Effect of the Medicare Part D coverage gap on medication use among patients with hypertension and hyperlipidemia.

BACKGROUND: Prior studies of the Medicare Part D coverage gap are limited in generalizability and scope. OBJECTIVE: To determine the effect of the coverage gap on drugs used for asymptomatic (antihypertensive and lipid-lowering drugs) and symptomatic (pain relievers, acid suppressants, and antidepressants) conditions in elderly patients with hypertension and hyperlipidemia. DESIGN: Quasi-experimental study using pre-post design and contemporaneous control group. SETTING: Medicare claims files from 2005 and 2006 for 5% random sample of Medicare beneficiaries. PATIENTS: Part D plan enrollees with hypertension or hyperlipidemia aged 65 years or older who had no coverage, generic-only coverage, or both brand-name and generic coverage during the gap in 2006. Patients who were fully eligible for the low-income subsidy served as the control group. MEASUREMENTS: Monthly 30-day supply prescriptions available, medication adherence, and continuous medication gaps of 30 days or more for antihypertensive or lipid-lowering drugs; monthly 30-day supply prescriptions available for pain relievers, acid suppressants, or antidepressants before and after coverage gap entry. RESULTS: Patients with no gap coverage had a decrease in monthly antihypertensive and lipid-lowering drug prescriptions during the coverage gap. Nonadherence also increased in this group (antihypertensives: odds ratio [OR], 1.60 [95% CI, 1.50 to 1.71]; lipid-lowering drugs: OR, 1.59 [CI, 1.50 to 1.68]). The proportion of patients with no gap coverage who had continuous medication gaps in lipid-lowering medication use and antihypertensive use increased by an absolute 7.3% (OR, 1.38 [CI, 1.29 to 1.46]) and 3.2% (OR, 1.35 [CI, 1.25 to 1.45]), respectively, because of the coverage gap. Decreases in use were smaller for pain relievers and antidepressants and larger for acid suppressants in patients with no gap coverage. Patients with generic-only coverage had decreased use of cardiovascular medications but no change in use of drugs for symptomatic conditions. No measures changed in the brand-name and generic coverage groups. Results of sensitivity analyses were consistent with the main findings. LIMITATION: Because this study was nonrandomized, unobserved differences may still exist between study groups. CONCLUSION: The Part D coverage gap was associated with decreased use of medications for hypertension and hyperlipidemia in patients with no gap coverage and generic-only gap coverage. The proposed phasing out of the gap by 2020 will benefit such patients; however, use of low-value medications may also increase. PRIMARY FUNDING SOURCE: Penn-Pfizer Alliance and American Heart Association.

Visualizing the dynamics of EGFR activity and antiglioma therapies in vivo.

Many altered pathways in cancer cells depend on growth factor receptors. In primary malignant gliomas, the amplification/alteration of the epidermal growth factor receptor (EGFR) has been shown to play a significant role in enhancing glioma burden. In an effort to dissect the role of EGFR expression in glioma progression in vivo and evaluate targeted therapies for gliomas, we have genetically engineered glioma cells to visualize the dynamics of EGFR and targeted therapies in real time in vivo. Using engineered lentiviral vectors bearing fusions between EGFR and its exon 2 to 7 deleted variant (EGFRvIII) with green fluorescent protein (GFP) and Renilla luciferase (Rluc), we show that there is a direct correlation between EGFR expression and glioma cell proliferation in the initial stages of glioma progression. To monitor and evaluate EGFR-targeted therapies, we have engineered (a) short hairpin RNAs (shRNA) and (b) clinically used monoclonal antibody, cetuximab. Using EGFR-GFP-Rluc/firefly luciferase (Fluc)-DsRed2 glioma model, we show that both shRNAs and cetuximab result in a considerable reduction in glioma cell proliferation in culture and glioma burden in vivo that can be monitored in real time at a cellular resolution. This study serves as a template to follow the role of growth factor receptor expression in tumor progression and to image therapeutic efficacy of targeted therapies in cancer.

Human breast cancer tumor models: molecular imaging of drug susceptibility and dosing during HER2/neu-targeted therapy.

