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ABSTRACT: Abstract Objective: To estimate the budget impact of everolimus as the first and second treatment option after letrozole or anastrozole (L/A) failure for post-menopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). Methods: Pharmacy and medical budget impacts (2011 USD) were estimated over the first year of everolimus use in HR+, HER2- ABC from a US payer perspective. Epidemiology data were used to estimate target population size. Pre-everolimus entry treatment options included exemestane, fulvestrant and tamoxifen. Pre- and post-everolimus entry market shares were estimated based on market research and assumptions. Drug costs were based on wholesale acquisition cost. Patients were assumed to be on treatment until progression or death. Annual medical costs were calculated as the average of pre- and post-progression medical costs weighted by the time in each period, adjusted for survival. One-way and two-way sensitivity analyses were conducted to assess the model robustness. Results: In a hypothetical 1,000,000 member plan, 72 and 159 patients were expected to be candidates for everolimus treatment as first and second treatment option, respectively, after L/A failure. The total budget impact for the first year post-everolimus entry was $0.044 per member per month [PMPM] (pharmacy budget: $0.058 PMPM; medical budget: -$0.014 PMPM), assuming 10% of the target population would receive everolimus. The total budget impacts for the first and second treatment options after L/A failure were $0.014 PMPM (pharmacy budget: $0.018; medical budget: -$0.004) and $0.030 PMPM (pharmacy budget: $0.040; medical budget: -$0.010), respectively. Results remained robust in sensitivity analyses. Limitations: Assumptions about some model input parameters were necessary and may impact results. Conclusions: Increased pharmacy costs for HR+, HER2- ABC following everolimus entry are expected to be partially offset by reduced medical service costs. Pharmacy and total budget increases were modest.
Journal of Medical Economics 11/2012;
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ABSTRACT: Abstract Objectives: To illustrate how claims data can be used to 1) develop outcome scores that predict response to a traditional treatment and 2) estimate the economic impact of individualized assignment to a newer treatment based on the outcome score. An example application is based on two treatments for attention deficit hyperactivity disorder (ADHD): osmotic-release oral system methylphenidate (OROS-MPH) and lisdexamfetamine dimesylate (LDX). Methods: Adolescents with ADHD initiating OROS-MPH (N=6,320) or LDX (N=6,394) were selected from the MarketScan claims database. A model was developed for predicting risk of switching/augmentation with OROS-MPH using multiple baseline characteristics. The model was applied to an independent sample to stratify patients by their predicted risk and, within each stratum, risk of switching/augmentation and ADHD-related total costs were compared between OROS-MPH and LDX patients using inverse probability of treatment weighting. Results: The prediction model resulted in substantial stratification, showing risk of switching/augmentation with OROS-MPH ranging from 11.3-42.1%. In the two strata where OROS-MPH had highest risk of switching/augmentation, LDX had significantly lower risk of switching/augmentation than OROS-MPH (by 7.0-8.2%) and lower ADHD-related annual total costs (by $264-$625 per patient). Limitations: The current study has used the risk of switching/augmentation as a proxy measure for treatment efficacy to establish the prediction model, future research using a clinical measure for ADHD symptoms is warranted to verify the findings. Conclusions: Combining multiple patient characteristics into a predicted score for treatment outcomes with a traditional treatment can help identify subgroups of patients who benefit most from a new treatment. In this analysis, ADHD patients with a high predicted score for switching/augmentation with OROS-MPH had a lower rate of switching/augmentation with LDX. Assigning OROS-MPH and LDX treatments based on the predicted scores that are heterogeneous in a patient population may help improve clinical outcomes and the cost-effectiveness of care.
Journal of Medical Economics 04/2012;
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ABSTRACT: To characterize treatment patterns and measure the economic burden associated with metastatic (mHNC) and recurrent, locally-advanced head and neck cancer (rHNC).
