Initiation of Triple Therapy with Multiple Inhalers in Chronic Obstructive Pulmonary Disease: An Analysis of Treatment Patterns from a U.S. Retrospective Database Study.

BACKGROUND: Evidence suggests that real-world treatment patterns of chronic obstructive pulmonary disease (COPD) do not always follow evidence-based treatment recommendations such as those of the Global Initiative for Chronic Obstructive Lung Disease, which recommends treatment escalation based on disease progression. This U.S. database study evaluated treatment patterns in patients with COPD, focusing on time to initiation of triple therapy using multiple inhalers. OBJECTIVES: To (a) estimate time from diagnosis to initiation of long-acting muscarinic antagonist (LAMA) monotherapy, inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) dual therapy, or LAMA/LABA dual therapy; (b) estimate time to initiation of triple therapy from LAMA monotherapy and ICS/LABA or LAMA/LABA dual therapies; and (c) estimate the likelihood of patient progression to triple therapy. METHODS: This study was a retrospective analysis of patients with COPD newly started on LAMA monotherapy, ICS/LABA, or LAMA/LABA therapy between July 1, 2010, and March 31, 2013, as identified in Humana's research database. Patients who were fully insured with commercial or Medicare Advantage insurance plans and were aged ≥ 40 years at index with at least 1 hospitalization, 1 emergency department, or 1 medical office visit claim with a COPD diagnosis in the pre-index year were included in the analysis. Time from diagnosis to initiation of index therapy and time to triple therapy after index therapy were assessed. Multivariable logistic regression models were used to estimate the likelihood of progression to triple therapy. RESULTS: Of 13,541 patients with a confirmed diagnosis of COPD, 4,000 received LAMA monotherapy; 8,207 received ICS/LABA therapy; and 77 received LAMA/LABA therapy at index; mean time (± SD) from COPD diagnosis to initiation of triple therapy was 178 (± 134) days, 185 (± 130) days, and 252 (± 124) days, respectively. During the study, 28% (n = 1,130) of patients receiving LAMA monotherapy and 20% (n = 1,647) of patients receiving dual therapy (ICS/LABA, n = 1,615; LAMA/LABA, n = 32) progressed to triple therapy. Of the patients who progressed to triple therapy, 63% and 57% of patients receiving monotherapy and dual therapy, respectively, progressed in the 12 months after the index date. In the 12 months before initiation of triple therapy, approximately 50% of patients in the LAMA monotherapy, ICS/LABA, and LAMA/LABA therapy groups had an exacerbation. In the multivariable analysis, discontinuation of therapy, smoking history, and concomitant use of xanthenes and short-acting beta2-agonists were significant predictors of progression from index therapy to triple therapy. CONCLUSIONS: Approximately 25% of patients with COPD progressed to triple therapy within 12 months of initiating treatment with monotherapy or dual therapy. Exacerbations were reported in only 50% of these patients, indicating that the other 50% may have escalated to triple therapy for other reasons. Treatment discontinuation, smoking history, the use of a LAMA, and concomitant medication use were significant predictors of progression to triple therapy. DISCLOSURES: This study was a GlaxoSmithKline-sponsored collaborative research study (HO-14-16145). GlaxoSmithKline funded this study and had a role in study design, data analysis, data interpretation, and writing of this report. Stemkowski is a paid employee of Comprehensive Health Insights, which is a wholly owned subsidiary of Humana and was contracted to conduct the study. No funding was provided to Comprehensive Health Insights for manuscript development. At the time of the study, Lane and Tao were paid employees of Comprehensive Health Insights. Stanford is an employee of and stockholder in GlaxoSmithKline.

Does site-of-care for oncology infusion therapy influence treatment patterns, cost, and quality in the United States?

