Comparing the effects of various ß-blockers on cardiovascular mortality in breast cancer patients.

BACKGROUND: Cardiovascular (CV) disease is a leading cause of death in breast cancer (BC) patients due to the increased age and treatments. While individual ß-blockers have been investigated to manage CV complications, various ß-blockers have not been compared for their effects on CV death in this population. We aimed to compare CV mortality in older BC patients taking one of the commonly used ß-blockers. METHODS: This retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) - Medicare data (2010-2015). Patients of age 66 years or older at BC diagnosis receiving metoprolol, atenolol, or carvedilol monotherapy were included. The competing risk regression model was used to determine the risk of CV mortality in the three ß-blocker groups. The multivariable model was adjusted for demographic and clinical covariates. The adjusted hazard ratio (HR) and 95% confidence intervals (CI) were reported for the risk of CV mortality. RESULTS: The study cohort included 6,540 patients of which 55% were metoprolol users, 30% were atenolol users, and 15% were carvedilol users. Metoprolol was associated with a 37% reduced risk of CV mortality (P = 0.03) compared to carvedilol after adjusting for the covariates (HR = 0.63; 95% CI 0.41-0.96). No significant difference in the risk of CV mortality between atenolol and carvedilol users was observed (HR = 0.74; 95% CI 0.44-1.22). CONCLUSIONS: Our findings suggest that metoprolol is associated with a reduced risk of CV mortality in BC patients. Future studies are needed to confirm these findings and understand the mechanism of action.

Risk of incident cardiovascular events with disease-modifying anti-rheumatic drugs among adults with rheumatoid arthritis: a nested case-control study.

OBJECTIVE: This study examined the risk of cardiovascular disease (CVD) associated with the disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA). METHOD: This nested case-control study used the MarketScan database (2012-2014), involving adult RA patients (aged ≥18 years) initiating either a conventional synthetic (cs) DMARD, biologic DMARD, or targeted synthetic (ts) DMARD between January 1, 2013 and December 31, 2014 (cohort entry) and had no CVD history. Cases were individuals with incident CVD identified using diagnosis codes or procedure codes from medical claims. For each case, 10 age- and sex-matched controls were selected using the incident density sampling with replacement. Prescriptions of DMARDs were measured 90 days before the event date. Conditional logistic regression examined the association of risk of CVD with DMARDs in combination treatment or individual use, with reference to methotrexate (MTX) monotherapy, adjusting for baseline confounders. Subgroup analyses were performed separately in DMARD combination therapy users or individual DMARD users, respectively. RESULTS: In total, 270 cases of incident CVD and 2700 controls were included (mean [standard deviation (SD)] age: 54 [1]; 75.6% women). The commonly prescribed DMARD therapies were csDMARD monotherapy (n = 795, 27.04%), followed by  tumor necrosis factor inhibitors (TNFi) monotherapy (n = 367, 12.48%), and TNFi in combination with MTX (n = 314, 10.68%). Compared with MTX monotherapy, overall use of DMARD agents was not associated with the differential risk of CVD, including various types of DMARD combination regimens. The findings were similar across subgroup analyses. CONCLUSIONS: The study found no differential risk of CVD with DMARDs in combination therapy or monotherapy compared to MTX monotherapy in patients with RA. Key Points • This study evaluated the risk of cardiovascular disease (CVD) associated with the disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA). • Findings suggest no differential CVD risk with DMARDs in combination with MTX or used individually compared with MTX monotherapy in patients with early RA. • Further efforts should focus on a better understanding of the mechanism of DMARD combination treatments with MTX in modifying CV risk.

Real-world Comparative Effectiveness of Methotrexate-based Combinations for Rheumatoid Arthritis: A Retrospective Cohort Study.

