Patient Knowledge of Safe Use of ER/LA Opioid Analgesics Following Implementation of the Class-Wide REMS: A Survey Study.

BACKGROUND/RATIONALE: The US Food and Drug Administration (FDA) approved a Risk Evaluation and Mitigation Strategy (REMS) for extended release/long-acting (ER/LA) opioids in 2012. The purpose of this study was to assess patient knowledge of the safe use of these products following implementation of the REMS and to determine possible effects of the REMS, including impact on medication access. OBJECTIVE: To assess patient knowledge of safe use of ER/LA opioids and use of REMS patient education tools such as the Medication Guide (MG) and Patient Counseling Document (PCD). METHODS: This was a cross-sectional survey of commercially insured (Commercial) and Medicare Advantage-insured (Medicare) adults with ≥1 pharmacy claim for an ER/LA opioid (10/01/2015 - 02/28/2017) in the HealthCore Integrated Research Database and Medicaid-insured (Medicaid) adult members of a research panel, about their knowledge of safe use of ER/LA opioids and receipt/comprehension of the MG and PCD. RESULTS: Survey respondents consisted of 382 Commercial, 43 Medicare and 40 Medicaid adults. While ≥95% of respondents received and read the MG, fewer were aware of the PCD (Commercial: 47%, Medicare: 65%, Medicaid: 53%). Almost 75% of the knowledge questions were answered correctly by ≥80% of all respondents; fewer respondents recognized that use of opioids as directed can lead to death (Commercial: 73%, Medicare: 56%, Medicaid: 63%), the MG should be read at each dispensing (Commercial: 78%, Medicare: 53%, Medicaid: 75%), opioids should not be stored in the medicine cabinet (Commercial: 77%, Medicare: 79%, Medicaid: 58%), missed doses should not be taken as soon as possible (Commercial: 56%, Medicare: 51%, Medicaid: 50%), and pills should not be crushed (Commercial: 85%, Medicare: 67%, Medicaid: 52%). CONCLUSION: Although most respondents reported reading and understanding the MG and exhibited knowledge of safe use of ER/LA opioids, providers' use of the PCD and increased understanding of safe use core messages need reinforcement.

Development of predictive models to identify advanced-stage cancer patients in a US healthcare claims database.

BACKGROUND: Although healthcare databases are a valuable source for real-world oncology data, cancer stage is often lacking. We developed predictive models using claims data to identify metastatic/advanced-stage patients with ovarian cancer, urothelial carcinoma, gastric adenocarcinoma, Merkel cell carcinoma (MCC), and non-small cell lung cancer (NSCLC). METHODS: Patients with ≥1 diagnosis of a cancer of interest were identified in the HealthCore Integrated Research Database (HIRD), a United States (US) healthcare database (2010-2016). Data were linked to three US state cancer registries and the HealthCore Integrated Research Environment Oncology database to identify cancer stage. Predictive models were constructed to estimate the probability of metastatic/advanced stage. Predictors available in the HIRD were identified and coefficients estimated by Least Absolute Shrinkage and Selection Operator (LASSO) regression with cross-validation to control overfitting. Classification error rates and receiver operating characteristic curves were used to select probability thresholds for classifying patients as cases of metastatic/advanced cancer. RESULTS: We used 2723 ovarian cancer, 6522 urothelial carcinoma, 1441 gastric adenocarcinoma, 109 MCC, and 12,373 NSCLC cases of early and metastatic/advanced cancer to develop predictive models. All models had high discrimination (C > 0.85). At thresholds selected for each model, PPVs were all >0.75: ovarian cancer = 0.95 (95% confidence interval [95% CI]: 0.94-0.96), urothelial carcinoma = 0.78 (95% CI: 0.70-0.86), gastric adenocarcinoma = 0.86 (95% CI: 0.83-0.88), MCC = 0.77 (95% CI 0.68-0.89), and NSCLC = 0.91 (95% CI 0.90 - 0.92). CONCLUSION: Predictive modeling was used to identify five types of metastatic/advanced cancer in a healthcare claims database with greater accuracy than previous methods.

Risk of severe acute liver injury among patients with brain cancer treated with temozolomide: a nested case-control study using the healthcore integrated research database.

