Validating the Simplified Endoscopic Mucosal Assessment for Crohn's Disease: A Novel Method for Assessing Disease Activity.

BACKGROUND: To demonstrate treatment efficacy in Crohn's disease (CD), regulatory authorities require that trials include an endoscopic remission/response end point; however, standardized endoscopic assessment of disease activity, such as the Simple Endoscopic Score for Crohn's Disease (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. The novel Simplified Endoscopic Mucosal Assessment for Crohn's Disease (SEMA-CD) was developed to be easy to use in routine clinical practice and as a trial end point. We conducted a study to assess and validate the reliability and feasibility of SEMA-CD as a measure of endoscopic disease activity. METHODS: Pre- and post-treatment ileocolonoscopy videos of pediatric (n = 36) and adult (n = 74) CD patients from 2 ustekinumab clinical trials were each scored with SEMA-CD by 2 to 3 professional central readers, blinded to clinical history and other video scorings; the correlation between SEMA-CD and SES-CD previously completed during the trials was assessed. Sensitivity to change, inter- and intrarater reliability, and comparative ease of scoring were also assessed. RESULTS: The SEMA-CD strongly correlated with SES-CD (Spearman ρ = 0.89; 95% confidence interval, 0.86-0.92). Pre- to post-treatment changes in SEMA-CD vs in SES-CD were strongly correlated, and the correlation remained strong between the scores when compared by study population (pediatric, adult), disease severity, and video quality. Intra- and inter-rater reliability were good, and SEMA-CD was rated easier than SES-CD to score 63.0% of the time, although slightly more difficult than SES-CD to score <1.0% of the time. CONCLUSIONS: The SEMA-CD is reliable, reproducible, sensitive to change, and easy to use in both pediatric and adult patients with CD.

Adherence to heart failure management medications following cardiac resynchronization therapy.

Objective: The purpose of this study is to assess the real-world impact of cardiac resynchronization therapy (CRT) on adherence to heart failure (HF) medications.Methods: MarketScan administrative health care claims data from 2008 to 2014 among patients with HF were used. The date of first CRT implantation served as the index date. Adherence to guideline-directed medical therapy (GDMT) classes were compared during pre- and post-index periods using proportion of days covered (PDC). Comparisons between the two periods were made using the Wilcoxon sign-rank test for continuous PDC and McNemar's test for dichotomized PDC.Results: Increases in medication adherence were observed for major classes of HF GDMT medications. Specifically, adherence to angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), beta blockers (BB), and furosemide increased by 22, 24, 32, and 28% (all p < .001), respectively, in the 12 months pre to 12 months post-CRT. Large increases between the pre- and post-CRT period were also observed when considering adherence as dichotomized PDC ≥0.80 in the 12 months pre- versus post-CRT.Conclusion: Adherence to HF medications significantly improved among HF patients post-CRT implantation. Further research is needed to better understand the underlying determinants of this effect, including whether the effect is attributable to factors such as enhanced patient monitoring and improved access to high-quality specialized HF care among patients receiving CRT.

Assessment of the real-world safety profile of vedolizumab using the United States Food and Drug Administration adverse event reporting system.

Vedolizumab is the first gut-selective integrin blocker indicated for patients with Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to examine the adverse events (AEs) profile of vedolizumab compared to anti-tumor necrosis factors (anti-TNFs) indicated for CD and UC using the FDA Adverse Event Reporting System (FAERS) database. AE reports with vedolizumab (5/20/2014-6/30/2015) and CD/UC-indicated anti-TNF drugs (adalimumab, infliximab, certolizumab pegol, and golimumab, during 8/1/1998-6/30/2015) as primary suspects were extracted from the FAERS database. AEs associated with vedolizumab were compared for signals of disproportionate reporting against anti-TNF drugs and all other drugs (1969-6/30/2015), using the proportional reporting ratio (PRR) and the empirical Bayesian geometric mean (EBGM) algorithms. The search retrieved 499 reports for vedolizumab and 119,620 reports for anti-TNFs, with 35.9% and 32.1% of these, respectively, being serious AEs. With the PRR approach, vedolizumab-associated reports had signals for 22 groups of AEs (9 were associated with serious outcomes) relative to anti-TNFs and had 34 signals relative to all other drugs. Signals detected included those reported as warnings in prescribing information and new AEs related to cardiovascular disease. Due to the voluntary nature of FAERS, this finding should be considered hypothesis generating (rather than hypothesis testing). Longer-term observational studies are required to evaluate the safety of vedolizumab.