PURPOSE: To use near-infrared (NIR) optical imaging to assess the therapeutic susceptibility and drug dosing of orthotopic human breast cancers implanted in mice treated with molecularly targeted therapy. MATERIALS AND METHODS: This study was approved by the institutional animal care and use committee. Imaging probes were synthesized by conjugating the human epidermal growth factor receptor type 2 (HER2)-specific antibody trastuzumab with fluorescent dyes. In vitro probe binding was assessed with flow cytometry. HER2-normal and HER2-overexpressing human breast cancer cells were orthotopically implanted in nude mice. Intravital laser scanning fluorescence microscopy was used to evaluate the in vivo association of the probe with the tumor cells. Mice bearing 3-5-mm-diameter tumors were intravenously injected with 0.4 nmol of HER2 probe before or after treatment. A total of 123 mice were used for all in vivo tumor growth and imaging experiments. Tumor fluorescence intensity was assessed, and standard fluorescence values were determined. Statistical significance was determined by performing standard analysis of variance across the imaging cohorts. RESULTS: HER2 probe enabled differentiation between HER2-normal and HER2-overexpressing human breast cancer cells in vitro and in vivo, with binding levels correlating with tumor trastuzumab susceptibility. Serial imaging before and during trastuzumab therapy revealed a significant reduction (P < .05) in probe binding with treatment and thus provided early evidence of successful HER2 inhibition days before the overall reduction in tumor growth was apparent. CONCLUSION: NIR imaging with HER2-specific imaging probes enables evaluation of the therapeutic susceptibility of human mammary tumors and of drug dosing during HER2-targeted therapy with trastuzumab. This approach, combined with tomographic imaging techniques, has potential in the clinical setting for determining patient eligibility for and adequate drug dosing in molecularly targeted cancer therapies.

Multiparameter noninvasive assessment of treatment susceptibility, drug target inhibition and tumor response guides cancer treatment.

New cancer therapies are increasingly molecular-pathway specific. The evaluation of these novel therapies would be greatly facilitated by the development of noninvasive methods to assess multiple tumor cellular and molecular parameters. Using fluorescent probes specific for HER2/neu (AF750-trastuzumab) and apoptosis (Cy5.5-Annexin), we demonstrate a multichannel near infrared molecular imaging approach that yields accurate and early assessment of treatment susceptibility, drug target inhibition and tumor response during HER2-targeted therapy of orthotopic human mammary carcinomas in mice with trastuzumab (Herceptin). This combined approach detects both partial treatment response (tumor growth inhibition without regression) as well as therapeutic resistance before alterations in tumor growth are apparent. Partially responsive tumors exhibit increased Annexin signal when trastuzumab is combined with a cytotoxic agent (paclitaxel), which predicts subsequent tumor regression and suggests that imaging can guide therapy optimization. This multiparametric imaging approach has great potential in the clinical setting for determining patient eligibility, adequate drug dosing and early biological response of molecularly-targeted cancer therapies.

Association of hypertension and hyperglycaemia with socioeconomic contexts in resource-poor settings: the Bangladesh Demographic and Health Survey.

BACKGROUND: Cardiovascular diseases and risk factors are disproportionally concentrated among the socioeconomically disadvantaged in high-income countries; however, this relationship is not well-understood or documented in resource-limited countries. METHODS: We analysed data from the 2011 Bangladesh Demographic and Health Survey to estimate age-, sex- and location-adjusted differences in blood pressure and blood glucose outcomes by categories of a standardized wealth index and education levels. Body mass index (BMI) was examined as a secondary outcome and also assessed as a potential confounder. RESULTS: There was strong evidence that the prevalence of hypertension was higher among Bangladeshi women than among men (33.6% vs 19.6%, P < 0.001), whereas the overall prevalence of hyperglycaemia was 7.1% with no evidence of sex differences. The likelihood of having hypertension was more than double for individuals in the highest vs lowest wealth quintile [odds ratio (OR) for men: 2.82, 95% confidence interval (CI): 2.32-3.44; OR for women: 2.25, 95% CI: 1.90-2.67], and for individuals with the highest level of education attained vs those with no education (OR for men: 2.55, 95% CI: 2.06-3.16; OR for women: 1.42, 95% CI: 0.99-2.03). Likewise, the likelihood of having hyperglycaemia was more than four times higher in the wealthiest compared with the poorest individuals (OR for men: 6.48, 95% CI: 5.11-8.22; OR for women: 4.77, 95% CI: 3.72-6.12), and in individuals with the highest level of education attained vs those with no education (OR for men: 4.68, 95% CI: 3.56-6.15; OR for women: 5.02, 95% CI: 3.30-7.64). There were no appreciable differences in these trends when stratified by geographical location. BMI did not attenuate these associations and exhibited similarly positive associations with education and wealth. CONCLUSIONS: Increasing levels of wealth and educational attainment were associated with an increased likelihood of having hypertension and hyperglycaemia in Bangladesh.

