Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation.

PURPOSE: Results of a study to determine trends in oral anticoagulant (OAC) use and OAC switching in patients with atrial fibrillation (AF) or atrial flutter are presented. METHODS: Warfarin has been the most prescribed anticoagulant in patients with AF for decades. Since 2010, several direct OACs (DOACs) have gained U.S. marketing approval for stroke prevention in AF or atrial flutter. A cross-sectional longitudinal analysis was conducted using healthcare and prescription claims databases to characterize OAC use and rates of OAC and DOAC switching during the period 2008-14 in cohorts of Medicare beneficiaries 65 years of age or older with AF or atrial flutter. RESULTS: Overall, 66% of patients with AF or atrial flutter were receiving OACs during the study period. The prevalence of warfarin use decreased from 69.8% in 2008 to 42.2% in 2014. This decrease in warfarin use was paralleled by an increase in dabigatran use, which rose from 1.3% in 2010 to 12.1% in 2011 and then declined to 7.6% in 2014. The prevalence of rivaroxaban use increased from 0.13% in 2011 to 13.87% in 2014. Among anticoagulated patients, an average of 6% annually were switched from one OAC to another. CONCLUSION: Overall OAC utilization in patients with AF or atrial flutter remained steady over the study period. Beginning in 2010, a gradual decrease in use of warfarin was paralleled by an increase in use of DOACs.

Stimulant use following the publicity of cardiovascular safety and the introduction of patient medication guides.

PURPOSE: To explore changes in stimulant utilization and pre-treatment electrocardiography (ECG) screening in response to cardiovascular (CV) safety concerns. METHODS: Two source populations were established from Florida Medicaid Fee-for-service beneficiaries between 2001 and 2008: approximately 44 571 newly diagnosed attention deficit/hyperactivity disorder patients and 33 000 new stimulant users. Time-series design and Joinpoint analysis were used to describe monthly trend changes in stimulant initiation, persistence, dosing, and pre-treatment ECG screening. RESULTS: Initial and maintenance daily dose declined 6 mg (95% confidence interval [CI] -14 to -1.9) methylphenidate (MPH) equivalent dose from a steady 27 mg after Canada withdrew Adderall XR in February 2005; the trend rebounded to a daily dose of 23 mg, after the remarketing of Adderall XR and a debate in the US over issuing a boxed warning on stimulant CV safety in early 2006. Monthly initiation increased 3.9% (CI -1.0 to 9.1) after the boxed warning debate to 54 per 100 patients per month (CI 44 to 68), but declined 2.4% (CI -3.6 to -1.2) after requirement of medication guides in February 2007. Monthly ECG screening increased 3.2% (CI 2.3 to 4.2) after Adderall XR withdrawal and further increased 13% (CI 4 to 23) after the American Heart Association recommended pre-treatment ECG screening to 40 per 100 patients per month (CI 17 to 48). CONCLUSIONS: The first signal of stimulant CV safety concerns was followed by varying responses depending on the outcome measure used, suggesting that patients and physicians responded at different times after the publicity of safety concerns. Clinical consequences of the changes are uncertain. Copyright © 2015 John Wiley & Sons, Ltd.

A Comparative Assessment of Observational Medical Outcomes Partnership and Mini-Sentinel Common Data Models and Analytics: Implications for Active Drug Safety Surveillance.