BACKGROUND: The increase in hospital acquisition of community oncology clinics in the US has led to a shift in the site-of-care (SOC) for infusion therapy from the physician office (PO) to the hospital outpatient (HO) setting. OBJECTIVE: To investigate differences by SOC in treatment patterns, quality, and cost among patients with cancer undergoing first-line infusion therapy. RESEARCH DESIGN AND METHODS: This retrospective analysis identified adult patients from Humana medical claims who initiated infusion therapy from 2008-2012 for five common cancer types in which infusion therapy is likely, including early stage breast cancer; metastatic breast, lung, and colorectal cancers; and non-Hodgkin's lymphoma or chronic lymphocytic leukemia. Differences by SOC in first-line treatment patterns and quality of care at end-of-life, defined as infusions or hospitalizations 30 days prior to death, were evaluated using Wilcoxon-Rank Sum and Chi-square tests where appropriate. Differences in cost by SOC were evaluated using risk-adjusted generalized linear models. MAIN OUTCOME MEASURES: Treatment patterns, quality of care at end of life, healthcare costs. RESULTS: There were differences in duration of therapy and number of infusions for some therapy regimens by SOC, in which patients in the HO had shorter duration of therapy and fewer infusions. There were no differences in quality of care at end-of-life by SOC. Total healthcare costs were 15% higher among patients in HO ($55,965) compared with PO ($48,439), p < .0001. LIMITATIONS: Analyses was restricted to a claims-based population of cancer patients within a health plan. CONCLUSION: This study, in an older, predominantly Medicare Advantage oncology cohort, found differences by SOC in treatment patterns and cost, but not quality. Where differences were found, patients receiving care in the HO had shorter duration of therapy and fewer infusions for specific treatment regimens, but higher healthcare costs than those treated in a PO.

Impact of Out-of-Pocket Cost on Herpes Zoster Vaccine Uptake: An Observational Study in a Medicare Managed Care Population.

Herpes zoster (HZ) vaccination is approved for adults aged 50+ for the prevention of HZ, but it is underutilized. The objective of this study was to evaluate the association between out-of-pocket cost and HZ vaccine utilization. Adults aged 65 or older enrolled for at least 12 months in Medicare Advantage/Part D (MAPD) and Medicare Part D only (PDP) plans from 1 January 2007 to 30 June 2014 were selected. Abandonment was defined as a reversed claim for HZ vaccine with no other paid claim within 90 days. Out-of-pocket costs used were actual amounts recorded in the claim. Overall, the HZ vaccine abandonment rate was 7.3%. Mean out-of-pocket costs were higher for individuals who abandoned versus those who did not ($88 (±$55) versus $80 (± $49)). Logistic regression indicated individuals with out-of-pocket costs of $80⁻$90 were 21% more likely (OR = 1.21, 1.16⁻1.27 95% CI), and those with out-of-pocket costs >$90 were 90% more likely (OR = 1.90, 1.85⁻1.96 95% CI) to abandon than those with out-of-pocket costs <$80. The models also suggested that socioeconomic, racial, and ethnic disparities in vaccine abandonment existed. Different vaccine targeting efforts and pharmacy benefit design strategies may be needed to increase use, improve adherence, and minimize disparities.

Patterns of Care in Patients with Metastatic Renal Cell Carcinoma Among a U.S. Payer Population with Commercial or Medicare Advantage Membership.