Administrative claims from Medicare- and privately-insured individuals during 2004-2008 were used in this retrospective database study of patients with advanced HNC. Patients diagnosed with HNC were matched 1:1 to cancer-free controls to measure the incremental economic burden of HNC. Outcomes of interest were measured during the 6 months following the date of a secondary tumor diagnosis for metastatic patients or the date of a diagnosis indicating rHNC. To assess treatment patterns, HNC patients were evaluated for the use frequency of treatments (radiotherapy, chemotherapy and surgery). Costs were reported in 2008 US$ from a third-party payer perspective and were analyzed using generalized linear models and two-part regression models adjusting for differences in age and baseline Charlson Comorbidity Index (excluding cancer diagnoses) between the HNC and control cohorts. Components of cost included inpatient, outpatient and other medical services as well as pharmacy costs.
The mHNC cohort consisted of 1042 patients and the rHNC cohort included 324 patients. The most common treatments for mHNC patients were supportive care (90.2%), radiation therapy (48.5%), surgery (41.9%) and chemotherapy (38.3%). Patients with rHNC frequently received HNC-related supportive care (71.0%), radiation therapy (67.9%) and chemotherapy (27.2%); HNC-related surgery was infrequent (12.7%) during the study period. The 6-month incremental adjusted total costs were $60,414 per patient for mHNC and $21,141 per patient for rHNC (p<0.0001). Approximately 46-58% of the incremental cost was attributable to outpatient visits, 27-37% to inpatient costs and 11-13% to pharmacy, depending on the HNC cohort. Limitations: The identification of mHNC/rHNC was based on diagnosis codes and treatment patterns with the limitation of the claims database.
Metastatic and recurrent, locally-advanced HNC patients frequently receive cancer-related treatments and incur substantial economic burden.
Journal of Medical Economics 04/2012; 15(4):786-95.
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ABSTRACT: To investigate the rate and impact of hypoglycemic events among patients with type 2 diabetes mellitus (T2DM) receiving different classes of oral antidiabetic drugs (OADs).
Adult patients with T2DM were extracted from the Ingenix IMPACT claims database. The mean number of health care visits due to hypoglycemic events per patient-year was estimated. Multivariate regression models were used to: 1) assess the risk factors for experiencing a hypoglycemic event; 2) assess the effect of experiencing hypoglycemic events on antidiabetic treatment discontinuation; and 3) compare 12-month post-index date costs between patients with and without hypoglycemic events.
212 061 patients with T2DM were included in the analysis. The estimated frequency of hypoglycemia-related health care visits was 0.054 per patient-year. Insulin use was associated with increased risk of developing hypoglycemia, followed by use of sulfonylureas and other OADs (eg, meglitinide and α-glucosidase inhibitors). The impacts of thiazolidinediones, metformin, and dipeptidyl peptidase-4 on hypoglycemia risk were relatively small. Having a hypoglycemic event was associated with significantly increased risk of antidiabetic treatment discontinuation. Patients with hypoglycemia showed significantly higher annual all-cause and diabetes-related health care costs than patients without hypoglycemia (adjusted Δ = +$5024 and +$3747, respectively; both P < 0.0001).
Different OAD classes were associated with different levels of risk for hypoglycemic events. Hypoglycemia was associated with a higher risk of antidiabetic treatment discontinuation and significantly increased health care costs.
Postgraduate Medicine 01/2012; 124(1):124-32. · 1.78 Impact Factor
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ABSTRACT: To compare the health care costs of patients with metastatic colorectal cancer (mCRC) who received second-line treatment with Avastin (bevacizumab) versus Erbitux (cetuximab), from the third-party payer's perspective.
Patients with mCRC were selected from the PharMetrics claims database if they received second-line therapy containing either bevacizumab (second-line bevacizumab cohort) or cetuximab (second-line cetuximab cohort). Six-month costs following second-line therapy start date and average monthly healthcare costs while on second-line therapy (in 2009 US$) were calculated and compared between the two groups.
