assurance efforts reliant on administrative claims data. Presently, there is little information regarding the use of these programs among a geriatric population. OBJECTIVES To (a) quantify the prevalence of LCGP users in a nationally representative population of Medicare beneficiaries; (b) compare clinical and demographic characteristics of LCGP users and nonusers; (c) assess determinants of LCGP use and medications acquired through these programs; and (d) analyze patterns of LCGP use during the years 2007-2012. METHODS This study relied on data from the Medical Expenditure Panel Survey (MEPS) from 2007 to 2012. The first 3 objectives were completed with a cohort of individuals in the most recent MEPS panel, while the fourth objective was completed with a separate cohort composed of individuals who participated in MEPS from 2007 to 2012. Inclusion in either study cohort required that individuals were Medicare beneficiaries aged 65 years or greater, used at least 1 prescription drug during their 2-year panel period, and participated in all 5 rounds of data collection during their panel period. MEPS captures medication utilization by surveying individuals on current and previous medication use and verifies this information at the pharmacy level, so prescription fills can be observed irrespective of payment by an insurer or a filed claim. Pharmaceutical utilization was assessed at the individual level for each year of the study period, and LCGP use was recorded as a binary variable for each individual. An LCGP medication fill was identified if the total cost of the drug was paid out of pocket and matched the cost of medications listed on LCGP formularies available from major pharmacy retailers during these years. Cohort demographics and characteristics of interest included age, gender, race, employment status, marital status, family income level, education level, residence in a metropolitan statistical area, geographic region, prescription drug coverage, Medicare type, comorbidities, number of unique medications used, and number of medication fills. Comparisons were made between users and nonusers using chi-square and t-tests. Multivariable logistic regression was used to identify factors associated with LCGP use. RESULTS From the most recent MEPS panel, 1,861 individuals were included in the study cohort, of which 53.5% were observed to be LCGP users. The 995 LCGP users in this cohort represented over 20 million Medicare beneficiaries who used LCGPs from 2011 to 2012. Significant differences between LCGP users and nonusers existed in terms of race, educational attainment, comorbidity burden, type of Medicare insurance, number of unique medications used, and number of medication fills. Each additional unique medication filled increased the odds of LCGP use by 12% (95% CI = 1.09-1.14). Individuals with insurance in addition to Medicare (i.e., Tricare/Veterans Affairs or Medicaid) had less than half the odds of using LCGPs compared with those with Medicare or Medicare managed care insurance coverage only. The proportion of LCGP users and the proportion of LCGP fills out of all medications available through LCGPs increased from 2007 to 2012. CONCLUSIONS There is a high rate of LCGP use among Medicare beneficiaries aged 65 years or greater. Claims-based research and quality assurance programs focusing on the benefits and harms of medications available through these programs are at risk of underestimating the true medication exposure in this population and should account for this possibility in sensitivity analyses. Managed care organizations should incentivize the reporting of LCGP medication use or make adjustments to generic medication benefit structures to more effectively capture true medication exposure. DISCLOSURES No direct sources of funding were used to conduct this study. Data acquisition was supported by the University of Kentucky Center for Clinical and Translational Science through funding from NIH NCATS grant #UL1TR000117. Brown is the Humana-Pfizer Research Fellow at the Institute for Pharmaceutical Outcomes & Policy at the University of Kentucky College of Pharmacy and is provided salary from these corporations. However, neither company provided any direct funding for the current study nor provided any input or guidance for the design, methods, or drafting of the manuscript. Pauly has no financial disclosures or conflicts of interest. Portions of these results were presented at the 20th International Society for Pharmacoeconomics and Outcomes Research International Meeting; May 16-20, 2015; Philadelphia, Pennsylvania. Study concept and design were primarily contributed by Brown, along with the other authors. Brown took the lead in data collection and interpretation, along with Pauly and Talbert. All authors participated in the writing and revision of the manuscript.

Adherence to Rivaroxaban, Dabigatran, and Apixaban for Stroke Prevention for Newly Diagnosed and Treatment-Naive Atrial Fibrillation Patients: An Update Using 2013-2014 Data

