Impact of the COVID-19 pandemic on new starts to oral oncology medications in the US.

INTRODUCTION: The COVID-19 pandemic has had a significant impact on healthcare delivery. Although others have documented the impact on new cancer diagnoses, trends in new starts for oncology drugs are less clear. We examined changes in new users of oral oncology medications in the US following COVID-19 stay-at-home orders in 2020 compared to prior years. METHODS: We examined prescription data for members enrolled with a national pharmacy benefits manager in the US from January 1-October 31 of 2018, 2019, and/or 2020. This is a retrospective, observational study comparing new users per 100,000 members per month for all oral oncology drugs, and separately for breast, lung, and prostate cancer, leukemia, and melanoma oral drugs. We performed a difference-in-differences analysis for change in new users from pre-period (prior to pandemic-induced disruption, January-March), to post-period (following pandemic-induced disruption, April-October), between 2020 and 2019, and 2020 and 2018. RESULTS: New oral oncology drug users per 100,000 members per month declined by an additional 11.3% in the 2020 post-period compared to 2019 (p = 0.048). New oral breast cancer drug starts declined by an additional 14.0% in the 2020 post-period compared to 2019 (p = 0.040). Similar but non-significant trends were found between 2020 and 2018. No significant differences were found between post-period monthly new starts of leukemia, melanoma, lung or prostate cancer disease-specific oral medications. CONCLUSIONS: Long-term implications of delays in cancer treatment initiation are unclear, although there is concern that patient outcomes may be negatively impacted.

Trends in add-on medications following metformin monotherapy for type 2 diabetes.

BACKGROUND: Although metformin is generally universally recommended as a first-line pharmacologic therapy for most people living with type 2 diabetes, second-line and third-line choices can require a tailored approach to achieve optimal blood glucose and glycated hemoglobin levels. OBJECTIVE: To examine national trends in second- and third-line antihyperglycemic medications following metformin monotherapy, comparing 2015 and 2019. METHODS: This retrospective cohort analysis of deidentified pharmacy claims from a large national pharmacy benefits manager from January 1, 2015, to December 31, 2015, and again in January 1, 2019, to December 31, 2019, included adults (aged ≥ 18 years) continuously enrolled in commercial or Medicare insurance plans who filled an index metformin prescription in either year. Proportions of patients by second-line and third-line antihyperglycemic class were calculated. RESULTS: Second-line use of sulfonylureas (-10.1%; P < 0.001), combination drugs (-3.0%; P < 0.001), and dipeptidyl peptidase-4 inhibitors (-2.0%; P = 0.031) significantly declined, whereas second-line use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) (+4.9%; P < 0.001) and glucagon-like peptide-1 receptor agonists (GLP-1Ras) (+10.0%; P < 0.001) significantly increased. Similarly, third-line use of sulfonylureas declined (-5.5%; P = 0.005), whereas third-line use of SGLT2is (+3.4%; P = 0.005) and GLP-1RAs (+8.3%; P < 0.001) increased. Similar trends between 2015 and 2019 were found in commercial and Medicare subgroups. Among all groups in 2015 compared with 2019, sulfonylureas were the most prescribed second-line class and insulins the most common third-line class. Although SGLT2i and GLP-1RA together represented more than one-third of second-line and third-line prescriptions for commercially insured patients in 2019 (34.3% and 35.0%, respectively), these classes were less frequently prescribed in the Medicare subgroup (18% and 25.6%, respectively). CONCLUSIONS: This report provides updated second-line and third-line antihyperglycemic medication prescribing trends in the United States, which suggests that evidence-based guidelines are being used in practice to prevent complications and individualize diabetes care. DISCLOSURES: Ms Swart and Drs Peasah and Good are employed by UPMC Health Plan. Dr Neilson was employed by UPMC Health Plan at the time of the study. Drs Munshi and Henderson were employed by Evernorth at the time of the study.

Twelve month oral contraceptive pill prescriptions: Role of policy mandates on utilization.