Health-care Cost Impact of Continued Anticoagulation With Rivaroxaban vs Aspirin for Prevention of Recurrent Symptomatic VTE in the EINSTEIN-CHOICE Trial Population.

BACKGROUND: Using data from the Reduced-Dose Rivaroxaban in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism (EINSTEIN-CHOICE) trial, this study assessed cost impact of continued anticoagulation therapy with rivaroxaban vs aspirin. METHODS: Total health-care costs (2016 USD) associated with rivaroxaban and aspirin were calculated as the sum of clinical event costs and drug costs from a US managed care perspective. Clinical event costs were calculated by multiplying event rate by cost of care. One-year Kaplan-Meier clinical event rates for recurrent pulmonary embolism, recurrent DVT, all-cause mortality, and bleeding were obtained from EINSTEIN-CHOICE. Cost of care was determined by literature review. Drug costs were the product of drug price (wholesale acquisition cost) and treatment duration. A one-way sensitivity analysis was conducted. RESULTS: Rivaroxaban users had lower per patient per month (PPPM) clinical event costs compared with aspirin users ($123, $243, and $381 for rivaroxaban 10 mg, rivaroxaban 20 mg, and aspirin, respectively). However, vs aspirin, PPPM total health-care costs were $24 higher for patients treated with rivaroxaban 10 mg ($143 higher for rivaroxaban 20 mg) due to higher cost of rivaroxaban. With a 15% discount for rivaroxaban 10 mg, the lower cost of clinical events for the rivaroxaban-treated patients more than fully offset the higher drug costs, and yielded a $19 lower total health-care cost. CONCLUSIONS: Continued therapy with rivaroxaban 10 and 20 mg vs aspirin was associated with lower clinical event costs but higher total health-care costs; with a 15% drug discount rivaroxaban 10 mg had lower total health-care costs than aspirin.

Retrospective cohort study comparing the risk of severe hepatotoxicity in hospitalized patients treated with echinocandins for invasive candidiasis in the presence of confounding by indication.

BACKGROUND: To compare the risk of severe hepatotoxicity with anidulafungin versus caspofungin and micafungin in hospitalized adults. METHODS: This retrospective cohort study combined data from two large US- based hospital electronic medical record databases. Severe hepatotoxicity was a Grade ≥ 3 liver function test (LFT) post-echinocandin initiation. Adjusted incidence rate ratios (IRRs) were estimated for anidulafungin versus caspofungin and micafungin, overall and in patients with normal baseline LFT (Grade 0). RESULTS: Treatments included anidulafungin (n = 1700), caspofungin (n = 4431), or micafungin (n = 6547). The proportions with LFT Grade ≥ 3 pre-echinocandin initiation were: anidulafungin 40.4% versus caspofungin 25.9% (p <  0.001) and micafungin 25.6% (p <  0.001). Rates of severe underlying diseases or comorbidities were: critical care admissions: 75.3% versus 52.6 and 48.6%; and organ failures: 69.4% versus 46.7 and 51.5%. Adjusted IRRs of severe hepatotoxicity for anidulafungin versus caspofungin and micafungin were 1.43 (p = 0.002) and 1.19 (p = 0.183) overall, and 0.88 (P = 0.773) and 0.97 (P = 0.945) for normal baseline LFT, respectively. CONCLUSIONS: Accounting for confounders, severe hepatotoxicity risk was not significantly different across echinocandins in this real-world head-to-head study. Anidulafungin was used more frequently in patients with more comorbidities. Those with normal baseline LFT (least susceptible to confounding by indication), showed no elevated hepatotoxicity risk for anidulafungin.

Clinical outcomes of prolonged anticoagulation with rivaroxaban after unprovoked venous thromboembolism.