Comparative effectiveness and cost-effectiveness analyses frequently agree on value.

The Patient-Centered Outcomes Research Institute, known as PCORI, was established by Congress as part of the Affordable Care Act (ACA) to promote evidence-based treatment. Provisions of the ACA prohibit the use of a cost-effectiveness analysis threshold and quality-adjusted life-years (QALYs) in PCORI comparative effectiveness studies, which has been understood as a prohibition on support for PCORI's conducting conventional cost-effectiveness analyses. This constraint complicates evidence-based choices where incremental improvements in outcomes are achieved at increased costs of care. How frequently this limitation inhibits efficient cost containment, also a goal of the ACA, depends on how often more effective treatment is not cost-effective relative to less effective treatment. We examined the largest database of studies of comparisons of effectiveness and cost-effectiveness to see how often there is disagreement between the more effective treatment and the cost-effective treatment, for various thresholds that may define good value. We found that under the benchmark assumption, disagreement between the two types of analyses occurs in 19 percent of cases. Disagreement is more likely to occur if a treatment intervention is musculoskeletal and less likely to occur if it is surgical or involves secondary prevention, or if the study was funded by a pharmaceutical company.

Albuterol and levalbuterol use and spending in Medicare beneficiaries with chronic obstructive pulmonary disease.

BACKGROUND: The evidence for the benefits of branded levalbuterol over generic albuterol in patients with chronic obstructive pulmonary disease (COPD) is inconclusive. However, there are significant cost differences between these products. OBJECTIVES: This study examined use and spending on albuterol and levalbuterol in a nationally representative sample of Medicare beneficiaries with COPD enrolled in Part D in 2006. It also examined differences in patient characteristics and use of other COPD drugs among recipients of these 2 short-acting ß-agonists. METHODS: Data were obtained from the 5% Medicare files for 2005-2006 linked to the 2006 Medicare Part D files. The sample consisted of all fee-for-service beneficiaries with COPD enrolled in stand-alone Part D plans in 2006. Patient characteristics and other COPD medication use were compared across albuterol-only users, levalbuterol-only users, and users of both albuterol and levalbuterol. Multinomial logistic regressions were used to identify factors independently associated with levalbuterol use. RESULTS: There were 5.5 times more albuterol users than levalbuterol users in 2006; however, mean annual spending on levalbuterol was 18.6 times higher per user in 2006 than spending on albuterol ($1876 vs $101 per user, respectively). Levalbuterol-only users were more likely to be older than albuterol-only users (mean age: 71.5 vs 68.7 years; P < 0.05), as well as sicker (mean prescription drug hierarchical condition category score: 1.72 vs 1.55; P < 0.05) and residing in the South (67.9% vs 41.6%; P < 0.05). Levalbuterol-only users were more likely to use nebulizer forms covered under Part B than inhaler forms covered under Part D (78.6% vs 26.8%, respectively; P < 0.05), whereas albuterol-only users were more likely to use inhaler forms covered under Part D than nebulizer forms covered under Part B (82.2% vs 33.0%, respectively; P < 0.05). CONCLUSIONS: In this sample of Medicare beneficiaries with COPD enrolled in Part D, mean annual spending in 2006 was significantly higher for levalbuterol than for albuterol. The differences between levalbuterol and albuterol users in terms of patient characteristics, geographic region, and drug formulation/device type, coupled with the inconclusive evidence for efficacy differences in the literature, highlight the need for further comparative clinical and cost-effectiveness studies of these agents.

Systems-level modeling of cancer-fibroblast interaction.

Cancer cells interact with surrounding stromal fibroblasts during tumorigenesis, but the complex molecular rules that govern these interactions remain poorly understood thus hindering the development of therapeutic strategies to target cancer stroma. We have taken a mathematical approach to begin defining these rules by performing the first large-scale quantitative analysis of fibroblast effects on cancer cell proliferation across more than four hundred heterotypic cell line pairings. Systems-level modeling of this complex dataset using singular value decomposition revealed that normal tissue fibroblasts variably express at least two functionally distinct activities, one which reflects transcriptional programs associated with activated mesenchymal cells, that act either coordinately or at cross-purposes to modulate cancer cell proliferation. These findings suggest that quantitative approaches may prove useful for identifying organizational principles that govern complex heterotypic cell-cell interactions in cancer and other contexts.