Recent studies have suggested that extended duration oral contraceptive pills (OCP), such as the 12-month duration, have a positive impact on pregnancy rates but negative impact on pill wastage. Several states have since been mandating health plans to offer extended duration OCP as an option for women. The objective of the study was to evaluate the impact of these mandates on utilization of extended duration OCPs. Using claims data of a large pharmacy benefit manager for commercially insured women from 2018 to 2019, use, adherence, continuity, and wastage of OCPs by women dispensed one-month only, three-months only, 6 or 12-months only, and other months (which includes other months and mixed duration OCP) was retrospectively analyzed. OCP dispensed by year, and adherence, continuity, wastage over a 15-month period were summarized using Chi square and ANOVA. There were 874,420 and 875,914 women in this study in 2018 and 2019 respectively. Of these, 34% were from states with the mandate (SWM). Most women filled the one-month and three-month duration, with very low overall 6 or 12-month duration claims. Proportion of utilizers of 6 or 12- month duration was higher in SWM than in those without, although differences in absolute rates were very low. Patients with OCP discontinuation, gaps ≥7 and 14 days, were fewer among those filling 6 or 12-month duration but conversely, wastage was higher in this group compared to those filling one or three-month duration. Our findings suggest that, among commercially insured women, extended duration OCP mandates have so far not had much influence on use of 6 or 12-month duration OCP prescriptions.

Identifying outcome measures for atrial fibrillation value-based contracting using the Delphi method.

BACKGROUND: Value-based contracts that tie payments for pharmaceuticals to predefined outcomes aim to promote value through shared risk and aligned incentives between manufacturers and payers. METHODS: We conducted a Delphi study among diverse stakeholders (patients, providers, payers, pharmacy benefits managers, pharmaceutical company representatives) to identify top meaningful outcomes for inclusion in value-based contracts for atrial fibrillation medications. The final panel (n = 55) rated the importance of each outcome on a 5-point Likert scale and selected their top 3 most meaningful outcomes. Non-patient participants rated the feasibility of collecting each outcome on a 5-point Likert scale. Consensus was defined as ≥75% agreement (Likert scores ≥4/5 or selection of an outcome as most meaningful). Differences between stakeholder groups were examined using Fisher's Exact Test. RESULTS: Consensus was achieved for importance of 10 outcomes (Likert scale), where "preventing stroke or mini-stroke" reached 100% agreement (55/55). Eighty-one percent (44/54) of participants selected "preventing stroke or mini-stroke" as the most meaningful outcome (rank order question). The measures rated as most feasibly collected were "reducing hospitalizations" (97%, 36/37) followed by "preventing stroke or mini-stroke" and "reducing emergency department visits" (both 92%, 34/37). There were statistically significant differences between patients and non-patients [0% (0/17) vs 22% (8/37), P = 0.047] and patients and providers [0% (0/17) vs 39% (7/18), P = 0.008] in selection of "improving health-related quality of life" as a most meaningful outcome. CONCLUSIONS: These findings will inform the design of atrial fibrillation value-based pharmaceutical contracts and provide additional insight into preferences for outcomes which could be used to improve the quality of atrial fibrillation care.

Real-World Use and Outcomes of Oral Antiplatelets Among Patients with Acute Coronary Syndrome: A Retrospective Cohort Study.

BACKGROUND: Acute coronary syndrome (ACS)-related readmission is an important hospital quality measure. Medication management therapy, especially adherence to antiplatelet agents post discharge, could play an important role in reducing readmission rates. Newer agents such as ticagrelor and prasugrel have been shown, in randomized control trials, to have superior effectiveness to cardiovascular outcomes compared to clopidogrel, but they are more expensive and have more common adverse events such as bleeding and dyspnea. OBJECTIVE: We compared real-world readmission rates and adherence to antiplatelet agents among patients who initiated these agents post discharge. METHODS: This was a retrospective cohortstudy of patients with an index ACS-related hospitalization between 1 July 2017 and 31 December 2018. Using integrated pharmacy and medical claims data from a large national pharmacy benefits manager for commercially insured adults aged ≥ 18 years, we compared ACS-related readmission and medication adherence (as medication possession ratio (MPR)) among the three agents. ANOVA and logistic regression, controlling for demographics such as age, gender, and Charlson Comorbidity Index, were used to estimate any association between the agents and 365-day readmission rates. RESULTS: Of the 948 eligible patients, 86, 342, and 520 were initiated on prasugrel, ticagrelor, and clopidogrel (PTC), respectively. There were 4.7%, 5.3%, and 8.5% readmissions rates in the PTC cohorts, respectively, but these were not statistically significant in either the ANOVA or the logistic regression analyses. MPR was highest in the ticagrelor (88.1%) cohort, followed by the prasugrel (79.1%) and clopidogrel (76.4%) cohorts. CONCLUSION: Ticagrelor cohort had the highest medication adherence. Clopidogrel cohort had the highest readmission rate but the difference with the other cohorts was statistically insignificant.