BACKGROUND: Randomized trial data demonstrate the gain of extended duration anticoagulation in patients with venous thromboembolic events (VTE); however, real-world data are limited. OBJECTIVES: Assess the risk of recurrent VTE and major bleeding in a real-world setting of patients who experienced unprovoked VTE and received extended treatment with rivaroxaban. METHODS: US claims databases (February 2011-April 2015) were used in this retrospective study. The study population included adult patients initiated on rivaroxaban within 7 days after their first unprovoked VTE (ie, deep vein thrombosis, pulmonary embolism) and received ≥3 months continuous rivaroxaban treatment (index date: end of 3-month treatment). Patients who were treated beyond 3 months formed the continued cohort and the remainder formed the discontinued cohort (ie, discontinued at 3 months). Adjusted Kaplan-Meier rates for recurrent VTE and major bleeding events were compared between cohorts with confounders being controlled through a propensity score weighting approach. RESULTS: Patients in the continued cohort (N = 3763) had significantly lower rates of recurrent VTE than those who discontinued (N = 1051): 0.57% vs 1.19% (P = .042), 1.07% vs 2.10% (P = .017), and 1.45% vs 2.60% (P = .023) at 3, 6, and 12 months, respectively. No significant differences in the rate of major bleeding were observed between cohorts. A sensitivity analysis among unprovoked VTE patients receiving rivaroxaban for ≥6 months showed similar results. CONCLUSIONS: Continued rivaroxaban treatment beyond an initial 3- or 6-month treatment period significantly lowered the risk of recurrent VTE without a significant increase of major bleeding, compared to treatment discontinued at 3 or 6 months.

Real-world Treatment Patterns Among Patients With Colorectal Cancer Treated With Trifluridine/Tipiracil and Regorafenib.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) and have similar indications with different side-effect profiles. The present study compared real-world treatment patterns with FTD/TPI and REG for mCRC in a large, representative US claims database. MATERIALS AND METHODS: Retrospective data from the US Symphony Health Solutions' Integrated Dataverse database were analyzed for adult mCRC patients receiving FTD/TPI or REG from October 2014 to July 2016. The index date was the first FTD/TPI or REG prescription date. The observation period spanned from the index date to the end of data collection, end of continuous clinical activity, or treatment switch. Adherence was assessed using the medication possession ratio and proportion of days covered at 3 months. The time to discontinuation was assessed over the observation period with gaps of 45, 60, or 90 days. Outcomes were compared between the cohorts using logistic regression and Cox proportional hazards models adjusting for baseline characteristic differences. RESULTS: A total of 1630 FTD/TPI patients and 1425 REG patients were identified. The FTD/TPI patients were 80% more likely to have a medication possession ratio of ≥ 0.80 compared with the REG patients (odds ratio, 1.80; P < .001) and more than twice as likely to have a proportion of days covered of ≥ 0.80 (odds ratio, 2.66; P < .001) at 3 months. The FTD/TPI patients were 37% less likely to discontinue their treatment compared with the REG patients when using the 60-day gap (hazard ratio, 0.63; P < .001). Similar results were found using the 45- and 90-day gaps. CONCLUSION: mCRC patients taking FTD/TPI were significantly more likely to adhere to and comply with therapy compared with those taking REG.

CMS hospital readmission reduction program and anticoagulants received following a total hip and knee arthroplasty discharge.

OBJECTIVES: To assess association between 30 day readmission rate and treatment received after total hip and knee arthroplasty (THA/TKA) discharge (rivaroxaban vs. warfarin or non-anticoagulant). To subsequently model impact of increasing rivaroxaban use on the Hospital Readmission Reduction Program (HRRP) penalty, which was imposed on hospitals with excess 30 day readmissions after hospitalizations for selected conditions, including THA/TKA. METHODS: The US Truven Health MarketScan Medicare Supplemental database from 1 July 2010 to 30 April 2015 was used. A retrospective claims analysis was conducted to assess the risk of all-cause 30 day readmission among patients receiving either rivaroxaban or warfarin, or no anticoagulation following THA/TKA discharge. Simulations were performed to estimate the impact of post-discharge treatment on the HRRP penalty. RESULTS: The risk-adjusted all-cause 30 day readmission rates were 1.21% (95% confidence interval [95% CI]: 0.94%-1.49%), 1.41% (95% CI: 1.19%-1.58%) and 1.95% (95% CI: 1.81%-2.11%) for rivaroxaban, warfarin and non-anticoagulant cohorts, respectively. Using these rates, simulations illustrated that when switching patients from warfarin or non-anticoagulant to rivaroxaban, annual penalty per hospital would be reduced up to 67% or 88%, respectively. CONCLUSIONS: Rivaroxaban treatment post-THA/TKA discharge reduced the risk of 30 day readmission compared to non-anticoagulants. Simulations illustrated that increasing rivaroxaban use could decrease the HRRP penalty.

