Real-World Treatment Patterns in Patients with Castrate-Resistant Prostate Cancer and Bone Metastases.

BACKGROUND: Prostate cancer is the most frequently diagnosed cancer in men in the United States. There is scant real-world evidence characterizing the care utilization and clinical outcomes associated with the use of therapies currently approved by the US Food and Drug Administration (FDA) for patients with metastatic castrate-resistant prostate cancer (CRPC). OBJECTIVE: To describe the real-world treatment patterns, healthcare costs, and survival rates of patients with metastatic CRPC and bone metastases who have commercial or Medicare coverage. METHODS: This retrospective observational study was conducted using medical and pharmacy claims from the Humana research database for male patients who had Medicare or commercial coverage and were aged 55 to 89 years at the initiation of treatment for metastatic CRPC. Three inclusion criteria were used to identify appropriate patients for the 2 cohorts, including (1) a diagnosis of prostate cancer (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 185.x); (2) a diagnosis of bone metastasis (ICD-9-CM code 198.5) between 2013 and 2014; and (3) a healthcare insurance claim indicating a prescription for an FDA-approved first-line treatment for metastatic CRPC. Subsequent lines of treatment were also identified through the healthcare claims data. The 2-year survival rate was calculated and controlled for demographic and clinical characteristics, and the total costs (medical plus pharmacy) were calculated for the 6 months postindex. RESULTS: A total of 1855 patients met the study inclusion criteria. Of these patients, 660 (35.6%) received at least 1 medication. The patient count by line of treatment was 660 (100%) who received first-line therapy, 380 (57.6%) who received second-line treatment, 204 (30.9%) who received third-line therapy, and 107 (16.2%) who received fourth-line therapy. The medication distribution by line of treatment (using first-, second-, third-, or fourth-line therapy for each drug) was abiraterone acetate (50.5%, 61.3%, 68.6%, 75.7%); enzalutamide (15.6%, 39.2%, 54.4%, 71.0%); sipuleucel-T (9.2%, 13.9%, 20.1%, 20.6%); radium-223 dichloride (1.7%, 2.6%, 7.4%, 13.1%); cabazitaxel (2.3%, 5.5%, 16.2%, 19.6%); and docetaxel (22.1%, 32.1%, 42.6%, 48.6%). The total monthly unadjusted healthcare costs for patients who received an FDA-approved treatment was much higher ($9435) than for patients with metastatic prostate cancer who did not receive an FDA-approved treatment ($5055), and the 2-year survival rate for patients who received an FDA-approved treatment was 57.1% (25th percentile, 250 days; 50th percentile, 541 days). CONCLUSIONS: The most common first-line treatment for patients with commercial or Medicare coverage who had metastatic CRPC was abiraterone or enzalutamide. Hormone therapies used as monotherapy were the most frequently used treatment, and their concomitant administration with other treatments was the second most common treatment pattern. Additional clinical studies are needed to further elucidate the treatment sequencing for patients with metastatic CRPC.

Association of obesity with healthcare utilization and costs in a Medicare population.

OBJECTIVES: To examine the association of obesity with healthcare resource utilization and costs in a Medicare population. METHODS: This study was a retrospective cohort study using Humana Medicare Advantage (MA) claims data. Body mass index (BMI) was assessed using ICD-9-CM status codes (V85 hierarchy) that have been validated in the data source to classify patients into BMI categories: normal (N), overweight (Ow), obese class I (ObI), obese class II (ObII), and obese class III (ObIII). Healthcare resource utilization (HRU) and costs were determined based on claims data. Descriptive statistics were used to examine baseline characteristics and HRU across BMI classes. Multivariable analysis was used to examine the association between BMI class and outcome measures. RESULTS: Among the 172,866 patients aged ≥65 years that were identified, BMI distribution was: N, 21%; Ow 37%; ObI, 24%, ObII, 10%; and ObIII, 9%. Inpatient, emergency department and outpatient utilization increased with greater BMI level, and greater BMI level was associated with higher total healthcare, medical and pharmacy costs. Greater prevalence of several cardiometabolic conditions, total medication use, and use of specific medication classes was observed with increasing BMI class. CONCLUSIONS: Greater BMI was associated with greater HRU and costs and observed increase in prevalence of cardiometabolic conditions. These results reflect an urgent need to address the epidemic of obesity and the resulting excessive clinical and economic burden on the healthcare system.

Healthcare utilization and costs for patients initiating Dabigatran or Warfarin.