INTRODUCTION: An often key component to coordinating surveillance activities across distributed networks is the design and implementation of a common data model (CDM). The purpose of this study was to evaluate two drug safety surveillance CDMs from an ecosystem perspective to better understand how differences in CDMs and analytic tools affect usability and interpretation of results. METHODS: Humana claims data from 2007 to 2012 were mapped to Observational Medical Outcomes Partnership (OMOP) and Mini-Sentinel CDMs. Data were described and compared at the patient level by source code and mapped concepts. Study cohort construction and effect estimates were also compared using two different analytical methods--one based on a new user design implementing a high-dimensional propensity score (HDPS) algorithm and the other based on univariate self-controlled case series (SCCS) design--across six established positive drug-outcome pairs to learn how differences in CDMs and analytics influence steps in the database analytic process and results. RESULTS: Claims data for approximately 7.7 million Humana health plan members were transformed into the two CDMs. Three health outcome cohorts and two drug cohorts showed differences in cohort size and constituency between Mini-Sentinel and OMOP CDMs, which was a result of multiple factors. Overall, the implementation of the HDPS procedure on Mini-Sentinel CDM detected more known positive associations than that on OMOP CDM. The SCCS method results were comparable on both CDMs. Differences in the implementation of the HDPS procedure between the two CDMs were identified; analytic model and risk period specification had a significant impact on the performance of the HDPS procedure on OMOP CDM. CONCLUSIONS: Differences were observed between OMOP and Mini-Sentinel CDMs. The analysis of both CDMs at the data model level indicated that such conceptual differences had only a slight but not significant impact on identifying known safety associations. Our results show that differences at the ecosystem level of analyses across the CDMs can lead to strikingly different risk estimations, but this can be primarily attributed to the choices of analytic approach and their implementation in the community-developed analytic tools. The opportunities of using CDMs are clear, but our study shows the need for judicious comparison of analyses across the CDMs. Our work emphasizes the need for ongoing efforts to ensure sustainable transparent platforms to maintain and develop CDMs and associated tools for effective safety surveillance.

Application of multicategory exposure marginal structural models to investigate the association between long-acting beta-agonists and prescribing of oral corticosteroids for asthma exacerbations in the Clinical Practice Research Datalink.

OBJECTIVE: To examine the comparative effectiveness of inhaled long-acting beta-agonist (LABA), inhaled corticosteroid (ICS), and ICS/LABA combinations. METHODS: We used a retrospective cohort design of patients older than 12 years with asthma diagnosis in the Clinical Practice Research Datalink to evaluate asthma-related morbidity measured by oral corticosteroid (OCS) initiation within 12 months of initiating LABAs, ICSs, or ICSs/LABAs. Asthma severity 12 months before drug initiation (use of OCSs, asthma-related hospital or emergency department visits, and number of short-acting beta-agonist prescriptions) and during follow-up (short-acting beta-agonist prescriptions and total number of asthma drug classes) was adjusted as a time-varying variable via marginal structural models. RESULTS: A total of 51,103 patients with asthma were followed for 12 months after receiving first prescription for study drugs from 1993 to 2010. About 92% initiated ICSs, 1% initiated LABAs, and 7% initiated ICSs/LABAs. Compared with ICSs, LABAs were associated with a 10% increased risk of asthma exacerbations requiring short courses of OCSs (hazard ratio [HR] 1.10; 95% confidence interval [CI] 1.07-1.18). ICS/LABA initiators were 62% less likely than ICS initiators (HR 0.38; 95% CI 0.12-0.66) and 50% less likely than LABA initiators to receive OCS prescriptions for asthma exacerbations (HR 0.50; 95% CI 0.14-0.78). CONCLUSIONS: In concordance with current asthma management guidelines, inhaled LABAs should not be prescribed as monotherapy to patients with asthma. The findings suggest the presence of time-dependent confounding by asthma severity, which was accounted for by the marginal structural model.

Pediatric exclusivity: evolving legislation and novel complexities within pediatric therapeutic development.

OBJECTIVE: To review the successes and omissions of the Food and Drug Administration (FDA) pediatric exclusivity incentive. DATA SOURCES: Pediatric drug development receives less attention and funding than drug development targeting adults resulting in fewer appropriately labeled pediatric drugs. Newly introduced legislation aims to correct this deficit using market exclusivity incentives. Under the Food and Drug Administration Modernization Act (FDAMA, 1997), the FDA established the exclusivity principle. This legislation was renewed and amended in 2007 under Food and Drug Administration Amendments Act (FDAAA) allowing drug companies to receive a 6-month patent extension for initiating clinical investigation in pediatric populations. Fostering improved knowledge in pediatric indications and dosing is the motivating force behind this program. STUDY SELECTION AND DATA EXTRACTION: We examined drugs granted exclusivity through FDA published database as well as relevant drug labeling and postmarket safety studies. Our examination shows that studies conducted in support of patent protection are often not designed to meet current pediatric needs. CONCLUSION: Amendments to FDAAA are needed to ensure that studies approved for exclusivity strive to meet the following requirements: relevant pediatric clinical indication ; disease addressed should represent a significant disease burden to the appropriate population; important age ranges should be covered; studies should not be allowed when a safety signal is identified prior to initiation of the study; and trials where endpoints are successfully achieved providing considerable contribution to pediatric dosing knowledge or result in labeling changes may gain an additional incentive.