Adherence to iron chelation therapy in patients who switched from deferasirox dispersible tablets to deferasirox film-coated tablets.

OBJECTIVE: To compare real-world adherence to and persistence with deferasirox film-coated tablets (DFX-FCT) and deferasirox dispersible tablets (DFX-DT) among patients who switched from DFX-DT to DFX-FCT, overall and by disease type (sickle cell disease [SCD], thalassemia, and myelodysplastic syndrome [MDS]). METHODS: Patients were ≥2 years old and had ≥2 DFX-FCT claims over the study period and ≥2 DFX-DT claims before the index date (first DFX-FCT claim). The DFX-DT period was defined from the first DFX-DT claim to the index date; the DFX-FCT period was defined from the index date to the end of the study period. Adherence was measured as medication possession ratio (MPR) and proportion of days covered (PDC). Persistence was defined as continuous medication use without a gap ≥30 or 60 days between refills. Comparisons were conducted using paired-sample Wilcoxon sign-rank and McNemar's tests. RESULTS: In total, 606 patients were selected (SCD: 348; thalassemia: 107; MDS: 106; other: 45). Adherence and persistence in the DFX-FCT vs DFX-DT period was significantly higher across all measures: mean MPR was 0.80 vs 0.76 (p < .001); 60.9% vs 54.3% of patients had MPR ≥ 0.8 (p = .009); mean 3-month PDC was 0.83 vs 0.71 (p < .001); 64.2% vs 45.4% of patients had 3-month PDC ≥ 0.8 (p < .001); 87.2% vs 63.4% of patients had 3-month persistence with no gap ≥30 days and 96.1% vs 79.9% with no gap ≥60 days (p < .001). Adherence and persistence improved after switching across all diseases, particularly MDS. CONCLUSIONS: Adherence and persistence improved significantly after switching from DFX-DT to DFX-FCT for all diseases, but especially MDS.

Health care burden and treatment patterns in commercially insured children with chronic idiopathic/spontaneous urticaria: A real-world study in the United States.

BACKGROUND: Chronic idiopathic urticaria (CIU)/spontaneous urticaria (CSU) is defined by the presence of wheals, angioedema, or both for ≥6 weeks, with or without an identifiable trigger. Real-world health care data among children with CIU/CSU remain scarce. OBJECTIVES: To describe treatment patterns, health care resource utilization (HRU), and costs in pediatric patients with CIU/CSU (<12 years old) and to compare these with pediatric patients without CIU/CSU. METHODS: A commercial administrative claims data base (September 2013 to June 2016) was used. The CIU/CSU cohort included pediatric patients with either two or more claims for a diagnosis of urticaria ≥6 weeks apart or one or more claims for a diagnosis of urticaria and one or more claims for a diagnosis of angioedema ≥6 weeks apart (index was defined as the first claim). The control cohort comprised pediatric patients without urticaria or angioedema (index randomly assigned). Patients with <6 months of eligibility before and after the index date were excluded. HRU and costs were compared between the cohorts during the observation period after propensity score matching. RESULTS: A total of 6109 pediatric patients with CIU/CSU were selected, and 6107 were 1:1 matched with controls. The patients with CIU/CSU who had a mean ± standard deviation age of 4.58 ± 3.36 years, and 47.9% were girls. CIU/CSU-related medication use increased after diagnosis (e.g., baseline versus 6-month follow-up, 2.2 versus 8.0% for nonsedating prescription H1 antihistamines; 7.4 versus 17.4% for oral corticosteroids). Relative to the controls, the patients with CIU/CSU had higher rates of HRU (incidence rate ratios of 1.71, 2.39, and 2.07 for inpatient, emergency department, and outpatient visits, respectively; all p < 0.01), and higher all-cause per patient per year costs (mean cost differences of $2090, $1606, and $483 for total, medical, and pharmacy costs, respectively; all p < 0.01). CONCLUSION: This study highlighted unmet needs in pediatric patients with CIU/CSU who had increased medication (e.g., oral corticosteroids) and HRU burden after a diagnosis for CIU/CSU, and higher rates of HRU and costs relative to those without CIU/CSU.