A total of 2188 patients with mCRC who met the eligibility criteria were included in the analysis, including 1808 patients receiving bevacizumab and 380 patients receiving cetuximab in second-line treatment. Demographic and baseline characteristics were similar between the two groups. Patients' mean age was 61 years and 56% were males. In second-line treatment, bevacizumab was commonly used with oxaliplatin (43.5%) and irinotecan-based regimens (40.4%), whereas cetuximab was commonly used with irinotecan-based regimens (68.2%). Bevacizumab patients had significantly lower total all-cause healthcare costs than cetuximab patients (adjusted difference: -$10,231, p = 0.020), and lower medical costs (-$10,796, p = 0.012) during the 6 months following second-line therapy initiation. Approximately half of the difference in total all-cause healthcare costs was attributable to the lower chemotherapy and targeted therapy costs (-$5635, p = 0.032) of bevacizumab patients than those of cetuximab patients. While on second-line therapy, bevacizumab patients also had lower average monthly all-cause healthcare costs than cetuximab patients.
Second-line treatment in the current study was defined based on changes in mCRC medications, not based on disease progression due to the limited clinical information available in claims.
The use of bevacizumab in second-line therapy was associated with significantly lower healthcare costs in mCRC patients, compared to the use of cetuximab.
Journal of Medical Economics 07/2011; 14(5):542-52.
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ABSTRACT: Exacerbations are a major contributor to the large burden of treating chronic obstructive pulmonary disease (COPD). Estimates of exacerbation costs in the United States are limited.
To estimate incremental costs associated with COPD exacerbation, particularly severe exacerbation, in the United States.
COPD patients with at least one exacerbation were identified in the Thomson Reuters MarketScan administrative claims database. A COPD exacerbation was defined as patient use of oral or parenteral corticosteroids on the same day or within 7 days following a claim with a COPD diagnosis. Severe exacerbation was further defined if the exacerbation was associated with hospitalization or death. Healthcare costs and exacerbations were evaluated at quarterly intervals starting from patients' first observed claim with COPD diagnostic code in the database. Incremental costs associated with exacerbation were estimated as cost differences between quarters with exacerbation and quarters without exacerbation.
A total of 2644,174 patient-quarters, derived from 228,978 COPD patients, were included in the analysis. The average patient was followed an average of 2.9 years. The mean total cost was $17,016 per patient-quarter with severe exacerbation, $6628 per patient-quarter with non-severe exacerbation, an average of $8726 per patient-quarters with any exacerbation compared to $4762 per patient-quarter with no exacerbation. After adjusting for patient demographics, the mean incremental total cost was $11,261 per patient-quarter with severe exacerbation, $1509 per patient-quarter for non-severe exacerbation, and $3439 per patient-quarter with any exacerbation compared with patient-quarters with no exacerbation.
The method used for defining exacerbations does not capture mild exacerbations. Additional limitations exist due to the nature of claims data.
Exacerbations, especially severe ones, result in a significant economic burden for third-party payers. Effective management of COPD and prevention of exacerbations may lead to improved patient outcomes and reduction in total healthcare costs for long-term management of COPD.
Journal of Medical Economics 01/2011; 14(3):315-23.
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ABSTRACT: Centric regions of eukaryotic genomes are packaged into heterochromatin, which possesses the ability to spread along the chromosome and silence gene expression. The process of spreading has been challenging to study at the molecular level due to repetitious sequences within centric regions. A heterochromatin protein 1 (HP1) tethering system was developed that generates "ectopic heterochromatin" at sites within euchromatic regions of the Drosophila melanogaster genome. Using this system, we show that HP1 dimerization and the PxVxL interaction platform formed by dimerization of the HP1 chromo shadow domain are necessary for spreading to a downstream reporter gene located 3.7 kb away. Surprisingly, either the HP1 chromo domain or the chromo shadow domain alone is sufficient for spreading and silencing at a downstream reporter gene located 1.9 kb away. Spreading is dependent on at least two H3K9 methyltransferases, with SU(VAR)3-9 playing a greater role at the 3.7-kb reporter and dSETDB1 predominately acting at the 1.9 kb reporter. These data support a model whereby HP1 takes part in multiple mechanisms of silencing and spreading.