Empirical assessment of methods for risk identification in healthcare data: results from the experiments of the Observational Medical Outcomes Partnership.

BACKGROUND: Expanded availability of observational healthcare data (both administrative claims and electronic health records) has prompted the development of statistical methods for identifying adverse events associated with medical products, but the operating characteristics of these methods when applied to the real-world data are unknown. METHODS: We studied the performance of eight analytic methods for estimating of the strength of association-relative risk (RR) and associated standard error of 53 drug-adverse event outcome pairs, both positive and negative controls. The methods were applied to a network of ten observational healthcare databases, comprising over 130 million lives. Performance measures included sensitivity, specificity, and positive predictive value of methods at RR thresholds achieving statistical significance of p < 0.05 or p < 0.001 and with absolute threshold RR > 1.5, as well as threshold-free measures such as area under receiver operating characteristic curve (AUC). RESULTS: Although no specific method demonstrated superior performance, the aggregate results provide a benchmark and baseline expectation for risk identification method performance. At traditional levels of statistical significance (RR > 1, p < 0.05), all methods have a false positive rate >18%, with positive predictive value <38%. The best predictive model, high-dimensional propensity score, achieved an AUC = 0.77. At 50% sensitivity, false positive rate ranged from 16% to 30%. At 10% false positive rate, sensitivity of the methods ranged from 9% to 33%. CONCLUSIONS: Systematic processes for risk identification can provide useful information to supplement an overall safety assessment, but assessment of methods performance suggests a substantial chance of identifying false positive associations.

Utilizing Medicare claims data for real­time drug safety evaluations:is it feasible?

PURPOSE: The Centers for Medicare & Medicaid Services claims comprise an administrative database of beneficiary-specific clinical information. This study evaluates the impacts of (i) claim information updates (claims adjudication) and (ii) delay in claim processing (claims delay) on real-time evaluation of health service and drug safety signals using the Medicare database. METHODS: Using Medicare claims data accumulated through May 2009 on health services rendered in 2006 and drugs dispensed in 2007, this study measures the frequency with which clinical information changes in the database as a result of (i) claims adjudication and (ii) claims delay. RESULTS: Over 85% of health services claims were processed within 8 weeks after the date of service, and 72% of drug claims were processed within 3 months after the dispense date. Clinical information changed for no more than 3% of unique claim groups in inpatient hospital, outpatient institutional, physician's office, and prescription drug Medicare claim settings. CONCLUSIONS: Claims delay is consistent across time and is minimal. Claims adjudication does not substantially impact the content of clinical information in the Medicare claims database. Therefore, the Medicare claims database provides consistent information regarding health services and prescription drugs in a manner that is prompt enough to facilitate medical product safety evaluations in real time.

Advancing the science for active surveillance: rationale and design for the Observational Medical Outcomes Partnership.

The U.S. Food and Drug Administration (FDA) Amendments Act of 2007 mandated that the FDA develop a system for using automated health care data to identify risks of marketed drugs and other medical products. The Observational Medical Outcomes Partnership is a public-private partnership among the FDA, academia, data owners, and the pharmaceutical industry that is responding to the need to advance the science of active medical product safety surveillance by using existing observational databases. The Observational Medical Outcomes Partnership's transparent, open innovation approach is designed to systematically and empirically study critical governance, data resource, and methodological issues and their interrelationships in establishing a viable national program of active drug safety surveillance by using observational data. This article describes the governance structure, data-access model, methods-testing approach, and technology development of this effort, as well as the work that has been initiated.