BACKGROUND: Novel oral anticoagulants (NOAC) such as dabigatran, when compared to warfarin, have been shown to potentially reduce the risk of stroke in patients with non-valvular atrial fibrillation (NVAF) together with lower healthcare resource utilization (HCRU) and similar total costs. This study expands on previous work by comparing HCRU and costs for patients newly diagnosed with NVAF and newly initiated on dabigatran or warfarin, and is the first study specifically in a Medicare population. METHODS: A retrospective matched-cohort study was conducted using data from administrative health care claims during the study period 01/01/2010-12/31/2012. Cox regression analyses were used to compare all-cause risk of first hospitalizations and emergency room (ER) visits. Medical, pharmacy, and total costs per-patient-per-month (PPPM) were compared between dabigatran and warfarin users. RESULTS: A total of 1110 patients initiated on dabigatran were propensity score-matched with corresponding patients initiated on warfarin. The mean number of hospitalizations (0.92 vs. 1.13, P = 0.012), ER visits (1.32 vs. 1.56, P < 0.01), office visits (21.43 vs. 29.41; P < 0.01), and outpatient visits (10.86 vs. 22.02; P < 0.01) were lower among dabigatran compared to warfarin users. Patients initiated on dabigatran had significantly lower risk of first all-cause ER visits [hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.73-0.98] compared to those initiated on warfarin. Adjusted mean pharmacy costs PPPM were significantly greater for dabigatran users ($510 vs. $250, P < 0.001); however, mean medical costs PPPM ($1912 vs. $1956, P = 0.55) and mean total costs PPPM ($2381 vs. $2183, P = 0.10) were not significantly different compared to warfarin users. CONCLUSIONS: Dabigatran users had significantly lower HCRU compared to warfarin users. In addition, dabigatran users had lower risk of all-cause ER visits. Despite higher pharmacy costs, the two cohorts did not differ significantly in medical or total all-cause costs.

Impact of Out-of-Pocket Costs on Prescription Fills Among New Initiators of Biologic Therapies for Rheumatoid Arthritis.

BACKGROUND: Biologic disease-modifying antirheumatic drug (DMARD) therapies are a mainstay of treatment for rheumatoid arthritis (RA), yet high member out-of-pocket (OOP) costs for such therapies may limit patient access to these therapies. OBJECTIVE: To understand whether there is a relationship between OOP costs and the initial fill and subsequent refills of biologic DMARD treatments for RA members. METHODS: Members of a national Medicare Advantage and Prescription Drug (MAPD) plan with an adjudicated (paid or reversed) claim for a biologic DMARD indicated for RA were identified from July 1, 2007, to December 31, 2012, and followed retrospectively. The first adjudicated claim date was the index date. Members were required to have 180 days of continuous enrollment pre- and post-index and ≥ 1 diagnosis for RA (ICD-9-CM: 714.0 or 714.2) during pre-index or ≤ 30 days post-index. Low-income subsidy and Medicaid-Medicare dual-eligible patients were excluded. The analysis used multivariate regression models to examine associations between initial prescription (Rx) abandonment rates and OOP costs and factors influencing the refill of a biologic DMARD therapy based on pharmacy claims. RESULTS: The final sample size included 864 MAPD members with an adjudicated claim for a biologic DMARD. The majority were female (77.4%) and mean age was 63.5 years (SD = 10.9). Most (78%) had conventional nonbiologic DMARD utilization during pre-index. The overall initial abandonment rate was 18.2% for biologic DMARDs, ranging from 1.3% for the lowest OOP cost group ($0-$250) to 32.7% for the highest OOP cost group (> $550; P < 0.0001 for Cochran-Armitage trend test). ORs for abandonment rose from 18.4 to 32.7 to 41.2 for OOP costs of $250.01-$400.00, $400.01-$550.00, and > $550.00 respectively, relative to OOP costs of ≤ $250.00 (all P < 0.0001). Meeting the catastrophic coverage limit and utilization of a specialty pharmacy for the index claim were both associated with a decreased likelihood of abandoning therapy (OR = 0.29 and OR = 0.14, respectively; both P < 0.05). Among the subset of 533 members with a paid claim, 82.4% had at least 1 refill post-index. The negative association between OOP cost and likelihood of refilling an Rx was highly significant (P < 0.0001). CONCLUSIONS: This study suggests that the higher the member OOP cost, the less likely an MAPD member is to initiate or refill a biologic DMARD therapy for RA. Further research is needed to understand reasons for initial Rx abandonment and lack of refills, including benefit design and adverse events.

The burden of diabetes mellitus for medicare beneficiaries.