Temozolomide (TMZ) is used to treat adult patients with glioblastoma multiforme (GBM). Cases of hepatotoxicity have been reported among patients using TMZ. The objective of the study was to assess the relation, if any, between exposure to TMZ and serious acute liver injury (SALI). We used the HealthCore Integrated Research Database to perform a case-control study nested within a retrospective cohort of adult patients aged 18-100 years with at least two diagnoses of brain cancer anytime between 2006 and 2014. Patients without continuous eligibility or with a SALI diagnosis within 6 months prior to the date of incident brain cancer diagnosis were excluded. Medical records were sought for potential SALI cases and reviewed by two hepatologists. Five controls were selected for each case using incidence density sampling, matched on age and calendar year of index date. The analysis included 61 confirmed SALI cases and 305 selected controls. Exposure to TMZ was classified according to dispensing date and days supply of medication dispensed. We estimated odds ratios using conditional logistic regression models. The odds ratio for any exposure to TMZ was 0.91 (95% CI 0.44-1.91), for recent exposure to TMZ was 0.62 (95% CI 0.21-1.85). There was no increased risk of SALI with increasing duration of exposure to TMZ. When patients with unconfirmed SALI were included in the analysis, results were similar (OR 1.04; 95% CI 0.70-1.54). In conclusion, this study did not find an association between TMZ and SALI risk among patients with brain cancer.

Comparative Effectiveness of Tacrolimus-Based Steroid Sparing versus Steroid Maintenance Regimens in Kidney Transplantation: Results from Discrete Event Simulation.

BACKGROUND: Corticosteroids used as immunosuppressants to prevent acute rejection (AR) and graft loss (GL) following kidney transplantation are associated with serious cardiovascular and other adverse events. Evidence from short-term randomized controlled trials suggests that many patients on a tacrolimus-based immunosuppressant regimen can withdraw from steroids without increased AR or GL risk. OBJECTIVES: To measure the long-term tradeoff between GL and adverse events for a heterogeneous-risk population and determine the optimal timing of steroid withdrawal. METHODS: A discrete event simulation was developed including, as events, AR, GL, myocardial infarction (MI), stroke, cytomegalovirus, and new onset diabetes mellitus (NODM), among others. Data from the United States Renal Data System were used to estimate event-specific parametric regressions, which accounted for steroid-sparing regimen (avoidance, early 7-d withdrawal, 6-mo withdrawal, 12-mo withdrawal, and maintenance) as well as patients' demographics, immunologic risks, and comorbidities. Regression-equation results were used to derive individual time-to-event Weibull distributions, used, in turn, to simulate the course of patients over 20 y. RESULTS: Patients on steroid avoidance or an early-withdrawal regimen were more likely to experience AR (45.9% to 55.0% v. 33.6%, P < 0.05) and GL (51.5% to 68.8% v. 37.8%, P < 0.05) compared to patients on steroid maintenance. Patients in 6-mo and 12-mo steroid withdrawal groups were less likely to experience MI (11.1% v. 13.3%, P < 0.05), NODM (30.7% to 34.4% v. 37.7%, P < 0.05), and cardiac death (29.9% to 30.5% v. 32.4%, P < 0.05), compared to steroid maintenance. CONCLUSIONS: Strategies of 6- and 12-mo steroid withdrawal post-kidney transplantation are expected to reduce the rates of adverse cardiovascular events and other outcomes with no worsening of AR or GL rates compared with steroid maintenance.

Sulfonylurea use and the risk of hospital readmission in patients with type 2 diabetes.

BACKGROUND: Hospital inpatient care for patients with diabetes was estimated to cost $76 billion in 2012. Substantial expense resulted from those patients having multiple hospitalizations. The objective was to compare the risk for diabetes-related hospital readmission in patients with type 2 diabetes treated with sulfonylureas (SUs) compared to those treated with other oral antihyperglycemic agents (AHAs). METHODS: A retrospective cohort analysis was conducted using two-year panels, from 1999 to 2010, from the Medical Expenditure Panel Survey. The study included patients with type 2 diabetes taking an oral AHA who experienced a diabetes-related hospitalization. A Cox proportional hazard regression predicting time to readmission was used to estimate and compare the risks of readmission for SU-monotherapy versus other-AHA-monotherapy patients. Covariates included age, gender, marital status, cardiovascular disease, kidney disease, and eye disease, along with a propensity score to control for selection bias. The lack of clinical data on disease severity and progression limited our ability to estimate causal relationships between drug use and risk of hospital readmission. RESULTS: From 1999 to 2010, an estimated 13.5 million patients experienced a diabetes-related hospital admission and subsequent AHA treatment. While 23.2 % (n = 746,579) of patients in the SU monotherapy cohort had a readmission, only 16.1 % (n = 881,984) in the other-AHA monotherapy group were readmitted. Average readmission expenditure for readmitted SU users (in 2010 dollars) was $11,148 (±$1,558) compared to $7,673 (±$763) for users of other oral AHAs. The estimated readmission hazard ratio was 1.29 (95 % CI: 1.01-1.65; p-value = 0.04) for SU monotherapy users. If a patient's first hospital admission was during the time period 2008-2010, a readmission was significantly less likely (HR 0.49, 95 % CI: 0.31-0.78; p = 0.003) relative to 2004-2007. CONCLUSIONS: Among patients with type 2 diabetes, SU use was associated with an approximately 30 % increased risk for readmission compared to other-AHA use, while each readmission for an SU user cost on average 45 % more than one for an other-AHA patient. Because of the rapidly rising prevalence of diabetes in the U.S. and the large number of patients with prediabetes, preventing hospital readmissions will continue to be an important cost-saving strategy in the future.