Lives in isolation: stories and struggles of low-income African American women with panic disorder.

Research evidence points to the existence of racial-ethnic disparities in both access to and quality of mental health services for African Americans with panic disorder. Current panic disorder evaluation and treatment paradigms are not responsive to the needs of many African Americans. The primary individual, social, and health-care system factors that limit African Americans' access to care and response to treatment are not well understood. Low-income African American women with panic disorder participated in a series of focus-group sessions designed to elicit (1) their perspectives regarding access and treatment barriers and (2) their recommendations for designing a culturally consistent panic treatment program. Fear of confiding to others about panic symptoms, fear of social stigma, and lack of information about panic disorder were major individual barriers. Within their social networks, stigmatizing attitudes toward mental illness and the mentally ill, discouragement about the use of psychiatric medication, and perceptions that symptoms were the result of personal or spiritual weakness had all interfered with the participants' treatment seeking efforts and contributed to a common experience of severe social isolation. None of the focus-group members had developed fully effective therapeutic relationships with either medical or mental health providers. They described an unmet need for more interactive and culturally authentic relationships with treatment providers. Although the focus-group sessions were not intended to be therapeutic, the women reported that participation in the meetings had been an emotionally powerful and beneficial experience. They expressed a strong preference for the utilization of female-only, panic disorder peer-support groups as an initial step in the treatment/recovery process. Peer-support groups for low-income African American women with panic disorder could address many of the identified access and treatment barriers.

The cost of health care for children and adults with sickle cell disease.

Although sickle cell disease (SCD) is marked by high utilization of medical resources, the full cost of care for patients with SCD, including care not directly related to SCD, is unknown. The purpose of this study was to estimate the total cost of medical care for a population of children and adults with SCD. We used data from individuals diagnosed with SCD enrolled in the Florida Medicaid program during 2001-2005 to estimate total, SCD-related, and non-SCD-related cost per patient-month based on patient age at the time of health care use. Across the 4,294 patient samples, total health care costs generally rose with age, from $892 to $2,562 per patient-month in the 0-9- and 50-64-year age groups, respectively. Average cost per patient-month was $1,389. Overall, 51.8% of care was directly related to SCD, the majority of which (80.5%) was associated with inpatient hospitalizations. Notably, non-SCD-related costs were substantially higher than those reported for the general US population. These results suggest a discounted (3% discount rate) lifetime cost of care averaging $460,151 per patient with SCD. Interventions designed to prevent SCD complications and avoid hospitalizations may reduce the significant economic burden of the disease.

Risk drinking behavior among psychotropic drug users in an aging Finnish population: the FinDrink study.

Psychotropic drug use and alcohol consumption is increasing among aging Finns. Alcohol use is not recommended with benzodiazepines and some other psychotropic medicines. Concomitant use may lead to accidents and other serious consequences. The aim of this study was to analyze the drinking behavior of psychotropic drug users in an aging Finnish population. This study is part of the ongoing epidemiologic FinDrink study. Self-reported data on alcohol consumption and psychotropic drug use were collected from the Kuopio Ischaemic Heart Disease Risk Factor Study examinations conducted in 1998-2001. Overall, 854 men and 920 women participated in the study. A total of 204 (11.5%) individuals used psychotropic drugs regularly (14.2% of women and 8.5% of men; P<.001). Three quarters of the study population had used alcohol weekly during the preceding year (68.9% of women and 87.5% of men; P<.001). Men who use anxiolytics and sedatives were more likely to drink alcohol at least twice a week (odds ratio=2.42; 95% confidence interval=1.30-4.51), to be binge drinkers (odds ratio=1.86; 95% confidence interval=1.01-3.43) and to be heavy alcohol consumers (odds ratio=2.22; 95% confidence interval= 1.13-4.39) than men not using psychotropics. In women, alcohol consumption and drinking patterns were same between the groups. Our results indicate the potential for alcohol-related health risks among aging Finnish men and women using psychotropic drugs.