Genetics 07/2009; 182(4):967-77. · 4.01 Impact Factor
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ABSTRACT: Antisera raised against individual sites of histone post-translational modification (PTM) have provided critical insights into the biology of many of these PTMs. However, limitations inherent to immunochemical approaches can skew results obtained with these reagents, possibly leading investigators to misjudge the role of a specific histone PTM in a given process. We have used mass spectrometry in conjunction with cell synchronization, metabolic labeling, RNA interference, and other approaches to show that the SET domain proteins PR-Set7 and Suv4-20 mediate progressive global mono-, di-, and trimethylation of lysine 20 (K20) in newly synthesized histone H4, beginning approximately at the G2/M transition, well after new H4 is deposited in replicating chromatin during S phase. Immunochemical and other approaches have implicated H4-K20 methylation in multiple processes, including gene activation, gene repression, chromatin condensation, S phase progression, mitosis, and DNA-damage checkpoint signaling. Here, we review recent data on the regulation and significance of K20 methylation.
Biochemistry and Cell Biology 03/2009; 87(1):151-61. · 2.67 Impact Factor
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ABSTRACT: Post-translational modifications of histone tails direct nuclear processes including transcription, DNA repair, and chromatin packaging. Lysine 20 of histone H4 is mono-, di-, or trimethylated in vivo, but the regulation and significance of these methylations is poorly understood. The SET domain proteins PR-Set7 and Suv4-20 have been implicated in mono- and trimethylation, respectively; however, enzymes that dimethylate lysine 20 have not been identified. Here we report that Drosophila Suv4-20 is a mixed product specificity methyltransferase that dimethylates approximately 90% and trimethylates less than 5% of total H4 at lysine 20 in S2 cells. Trimethylation, but not dimethylation, is reduced in Drosophila larvae lacking HP1, suggesting that an interaction with HP1 regulates the product specificity of Suv4-20 and enrichment of trimethyllysine 20 within heterochromatin. Similar to the Drosophila enzyme, human Suv4-20h1/h2 enzymes generate di- and trimethyllysine 20. PR-Set7 and Suv4-20 are both required for normal levels of methylation, suggesting they have non-redundant functions. Alterations in the level of lysine 20 methylation following knock-down or overexpression of Suv4-20 did not affect lysine 16 acetylation, revealing that these two modifications are not competitive in vivo. Depletion of Suv4-20h1/h2 in HeLa cells impaired the formation of 53BP1 foci, suggesting dimethyllysine 20 is required for a proper DNA damage response. Collectively, the data indicate that Suv4-20 generates nearly ubiquitous dimethylation that facilitates the DNA damage response and selective trimethylation that is involved in heterochromatin formation.
Journal of Biological Chemistry 06/2008; 283(18):12085-92. · 4.77 Impact Factor
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ABSTRACT: Methylation of histone H4 at lysine 20 (K20) has been implicated in transcriptional activation, gene silencing, heterochromatin formation, mitosis, and DNA repair. However, little is known about how this modification is regulated or how it contributes to these diverse processes. Metabolic labeling and top-down mass spectrometry reveal that newly synthesized H4 is progressively methylated at K20 during the G(2), M, and G(1) phases of the cell cycle in a process that is largely inescapable and irreversible. Approximately 98% of new H4 becomes dimethylated within two to three cell cycles, and K20 methylation turnover in vivo is undetectable. New H4 is methylated regardless of prior acetylation, and acetylation occurs predominantly on K20-dimethylated H4, refuting the hypothesis that K20 methylation antagonizes H4 acetylation and represses transcription epigenetically. Despite suggestions that it is required for normal mitosis and cell cycle progression, K20 methylation proceeds normally during colchicine treatment. Moreover, delays in PR-Set7 synthesis and K20 methylation which accompany altered cell cycle progression during sodium butyrate treatment appear to be secondary to histone hyperacetylation or other effects of butyrate since depletion of PR-Set7 did not affect cell cycle progression. Together, our data provide an unbiased perspective of the regulation and function of K20 methylation.
Molecular and cellular biology 02/2008; 28(1):468-86. · 6.06 Impact Factor
