Real-World Analysis of Treatment Patterns Among Hospitalized Patients with Pulmonary Arterial Hypertension.

INTRODUCTION: Hospitalization is an important clinical factor associated with survival and rehospitalization in patients with pulmonary arterial hypertension (PAH). Thus, this study examined treatment patterns before and after hospitalization in the US-specific population. METHODS: Adult PAH patients in the United States were identified using the Optum® Clinformatics® database from January 1, 2014, to June 30, 2019, and were required to have continuous health plan enrollment for at least 6 months prior to the first (index) hospitalization through at least 90 days post-discharge. Baseline patient characteristics were evaluated from 6 months prior to through the index hospitalization. PAH treatment patterns were examined from 30 days pre-index admission (pre-hospitalization) and 90 days post-index hospital discharge (post-hospitalization), and stratified by therapy type: monotherapy, double- or triple-combination therapy, or no PAH therapy. RESULTS: A total of 3116 hospitalized patients with PAH met selection criteria. The mean age and Charlson comorbidity index score were 68.1 years and 5.1, respectively. In the pre- and post-hospitalization periods (all-cause), respectively, patients prescribed monotherapy were most common (from 64.8% pre- to 51.9% post-hospitalization), followed by patients with no evidence of PAH therapy (from 14.6 to 28.5%). Among PAH-related hospitalizations, patients with monotherapy were also most common (from 60.8% pre- to 49.1% post-hospitalization), followed by patients with no evidence of PAH therapy (from 10.0 to 22.8%). The majority of patients with all-cause hospitalizations (72.8%) had no therapy modification; 20.0% de-escalated therapy (including 15.0% from monotherapy to no therapy) and 6.1% escalated therapy (including 2.2% from no therapy to monotherapy and 3.2% from monotherapy to double or triple therapy). CONCLUSION: Inpatient admissions did not appear to drive changes in PAH therapy management, as monotherapy predominated, and most patients had no therapy modification within 90 days of a hospitalization. These results warrant future research to understand the reasons behind the limited treatment intensification observed and the impact of post-hospitalization optimization on clinical and economic outcomes.

Burden of Pneumonia Among Hospitalized Patients with Influenza: Real-World Evidence from a US Managed Care Population.

INTRODUCTION: Pneumonia is among the most prevalent complications of influenza. The purpose of this study is to quantify the burden of pneumonia among hospitalized patients with influenza. METHODS: Real-world retrospective data from 01JAN2014-30JUN2019 (study period) were obtained from Optum's de-identified Clinformatics® Data Mart Database (2007-2020) for patients who had ≥ 1 diagnosis for influenza during the identification period and ≥ 1 all-cause inpatient visit within 1 day of diagnosis. Cases had ≥ 1 diagnosis claim for an influenza-related pneumonia within the 30 days after the initial influenza diagnosis date. Controls had no evidence of influenza-related pneumonia in the 30 days following the initial influenza diagnosis. Final 1:1 matching was determined using propensity score matching (PSM). Statistical significance between the cohorts was tested. RESULTS: After PSM, there were 4878 hospitalized patients with influenza in each of the case and control groups. During the index hospitalization, cases vs. controls had longer length of stay [Mean (standard deviation): 6.5 (8.3) vs. 1.9 (3.7)], greater intensive care unit (ICU) use (38.4 vs. 16.8%), and greater mechanical ventilation use (invasive: 11.4 vs. 2.3%; non-invasive: 6.8 vs. 2.6%) (all p < 0.001). Cases also had higher readmission rates than controls (12.3 vs. 3.5% within 30 days; 20.0 vs. 6.1% within 90 days; p < 0.001 for both). Post-index date direct all-cause healthcare costs were higher for cases than for controls (median total cost: $18,428 vs. $621 for 30 days; $21,774 vs. $3312 for 90 days; $25,960 vs. $8699 for 6 months; $35,875 vs. $21,619 for 1 year; all p < 0.001). CONCLUSIONS: Pneumonia as a complication of influenza increases risk of mortality and leads to greater healthcare resource use and direct medical costs among patients hospitalized with influenza. These effects are seen early during the index hospitalization and within the first 30 days after diagnosis, but their impact continues throughout a year of follow-up.

Predictors and Outcomes of Hospitalization for Influenza: Real-World Evidence from the United States Medicare Population.