BACKGROUND Few studies have assessed adherence to non-vitamin K antagonist oral anticoagulants (NOACs), especially using contemporary data now that multiple NOACs are available. OBJECTIVE To compare adherence and treatment patterns among NOACs for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). METHODS Incident and treatment-naive NVAF patients were identified during 2013-2014 from a large claims database in this retrospective cohort study. Patients were included who initiated rivaroxaban, dabigatran, or apixaban within 30 days after diagnosis. Adherence to the index medication and adherence to any oral anticoagulant was assessed using the proportion of days covered (PDC) at 3, 6, and 9 months. The number of switches and gaps in therapy were also evaluated. Analyses were stratified by stroke risk scores, and a logistic regression model was used to control for factors that may predict high adherence. RESULTS Dabigatran had lower adherence (PDC = 0.76, 0.64, 0.57) compared with rivaroxaban (PDC = 0.83, 0.73, 0.66; P < 0.001) and apixaban (PDC = 0.82, 0.72, 0.66; P < 0.001) at 3, 6, and 9 months of follow-up and twice the number of switches to either other anticoagulants or antiplatelet therapy. Adherence was higher overall as stroke risk increased, and dabigatran had consistently lower adherence compared with the other NOACs. Multivariable logistic regression predicting PDC ≥ 0.80 showed rivaroxaban users with higher odds of high adherence compared with dabigatran or rivaroxaban across all time periods. Adjusted analyses showed that increasing age and comorbid hypertension and diabetes were associated with higher adherence. CONCLUSIONS In this real-world analysis of adherence to NOACs, rivaroxaban and apixaban had favorable unadjusted adherence profiles compared with dabigatran, while rivaroxaban users had higher odds of high adherence (PDC ≥ 0.80) among the NOACs in adjusted analyses. Clinicians and managed care organizations should consider the implications of lower adherence on clinical outcomes and quality assessment. DISCLOSURES This project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors have nothing to disclose. Study concept and design were contributed by Brown and Shewale. Brown and Talbert collected the data, and data analysis was performed primarily by Brown, along with Shewale and Talbert. The manuscript was written primarily by Brown, along with Shewale, and revised by all the authors.

Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Application of the HAS‐BLED Bleeding Score During the First 6 Months of Anticoagulant Treatment

Background The Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile International Normalized Ratio (INR), Elderly, Drugs or alcohol use (HAS‐BLED) score has strong predictive validity for major bleeding complications, but limited validation has been conducted in venous thromboembolism (VTE). This study evaluates the HAS‐BLED score in a large cohort of VTE patients. Methods and Results A retrospective cohort of adults ≥18 years with primary diagnosis of VTE between January 1, 2010 and November 31, 2013 were identified in an insurance claims database. Patients were tracked until death, any bleed event, or end of study period. HAS‐BLED score and components were evaluated via proportional hazard models. Cumulative incidence functions were reported at 30, 60, 90, and 180 days. N=132 280 patients with a VTE were identified, with 73.8% having HAS‐BLED scores of 0 to 2, 3.6% score ≥4, and 4789 bleeding events (3.6% all patients). A 1‐point HAS‐BLED score increase was associated with 20% to 30% bleeding rate increase overall, but in a cancer cohort only the increase from 3‐ to 4‐points was significant for all bleeds (csHR=1.41, 95% CI: 1.17–1.69; sdHR=1.40, 95% CI: 1.17–1.69) and major bleeds (csHR=1.66, 95% CI: 1.26–2.20; sdHR=1.66, 95% CI: 1.25–2.19). Adding cancer to the model as an independent covariate provided the strongest association among all covariates, with csHR=2.25 (95% CI: 1.98–2.56) and sdHR=2.11 (95% CI: 1.85–2.41) in the model for major bleeds. Conclusions The HAS‐BLED score has good predictive validity for bleeding risks in patients with VTE. The addition of cancer as an independent bleeding risk factor merits consideration, possibly as part of the “B” criterion (“bleeding tendency or predisposition”).

Statin use and venous thromboembolism in cancer: A large, active comparator, propensity score matched cohort study

BACKGROUND Statins have been shown to have a protective effect for venous thromboembolism (VTE) in the general population. This study sought to assess the association between statins and the risk for cancer-associated deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS Patients with newly diagnosed cancer were followed for up to one year in a healthcare claims database (2010-2013). Three treatment groups included statin users, non-statin cholesterol lowering medication users, and an untreated group with pre-existing indications for statin therapy (hyperlipidemia, diabetes, or heart disease). Propensity score matched groups were compared using competing risks survival models for DVT and PE outcomes reporting the hazard ratios (HR) between the treatment groups. Sensitivity analyses assessed the influence of age and individual medications. RESULTS The total cohort included 170,459 patients, which, after matching, were similar on baseline characteristics. The overall model showed a statistically significant protective effect for statins compared to no treatment attributed only to leukemia for DVT (HR=0.77, 95% CI 0.61-0.99) and colorectal cancers for PE (HR=0.80, 95% CI 0.64-0.99) in stratified analyses. There were generally no differences in outcomes between statins and non-statins and no individual statin use showed results different from the class effect. CONCLUSIONS In this propensity score matched sample of patients with cancer, statins were shown to have a small protective effect in some cancers for DVT or PE compared to no treatment and little difference compared to an active control group. The lack of effect was consistent across statins and was also not found for any of the sensitivity analyses included.