Changes in Type 2 Diabetes Medication Utilization and Costs in the United States, 2014-2019.

OBJECTIVE: The objective of this study was to describe national changes in utilization and associated costs of antidiabetic medications in the United States from 2014 to 2019, across different drug classes and insurance plans. RESEARCH DESIGN AND METHODS: This retrospective, cross-sectional study examined administrative claims from a large national pharmacy benefits manager from January 1, 2014, to December 31, 2019. Patients aged 18 years and above enrolled in commercial, Medicare, or Medicaid health plans who filled ≥1 prescription claim for an antidiabetic medication(s) during the 6-year period were included. Utilization was examined as the total number of 30-day adjusted prescription fills per user per month (PUPM). Gross costs were calculated as the sum of plan costs (net of rebates) and member out-of-pocket costs. Differences in mean utilization and costs PUPM between 2014 and 2019 for each medication class were calculated. RESULTS: The final analytic sample increased from 745,290 patients in 2014 to 1,596,006 in 2019. Antidiabetic medication utilization increased by 8.8% from 2014 to 2019, driven by increases in sodium-glucose cotransporter 2 inhibitor (48.7%; P<0.001), glucagon-like peptide 1 receptor agonist (11.8%; P<0.001), insulin (8.1%; P<0.001), and metformin (2.9%; P<0.05) utilization. Average costs PUPM rose 47.5% (P<0.001), from $126.52 in 2014 to $186.58 in 2019. Sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and combination drugs contributed significantly to these increased costs, with 6-year cost differences of 57.3%, 46.9%, and 47.2%, respectively (all P<0.001). CONCLUSION: Our study demonstrates a shift in antidiabetic medication class utilization from 2014 to 2019, where associated costs net of rebates significantly increased to a disproportionately greater extent than the significant increase in utilization PUPM.

Health care utilization and costs associated with switching from DPP-4i to GLP-1RA or SGLT2i: an observational cohort study.

BACKGROUND: Because of improved clinical outcomes, recent American Diabetes Association guidelines recommend the use of newer antidiabetic agents-glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i)-by those with cardiovascular disease. It is unclear, however, how switching to these newer agents affects health care utilization and costs. OBJECTIVE: To compare health care utilization and costs between users of dipeptidyl peptidase-4 inhibitors (DPP-4i) who switch to GLP-1RA or SGLT2i and nonswitchers. METHODS: We used claims data from a large pharmacy benefit manager. Patients included were commercially insured adults with type 2 diabetes and a prescription claim for DPP-4i in 2016 or 2017. Using propensity score methods, we matched patients who switched to SGLT2i or GLP-1RA with those who remained on DPP-4i. Among matched samples, we conducted multivariable negative binomial regression to examine differences in the incidence of inpatient and emergency room (ER) visits and generalized linear regression to examine differences in health care costs. RESULTS: Among 47,953 patients who used DPP-4i in 2016 and 2017, 507 switched to SGLT2i and 808 switched to GLP-1RA. Propensity score matching of 1:6 resulted in 3,042 nonswitchers/507 switchers for the SGLT2i cohort and 4,848 nonswitchers/808 switchers for the GLP-1RA cohort. Switchers to SGLT2i experienced a 39% reduction (incidence rate ratio [IRR] = 0.61, 95% CI = 0.38-0.96), and GLP-1RA switchers experienced a 29% reduction (IRR = 0.71, 95% CI = 0.52-0.97) in inpatient hospitalizations. ER visit rates did not differ significantly between switchers and nonswitchers. Switchers to SGLT2i did not have statistically significant differences in medical or pharmacy costs compared with DPP-4i users, while switchers to GLP-1RA had significantly higher total pharmacy costs (adjusted difference of $2,453.10, 95% CI = $1,837.20-$3,069.00). CONCLUSIONS: Switching from DPP-4i to GLP-1RA or SGLT2i was associated with fewer hospitalizations; however, higher pharmacy costs may outweigh savings from reduced hospitalizations, especially for GLP-1RAs. As newer diabetes guidelines steer specific populations to these drug classes, it is important to optimize drug pricing to realize their true value. DISCLOSURES: No outside funding supported this study. Neilson, Good, Swart, and Huang are employees of UPMC Center for Value-Based Pharmacy Initiatives and High-Value Care. Parekh reports employment at UPMC until July 2019. Munshi and Henderson are employed by Express Scripts. Newman has no disclosures to report.

Impact of Marijuana Legalization on Opioid Utilization in Patients Diagnosed with Pain.