BACKGROUND: Several systemic therapies are now approved for first- and second-line treatment of metastatic renal cell carcinoma (mRCC). Although the National Comprehensive Cancer Network (NCCN) guidelines offer physicians evidence-based recommendations for therapy, there are few real-world studies to help inform the utilization of these agents in clinical practice. OBJECTIVES: To (a) describe the patterns of use associated with systemic therapies for mRCC among Humana members in the United States diagnosed with mRCC, (b) assess consistency with the NCCN guidelines for treatment, and (c) to describe the initial first-line therapy regimen by prescriber specialty and site of care. METHODS: This was a retrospective study using Humana's claims database of commercially insured patients and patients insured by the Medicare Advantage Prescription Drug plan. The study period was from January 1, 2007, to December 31, 2013. Patients with mRCC were identified by ICD-9-CM codes 189.0/189.1 and 196.xx to 199.xx; all patients were between 18 and 89 years of age, had received systemic therapy for their disease, and were followed up for 180 days. Outcome measures included choice of initial systemic therapy, starting and ending doses, first-line treatment persistence and compliance, and choice of second-line therapy. Persistence was measured using time to discontinuation of first-line therapy and proportion of days covered (PDC; the ratio of [total days of drug available minus days of supply of last prescription] to [last prescription date minus first prescription date]). Compliance was measured using the medication possession ratio (MPR; the ratio of [total days supply minus days supply of last prescription] to [last prescription date minus first prescription date]). RESULTS: A total of 649 patients met all inclusion criteria; 109 were insured by commercial plans and 540 were insured by Medicare. The mean ± SD age of patients was 68.6 ± 9.4 years, and 68.6% were male; Medicare patients were older than commercial patients (71.7 ± 7.4 vs. 56.6 ± 9.1 years, respectively; P < 0.001). The most common comorbidities among the patient population were hypertension, hyperlipidemia, diabetes, and heart disease. The majority of patients (68.6%) received an oral tyrosine kinase inhibitor (TKI) as their first line of therapy: 43.9% received sunitinib, 14.0% received sorafenib, 10.0% received pazopanib, and 0.6% received axitinib. Mean ± SD time to discontinuation of first-line TKI treatment was 169.1 ± 29.5 days with sunitinib, 160.3 ± 41.1 days with pazopanib, and 160.1 ± 41.4 days with sorafenib. Other first-line therapies included inhibitors of mammalian target of rapamycin (mTOR) (19.7%) and the antivascular endothelial growth factor agent bevacizumab (9.4%). Among patients receiving mTOR inhibitors, 14.8% were started on temsirolimus and 4.9% were started on everolimus. The median starting and ending doses were the same for each drug except for sunitinib. Mean ± SD times to discontinuation of temsirolimus, everolimus, and bevacizumab were 171.8 ± 26.2, 137.0 ± 62.2, and 150.8 ± 56.0 days, respectively. Persistence on first-line regimen as measured by PDC was high (PDC ≥ 80%) for 89% of oral therapies and 77% of injectable therapies; first-line compliance was high (MPR ≥ 80%) for 77% of oral therapies and 68% of injectables. Among patients who received second-line therapy, the most common regimen was everolimus (29.2%), followed by bevacizumab (19.8%), temsirolimus (15.6%), and sunitinib (13.6%). Specialty codes obtained from the database provider identified internal medicine specialists and oncologists as the most common prescribers of TKIs and mTOR inhibitors. CONCLUSIONS: Patterns of use were similar for each of the prescribed systemic treatments for mRCC, and the majority of patients were highly persistent and compliant with first-line therapies. Time to treatment discontinuation was slightly longer with oral agents compared with injectable drugs.

Antihypertensive medication adherence and subsequent healthcare utilization and costs.

OBJECTIVES: To evaluate the relationship between adherence to antihypertensive medications (AHMs) and subsequent hospitalizations, emergency department (ED) visits, and costs of care. STUDY DESIGN: Retrospective analysis of a national pharmacy benefits database of deidentified pharmacy and medical claims among patients with a diagnosis of hypertension. Adherence was estimated using the medication possession ratio (MPR). METHODS: Multivariate logistic and 2-part general linear models were estimated to study the relationship between adherence level (estimated by the MPR) and subsequent association with healthcare costs and cardiovascular (CV)-related hospitalizations and ED visits. RESULTS: We identified 625,620 patients with at least 2 claims for AHMs and divided them into 3 cohorts based on year 1 MPR of less than 60% (62,388 patients with low adherence), 60% to 79% (96,226 patients with moderate adherence), and 80% or higher (467,006 patients with high adherence). Patients with high adherence to AHMs were more likely to be older and male, have higher chronic disease scores and lower AHM copayments, and fill a greater percentage of prescriptions by mail order. Year 2 total mean (SD) adjusted healthcare costs were significantly lower for patients with an MPR of 80% or higher ($7182 [$27]) vs 60% to 79% ($7560 [$59]) or less than 60% ($7995 [$73]) (P <.001 for both). In addition, patients with low or moderate adherence had higher age- and sex-adjusted odds of CV-related hospitalizations (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.25-1.41) and ED visits (OR, 1.45; 95% CI, 1.33-1.58) (P <.001 for both). CONCLUSION: Adherence to AHMs is associated with significantly lower total healthcare costs and with significantly lower odds of CV-related hospitalizations and ED visits.

Transforming growth factor-beta1 regulates fibronectin isoform expression and splicing factor SRp40 expression during ATDC5 chondrogenic maturation.