INTRODUCTION: The purpose of this study was to identify predictors of initial hospitalization and describe the outcomes of high-risk patients hospitalized with influenza. METHODS: Data were taken from the 5% national US Medicare database from 2012 to 2015. Patients (aged at least 13 years) were required to have at least one diagnosis for influenza and have continuous health plan enrollment for 6 months before (baseline) and 3 months (follow-up) after the date of influenza diagnosis. Patients who died during follow-up were included. Patients were categorized as initially hospitalized if hospitalized within 0-1 day of diagnosis. High-risk initially hospitalized patients were defined as patients aged at least 65 years or those that had a diagnostic code for chronic lung disease, cardiovascular or cerebrovascular disease, or weakened immune system during baseline period. Logistic regression models were developed to determine predictors of initial hospitalization. RESULTS: The study population included 8127 high-risk patients who were initially hospitalized and 16,784 who were not hospitalized. Among high-risk patients, 89.3% were diagnosed in the emergency room, whereas 7.5% and 3.2% were diagnosed in a physician's office or other Medicare settings, respectively. Chronic obstructive pulmonary disorder, congestive heart failure, chronic kidney disease, older age, being male, other comorbidities, number of comorbidities, and baseline healthcare resource use were the predictors of hospitalization. Median length of stay for the hospitalization was 5.0 days, and the 30-day readmission rate was 14%. All-cause mortality rate was 5.1% during the inpatient stay and 9.2% within 30 days of diagnosis. Hospitalized patients with influenza incurred an increase of $16,568 per patient in total all-cause healthcare costs from pre-influenza to post-influenza diagnosis. CONCLUSION: The study characterized the burden of hospitalization for influenza and found that hospitalized high-risk patients experience greater comorbidity burden, higher likelihood of multiple inpatient admissions, and costly medical interventions compared to patients who were not hospitalized.

Evaluating the Effect of Standard of Care Treatment on Burden of Chronic Hepatitis B: A Retrospective Analysis of the United States Veterans Population.

INTRODUCTION: This study aimed to characterize chronic hepatitis B (CHB)-infected patients and estimate the association between nucleos(t)ide analogue (NA) persistence and economic outcomes using data from the Veterans Health Administration (VHA) database. METHODS: Patients (at least 18 years of age) with two or more claims for CHB and at least one pharmacy claim for NA were identified using VHA data from 1 April 2013 to 31 March 2018. The index date was the first NA prescription fill date during 1 October 2014 to 31 March 2017. Persistence and non-persistence to NA treatment were assessed during the first 2 years post index date. Non-persistence was defined as at least one failure to refill medication within 30 days from the run-out date. Generalized linear models were used to compare health care utilization and costs between persistent and non-persistent patients. RESULTS: Among patients treated with NAs (N = 2368), 1428 (60%) were CHB mono-infected and 748 (32%) were HIV co-infected. Total costs per patient per year (PPPY) were $39,240, $29,957, and $55,220 PPPY for NA-treated, mono-infected, and HIV co-infected patients, respectively. An inception cohort of 564 patients (24%), without a NA prescription in the 6 months pre-index period and at least 2 years of follow-up, was created. Persistence among the inception cohort was 29% for first year and 14% for first 2 years. After adjustment for baseline differences, persistent patients had lower cumulative overall health care costs compared to non-persistent patients, with a net cost saving of $851 (p > 0.05) in the first 2 years. CONCLUSION: CHB is associated with considerable economic burden. We observed suboptimal persistence to NAs which decreased over time. Short-term savings could be generated for CHB-infected patients when they remain persistent to NAs.

A Real-World Analysis of Patient Characteristics and Predictors of Hospitalization Among US Medicare Beneficiaries with Respiratory Syncytial Virus Infection.