BACKGROUND: Given efforts to reduce opioid use, and because marijuana potentially offers a lower-risk alternative for treating chronic pain, there is interest in understanding the public health impact of marijuana legalization on opioid-related outcomes. OBJECTIVE: Assess the impact of recreational and medical marijuana legalization on opioid utilization among patients receiving pharmacotherapy for pain. DESIGN: Retrospective claims-based study of commercially insured patients continuously eligible for pharmacy and medical benefits from July 8, 2014 to June 30, 2017. Index pain prescription period was defined between January 8, 2015 and June 30, 2015, and longer-term opioid use examined during 2-year follow-up. Marijuana state policy on July 1, 2015, was assigned: none; medical only; or medical and recreational. PARTICIPANTS: Patients aged 18-62 without cancer diagnosis. MAIN MEASURES: Patient receiving (1) opioid at index; (2) > 7 days' supply of index opioid; (3) opioid during follow-up; and (4) ≥ 90 days' opioid supply during follow-up. Multivariable regression assessed associations between opioid utilization and state marijuana policy, adjusting for age, gender, overall disease burden, mental health treatment, concomitant use of benzodiazepine or muscle relaxant, and previous pain prescription. KEY RESULTS: Of 141,711 patients, 80,955 (57.1%) resided in states with no policy; 56,494 (39.9%) with medical-only; and 4262 (3.0%) with medical and recreational. Patients in states with both policies were more likely to receive an index opioid (aOR = 1.72, 95% CI = 1.61-1.85; aOR = 1.90, 95% CI = 1.77-2.03; P < 0.001) but less likely to receive > 7 days' index supply (aOR = 0.84, 95% CI = 0.77-0.91; aOR = 0.76, 95% CI = 0.70-0.83; P < 0.001) than patients in states with no policy or medical-only, respectively. Those in states with both policies were more likely to receive a follow-up opioid (aOR = 1.87, 95% CI = 1.71-2.05; aOR = 2.20, 95% CI = 2.01-2.42; P < 0.001) than those in states with no policy or medical-only, respectively, and more likely to receive ≥ 90 cumulative follow-up opioid days' supply (aOR = 1.18, 95% CI = 1.07-1.29; P < 0.001) than those in states with no policy. CONCLUSIONS: Our analysis does not support the supposition that access to marijuana lowers use of chronic opioids for pain.

Using the Delphi method to identify meaningful and feasible outcomes for pharmaceutical value-based contracting.

In an effort to demonstrate measurable value of pharmaceuticals in the United States, many payers and drug manufacturers have entered into value-based purchasing contracts that link payment for prescription medications to patient outcomes, creating shared risk between the 2 entities. These agreements have emerged as part of a larger movement within the health care landscape to transition away from volume-based payment models and towards value-based designs that promote high-quality and affordable care. Key to the success of pharmaceutical value-based contracting is agreement on meaningful and measurable outcomes that reflect drug performance. Traditional value-based contracts are developed by pharmaceutical companies and payers and may not reflect values of other important stakeholders, such as patients, providers, and employers (when applicable). One approach to more effectively align the interests of all key stakeholders and to maximize the effect and transparency of value-based pharmaceutical contracts is to use the validated Delphi surveying technique, which can gather information and build stakeholder consensus on key elements before contract development. In this Viewpoints article, we describe our experience conducting Delphi studies in 5 disease contexts to inform pharmaceutical value-based contract development, including insights learned and practical considerations for real-world application. In addition, we outline advantages to using this validated consensus-building tool to solicit vital and underrepresented stakeholder input, foster transparency in the contract development process, and promote shared learning for future value-based initiatives. DISCLOSURES: No outside funding supported this project. All authors are or were employed by UPMC Health Plan at the time of this study and have no other disclosures to declare.

Identifying Outcome Measures for Migraine Value-Based Contracting Using the Delphi Method.