PURPOSE: Guidelines recommend using disease-modifying antirheumatic drugs (DMARDs) in combination with methotrexate (MTX) for patients with rheumatoid arthritis (RA) after monotherapy. Little is known about the real-world comparative effectiveness of these MTX-DMARD combinations. This study compared the effectiveness of various MTX-based DMARD combinations for patients with RA initiating MTX-DMARD combination therapy using administrative claims database. METHODS: This retrospective cohort study included adults (aged ≥18 years) with RA who initiated MTX combination treatment with conventional synthetic DMARDs (csDMARDs), tumor necrosis factor inhibitor (TNFi) biologic DMARDs (bDMARDs), non-TNFi bDMARDs, or targeted synthetic DMARDs (tsDMARDs) between July 1, 2012, and December 31, 2013 (index date), from the MarketScan Commercial Claims Data. Patients had continuous enrollment from the 6 months of preindex period until the 12 months of postindex period. The MTX-based DMARD combination therapy cohort was defined as ≥1 MTX prescription in the first 30 days from the index date and ≥14 days overlapping use of the prescription fills of the MTX and the index DMARD. Effectiveness was measured by using the claims algorithm (dosing, switching, addition, oral glucocorticoid use, or multiple glucocorticoid injection). Propensity score analysis with the inverse probability of treatment weighting (PS-IPTW), estimated by using the generalized boosted machine learning method, was used to balance the distribution of baseline variables between the combination groups. Multivariable logistic regression using PS-IPTW was conducted to compare the effectiveness of the combination groups. Sensitivity analysis evaluated the modified effectiveness algorithms or the time to the first treatment failure. FINDINGS: A total of 3174 adult patients with RA starting an MTX-DMARD combination therapy were identified (mean [SD] age, 50 [9] years), including 1568 (49%) initiating a csDMARD + MTX, 1343 (42%) initiating TNFi + MTX, and 240 (8%) initiating non-TNFi bDMARD + MTX, and 23 (1%) initiating tsDMARD + MTX. Owing to the small sample, the tsDMARD combination group was not included in the comparative analysis. Algorithm-based therapy effectiveness was found in 9.95% of the csDMARD + MTX, 20.48% of the TNFi + MTX, and 20.83% of the non-TNFi + MTX groups. PS-IPTW showed that the csDMARD combination is less effective (adjusted odds ratio, 0.422; 95% CI, 0.341-0.524) than the TNFi combination; however, the non-TNFi biologic combination had similar effectiveness (aOR, 1.063; 95% CI, 0.680-1.662) compared to the TNFi combination. Sensitivity analyses confirmed the main results. IMPLICATIONS: Among RA patients initiating MTX-DMARD combinations, both non-TNFi biologics and TNFi-based combinations with MTX were equally effective, but csDMARD + MTX was less effective than the TNFi plus MTX.

Factors influencing prescribing the first add-on disease-modifying antirheumatic drugs in patients initiating methotrexate for rheumatoid arthritis.

Background: Advances in Disease-Modifying Antirheumatic Drugs (DMARDs) have expanded the treatment landscape for Rheumatoid Arthritis (RA). Guidelines recommend adding either conventional synthetic (cs), biologic (b), or targeted synthetic (ts) DMARDs to methotrexate (MTX) for managing RA. Limited evidence exists regarding the factors that contribute to adding a DMARD agent to the MTX regimen. This study examined the factors associated with adding the first DMARD in RA patients initiating MTX. Methods: This retrospective cohort study utilized the MarketScan data (2012-2014) involving adults (aged ≥18) with RA initiating an MTX (index date) between Jul 1, 2012 and Dec 30, 2013, and with continuous enrollment for the 6-month pre-index period. The combination therapy users received the first treatment addition of DMARD starting from day 30 after the index MTX over one year period. The study focused on the addition of csDMARDs, Tumor Necrosis Factor Inhibitors (TNFi) bDMARDs, non-TNFi bDMARDs, or tsDMARDs. Baseline covariates were measured in the 6-month pre-index and grouped into predisposing, enabling, and need factors, as per the Andersen Behavior Model. Multivariable logistic regression examined the factors associated with the addition of TNFi compared to adding a csDMARD. An additional regression model evaluated the factors associated with adding any biologic (combining TNFi and non-TNFi biologics). Results: Among 8350 RA patients starting MTX, 31.92% (n = 2665) initiated any DMARD within the 1-year post-index period. Among RA patients initiating a DMARD prescription after starting MTX, 945 (11.32%) received combination therapy with treatment addition of a DMARD to MTX regimen; majority added TNFi (550, 58%), followed by csDMARD (352, 37%); non-TNF biologic (40, 4%), or tsDMARD (3, 0.3%). The tsDMARD group was limited and was not included for further analysis. The multivariable model found Preferred Provider Organization insurance coverage (odds ratio [OR], 1.43; 95% confidence interval (CI), 1.06-1.93), chronic pulmonary disease (OR, 1.98; 95% CI, 1.14-3.44), liver disease (OR, 5.24; 95% CI, 1.77-15.49), and Elixhauser score (OR, 0.91; 95% CI, 0.86-0.97) were significantly associated with the addition of TNF-α inhibitors. The separate multivariable model additionally found that patients from metropolitan areas (OR, 1.50; 95% CI, 1.04-2.16) were positively associated with adding any biological agent. Conclusions: TNFi are often added to MTX for managing RA. Enabling and need factors contribute to the prescribing of a TNFi add-on therapy in RA. Future research should examine the impact of these combination therapies on RA management.

Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer in the United States: A SEER-Medicare population-based study.

BACKGROUND: Evidence on overall survival (OS) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors is generally limited to data from clinical trials or a few observational studies with limited generalizability to Medicare population. The aim of this study was to determine OS benefits associated with CDK4/6 inhibitors in older Medicare patients with hormone receptor (HR)-positive and human epidermal growth factor receptor-2 overexpressing (HER2-) metastatic breast cancer (MBC). METHODS: In a retrospective cohort design, female patients aged ≥65 years with diagnosis of HR+/HER2- MBC from 2015 to 2017 who initiated first-line systemic therapy within 12 months of MBC diagnosis were selected from the Survey Epidemiology and End Results-Medicare database. The effect of treatment type (endocrine therapy [ET]+CDK4/6 inhibitor vs. ET alone) on OS was analyzed using Kaplan-Meier methods and multivariable Cox regression models. Adjusted hazard ratio (aHR) and 95% CIs were estimated. RESULTS: A total of 630 eligible patients were identified (169 patients treated with ET+CDK4/6 inhibitor and 461 patients treated with ET alone). In the Kaplan-Meier analysis, OS rate at 3 years after first-line treatment initiation was 73.0% for ET+CDK4/6 inhibitor versus 49.1% for ET alone (log-rank p < .0001). In Cox regression analysis, first-line ET+CDK4/6 inhibitor therapy was associated with 41% lower rate of mortality versus ET alone (aHR, 0.590; 95% CI, 0.423-0.823). CONCLUSIONS: The findings of this real-world study demonstrate significant OS benefit associated with ET+CDK4/6 inhibitor therapy over ET alone in an older Medicare population of patients with HR+/HER2- MBC, largely consistent with the evidence from clinical trials.

Impact of CDK4/6 inhibitors on chemotherapy utilization in earlier therapy lines for HR+/HER2- metastatic breast cancer in the United States.

PURPOSE: Delaying chemotherapy remains a vital goal in therapeutic management of HR+/HER2- metastatic breast cancer (MBC). However, recent reports continue to highlight substantially high chemotherapy utilization in earlier therapy lines. In this study, we explored the impact of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy class, introduced in 2015, on early chemotherapy utilization in an older population of patients with HR+/HER2- MBC in the United States (US). METHODS: Using an interrupted time series design, patients with a confirmed diagnosis of MBC aged ≥ 65 years initiating systemic therapy during 2010-2019 were selected from the SEER-Medicare database. The proportion of chemotherapy use was summarized quarterly based on the date of treatment initiation separately in the first, second, and third lines. Segmented regression models adjusted for autocorrelation over time were fitted to estimate trends before and after the availability of CDK4/6 inhibitors in the first quarter of 2015. RESULTS: Of the 3244 eligible women (median age at diagnosis: 74 years), all initiated first-line therapy; 47.9% (n = 1581) initiated second-line therapy, and 50.1% (n = 792) initiated third-line therapy. Overall utilization of chemotherapy (alone or in combination) during the study period was 15.7% for the first line, 19.6% for the second line, and 24.8% for the third line. Chemotherapy utilization in the period immediately after introduction of CDK4/6 inhibitor therapy decline by estimated 2.5% in the first line (P = 0.408), 15.5% in the second line (P = 0.005), and 16.3% in the third line (P = 0.003). CONCLUSIONS: This population-based study illustrates that chemotherapy utilization in earlier therapy lines for HR+/HER2- MBC declined steadily between 2010 and 2019. These declines were significantly accelerated by the introduction of CDK4/6 therapy class in 2015, notably in the second- and third-line settings.