INTRODUCTION: Little has been published on respiratory syncytial virus (RSV) among Medicare patients at high risk (HR) of RSV complications due to age or comorbidity. METHODS: Adult patients (at least 18 years of age) with at least 1 diagnostic code for RSV were identified using the 5% US Medicare database from 2011 through 2015. Patients were required to have continuous health plan enrollment for 180 days pre- and 180 days post-RSV diagnosis (baseline and follow-up periods, respectively). HR was defined as diagnosis of chronic lung disease, congestive heart failure, or weakened immune system for 180 days during the baseline period. Patients were categorized as initially hospitalized if hospitalized within 1 day of RSV diagnosis. Logistic regression models were developed to determine predictors of initial hospitalization. Healthcare utilization and costs for 180 days pre- and post-RSV diagnosis were compared. RESULTS: The study included 756 HR patients who were initially hospitalized with RSV diagnoses. Among these, 61.7% were diagnosed in the emergency department vs 15.3% in a physician's office, with hypertension (76.3%), chronic obstructive pulmonary disease (COPD) (53.7%), and high cholesterol (52.0%) observed as the most prevalent comorbidities. Of these, COPD, congestive heart failure, chronic kidney disease, and previous evidence of pneumonia were significant predictors of hospitalization. Other significant predictors of hospitalization included older age, hematological malignancies, stroke, and baseline healthcare resource use. Among both HR and non-HR hospitalized patients, there was a significant increase in healthcare resource utilization following hospitalization, including the number of inpatient admissions and longer hospital stays post-RSV diagnosis. The total mean all-cause healthcare costs among HR hospitalized patients increased by $9210 per patient (p < 0.0001) post-RSV diagnosis. CONCLUSION: Hospitalized Medicare beneficiaries with RSV infections pose a significant healthcare burden as compared with non-hospitalized patients, mainly driven by higher comorbidity, higher likelihood of multiple inpatient admissions, and costly medical interventions.

Real-world medication use and economic outcomes in incident systemic lupus erythematosus patients in the United States.

Aims: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disease involving multiple organs systems and places a significant economic burden on SLE patients. There is a literature gap regarding the standard of care and economic burden in SLE patients, their families, and society. This study assessed medication use patterns among SLE patients and generated the annual and total economic burden associated with the illness.Materials and methods: Adult patients with ≥2 medical claims on different dates for SLE diagnoses were identified from 01 January 2013 to 31 December 2015 using two large administrative claims databases representative of the commercially insured US population. Patient demographics and clinical characteristics during 1-year pre-SLE diagnosis were assessed. Outcomes including the proportion of patients who used SLE medications and annual costs were assessed 1-year post-SLE diagnosis. Total costs related to SLE were extrapolated to the US population to estimate the economic burden based on SLE prevalence.Results: A total of 30,086 SLE patients were identified. The most common baseline comorbidities were hypertension and infections. Corticosteroids and hydroxychloroquine were the most common SLE medications. Biologics utilization was minimal. SLE patients had, on average, 26.0 physician visits, 23.7 prescription claims, 1.7 inpatient admissions, and 2.0 hospital days per patient 1-year post-SLE diagnosis. Annual all-cause median costs among all SLE patients were $8712 per patient per year. Total costs ranged between $1.4-1.6 and $2.8-3.2 billion per year, depending on prevalence estimates.Conclusions: Our findings indicate a nominal use of biologics (∼2%) among SLE patients; despite belimumab being one of the few approved treatments for SLE in the USA. These data reveal an unmet need for availability of advanced SLE therapy, and future studies are warranted concerning the underlying causes. SLE is also associated with a substantial economic burden of ≤3.2 billion per year. These findings may assist in future planning and resource allocation.

Patients with Idiopathic Membranous Nephropathy: A Real-World Clinical and Economic Analysis of U.S. Claims Data.