OBJECTIVE: To identify meaningful migraine outcome measures among key stakeholders to inform value-based contracts for migraine medications. BACKGROUND: Value-based contracts linking medication payments to predefined performance metrics aim to promote value through aligned incentives and shared risk between manufacturers and payers. The emergence of new and expensive pharmaceuticals for migraine presents an opportunity for value-based contract development. However, uncertainty remains around which outcomes are most meaningful to all migraine stakeholders. METHODS: This study utilized a Delphi survey to incorporate views from 82 stakeholders, including patients (n = 21), providers (n = 23), payers (n = 10), employers (n = 18), and pharmaceutical company representatives (n = 10). A list of 15 migraine-related outcomes was created from a literature review and subject matter expert consultation. Stakeholders reported on the value of these outcomes through a 5-point Likert scale and selection of their top 3 most meaningful outcomes. All participants except patients and employers also used a 5-point Likert scale to rate the feasibility of collecting each outcome measure. Consensus was defined as ≥75% agreement on the importance and feasibility of an outcome (Likert scores ≥4/5 or selection of an outcome as most meaningful). RESULTS: After 2 rounds, consensus was achieved for importance of 9 outcomes on the Likert scale. "Decrease in migraine frequency" reached 100% agreement (82/82), followed by "increased ability to resume normal activities" (96%, 79/82). When asked to choose the 3 most meaningful outcomes, stakeholders selected "decrease in migraine frequency" (88%, 72/82) followed by "decrease in migraine severity" (80%, 66/82). The 2 measures rated as most feasibly collected were "decrease in emergency department/urgent care visits" (95%, 40/42) and "decrease in migraine frequency" (90%, 38/42). There were statistically significant differences between non-patient and patient stakeholders in selection of "decrease in emergency department/urgent care visits" [20% (12/61) vs 0% (0/21), P = .031]; and employer and patient stakeholders in selection of "decrease in work days missed" [44% (8/18) vs 5% (1/21), P = .006] and "decrease in emergency department/urgent care visits" [22% (4/18) vs 0% (0/21), P = .037] as most meaningful outcomes. CONCLUSIONS: The measures "decrease in migraine frequency" followed by "decrease in migraine severity" were identified as top priority migraine outcome measures.

Determination of Multiple Sclerosis Indicators for Value-Based Contracting Using the Delphi Method.

BACKGROUND: Value-based contracts link medication payments to performance measures with the ultimate goal of lowering costs while improving patient outcomes. Previous multiple sclerosis (MS) value-based contracts have focused on indicators easily collected from claims or electronic health record data as their value-based outcomes, even though numerous other MS clinical indicators of interest exist. Uncertainty remains regarding which MS indicators are most meaningful to all stakeholders affected by a value-based contract. OBJECTIVE: To identify meaningful MS indicators among key stakeholders for the purpose of informing a value-based contract for MS medications. METHODS: Using a modified Delphi method, we surveyed 26 diverse stakeholders, including 8 patients and caregivers; 9 providers (neurologists, nurses, physician assistants, and specialty pharmacists); 2 pharmaceutical company representatives; 5 payers; and 2 pharmacy benefits managers. A list of 12 MS indicators was created from subject matter expert consultation and a literature review. All stakeholders reported on the meaningfulness and value of these 12 indicators through a 5-point Likert scale and forced selection of the 3 most meaningful indicators. All nonpatient stakeholders were additionally surveyed on collection feasibility of the same 12 indicators using a 5-point Likert scale. We defined consensus as ≥ 75% agreement on the meaningfulness and feasibility of an indicator (Likert scores 4 or 5). We performed a Fisher's exact test to assess differences between nonpatient and patient stakeholder rankings of indicators. RESULTS: Consensus was reached for at least 1 indicator for all questions after 2 rounds. "Worsening physical disability" and "functional impairment" achieved 92% agreement on a Likert-scale question assessing indicator value, and 100% of participants selected "worsening physical disability" when asked to choose the 3 most meaningful indicators. "MS flares requiring an emergency department visit" and "MS flares requiring inpatient admission" were rated as the 2 most feasibly collected indicators (both received 89% agreement). CONCLUSIONS: Using the Delphi method, we identified that disability and functional impairment are meaningful MS indicators to diverse stakeholders. These findings support the incorporation of important patient-reported outcomes into value-based contracts for MS medications. DISCLOSURES: This study was supported by a grant from Express Scripts Holding Company, which provided research funding to the UPMC Center for Value-Based Pharmacy Initiatives for work on this study. Swart, Neilson, Good, and Parekh are employed by the UPMC Center for Value-Based Pharmacy Initiatives. Manolis is the Chief Pharmacy Officer of UPMC Health Plan, and Shrank was the Chief Medical Officer of UPMC Insurance Services Division at the time of this study. Henderson is employed by Express Scripts Holding Company.

Identifying Outcome Measures for Coronary Artery Disease Value-Based Contracting Using the Delphi Method.