Treatment Patterns, Healthcare Resource Utilization, and Spending Among Medicaid-Enrolled Children with Chronic Idiopathic/Spontaneous Urticaria in the United States.

INTRODUCTION: Few studies have described chronic idiopathic/spontaneous urticaria (CIU/CSU) healthcare burden in adults, while this information remains largely unknown in children. We aimed to describe treatment patterns, healthcare resource utilization (HRU), and costs in CIU/CSU pediatric patients, as well as to compare HRU and costs in CIU/CSU and CIU/CSU-free pediatric patients. METHODS: Medicaid claims from four states (09/01/2013-03/31/2016) were used to identify patients less than 12 years old. The CIU/CSU cohort included patients with either at least two claims for idiopathic, other, or unspecified urticaria at least 6 weeks apart, or at least one claim for urticaria and at least one claim for angioedema at least 6 weeks apart (index date defined as the first claim). The control cohort included patients without urticaria/angioedema claims (index date randomly assigned). Patients without at least 6 months of continuous Medicaid eligibility pre- and post-index were excluded. HRU and costs were compared between propensity score-matched cohorts during the post-index follow-up. RESULTS: A total of 548 CIU/CSU patients (mean [SD] age 4.5 [3.3] years; 51.3% male) were matched 1:1 with controls. In the CIU/CSU cohort, 51.8% used non-sedating prescription H1-antihistamines, 24.3% used oral corticosteroids, and 23.5% used other prescription H1-antihistamines; 13.5% consulted allergist/immunologists and 2.4% consulted dermatologists in the first 6 months of follow-up. Compared to controls, CIU/CSU patients had significantly more per patient per year (PPPY) inpatient (incidence rate ratio [IRR] 2.05), outpatient (IRR 2.20), and emergency department (IRR 1.64) visits (all p values < 0.05). Moreover, CIU/CSU patients also had significantly higher PPPY healthcare costs (mean cost difference [MCD] $1853), driven by incremental outpatient (MCD $1286) costs (all p values < 0.01). CONCLUSIONS: CIU/CSU pediatric patients had low use of non-sedating H1-antihistamines and high use of oral corticosteroids. Compared to CIU/CSU-free controls in the same age group, CIU/CSU pediatric patients had higher HRU and healthcare costs. FUNDING: Novartis Pharmaceuticals Corporation.

Cost comparison of continued anticoagulation with rivaroxaban versus placebo based on the 1-year EINSTEIN-Extension trial efficacy and safety results.

AIMS: The EINSTEIN-Extension trial (EINSTEIN-EXT) found that continued treatment with rivaroxaban for an additional 6 or 12 months (vs placebo) after 6-12 months of initial anticoagulation significantly reduced the risk of recurrent venous thromboembolism (VTE) with a small non-significant increased risk of major bleeding (none fatal or in critical site). This study aimed to compare total healthcare cost between rivaroxaban and placebo, based on the EINSTEIN-EXT event rates. METHODS: Total healthcare cost was calculated as the sum of treatment and clinical event costs from a US managed care perspective. Treatment duration and event rates were obtained from the EINSTEIN-EXT study. Adjustment on treatment duration was made by assuming a 10% non-adherence rate. Drug costs were based on wholesale acquisition costs. Cost estimates for clinical events (i.e. recurrent deep vein thrombosis [DVT], recurrent pulmonary embolism, major bleeding, clinically relevant non-major bleeding) were determined from the literature. Results were examined over a ±20% range of each cost component and over 95% confidence intervals (CIs) of event rate differences in deterministic (one-way) and probabilistic sensitivity analyses (PSA). RESULTS: Total healthcare cost was $1,454 lower for rivaroxaban-treated (vs placebo-treated) patients in the base-case, with a lower clinical event cost fully offsetting drug cost. The cost savings of recurrent DVT alone (-$3,102) was greater than drug cost ($2,723). Total healthcare cost remained lower for rivaroxaban in the majority (73%) of PSA (cost difference [95% CI] = -$1,454 [-$2,396, $1,231]). LIMITATIONS: This study was conducted over the 1-year observation period of the EINSTEIN-EXT trial, which limited "real-world" applicability and examination of long-term economic impact. Assumptions on drug and clinical event costs were US-based and, thus, not applicable to other healthcare systems. CONCLUSIONS: Total healthcare costs were estimated to be lower for patients continuing rivaroxaban therapy compared to those receiving placebo in VTE patients who had completed 6-12 months of VTE treatment.