Patient-Reported Barriers to Adherence Among ACEI/ARB Users from a Motivational Interviewing Telephonic Intervention.

Purpose: Hypertension is a common comorbidity among type 2 diabetes mellitus (T2DM) patients, which increases the risk of cardiovascular diseases. Despite the proven benefit of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in this population, poor medication adherence is prevalent, resulting in higher complications and mortality rate. Motivational interviewing (MoI) has demonstrated effectiveness in improving medication adherence and identifying barriers. This study aimed to assess and identify patient-reported barriers to adherence to ACEI/ARB from an MoI telephonic intervention conducted by student pharmacist interns. Patients and Methods: This retrospective study was conducted within an MoI intervention customized by past ACEI/ARB adherence trajectories for nonadherent patients with T2DM and hypertension enrolled in a Medicare Advantage Plan. Adherence barriers were extracted from the interviewers' notes by two independent researchers. Descriptive analysis was performed to summarize the overall frequency of barriers as well as across trajectory groups, identified from the initial and follow-up calls. Results: In total, 247 patients received the initial MoI call from which 41% did not communicate any barrier for ACEI/ARB use despite having low adherence. About 59% of the patients reported at least one barrier during the initial call. The most common barriers included forgetfulness, discontinuation by physicians, side effects, multiple comorbidities, polypharmacy, lack of knowledge about disease/medication, and cost issues. The follow-up calls helped with uncovering at least one new barrier for 28 patients who previously communicated a different issue with their medication during the first call. Additionally, 18 patients with initial denial for having any barrier to adherence reported at least one barrier throughout the follow-up calls. Conclusion: This study summarized patient-reported barriers to ACEI/ARB adherence from an MoI telephonic intervention performed among nonadherent patients. Identifying specific barriers for patients may help to further design tailored interventions that address the barriers and improve adherence.

Dose-dependent relation between metformin and the risk of hormone receptor-positive, her2-negative breast cancer among postmenopausal women with type-2 diabetes.

PURPOSE: Metformin has demonstrated a chemoprotective effect in breast cancer but there is limited evidence on the effect of cumulative exposure to metformin and the risk of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2-) breast cancer. This study assessed this risk with dose and intensity of metformin in postmenopausal women with type-2 diabetes mellitus (T2DM). METHODS: This nested case-control study used the Surveillance, Epidemiology, and End Results-Medicare data (2008-2015). Cohort entry was the date of incident T2DM diagnosis. Cases were those diagnosed with HR + /HER2- breast cancer (event date) as their first/only cancer. Non-cancer T2DM controls were matched using variable-ratio-matching. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period. Dose(mg) was categorized as: (1)0, (2)0-30,000, (3)30,001-136,000, (4)136,001-293,000, and (5) > 293,000, and intensity(mg/day) as: 0, 1-500, and > 500. Covariates were conceptualized using the Andersen Behavioral Model. Conditional logistic regression was used to assess the risk of HR + /HER2- breast cancer with metformin-use. RESULTS: There were 690 cases and 2747 controls. The median duration of T2DM was 1178 days in controls and 1180 days in cases. Higher cumulative dose categories: 4 (adjusted odds ratio(aOR) = 0.72, 95% CI 0.55-0.95,p = 0.02), and 5 (OR = 0.60, 95% CI 0.42-0.85,p < 0.01) had significantly lower odds of HR + /HER2- breast cancer compared to category 0. The highest intensity category of metformin had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46-0.82,p < 0.01) compared to the 0 mg/day group. CONCLUSIONS: Higher metformin exposure was associated with reduced risk of HR + /HER2- breast cancer, adding to the evidence supporting metformin's chemoprotective effect.

Racial and ethnic differences in capecitabine toxicity in patients with gastrointestinal tract cancers.