INTRODUCTION: Value-based contracts (VBCs) that link drug payments to disease-related performance metrics aim to increase the value and lower the cost of medications by aligning incentives and sharing risk between payers and pharmaceutical manufacturers. This study sought to identify outcome measures that are meaningful to key stakeholders to inform VBCs for coronary artery disease (CAD) medications. METHODS: We administered a modified Delphi survey to gather expert opinion from a diverse panel of patients (n = 9), cardiologists (n = 4), primary care physicians (n = 5), payers (n = 2), pharmacy benefits managers (n = 3), and pharmaceutical company representatives (n = 2). A list of 16 CAD-associated clinical indicators was generated from the literature and expert consultation. Delphi participants rated the importance of each outcome on a five-point Likert scale, and selected the three most meaningful outcomes. We defined consensus as ≥ 75% agreement on the importance of an outcome (Likert scores 4 or 5 or selection of an outcome as most meaningful). RESULTS: Eleven of 13 outcomes reached consensus for importance on the Likert scale. "Preventing heart attacks" was selected as the most meaningful outcome (80%) while "preventing death" ranked second (76%). CONCLUSIONS: Our study results verify the utility of a widely used clinical CAD outcome measure, myocardial infarction events, for the purpose of pharmaceutical value-based contracting.

Identifying Outcome Measures for Type 2 Diabetes Value-Based Contracting Using the Delphi Method.

BACKGROUND: Value-based contracts (VBCs) between payers and pharmaceutical manufacturers link drug payments to predefined performance measures and require shared risk between both entities. It is unclear how outcome measures were selected in previously reported VBCs, and many VBCs have focused on surrogate endpoints often used in the conduct of clinical trials, which may not be valued by or of importance to patients. OBJECTIVE: To identify outcome measures that are meaningful to key stakeholders and feasibly measured to inform VBCs for diabetes medications. METHODS: We conducted a modified Delphi survey to incorporate views from patients (n = 9), endocrinologists (n = 5), primary care physicians (n = 4), payers (n = 3), pharmacy benefit managers (n = 3), and pharmaceutical company representatives (n = 2). A list of 12 diabetes-related outcome measures was generated from the literature and consultations with subject matter experts. Participants rated the importance of each outcome on a 5-point Likert scale and selected the 3 most meaningful outcomes. Nonpatient participants then used a Likert scale to rate the feasibility of collecting each outcome. Consensus was defined as ≥ 75% agreement on the importance and feasibility of an outcome (Likert scores 4 or 5 or selection of an outcome as most meaningful). A 2-sample test of proportions was performed to examine differences between patient and nonpatient stakeholder rankings of outcomes. RESULTS: All 12 outcomes reached consensus for importance on the Likert scale. The measure "reducing risk of heart attacks" was the most meaningful outcome (84%), while "reducing A1c levels" ranked second (68%). The 2 measures rated as most feasibly collected were "reducing A1c levels" and "reducing risk of hospitalizations from diabetes" (93.8% each). The measures "weight loss," "reducing risk of diabetes-related kidney disease," "reducing risk of emergency room visits from diabetes," and "reducing risk of diabetes-related amputations and foot ulcers" also reached consensus for feasibility. There were statistically significant differences between patient and nonpatient stakeholders in the selection of "reducing A1c levels" (37.5% vs. 82.3%, respectively; P = 0.03) and "reducing risk of diabetes-related kidney disease" (50.0% vs. 11.8%, respectively; P = 0.03) as most meaningful outcomes. CONCLUSIONS: The measures "reducing risk of heart attacks" and "reducing A1c levels" were identified as top priority diabetes outcome measures. DISCLOSURES: Express Scripts provided research funding for this study to the UPMC Center for Value-Based Pharmacy Initiatives. Henderson is employed by Express Scripts and was involved in the conception and design of the study and manuscript approval. The other authors are employed by the UPMC Center for Value-Based Pharmacy Initiatives and have nothing to disclose.

Deprescribing in Advanced Illness: Aligning Patient, Clinician, and Health Plan Goals.

Polypharmacy has been linked to adverse outcomes including increased risk of hospitalization, falls, and death and contributes to unnecessary healthcare spending. Deprescribing efforts aim to reduce medication burden while improving or maintaining patients' quality of life. While the practice of deprescribing is gaining momentum, quality measurement and provider reimbursement are barriers that must be addressed for deprescribing to achieve widespread adoption. Because many quality measures are focused on medication use and adherence, deprescribing efforts may negatively impact primary care provider and health plan quality ratings and value-based reimbursement. In addressing this conflict, there are opportunities to proactively align the priorities and incentives of patients, providers, and plans to promote deprescribing. In this report, we propose several actionable steps to address quality and reimbursement-based barriers such as facilitating the exclusion of those engaged in deprescribing efforts from quality measures and the development of deprescribing-based quality measures.