BACKGROUND: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in nondiabetic adults. Approximately one third of patients with MN progress to end-stage renal disease (ESRD), while others may be successfully treated to remission. Patients with MN represent a high-risk population for whom management strategies can alter and improve outcomes. Currently, there is little real-world evidence regarding the burden of MN on health plans. OBJECTIVES: To (a) characterize clinical and economic outcomes during a 1-year time frame among a prevalent cohort of patients with MN and (b) compare the 5% of patients incurring the highest cost with the remaining 95%. METHODS: A retrospective analysis of commercially insured patients was conducted using MarketScan administrative health care claims data from January 1, 2012, to December 31, 2015. Patients were aged ≥ 18 years, enrolled In a fee-for-service plan, and had ≥ 2 medical claims for an MN diagnosis (ICD-9-CM codes 581.1, 582.1, and 583.1). Diagnoses indicating clear secondary causes were excluded wherever possible. Demographics were determined as of the first diagnosis date; clinical characteristics (e.g., MN-specific therapy, complications, and procedures), health care resource utilization (HCRU; inpatient, outpatient including other outpatient and emergency department [ED], and prescriptions), and costs were evaluated for 1 year following MN diagnosis. Total costs and cost distribution (2017 U.S. dollars) were examined using plan-paid and patient-paid amounts. The 95th percentile was used to categorize and compare the subcohorts: high-cost cohort (HCC) patients (top 5%) and non-high-cost cohort (NHCC) patients (the remaining 95%). Descriptive analyses, chi-square tests, and Wilcoxon rank-sum tests were conducted. RESULTS: 2,689 patients were identified (60.0% male, mean age = 46.4 years). Severity and advanced disease were observed In a higher proportion of HCC patients (n = 134) versus NHC patients (n = 2,555) via adverse health outcomes, procedures, and immunosuppressant use. HCC patients used significantly more resources on average than NHCC patients (additional use): 1.7 inpatient, 1.2 ED, and 4.8 outpatient office visits; 15 prescriptions; and 64.8 other outpatient visits (i.e., outpatient, hospital, and ESRD facilities). Total MN-related cost and mean (SD) cost per patient were $123.2 million and $45,814 ($101,353); HCC patients accounted for 43.7% of total costs for a mean cost per patient of $401,608 versus NHCC patients at 56.3% and mean cost per patient of $27,154. The greatest costs for both groups were related to outpatient visits (HCC = 46.7%; NHCC = 52.8%), inpatient visits (HCC = 27.7%; NHCC = 28.6%), and prescriptions (HCC = 25.7%; NHCC = 18.6%). CONCLUSIONS: Patients with MN are significantly burdened with high disease severity and adverse health outcomes, resulting In substantial HCRU and costs. Health plan cost drivers for MN (HCC and NHCC patients) occurred primarily In the outpatient setting, followed by the inpatient setting and prescriptions. Modifiable aspects preceding progression to advanced renal disease and worse outcomes should be explored to Identify effective interventions and improve resource allocation earlier In the disease pathway, before ESRD. DISCLOSURES: This study was funded by Mallinckrodt Pharmaceuticals. Kirkemo, Pavlova-Wolf, and Bartels-Peculis are employees and stockholders of Mallinckrodt Pharmaceuticals. Nazareth was an employee of Mallinckrodt Pharmaceuticals at the time of this study. Kariburyo, Xie, and Vaidya are employees of STATinMED Research, a paid consultant to Mallinckrodt Pharmaceuticals. Sim received an investigator-initiated research grant from Mallinkcrodt Pharmaceuticals. A portion of the study results were previously presented at the American Society of Nephrology (ASN) Kidney Week 2017; November 2, 2017; New Orleans, LA.

Treatment Patterns, Healthcare Resource Utilization and Costs Among Schizophrenia Patients Treated with Long-Acting Injectable Versus Oral Antipsychotics.

INTRODUCTION: Long-acting injectable (LAI) antipsychotic use may reduce healthcare resource utilization compared with oral antipsychotic use by improving adherence and reducing dosing frequency. Our goal was to examine treatment patterns, healthcare utilization, and costs among recently diagnosed schizophrenia patients receiving oral versus LAI antipsychotics. METHODS: The MarketScan Multi-state Medicaid database was used to identify schizophrenia patients aged ≥ 18 years who received an LAI or oral antipsychotic between January 1, 2011 and December 31, 2014. Primary outcomes included treatment patterns such as adherence (measured as proportion of days covered-PDC), persistence, discontinuation, switching, and healthcare resource utilization and costs. Propensity score matching (PSM) was used to control for differences in baseline characteristics between the cohorts. Outcomes were assessed over a 12-month post-index period and compared between treatment cohorts. RESULTS: After PSM, 2302 patients were included in each of the LAI and oral antipsychotics cohorts. There were no differences in PDC or therapy switching between the two cohorts. Compared with the oral cohort, patients receiving LAIs had lower discontinuation rates (46.1 vs. 61.6%, p < 0.001), fewer inpatient admissions (0.5 vs. 0.9, p < 0.001), hospital days (3.9 vs. 6.5, p < 0.001), and ER visits (2.4 vs. 2.9, p = 0.007), and a higher number of prescription fills (29.5 vs. 25.3, p < 0.001). Patients prescribed LAIs had lower monthly inpatient ($US4007 vs. 8769, p < 0.001) and ER visits costs ($682 vs. 891, p < 0.001) but higher monthly medication costs ($10,713 vs. $655, p < 0.001) compared with the oral cohort over the 12-month post-index period. Overall, both cohorts had similar total medical costs (LAI vs. oral: $24,988 vs. 23,887, p = 0.354) during the follow-up period. CONCLUSION: Patients receiving LAIs were more likely to remain on medication compared with the oral group, which may account for reduced inpatient admissions. Hospitalization cost reductions offset the higher costs of LAI medications, resulting in no increase in total healthcare costs relative to oral antipsychotic use. FUNDING: Alkermes Inc.