The objective was to estimate health care costs and utilization for Medicare beneficiaries with type 1 (T1DM) or type 2 (T2DM) diabetes and their respective matched control cohorts. A retrospective claims cohort analysis was used to assess direct health care cost and utilization of health services in 2009 for patients aged 65-89 who were enrolled in a Medicare Advantage Plus prescription drug plan. Patients were matched 1:1 with patients without diabetes. All-cause health care costs for 2009 were calculated as the sum of all medical and pharmacy claims. The analysis included 6562 patients with T1DM and an equal number of matched controls, and 194,775 patients with T2DM and an equal number of matched controls. There were no significant demographic differences between cohorts for matched variables. Patients with T2DM had significantly higher mean Deyo/Charlson Comorbidity Index scores compared with their controls (2.47 versus 0.77; P<0.001), although all groups reported a high rate of costly comorbidities such as hypertension and heart disease. Mean all-cause health care costs per patient per year were significantly higher for patients with T1DM and T2DM versus controls for inpatient hospitalizations; outpatient, office, and emergency room visits; pharmacy expenditures; and total health care costs for 2009 (T1DM group: $20,701±$30,201; T1DM-matched control group: $6,537±$10,441; T2DM group: $10,437±$18,518; T2DM-matched control group: $6,505±$11,140). Diabetes escalates health care costs for Medicare Advantage Plus patients compared with patients in the same plan without diabetes, regardless of comorbidities.

The influence of a postdischarge intervention on reducing hospital readmissions in a Medicare population.

Hospital readmissions in the Medicare population may be related to a number of factors, including reoccurrence of illness, failure to understand or follow physician direction, or lack of follow-up care, among others. These readmissions significantly increase cost and utilization in this population, and are expected to increase with the projected growth in Medicare enrollment. The authors examined whether a postdischarge telephonic intervention for patients reduced 30-day hospital readmissions as compared to a matched control population. Postdischarge telephone calls were placed to patients after discharge from a hospital. Readmissions were monitored through health care claims data analysis. Of 48,538 Medicare members who received the intervention, 4504 (9.3%) were readmitted to the hospital within 30 days, as compared to 5598 controls (11.5%, P<0.0001). A direct correlation was observed between the timing of the intervention and the rate of readmission; the closer the intervention to the date of discharge the greater the reduction in number of readmissions. Furthermore, although emergency room visits were reduced in the intervention group as compared to controls (8.1% vs. 9.4%, P<0.0001), physician office visits increased (76.5% vs. 72.3%, P<0.0001), suggesting the intervention may have encouraged members to seek assistance leading to avoidance of readmission. As a group, overall cost savings were $499,458 for members who received the intervention, with $13,964,773 in savings to the health care plan. Support for patients after hospital discharge clearly affected hospital readmission and associated costs and warrants further development.

The zinc finger transcription factor ZFHX1A is linked to cell proliferation by Rb-E2F1.

ZFHX1A is expressed in proliferating cells in the developing embryo, and in the present study we provide evidence that its expression is confined to proliferating cells through dependence on the Rb (retinoblastoma protein) family/E2F cell cycle pathway. Mutation of the Rb or E2F1 genes lead to induction of ZFHX1A mRNA, implying that the Rb-E2F1 repressor complex is important for repression of ZFHX1A. This repression is associated with recruitment of an E2F-Rb-histone deacetylase repressor complex to the promoter. A dominant-negative form of E2F1 inhibited ZFHX1A expression in p16INK4a- cells where Rb is constitutively hyperphosphorylated and inactive, suggesting that E2F can contribute to ZFHX1A transactivation in the absence of functional Rb. ZFHX1A is an E-box-binding transcription factor whose binding sites overlap with those bound by Snail1 and 2, and ZFHX1B/SIP1 (leading to at least partially overlapping function; for example, each of the proteins can repress E-cadherin expression). We found that expression of Snail1 and ZFHX1B/SIP1 is also regulated by E2Fs, but in contrast with ZFHX1A this regulation is Rb-family-independent. Snail2 expression was unaffected by either E2F or the Rb family. We propose that the differential effects of the Rb family/E2F pathway on expression of these E-box-binding proteins are important in maintaining their distinct patterns (and thus distinct functions) during embryogenesis.

Cell-specific phosphorylation of Zfhep transcription factor.

Zinc finger homeodomain enhancer-binding protein (Zfhep/Zfhx1a) is a transcription factor essential for immune system development, skeletal patterning, and life. Regulation of the interleukin-2 gene in T cells has been suggested to depend on post-translational processing of Zfhep, however, no modifications of Zfhep are known. Here we demonstrate that Zfhep is present in both hyperphosphorylated and hypophosphorylated forms. Western blot analysis demonstrates two forms of Zfhep with different mobilities. Differences in phosphorylation are sufficient to explain the difference in mobilities. Zfhep is primarily phosphorylated on Ser and Thr residues since PP2A dephosphorylates the slower mobility band. Treatment of nuclear extract with O-GlcNAcase did not detect O-linked sugar. Importantly, post-translational processing is cell-specific. Doublets of Zfhep were detected in five cell lines, whereas 6 cell lines contain only, or predominantly, non-phosphorylated Zfhep, and Saos-2 cells contain predominantly the phosphorylated form. These data provide the first demonstration that Zfhep is post-translationally modified.