Background: Capecitabine is used as a first-line treatment for gastrointestinal (GI) tract cancers. Common toxicities of capecitabine include diarrhea and hand-foot syndrome, which frequently require dose reduction, interruption, or discontinuation. While racial and ethnic differences in capecitabine toxicities have been suggested, they have not been evaluated in a diverse "real-world" setting. We examined differences in capecitabine-related toxicities in different racial and ethnic populations. Methods: The electronic medical records of patients receiving first-line capecitabine-containing regimens for GI malignancies were reviewed. Patients on irinotecan-containing regimens or radiation were excluded because of overlapping toxicities. Multiple logistic regression models were used to test the association between race or ethnicity and capecitabine toxicities while adjusting for other demographic characteristics. Results: One hundred twenty-five patients diagnosed with colon (N=76, 60.8%), rectal (N=22, 17.6%), gastric (N=16, 12.8%), or other GI cancers (N=11, 8.8%) were included. In logistic regression analysis, diarrhea occurrence was significantly lower in the African-American/non-Hispanic (odds ratio [OR] 0.25, 95% confidence interval [CI] 0.08-0.75; P=0.01) compared to Caucasian non-Hispanic population. The occurrence of dose-reduction was significantly higher in the African-American/non-Hispanic population (OR 5.83, 95%CI 1.49-22.80; P=0.01) and in the Caucasian/Hispanic population (OR 4.49, 95%CI 1.09-18.42; P=0.03) compared to Caucasian non-Hispanic population. Conclusions: We have identified racial and ethnic differences in the incidence of capecitabine toxicities, which may help clinicians counsel patients with GI malignancies on capecitabine. There is a need for prospective studies to confirm our findings and to understand the relationship between the incidence of toxicities and dose reductions or discontinuation.

Patient-reported outcomes in light of supportive medications in treatment-naïve lung cancer patients.

PURPOSE: The impact of supportive medications on patient-reported outcomes (PROs) has not been systematically evaluated. We describe the supportive medications used by treatment-naïve lung cancer patients and assess their association with PROs from MD Anderson Symptom Inventory (MDASI). METHODS: Treatment-naïve lung cancer patients who completed PROs from MDASI at the initial visit to MD Anderson Cancer Center were included. Medications from the initial visit were abstracted from the electronic medical records system and categorized into therapeutic classes based on U.S. Pharmacopeia v7.0. A chi-square or Mann-Whitney U test was conducted as appropriate. RESULTS: Among 459 patients, ~ 50% took any analgesics and 25% were on opioids. One-third of patients with moderate-severe pain were not on any analgesics. Patients taking opioids had significantly worse median pain scores (6 vs. 0) compared with those not taking any analgesics (p < 0.0001). Higher proportion of patients with moderate-severe pain took opioids compared with those with mild pain (52% vs. 16%, p < 0.0001). Patients on opioids also reported significantly worse scores for five other cancer-specific core symptoms and all six symptoms rating interference with daily life. Only 15% of patients with higher composite score for depression-related symptoms were on antidepressants. However, patients taking antidepressants did not significantly differ in any individual MDASI symptom scores compared with those not on antidepressants (p = 0.4858). CONCLUSIONS: Our results suggest a need for better screening for pain and depression and optimization of pain management in treatment-naïve lung cancer patients since their poor functional status may result in suboptimal cancer therapy.

Clinical Outcomes Associated with Drug-Drug Interactions of Oral Chemotherapeutic Agents: A Comprehensive Evidence-Based Literature Review.

BACKGROUND: Oral chemotherapy use is increasing due to new drug approvals as well as the convenience of the administration of oral drugs. This increased use also raises concern regarding drug-drug interactions (DDIs) with concomitantly administered drugs, resulting in loss of therapeutic effect, decreased tolerability, and/or increased toxicity. OBJECTIVE: The objective of this study was to review existing evidence of the clinical impact of DDIs with oral chemotherapeutic agents. METHODS: A comprehensive search of literature using PubMed was conducted in April 2018 for studies of DDIs associated with oral chemotherapy. Included studies were in English. We included randomized clinical trials, observational studies, and case reports evaluating a DDI between any oral chemotherapy drug and any other drug. Included studies needed to have at least one outcome of clinical relevance potentially attributed to the DDI, for example, effects on survival or toxicity. The quality of the articles was determined using published metrics appropriate for the study design. RESULTS: There were 2626 studies identified in the initial search, of which 35 met all eligibility criteria. These included 15 retrospective cohort studies, 16 case reports or case series and four post hoc analyses of clinical trials. Among these, DDIs contributed to a statistically significant change in a clinical outcome in 12 studies. Eight of these studies evaluated overall survival and progression-free survival and found that the presence of the DDI was associated with reduced survival. CONCLUSION: Our findings suggest that more real-world studies evaluating the association between oral chemotherapy DDIs and clinical outcomes are needed. The adverse clinical outcomes due to DDIs may be a reason for treatment failures and therapy discontinuation.