Observation versus treatment among men with favorable risk prostate cancer in a community-based integrated health care system: a retrospective cohort study.

BACKGROUND: The objective of this study was to describe overall survival and the management of men with favorable risk prostate cancer (PCa) within a large community-based health care system in the United States. METHODS: A retrospective cohort study was conducted using linked electronic health records from men aged ≥40 years with favorable risk PCa (T1 or 2, PSA ≤15, Gleason ≤7 [3 + 4]) diagnosed between January 2005 and October 2013. Cohorts were defined as receiving any treatment (IMT) or no treatment (OBS) within 6 months after index PCa diagnosis. Cohorts' characteristics were compared between OBS and IMT; monitoring patterns were reported for OBS within the first 18 and 24 months. Cox Proportional Hazards models were used for multivariate analysis of overall survival. RESULTS: A total of 1425 men met the inclusion criteria (OBS 362; IMT 1063). The proportion of men managed with OBS increased from 20% (2005) to 35% (2013). The OBS group was older (65.6 vs 62.8 years, p < 0.01), had higher Charlson comorbidity index scores (CCI ≥2, 21.5% vs 12.2%, p < 0.01), and had a higher proportion of low-risk PCa (65.2% vs 55.0%, p < 0.01). For the OBS cohort, 181 of the men (50%) eventually received treatment. Among those remaining on OBS for ≥24 months (N = 166), 88.6% had ≥1 follow-up PSA test and 26.5% received ≥1 follow-up biopsy within the 24 months. The unadjusted mortality rate was higher for OBS compared with IMT (2.7 vs 1.3/100 person-years [py]; p < 0.001). After multivariate adjustment, there was no significant difference in all-cause mortality between OBS and IMT groups (HR 0.73, p = 0.138). CONCLUSIONS: Use of OBS management increased over the 10-year study period. Men in the OBS cohort had a higher proportion of low-risk PCa. No differences were observed in overall survival between the two groups after adjustment of covariates. These data provide insights into how favorable risk PCa was managed in a community setting.

A Real-world Analysis of Treatment Patterns for Cholinesterase Inhibitors and Memantine among Newly-diagnosed Alzheimer's Disease Patients.

INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative form of dementia. Pharmacological therapies for symptomatic treatment, such as acetylcholinesterase inhibitors (AChEIs) and memantine, have been available in the USA since 2000. Over the past decade, few studies have analyzed real-world anti-dementia treatment patterns in the USA. This study evaluated monotherapy AChEIs and memantine treatment patterns among newly diagnosed AD patients. METHODS: A retrospective cohort study was conducted using Medicare data and the Minimum Data Set from 2008 to 2012. Patients aged 65-100 years with newly diagnosed AD (ICD-9 code: 331.0) and monotherapy AChEI or memantine treatment initiated after diagnosis were included. Descriptive treatment pattern analyses, including discontinuation and switch, were undertaken. Kaplan-Meier curves were developed to examine the treatment duration. RESULTS: A total of 9812 newly diagnosed AD patients were identified, with 56.7% (n = 5567) first receiving anti-dementia treatment after the initial AD diagnosis. Among patients initiating monotherapy AChEIs or memantine after AD diagnosis (N = 5200), 51.6% continued index treatment during the entire follow-up period (mean follow-up: 659.7 days) and 21.7% discontinued treatment. Of those who initiated monotherapy treatment with an AChEI, 11.1% received adjunct therapy with memantine. Among patients with ≥1 year of continuous treatment (mean follow-up: 834 days), 75.6% remained on the index drug, 10.2% discontinued during the remaining follow-up period, and 9.5% of the AD patients initiating AChEIs received adjunct memantine therapy during the remaining follow-up period. CONCLUSION: In the USA Medicare population, about 50% of the patients who initiated treatment with AChEI or memantine after diagnosis continued the index treatment, and more than 20% discontinued and were untreated afterwards over the observation period. AD patients initiating AChEIs or memantine were more likely to remain on their treatment if they were persistently treated for the first year.