Adherence, persistence, and inpatient utilization among adult schizophrenia patients using once-monthly versus twice-monthly long-acting atypical antipsychotics.

AIMS: This study compared healthcare resource utilization (HRU), healthcare costs, adherence, and persistence among adult patients with schizophrenia using once-monthly (OM) vs twice-monthly (TM) atypical long-acting injectable (LAI) antipsychotic (AP) therapy. MATERIALS AND METHODS: A longitudinal retrospective cohort study was conducted using Medicaid claims data from six states. Patients initiated on aripiprazole or paliperidone palmitate were assigned to the OM cohort; risperidone-treated patients were assigned to the TM cohort. HRU and healthcare costs were assessed during the first 12 months following stabilization on the medication. Adherence was measured using the proportion of days covered (PDC) during the first year of follow-up. Persistence to the index medication was measured during the first 2 years following the index date. Comparison between the cohorts was achieved using multivariable generalized linear models, adjusting for demographic and clinical characteristics. RESULTS: Patients in the OM LAI cohort had lower inpatient HRU and medical costs when compared with patients in the TM cohort. Higher medical costs in the TM LAI cohort offset the higher pharmacy costs in the OM LAI cohort. Mean PDC during the first 12 months of follow-up was higher in the OM cohort than in the TM cohort (0.56 vs 0.50, p < .01). Median persistence was longer in the OM cohort than in the TM cohort (7.5 months vs 5.5 months), as was the hazard of discontinuing the index medication (hazard ratio = 0.83, p = .01). Kaplan-Meier rates of persistence at 1 year were higher for OM patients than for TM patients (37.6% vs 29.6%, p < .01). LIMITATIONS: This was a Medicaid sample with few aripiprazole LAI patients (5.4% of OM cohort). Medication use was inferred from pharmacy claims. CONCLUSIONS: Among Medicaid patients in these six states, OM AP treatment was associated with lower HRU, better adherence and persistence, and similar total costs compared to patients on TM treatment.

Medication Adherence, Treatment Patterns, and Dose Reduction in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Abiraterone Acetate or Enzalutamide.

BACKGROUND: The efficacy of and overall survival associated with metastatic castration-resistant prostate cancer (CRPC) treatments rely on patients' consistent adherence to the recommended dosage regimens. OBJECTIVES: To evaluate treatment patterns and patient adherence to abiraterone acetate or enzalutamide therapy in real-world practice, and to examine the factors that may be associated with medication dose reduction in patients with metastatic CRPC. METHODS: Retrospective analyses were conducted using the Truven Health MarketScan research databases among patients with metastatic CRPC who initiated treatment with abiraterone acetate or enzalutamide between October 1, 2012, and December 31, 2014 (index date). The patients were followed for up to 12 months, and their baseline characteristics were assessed during the 6 months before the index date. Medication adherence was measured at 3, 6, 9, and 12 months postindex using medication possession ratios (MPRs), and dose reduction was measured using refill gaps and relative dose intensity over the entire observation period. Kaplan-Meier survival analyses and Cox proportional hazards models were used to assess the association between the initial treatment and the risk for dose reduction. RESULTS: The study included 2591 and 807 patients who initiated treatment with abiraterone acetate and enzalutamide, respectively. At 6, 9, and 12 months postindex, the patients who initiated abiraterone acetate had higher MPRs than the patients who initiated enzalutamide. In addition, the patients who initiated abiraterone acetate had lower Kaplan-Meier rates of dose reduction across 4 measurements for dose reduction. All hazard ratios for treatment (abiraterone acetate vs enzalutamide) were significantly lower than 1 (range, 0.57-0.80), indicating a lower risk for dose reduction associated with abiraterone acetate. CONCLUSION: Patients who initiated abiraterone acetate therapy had higher medication adherence and lower risk for dose reduction than those who initiated enzalutamide therapy. Improved medication adherence may be associated with longer duration of treatment, which in turn may lead to better survival. Further research is needed to assess the potential effect of medication adherence on the overall survival of patients with metastatic CRPC.