Fibronectin (FN) isoform expression is altered during chondrocyte commitment and maturation, with cartilage favoring expression of FN isoforms that includes the type II repeat extra domain B (EDB) but excludes extra domain A (EDA). We and others have hypothesized that the regulated splicing of FN mRNAs is necessary for the progression of chondrogenesis. To test this, we treated the pre-chondrogenic cell line ATDC5 with transforming growth factor-beta1, which has been shown to modulate expression of the EDA and EDB exons, as well as the late markers of chondrocyte maturation; it also slightly accelerates the early acquisition of a sulfated proteoglycan matrix without affecting cell proliferation. When chondrocytes are treated with TGF-beta1, the EDA exon is preferentially excluded at all times whereas the EDB exon is relatively depleted at early times. This regulated alternative splicing of FN correlates with the regulation of alternative splicing of SRp40, a splicing factor facilitating inclusion of the EDA exon. To determine if overexpression of the SRp40 isoforms altered FN and FN EDA organization, cDNAs encoding these isoforms were overexpressed in ATDC5 cells. Overexpression of the long-form of SRp40 yielded an FN organization similar to TGF-beta1 treatment; whereas overexpression of the short form of SRp40 (which facilitates EDA inclusion) increased formation of long-thick FN fibrils. Therefore, we conclude that the effects of TGF-beta1 on FN splicing during chondrogenesis may be largely dependent on its effect on SRp40 isoform expression.

Transforming growth factor-beta1 (TGF-beta1) regulates ATDC5 chondrogenic differentiation and fibronectin isoform expression.

Regulated splicing of fibronectin (FN) occurs during the mesenchymal to chondrocyte transition and ultimately results in the relative enrichment of an extra domain B (EDB) exon-containing FN isoform with the suggestion that FN isoforms may play a functional role in chondrogenesis. Promotion of chondrogenesis can also be achieved by treatment with transforming growth factor-beta (TGF-beta), which also regulates FN isoform expression. We have examined the effects of TGF-beta treatment on the assumption of the chondrogenic phenotype in the teratoma-derived cell line ATDC5 and tested whether these effects on chondrogenesis are paralleled by appropriate changes in FN isoform expression. ATDC5 cells were maintained in a pre-chondrogenic state and, in this state, treated with 10 ng/ml TGF-beta. The cells started to elaborate a matrix rich in sulfated proteoglycans, such that within the first 12 days of culture, TGF-beta1 treatment appeared to slightly accelerate early acquisition of an Alcian blue-stained matrix, and caused a dose- and time-dependent decrease in collagen type I expression; changes in collagen type II expression were variable. At later times, cells treated with TGF-beta became indistinguishable from those of the controls. Interestingly, TGF-beta treatment caused a significant dose- and time-dependent decrease in the proportion of FN containing the extra domain A (EDA) and the EDB exons. These data suggest that TGF-beta induces the early stages of chondrogenic maturation in this pre-chondrogenic line and that TGF-beta treatment increases expression of FN isoforms that lack the EDA and EDB exons.

Linking hematopoiesis to endochondral skeletogenesis through analysis of mice transgenic for collagen X.

Each skeletal element where marrow develops is first defined by a hypertrophic cartilage blueprint. Through programmed tissue substitution, the cartilaginous skeletal model is replaced by trabecular bone and marrow, with accompanying longitudinal tissue growth. During this process of endochondral ossification, hypertrophic cartilage expresses a unique matrix molecule, collagen X. Previously we reported that transgenic mice with dominant interference collagen X mutations develop variable skeleto-hematopoietic abnormalities, manifested as growth plate compressions, diminished trabecular bone, and reduced lymphatic organs (Nature 1993, 365:56). Here, histology and flow cytometry reveal marrow hypoplasia and impaired hematopoiesis in all collagen X transgenic mice. A subset of mice with perinatal lethality manifested the most severe skeletal defects and a reduction of marrow hematopoiesis, highlighted by a lymphocyte decrease. Thymic reduction is accompanied by a paucity of cortical immature T cells, consistent with the marrow's inability to replenish maturing cortical lymphocytes. Diminished spleens exhibit indistinct lymphatic nodules and red pulp depletion; the latter correlates with erythrocyte-filled vascular sinusoids in marrows. All mice display reduced B cells in marrows and spleens, and elevated splenic T cells. These hematopoietic defects underscore an unforeseen link between hypertrophic cartilage, endochondral ossification, and establishment of the marrow microenvironment required for blood cell differentiation.