Healthcare costs among men with favorable risk prostate cancer managed with observation strategies versus immediate treatment in an integrated healthcare system.

OBJECTIVE: This study explored short-term healthcare costs of men managed with observation strategies (OBS) vs immediate treatment (IMT) for favorable risk prostate cancer (PCa) from the Geisinger Health System, a single integrated health system in Pennsylvania, as evidence from the community setting is limited. METHODS: A retrospective cohort study was conducted using electronic health records from men aged ≥40 years diagnosed with favorable risk PCa (T1 or 2, PSA ≤15 ng/mL, Gleason ≤7 [3 + 4]) between January 2005 and October 2013. Prostate-specific healthcare costs were compared between the OBS and IMT cohorts in men with ≥3 years of follow-up and available linked claims data. Sub-group analyses focused on those men with low-risk PCa (T1-2a, PSA ≤10 ng/mL, Gleason ≤6). Sensitivity analysis stratified the study sample in three cohorts: OBS, switched from OBS to definitive treatment (OBS switch), and IMT. RESULTS: A total of 352 patients were included (OBS = 70 and IMT = 282). Compared with IMT, OBS resulted in significantly lower cumulative PCa-related healthcare costs for the first 3 years ($15,785 vs $23,177; p-value <.001). The main cost drivers were outpatient procedures. The OBS cohort had the lowest incremental PCa-related healthcare costs in the first 3 years (OBS: $5,011 vs OBS switch: $26,040, net cost savings = $21,029, p < .001; OBS: $5,011 vs IMT: $24,064, net cost savings = $19,053, p < .001). CONCLUSIONS: In favorable risk PCa, half of the patients who initially chose OBS eventually underwent treatment after their PCa diagnosis. As expected, OBS was associated with reduced disease management costs compared with IMT.

Development of a Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Veterans' Health Administration Patients.

OBJECTIVE: Develop a risk index to estimate the likelihood of life-threatening respiratory depression or overdose among medical users of prescription opioids. SUBJECTS, DESIGN, AND METHODS: A case-control analysis of administrative health care data from the Veterans' Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid-induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n = 8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. RESULTS: Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C-statistic was 0.88 and Hosmer-Lemeshow goodness-of-fit statistic 10.8 (P > 0.05). CONCLUSION: RIOSORD performed well in identifying medical users of prescription opioids within the Veterans' Health Administration at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated.

Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients.

OBJECTIVE: Prescription opioid use and deaths related to serious toxicity, including overdose, have increased dramatically in the United States since 1999. However, factors associated with serious opioid-related respiratory or central nervous system (CNS) depression or overdose in medical users are not well characterized. The objective of this study was to examine the factors associated with serious toxicity in medical users of prescription opioids. DESIGN: Retrospective, nested, case-control analysis of Veterans Health Administration (VHA) medical, pharmacy, and health care resource utilization administrative data. SUBJECTS: Patients dispensed an opioid by VHA between October 1, 2010 and September 30, 2012 (N=8,987). METHODS: Cases (N=817) experienced life-threatening opioid-related respiratory/CNS depression or overdose. Ten controls were randomly assigned to each case (N=8,170). Logistic regression was used to examine associations with the outcome. RESULTS: The strongest associations were maximum prescribed daily morphine equivalent dose (MED)≥ 100 mg (odds ratio [OR]=4.1, 95% confidence interval [CI], 2.6-6.5), history of opioid dependence (OR=3.9, 95% CI, 2.6-5.8), and hospitalization during the 6 months before the serious toxicity or overdose event (OR=2.9, 95% CI, 2.3-3.6). Liver disease, extended-release or long-acting opioids, and daily MED of 20 mg or more were also significantly associated. CONCLUSIONS: Substantial risk for serious opioid-related toxicity and overdose exists at even relatively low maximum prescribed daily MED, especially in patients already vulnerable due to underlying demographic factors, comorbid conditions, and concomitant use of CNS depressant medications or substances. Screening patients for risk, providing education, and coprescribing naloxone for those at elevated risk may be effective at reducing serious opioid-related respiratory/CNS depression and overdose in medical users of prescription opioids.