Impact of Time-Varying Treatment Exposures on the Risk of Venous Thromboembolism in Multiple Myeloma

Multiple myeloma (MM) has one of the highest risks of venous thromboembolism (VTE) of all cancers due to pathologic changes and treatment-related exposures. This study assessed the one-year incidence of VTE in newly diagnosed MM and to determine the baseline and time-varying treatment-related factors associated with VTE risk in a U.S.-based cohort. MM patients were identified and age, gender, and baseline comorbidities were determined. Treatment-related exposures included thalidomide derivatives (IMIDs), proteasome inhibitors, cytotoxic chemotherapy, steroids, erythropoietin-stimulating agents (ESAs), stem cell transplants (SCT), hospitalizations, infection, and central venous catheters (CVC). Multiple statistical models were used including a baseline competing risks model, a time-varying exposure Cox proportional hazard (CPH) model, and a case-time-control analysis. The overall incidence of VTE was 107.2 per 1000 person-years with one-half of the VTEs occurring in the first 90 days. The baseline model showed that increasing age, heart failure, and hypertension were associated with one-year incidence of VTE. MM-specific IMID treatment had lower than expected associations with VTE based on prior literature. Instead, exposure to ESAs, SCT, CVC, and infection had higher associations. Based on these results, VTE risk in MM may be less straightforward than considering only chemotherapy exposures, and other treatment-related exposures should be considered to determine patient risk.

Immune Checkpoint Inhibition and the Prevalence of Autoimmune Disorders Among Patients With Lung and Renal Cancer

PURPOSE Immune checkpoint inhibition reactivates the immune response against cancer cells in multiple tissue types and has been shown to induce durable responses. However, for patients with autoimmune disorders, their conditions can worsen with this reactivation. We sought to identify, among patients with lung and renal cancer, how many harbor a comorbid autoimmune condition and may be at risk of worsening their condition while on immune checkpoint inhibitors such as nivolumab and pembrolizumab. METHODS An administrative health care claims database, Truven MarketScan, was used to identify patients diagnosed with lung and renal cancer from 2010 to 2013. We assessed patients for diagnosis of autoimmune diseases 1 year prior to or after diagnosis of cancer using International Classification of Diseases, Ninth Revision codes for 41 autoimmune diseases. Baseline characteristics and other comorbid conditions were recorded. RESULTS More than 25% of patients with both lung and renal cancer had a comorbid autoimmune condition between 2010 and 2013 and were more likely to be women, older, and have more baseline comorbidities. CONCLUSIONS This population presents a dilemma to physicians when deciding to treat with immune checkpoint inhibitors and risk immune-related adverse events. Future evaluation of real-world use of immune checkpoint inhibitors in patients with cancer with autoimmune diseases will be needed.

Payer and Pharmaceutical Manufacturer Considerations for Outcomes-Based Agreements in the United States☆

BACKGROUND Considerable interest exists among health care payers and pharmaceutical manufacturers in designing outcomes-based agreements (OBAs) for medications for which evidence on real-world effectiveness is limited at product launch. OBJECTIVES To build hypothetical OBA models in which both payer and manufacturer can benefit. METHODS Models were developed for a hypothetical hypercholesterolemia OBA, in which the OBA was assumed to increase market access for a newly marketed medication. Fixed inputs were drug and outcome event costs from the literature over a 1-year OBA period. Model estimates were developed using a range of inputs for medication effectiveness, medical cost offsets, and the treated population size. Positive or negative feedback to the manufacturer was incorporated on the basis of expectations of drug performance through changes in the reimbursement level. Model simulations demonstrated that parameters had the greatest impact on payer cost and manufacturer reimbursement. RESULTS Models suggested that changes in the size of the population treated and drug effectiveness had the largest influence on reimbursement and costs. Despite sharing risk for potential product underperformance, manufacturer reimbursement increased relative to having no OBA, if the OBA improved market access for the new product. Although reduction in medical costs did not fully offset the cost of the medication, the payer could still save on net costs per patient relative to having no OBA by tying reimbursement to drug effectiveness. CONCLUSIONS Pharmaceutical manufacturers and health care payers have demonstrated interest in OBAs, and under a certain set of assumptions both may benefit.