Global profiling of prolactin-modulated transcripts in breast cancer in vivo.

BACKGROUND: Prolactin (PRL) is essential for normal mammary gland development. PRL promotes mammary tumor formation in rodents and elevated serum prolactin is associated with increased risk of estrogen-receptor positive breast cancer in women. On the other hand, PRL may also exert pro-differentiation effects and act to suppress invasive features of established breast cancer. Previously published limited global transcript profiling analyses of prolactin-regulated gene expression in human breast cancer cells have exclusively been performed in vitro. The present study aimed to shed new light on how PRL modulates estrogen receptor (ER)-positive breast cancer through global transcript profiling of a human breast cancer xenograft model in vivo. METHODS: The prolactin-responsive human T47D breast cancer cell line was xenotransplanted into nude mice and global transcript profiling was carried out following treatment with or without human PRL for 48 h. A subset of PRL-modulated transcripts was further validated using qRT-PCR and immunohistochemistry. RESULTS: The in vivo analyses identified 130 PRL-modulated transcripts, 75 upregulated and 55 downregulated, based on fold change >1.6 and P-value <0.05. From this initial panel of transcripts, a subset of 18 transcripts with established breast cancer-relevance were selected and validated by qRT-PCR. Some but not all of the transcripts were also PRL-modulated in vitro. The selected PRL-modulated transcripts were tested for dependence on Stat5, Jak1 or Jak2 activation, and for co-regulation by 17ß-estradiol (E2). The protein encoded by one of the PRL-regulated transcripts, PTHrP, was examined in a panel of 92 human breast cancers and found by in situ quantitative immunofluorescence analysis to be highly positively correlated with nuclear localized and tyrosine phosphorylated Stat5. Gene Ontology analysis revealed that PRL-upregulated genes were enriched in pathways involved in differentiation. Finally, a gene signature based on PRL-upregulated genes was associated with prolonged relapse-free and metastasis-free survival in breast cancer patients. CONCLUSIONS: This global analysis identified and validated a panel of PRL-modulated transcripts in an ER-positive human breast cancer xenotransplant model, which may have value as markers of relapse-free and metastasis-free survival. Gene products identified in the present study may facilitate ongoing deciphering of the pleiotropic effects of PRL on human breast cancer.

Signal transducer and activator of transcription-3 and breast cancer prognosis.

Signal transducer and activator of transcription-3 (Stat3) is frequently activated in breast cancer and multiple lines of evidence suggest that Stat3 promotes tumor progression. However, the prognostic value of Stat3 in human breast cancer remains controversial and associations range from favorable to unfavorable based on four outcome studies of 62, 102, 255 and 517 patients. Cellular Stat3 protein expression was measured in three studies whereas nuclear localized, tyrosine phosphorylated Stat3 (Nuc-pYStat3) was used as the readout in only one study. We therefore retrospectively analyzed the prognostic value of Nuc-pYStat3 in a larger material of 721 breast cancer specimens. Overall, patients whose tumors were positive for Nuc-pYStat3 tended to have improved survival, but the trend did not reach statistical significance (P=0.08). When specimens were stratified by tumor grade, patients with low grade but not high grade tumors that were positive for Nuc-pYStat3 had significantly prolonged overall survival in univariate analysis (P=0.014) but not in multivariate analyses. Unexpectedly, quantitative immunofluoresence detection revealed highest levels of Nuc-pYStat3 in normal breast epithelia and gradual loss of Nuc-pYStat3 during progression from DCIS, invasive ductal carcinoma, and lymph node metastases. Levels of Nuc-pYStat3 correlated positively with levels of Nuc-pYStat5, a favorable prognostic marker, in invasive ductal carcinomas. Furthermore, NucpYStat3 levels correlated strongly with protein levels of nuclear localized Stat5a (r=0.633, P<0.001) but not Stat5b. Our data does not support the notion that Nuc-pYStat3 is an independent marker of prognosis in breast cancer, although future studies may reveal prognostic utility within molecularly characterized subtypes of breast cancer.

Prolactin inhibits BCL6 expression in breast cancer through a Stat5a-dependent mechanism.