Cost-utility analysis of rimonabant in the treatment of obesity.

OBJECTIVE: To estimate the incremental cost-utility ratio (ICUR) of rimonabant 20 mg/day in the treatment of obesity from a third-party payer's perspective. METHODS: Pooled data from three randomized clinical trials were used to develop a decision tree with five treatment alternatives: 1- and 2-year treatment with rimonabant, 2-year placebo, 1-year rimonabant followed by 1-year placebo, and no treatment. All alternatives, except no treatment, were accompanied by lifestyle interventions. Treatment benefits included gains in quality-adjusted life-years (QALYs) and reduced incidence of type-2 diabetes mellitus and coronary heart disease (CHD). Drug acquisition cost was based on the average wholesale price of a comparator drug minus 15%. One-way and probabilistic sensitivity analyses were conducted to assess the stability of the base-case results. RESULTS: One-year rimonabant and 1-year rimonabant followed by placebo were extensively dominated. Rimonabant for 2 years showed an average weight reduction of 8.49 kg, a body mass index reduction of 2.98 kg/m(2) and reduced waist circumference by 8.24 cm (placebo: 3.55 kg, 1.22 kg/m(2), 4.18 cm). Two-year rimonabant was associated with a relative reduction in the 5-year incidence of CHD by 7.15% and of diabetes by 9.28%. Incremental benefits (costs) were 0.0984 QALYs ($5209) compared to no treatment and 0.0581 QALYs ($4182) compared to placebo, producing ICURs of $52,936/QALY (95% confidence interval $39K-$69K) and $71,973/QALY ($51K-$98K), respectively. CONCLUSIONS: Rimonabant combined with lifestyle interventions has the potential to decrease the rate of obesity-related comorbidities and improve health-related quality of life, albeit at considerable cost.

Pharmacoeconomic modeling of nesiritide versus dobutamine for decompensated heart failure.

STUDY OBJECTIVE: To model the cost-effectiveness of nesiritide compared with dobutamine in patients with decompensated heart failure. DESIGN: Cost-effectiveness analysis. MEASUREMENTS AND MAIN RESULTS: A decision tree model was derived from randomized clinical trial data and data from a previously published economic study. Four cost-effectiveness analyses were performed: analysis 1 -- full probabilistic analysis, repeatedly sampled probabilities for 6-month mortality and hospital readmission from distributions based on 95% confidence intervals (CIs); analysis 2 -- best-case nesiritide analysis, used the limiting values of the 95% CI favorable to nesiritide; analysis 3 -- best-case dobutamine analysis, used the limiting values of the 95% CI favorable to dobutamine; and analysis 4 -- replicated the previously published cost-effectiveness study and served as a methodologic control. Fifty-one consecutive Monte Carlo simulations for cohorts of 1000 hypothetical patients were performed for each analysis. Incremental cost, incremental effectiveness, and incremental cost-effectiveness ratios (ICERs) were calculated for nesiritide versus dobutamine. Analysis 1 showed a mean ICER of 767 US dollars/life-year gained for nesiritide versus dobutamine (incremental cost 251 US dollars +/- 290 US dollars, incremental effectiveness 0.33 +/- 0.22 yr). The 95% confidence region surrounding this point estimate spanned all four quadrants of the incremental cost-effectiveness scatterplot, suggesting inconclusive results. Nesiritide was the dominant treatment strategy in analysis 2 (incremental cost -734 US dollars+/- 106 US dollars, incremental effectiveness 1.19 +/- 0.07 yrs), whereas dobutamine was dominant in analysis 3 (incremental cost 1242 +/- 73 US dollars, incremental effectiveness -0.57 +/- 0.05 yr). Analysis 4 was comparable to the previously published cost-effectiveness analysis (incremental cost -77 +/- 87 US dollars, incremental effectiveness 0.48 +/- 0.05 yr). CONCLUSIONS: Based on available randomized clinical trial data, nesiritide did not exhibit robust economic superiority over dobutamine. When incorporating the uncertainty (i.e., 95% CIs) in clinical effectiveness as reported in available clinical trial data into the economic analysis, either nesiritide or dobutamine may be the dominant treatment (i.e., more effective at lower cost) for the studied population. Economic analyses of nesiritide and any comparator must account for uncertainty in estimates of cost as well as in clinical effectiveness.