The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: Prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer.

BACKGROUND: The concomitant use of tyrosine kinase inhibitors (TKIs) and proton pump inhibitors (PPIs) is a significant concern because of potential drug-drug interaction that reduces TKI absorption, thus potentially reducing the effectiveness of TKIs. The objective of this study was to evaluate the prevalence and predictors of concomitant TKI-PPI receipt and its impact on survival and therapy discontinuation in older adults with cancer. METHODS: This retrospective study used linked Surveillance, Epidemiology, and End Results-Medicare data for the years 2007 through 2012. In total, 12,538 patients with lung cancer, renal cell cancer, chronic myelogenous leukemia, liver cancer, or pancreatic cancer were included. The primary exposure variable was concomitant receipt of TKI-PPI, defined as at least 30 days of PPI use in the first 90 days from the start of the TKI (exposure period). The outcomes measured were overall survival and discontinuation of therapy in 90 days and 1 year after the end of the exposure period. Cox proportional-hazards regression with inverse probability of treatment weighting was used to evaluate the association between exposure and outcome. RESULTS: The overall prevalence of TKI-PPI receipt was 22.7%. Predictors that were associated with increased use included polypharmacy and prior PPI receipt. TKI-PPI use decreased survival in 90 days (hazard ratio, 1.16; 95% confidence interval, 1.05-1.28) and in 1 year (hazard ratio, 1.10; 95% confidence interval, 1.04-1.18) but was not associated with discontinuation. CONCLUSIONS: Nearly 1 in 4 older adults with cancer who receive TKIs also receive PPIs concomitantly, and concomitant use is associated with an increased risk of death. Concerted efforts to manage medications are needed to identify and reduce the receipt of PPIs when TKIs are initiated.

Physician Care Coordination and the Use of Psychotropic Polypharmacy in the Management of Pediatric Mental Disorders.

BACKGROUND: Psychotropic polypharmacy is a concern in the management of pediatric mental disorders due to the lack of pediatric data to support the practice. Although seeing multiple providers has been identified as an important predictor of polypharmacy, no study has yet assessed the effect of care coordination between providers on receipt of psychotropic polypharmacy. OBJECTIVE: To examine the association between the intensity of care coordination within a patient's care team and the likelihood of the patient receiving multiclass psychotropic polypharmacy. METHODS: A retrospective study was conducted using the 2013-2015 administrative claims data from a Medicaid managed care organization (Texas Children's Health Plan). Children and adolescents aged 18 years or younger with a diagnosis of a mental/behavioral disorder and receipt of psychotropic prescriptions from multiple prescribers were included in the study. Psychotropic polypharmacy was defined as the receipt of 2 or more psychotropic medications from different drug classes concurrently for 60 days or more. Care coordination was measured using social network analysis (SNA), a new technique included in the Agency for Healthcare Research and Quality Care Coordination Measures Atlas. Care density, an SNA surrogate for care coordination, was calculated as the ratio of the sum of patients shared by physician pairs within a patient's care team to the total number of physician pairs. The Andersen behavioral model was used to guide multivariate logistic regression analyses conducted to assess the association between care density and the likelihood of patients receiving psychotropic polypharmacy after controlling for predisposing and need factors. RESULTS: A total of 24,147 children and adolescents diagnosed with a mental/behavioral disorder were identified. About 34.0% (n = 8,092) of these individuals received psychotropic medications from multiple prescribers who were either primary care physicians (PCPs) or specialists. Logistic regression analysis showed a significant association between care density and the use of psychotropic polypharmacy. However, the direction of this relationship varied depending on the composition of the patient's care team. Among patients with only PCPs involved in their care team, patients in the higher care-density group were 28% less likely to receive psychotropic polypharmacy (OR = 0.72; 95% CI = 0.62-0.96) than those in the lower care-density group. In contrast, among patients who had both PCPs and specialists involved in their care team, those in the higher care-density group were 2 times more likely to experience psychotropic polypharmacy (OR = 2.01; 95% CI = 1.68-2.40). Care density was not significantly associated with the receipt of psychotropic polypharmacy in the specialist-only group. CONCLUSIONS: This study found significant associations between care density and prescription of psychotropic polypharmacy. This relationship varied depending on the patient's diagnosis, disease complexity, and composition of the patient's care team. DISCLOSURES: No outside funding supported this study. The authors do not have any financial relationships or potential conflicts of interest relevant to this article to disclose. The abstract for part of this study, titled "Association Between Physician Care Coordination and the Use of Psychotropic Polypharmacy in the Management of Pediatric Mental Disorders," was selected as a silver medal abstract and was presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2017; March 27-30, 2017; Denver, CO.