BCL6 is a transcriptional repressor that recognizes DNA target sequences similar to those recognized by signal transducer and activator of transcriptions 5 (Stat5). BCL6 disrupts differentiation of breast epithelia, is downregulated during lactation, and is upregulated in poorly differentiated breast cancer. In contrast, Stat5a mediates prolactin-induced differentiation of mammary epithelia, and loss of Stat5 signaling in human breast cancer is associated with undifferentiated histology and poor prognosis. Here, we identify the mammary cell growth factor prolactin as a potent suppressor of BCL6 protein expression in human breast cancer through a mechanism that requires Stat5a, but not prolactin-activated Stat5b, MEK-ERK, or PI3K-AKT pathways. Prolactin rapidly suppressed BCL6 mRNA in T47D, MCF7, ZR75.1, and SKBr3 breast cancer cell lines, followed by prolonged reduction of BCL6 protein levels within 3 hours. Prolactin suppression of BCL6 was enhanced by overexpression of Stat5a but not Stat5b, was mimicked by constitutively active Stat5a, but did not require the transactivation domain of Stat5a. Stat5 chromatin immunoprecipitation demonstrated physical interaction with a BCL6 gene regulatory region, and BCL6 transcript repression required histone deacetylase activity based on sensitivity to trichostatin A. Functionally, BCL6 overexpression disrupted prolactin induction of Stat5 reporter genes. Prolactin suppression of BCL6 was extended to xenotransplant tumors in nude mice in vivo and to freshly isolated human breast cancer explants ex vivo. Quantitative immunohistochemistry revealed elevated BCL6 in high-grade and metastatic breast cancer compared with ductal carcinoma in situ and nonmalignant breast, and cellular BCL6 protein levels correlated negatively with nuclear Stat5a (r = -0.52; P < 0.001) but not with Stat5b. Loss of prolactin-Stat5a signaling and concomitant upregulation of BCL6 may represent a regulatory switch facilitating undifferentiated histology and poor prognosis of breast cancer.

Coactivation of janus tyrosine kinase (Jak)1 positively modulates prolactin-Jak2 signaling in breast cancer: recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways.

Prolactin (PRL) receptors (PRLRs) have been considered selective activators of Janus tyrosine kinase (Jak)2 but not Jak1, Jak3, or Tyk2. We now report marked PRL-induced tyrosine phosphorylation of Jak1, in addition to Jak2, in a series of human breast cancer cell lines, including T47D, MCF7, and SKBR3. In contrast, PRL did not activate Jak1 in immortalized, noncancerous breast epithelial lines HC11, MCF10A, ME16C, and HBL-100, or in CWR22Rv1 prostate cancer cells or MDA-MB-231 breast cancer cells. However, introduction of exogenous PRLR into MCF10A, ME16C, or MDA-MB-231 cells reconstituted both PRL-Jak1 and PRL-Jak2 signals. In vitro kinase assays verified that PRL stimulated enzymatic activity of Jak1 in T47D cells, and PRL activated Jak1 and Jak2 with indistinguishable time and dose kinetics. Relative Jak2 deficiency did not cause PRLR activation of Jak1, because overexpression of Jak2 did not interfere with PRL activation of Jak1. Instead, PRL activated Jak1 through a Jak2-dependent mechanism, based on disruption of PRL activation of Jak1 after Jak2 suppression by 1) lentiviral delivery of Jak2 short hairpin RNA, 2) adenoviral delivery of dominant-negative Jak2, and 3) AG490 pharmacological inhibition. Finally, suppression of Jak1 by lentiviral delivery of Jak1 short hairpin RNA blocked PRL activation of ERK and signal transducer and activator of transcription (Stat)3 and suppressed PRL activation of Jak2, Stat5a, Stat5b, and Akt, as well as tyrosine phosphorylation of PRLR. The data suggest that PRL activation of Jak1 represents a novel, Jak2-dependent mechanism that may serve as a regulatory switch leading to PRL activation of ERK and Stat3 pathways, while also serving to enhance PRL-induced Stat5a/b and Akt signaling.

Ultrahigh density microarrays of solid samples.

We present a sectioning and bonding technology to make ultrahigh density microarrays of solid samples, cutting edge matrix assembly (CEMA). Maximized array density is achieved by a scaffold-free, self-supporting construction with rectangular array features that are incrementally scalable. This platform technology facilitates arrays of >10,000 tissue features on a standard glass slide, inclusion of unique sample identifiers for improved manual or automated tracking, and oriented arraying of stratified or polarized samples.