Correction for errors in measuring adherence to prenatal multivitamin/mineral supplement use among low-income women.

Adherence to prenatal multivitamin/mineral supplement use is often measured by self-reports or pill counts. Although both measures were shown to overestimate adherence, measurement error is rarely considered. In this study, we examined measurement error in adherence to prenatal supplement use among pregnant women and demonstrated a calibration method to adjust for error. In a validation subsample (n=51) from a larger clinical study of supplementation, adherence was assessed by self-reports, pill counts, and a Medication Event Monitoring System (MEMS) bottle cap that recorded the date and time of each opening of the pill bottle. Mean adherence in the validation sample as measured by the MEMS (the gold standard) was 68%; thus, adherence measured by self-report (77%) and pill count (84%) reflected overestimation. The Pearson correlation coefficients of self-reports and pill counts to MEMS were 0.35 and 0.62, respectively. When adherence was defined as taking >or=75% of the pills prescribed, sensitivity and specificity were greater for pill counts (93 and 52%, respectively) than for self-reports (88 and 44%). The regression coefficient for pill count adherence from a linear regression on MEMS adherence was applied to pill counts from a larger sample (n=244). The adjustment significantly lowered the estimate of adherence from 74 to 64% (P<0.001) in this larger sample. In conclusion, our data show that both self-reports and pill counts overestimate adherence and that linear regression in comparison to an external standard such as MEMS can be used to correct for measurement error in adherence.

The roles of teaching hospitals, insurance status, and race/ethnicity in receipt of adjuvant therapy for regional-stage breast cancer in Florida.

OBJECTIVES: We examined the roles of teaching hospitals, insurance status, and race/ ethnicity in women's receipt of adjuvant therapy for regional-stage breast cancer. METHODS: Data were taken from the Florida Cancer Data System for cases diagnosed from July 1997 to December 2000. We evaluated the impact of health insurance status and hospital type on use of adjuvant therapy (after adjustment for age, race/ethnicity, and marital status). Interaction terms for hospital type, insurance status, and race/ethnicity were entered in each model. RESULTS: Teaching facilities diagnosed 12.5% of the cases; however, they cared for a disproportionate percentage (21.3%) of uninsured and Medicaid-insured women. Among women who received adjuvant chemotherapy only, those diagnosed in teaching hospitals were more likely than those diagnosed in nonteaching hospitals to receive therapy regardless of insurance status or race/ethnicity. Among women who received chemotherapy with or without hormonal therapy, Hispanics were more likely than White non-Hispanic women to receive therapy, whereas women with private insurance or Medicare were less likely than uninsured and Medicaid-insured women to receive this type of therapy. CONCLUSIONS: Teaching facilities play an important role in the diagnosis and treatment of regional-stage breast cancer among Hispanics, uninsured women, and women insured by Medicaid.

Pill count adherence to prenatal multivitamin/mineral supplement use among low-income women.

In the United States, the prevalence of third trimester anemia among low-income pregnant women is 29% and has not improved since the 1980s. Although low adherence has been linked to the ineffectiveness of iron supplementation programs, data regarding adherence to supplementation in low-income women are currently lacking. Hence this study was conducted to better understand the factors associated with adherence to the use of iron-containing prenatal multivitamin/mineral supplements among low-income pregnant women. Adherence to supplement use was assessed by pill counts among 244 pregnant women of 867 women who were initially randomized to receive 1 of 3 prenatal supplements. All women received care at a public prenatal clinic. Maternal characteristics associated with adherence were identified using predictive modeling. Women took 74% of supplements as prescribed. Adherence was higher among non-Hispanic white women than among non-Hispanic black women (79% vs. 72%, P