Comparing Clinical and Economic Outcomes Associated with Early Initiation of Combination Therapy of an Alpha Blocker and Dutasteride or Finasteride in Men with Benign Prostatic Hyperplasia in the United States.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common disease in men that is characterized by lower urinary tract symptoms. Pharmacologic treatment with alpha blockers (ABs) and 5-alpha reductase inhibitors (5ARIs) is recommended to alleviate symptoms, prevent disease progression that can lead to complications, and reduce health care costs. OBJECTIVE: To compare clinical, economic, and health care resource utilization outcomes among BPH patients treated with early continuous combination AB and 5ARI therapy (dutasteride vs. finasteride) using administrative claims data from the United States. METHODS: A retrospective analysis of administrative claims data from 2003-2013 was conducted to compare outcomes between patients with claims for early combination therapy with dutasteride + AB and patients with claims for early finasteride + AB. The study population included males aged older than 50 years with at least 1 medical claim with a diagnosis of BPH and pharmacy dispensing for AB and 5ARI therapies. Outcomes included acute urinary retention (AUR), prostate-related surgery, clinical progression, medical and pharmacy costs, and health care resource utilization. Inverse probability of treatment (IPT) weighted Cox proportional hazards, linear, and Poisson regression models were used to assess the association between outcomes and early combination therapy as appropriate. RESULTS: A total of 2,778 patients were included in the early finasteride + AB treatment cohort, and 4,125 patients were included in the early dutasteride + AB cohort. Dutasteride users were younger than finasteride users (mean age: 64.8 vs. 67.5 years, P < 0.001) and had a greater mean number of urologist visits (10.7 vs. 7.9, P < 0.001) during baseline. After adjusting for confounding using IPT weighting, no statistically significant difference was observed between dutasteride and finasteride for AUR (hazard ratio [HR] = 0.845, 95% CI = 0.660-1.070, P = 0.1643), prostate-related surgery (HR = 0.806, 95% CI = 0.568-1.171, P = 0.2525), and clinical progression (HR = 0.834, 95% CI = 0.663-1.043, P = 0.1122). While dutasteride was associated with higher pharmacy costs per month (adjusted monthly cost difference = $79, 95% CI = $45-$105), total all-cause medical costs were not significantly different between the 2 cohorts (adjusted monthly cost difference = -$44, 95% CI = -$110-$22). CONCLUSIONS: Clinical and economic outcomes were similar between the early dutasteride + AB and early finasteride + AB cohorts, with no statistically significant differences detected. DISCLOSURES: Funding for this study was provided by GlaxoSmithKline (HO-14-15325 and AVO110072). Bell and Swensen are employees of GlaxoSmithKline. DerSarkissian, Xiao, Duh, and Lefebvre are employed by Analysis Group, a consulting company that received research grants from GlaxoSmithKline to conduct this study. Study concept and design were contributed by Bell, Swensen, Lefebvre, and Duh. Bell and Duh acquired the data. DerSarkissian and Xiao performed the statistical analysis and interpreted the data along with Lefebvre, Duh, and Bell. DerSarkissian and Bell drafted the manuscript. All authors contributed equally to critically revising the manuscript and providing final approval of the submitted manuscript.

Disruption of BSEP Function in HepaRG Cells Alters Bile Acid Disposition and Is a Susceptive Factor to Drug-Induced Cholestatic Injury.

In the present study, we characterized in vitro biosynthesis and disposition of bile acids (BAs) as well as hepatic transporter expression followed by ABCB11 (BSEP) gene knockout in HepaRG cells (HepaRG-KO cells). BSEP KO in HepaRG cells led to time-dependent BA accumulation, resulting in reduced biosynthesis of BAs and altered BA disposition. In HepaRG-KO cells, the expression of NTCP, OATP1B1, OATP2B1, BCRP, P-gp, and MRP2 were reduced, whereas MRP3 and OCT1 were up-regulated. As a result, BSEP KO altered the disposition of BAs and subsequently underwent adaptive regulations of BA synthesis and homeostasis to enable healthy growth of the cells. Although BSEP inhibitors caused no or slight increase of BAs in HepaRG wild type cells (HepaRG-WT cells), excessive intracellular accumulation of BAs was observed in HepaRG-KO cells exposed to bosentan and troglitazone, but not dipyridamole. LDH release in the medium was remarkably increased in HepaRG-KO cultures exposed to troglitazone (50 µM), suggesting drug-induced cellular injury. The results revealed that functional impairment of BSEP predisposes the cells to altered BA disposition and is a susceptive factor to drug-induced cholestatic injury. In total, BSEP inhibition might trigger the processes but is not a sole determinant of cholestatic cellular injury. As intracellular BA accumulation is determined by BSEP function and the subsequent adaptive gene regulation, assessment of intracellular BA accumulation in HepaRG-KO cells could be a useful approach to evaluate drug-induced liver injury (DILI) potentials of drugs that could disrupt other BA homeostasis pathways beyond BSEP inhibition.