Comparative persistence on ß-blockers versus calcium channel blockers for ventricular rate control in nonelderly patients with atrial fibrillation.

BACKGROUND: For patients with atrial fibrillation (AF), early treatment is essential to prevent serious complications such as stroke. Several randomized clinical trials have shown that rate-control may be as effective as rhythm-control medications, whereas the latter have serious side effects. Little evidence exists, however, about which class of rate-control medication-ß-blockers (BBs) or calcium channel blockers (CCBs)-may be superior. OBJECTIVE: The objective was to compare the long-term persistence on BBs versus CCBs in nonelderly adult patients with AF. METHODS: A longitudinal retrospective cohort study for patients 40 to 60 years old with newly diagnosed AF (identified by ICD-9 code 427.31) was performed using data from Ohio Medicaid physician, institutional, and pharmacy claims from January 2006 through June 2011. A Cox proportional hazard regression, with time to change out of rate-control therapy as the dependent variable, was estimated to compare persistence on (proxy for effectiveness of) rate-control medication across drug classes. A propensity-score analysis was used to control for selection bias. Additional covariates included age, development of heart failure, and medication adherence. RESULTS: Out of 1239 patients included in the cohort, 1016 received a BB; 223 received a CCB. Over time, patients on CCBs were significantly more likely to switch out of rate-control therapy (hazard ratio = 1.89; 95% CI = 1.14-3.09) than patients on BBs. CONCLUSIONS: Evidence suggests that nonelderly AF patients, when prescribed rate-control therapy, persist longer on BBs than CCBs. Because this is the first long-term study comparing the 2 drug classes in the nonelderly population, further research is suggested.

Trends in the outpatient treatment of atrial fibrillation in the USA from 2001 to 2010.

PURPOSE: Several clinical trials have shown that rhythm-control drugs have serious adverse events and no survival advantage over rate-control drugs in patients with atrial fibrillation. The objectives were to determine and explain the recent trends in outpatient prescribing of both drug classes. METHODS: Data were obtained over 10 years from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. Visits by patients with atrial fibrillation were identified by ICD-9 diagnosis code 427.31. Trend lines were estimated for drug prescribing and comorbidities. A multinomial logistic model was estimated to predict treatment on the basis of visit characteristics. RESULTS: The percentage of visits mentioning only a rate-control medication trended upward (p = 0.07) from 41.9% in 2001 to 47.3% in 2010; the percentage mentioning both rhythm-control and rate-control drugs also had an upward trend (p < 0.05) from 3.1% to 12.5%; finally, the percentage mentioning rhythm-control drugs alone remained steady (p = 0.37). Consistent with the increase (p = 0.10) in the percentage of visits mentioning hypertension, there was a statistically significant (p < 0.01) rise in the prescribing of ß-blockers from 20.5% to 43.4%. The odds that a patient aged 65 years or younger was prescribed a rhythm-control medication were significantly higher (p < 0.01) than those for a patient older than 65 years. The estimated odds that a diabetic patient was prescribed both rhythm-control and rate-control medications was only 0.269 (p < 0.05). CONCLUSIONS: This study documents change in the outpatient treatment of atrial fibrillation in the USA from 2001-2010. In clinical practice, there has been a growing reliance on rate-control medications.

Frequencies, costs, and complications of catheter ablation for tachyarrhythmias in children: 2000-2009.

BACKGROUND: Over the past two decades, catheter ablation (CA) has revolutionized the treatment of tachyarrhythmias in children by providing a relatively safe and effective alternative to open heart surgery or lifelong pharmacotherapy. This study (1) described national trends in pediatric CAs and their associated costs and complications and (2) predicted the likelihood of major complications based on patient and hospital characteristics. METHODS: Inpatient data were obtained from the Kids' Inpatient Database for the years 2000, 2003, 2006, and 2009. Outpatient data were obtained from the California, Maryland, and New Jersey State Ambulatory Surgery Databases for the years 2006 and 2009. Logistic regression was used to predict the odds of major complications from CA. RESULTS: There was a 20% increase (4,134-4,967) in the number of pediatric CAs performed from 2006 to 2009 that was concomitant with a decrease in the percentage of those procedures being performed as inpatient procedures (2,254-1,846). In 2009, a complication rate of 4.81% was estimated. For inpatient CAs, higher risk patients (with congenital heart disease, congestive heart failure, or heart transplant), ablations for ventricular tachycardias, and low-CA-volume hospitals were associated with increased risk of complications. In 2009, the mean cost of a hospitalization involving CA, but no cardiac surgery, was $17,204 (standard error = $1,015). CONCLUSIONS: CA has increasingly been used over the past decade for pediatric patients with a multitude of tachycardia mechanisms. There continues to be a small risk of major complications, especially for higher risk children and in hospitals with more limited experience with the procedure.

Trends in the utilization of, spending on, and prices for outpatient antifungal agents in US Medicaid programs: 1991-2009.

BACKGROUND: The incidence of invasive fungal infections (IFIs) has increased substantially in the recent past. Advances in medical technology, including broad-spectrum antibiotics, may increase the risk for fungal infections. Moreover, immunocompromised patients with cancer, HIV/AIDS, and/or transplants are susceptible to IFIs. Meanwhile, superficial fungal infections (SFIs) are common and can be difficult to cure. OBJECTIVE: To provide a historical perspective on a dynamic market with expensive medications, this study describes trends in the utilization of, spending on, and average per-prescription spending on outpatient antifungal medications individually, in classes (for IFIs or SFIs), and overall, by the US Medicaid programs from 1991 to 2009. METHODS: The publicly available Medicaid State Drug Utilization Data, maintained by the Centers for Medicare & Medicaid Services, were used. Annual prescription counts and reimbursement amounts were calculated for each of the antifungals reimbursed by Medicaid. Average per-prescription spending as a proxy for drug price was calculated by dividing reimbursement by the number of prescriptions. RESULTS: Overall utilization for Medicaid beneficiaries remained steady, with 4.56 million prescriptions in 1991 and 4.51 million in 2009. Expenditures rose from $93.87 million to $143.76 million (in current-year US$) over the same time period. The drop in the utilization of first-generation azoles over the last 5 years of the study period can be explained in part by the movement of dual-eligibles from Medicaid to Medicare Part D and in part to a rise in fungal infections better treated with second-generation azoles or echinocandins. Whereas the average per-prescription price for generic (oral) fluconazole was $8 in 2009, the price per prescription of branded (intravenous) voriconazole was $2178. CONCLUSIONS: Overall spending by Medicaid on outpatient antifungal medications increased more slowly than did the growth of the Medicaid programs from 1991 to 2009. However, the utilization of antifungal agents for IFIs increased almost 10-fold over this period, far outpacing the rise in the number of Medicaid beneficiaries.

Impact of the Food and Drug Administration's antipsychotic black box warning on psychotropic drug prescribing in elderly patients with dementia in outpatient and office-based settings.

BACKGROUND: Most patients with dementia also suffer from behavioral and psychological symptoms of dementia, for which there is no Food and Drug Administration-approved treatment. OBJECTIVES: To determine whether the Food and Drug Administration's black box warning in April 2005 has led to a decline in prescriptions of atypical antipsychotics for behavioral and psychological symptoms of dementia, as well as whether prescriptions for other psychotropic drugs, including antidepressants, anxiolytics, and antiepileptics, as substitutes, have increased. METHODS: Data on outpatient visits by elderly dementia patients were obtained from two large national surveys from 2003 to 2008. Any psychotropic drug mentions were identified. Percentage utilization statistics were calculated. RESULTS: The percentage of visits mentioning an atypical antipsychotic decreased from 12.5% prewarning to 11.5% postwarning. Postwarning, 34.4% of patients were taking none of the study medications, as opposed to 26.1% prewarning. CONCLUSIONS: After the warning, there was a small decline in the use of atypical antipsychotics and no evidence of substitution of other psychotropic medications.