Comparison of Medicaid spending in schizoaffective patients treated with once monthly paliperidone palmitate or oral atypical antipsychotics.

BACKGROUND: Compared to oral atypical antipsychotics (OAAs), long-acting injectable antipsychotics require less frequent administration, and thus may improve adherence and reduce risk of relapse in schizoaffective disorder (SAD) patients. OBJECTIVE: To evaluate the impact of once monthly paliperidone palmitate (PP) versus OAAs on healthcare resource utilization, Medicaid spending, and hospital readmission among SAD patients. METHODS: Using FL, IA, KS, MS, MO, and NJ Medicaid data (January 2009-December 2013), adults with ≥2 SAD diagnoses initiated on PP or OAA (index date) were identified. Baseline characteristics and outcomes were assessed during the 12month pre- and post-index periods, respectively. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to reduce confounding and compare the estimated treatment effect for PP versus OAA. RESULTS: A total of 10,778 OAA-treated patients and 876 PP-treated patients were selected. Compared to OAAs, PP was associated with significantly lower medical costs (PSM: mean monthly cost difference [MMCD] = -$383, p < 0.001; IPTW: MMCD = -$403, p = 0.016), which offset the higher pharmacy costs associated with PP (PSM: MMCD = $270, p < 0.001; IPTW: MMCD = $350, p < 0.001) and resulted in similar total healthcare cost (PSM: MMCD = -$113, p = 0.414; IPTW: MMCD = -$53, p = 0.697) for PP versus OAA. Reduced risk of hospitalization (PSM: incidence rate ratio [IRR] = 0.85, p = 0.128; IPTW: IRR = 0.96, p = 0.004) and fewer hospitalization days (PSM: IRR = 0.74, p = 0.008; IPTW: IRR = 0.85, p < 0.001) were observed in PP versus OAA patients. Among hospitalized patients, PP was associated with a lower risk of 30 day hospital readmission compared to OAA (IPTW: odds ratio = 0.89, p = 0.041). Limitations The Medicaid data may not be representative of the nation or other states, and includes pre-rebate pharmacy costs (potentially over-estimated). Also changes in treatment over time were possible. CONCLUSIONS: Total healthcare costs associated with the use of once monthly PP versus OAAs appeared comparable; higher pharmacy costs for PP users were offset by lower medical costs related to fewer and shorter inpatients visits.

Impact of paliperidone palmitate versus oral atypical antipsychotics on healthcare outcomes in schizophrenia patients.

AIM: To assess impact of initial treatment and time-dependent treatment with paliperidone palmitate (PP) versus oral atypical antipsychotics (OAAs) on healthcare resource utilization and costs. PATIENTS & METHODS: A retrospective longitudinal study was conducted among Medicaid beneficiaries with schizophrenia. Inverse probability treatment weighting method and marginal structural models were used to estimate the impact of treatment on healthcare resource utilization and costs, respectively. RESULTS: Compared to OAAs, PP was associated with lower medical costs (mean monthly cost difference [MMCD] = -US$256; p = 0.008), which offset the higher pharmacy expense (MMCD = US$122; p < 0.001) resulting in nonsignificant cost savings associated with PP (MMCD = -US$91; p = 0.689). CONCLUSION: PP was associated with comparable overall costs to OAAs, but with significantly lower medical costs, particularly attributable to reduced inpatient visits and long-term care admissions.

Effect of Cumulating Exposure to Abacavir on the Risk of Cardiovascular Disease Events in Patients From the Swiss HIV Cohort Study.

BACKGROUND: Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channeling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. METHODS: We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD. RESULTS: A total of 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient-years). In a conventional Cox model, recent--but not cumulative--exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past 4 years increased the risk of a CVD event (hazard ratio = 2.06; 95% confidence interval: 1.43 to 2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6-36 months caused the greatest increase in risk. CONCLUSIONS: Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.