Long-Term Recordings of Arcuate Nucleus Kisspeptin Neurons Reveal Patterned Activity That Is Modulated by Gonadal Steroids in Male Mice.

Pulsatile release of gonadotropin-releasing hormone (GnRH) is key to fertility. Pulse frequency is modulated by gonadal steroids and likely arises subsequent to coordination of GnRH neuron firing activity. The source of rhythm generation and the site of steroid feedback remain critical unanswered questions. Arcuate neurons that synthesize kisspeptin, neurokinin B, and dynorphin (KNDy) may be involved in both of these processes. We tested the hypotheses that action potential firing in KNDy neurons is episodic and that gonadal steroids regulate this pattern. Targeted extracellular recordings were made of green fluorescent protein-identified KNDy neurons in brain slices from adult male mice that were intact, castrated, or castrated and treated with estradiol or dihydrotestosterone (DHT). KNDy neurons exhibited marked peaks and nadirs in action potential firing activity during recordings lasting 1 to 3.5 hours. Peaks, identified by Cluster analysis, occurred more frequently in castrated than intact mice, and either estradiol or DHT in vivo or blocking neurokinin type 3 receptor in vitro restored peak frequency to intact levels. The frequency of peaks in firing rate and estradiol regulation of this frequency is similar to that observed for GnRH neurons, whereas DHT suppressed firing in KNDy but not GnRH neurons. We further examined the patterning of action potentials to identify bursts that may be associated with increased neuromodulator release. Burst frequency and duration are increased in castrated compared with intact and steroid-treated mice. The observation that KNDy neurons fire in an episodic manner that is regulated by steroid feedback is consistent with a role for these neurons in GnRH pulse generation and regulation.

Comparative Effectiveness of Smoking Cessation Medications to Attenuate Weight Gain Following Cessation.

OBJECTIVE: To compare the postcessation weight gain following the use of different FDA-approved smoking cessation medications among obese smokers. METHODS: A retrospective cohort study was conducted using the General Electric (GE) electronic medical record database (2006-2011). The cohort consisted of obese adult smokers newly initiating use of an FDA-approved smoking cessation medication (i.e., bupropion vs. varenicline). The outcome variable was weight change at 3, 6, or 12 months following the first prescription. Descriptive analyses and t-tests were conducted to assess the frequency distribution of sample characteristics and their association with the postcessation weight change. Multivariate linear regression models were carried out to compare the weight change among the FDA-approved smoking cessation medications and to identify predictors of weight change at 3, 6, and 12 months after assessing the model assumptions. RESULTS: The mean weight gain was 1.14 pounds (±17.26), 2.06 pounds (±18.46), and 3.06 pounds (±20.78) at 3-, 6-, and 12-month, respectively. Obese smokers who were prescribed varenicline had a mean weight gain of 1.18 pounds (±16.75), 2.14 pounds (±18.14), and 3.12 pounds (±20.89) for each follow up, while those who were prescribed bupropion had a mean weight gain of 0.23 pounds (±25.90), 0.22 pounds (±25.32), and 1.47 pounds (±17.50), respectively. Descriptive analysis showed that obese smokers taking bupropion had less weight gain than those taking varenicline at each follow up; however, this association was not statistically significant after accounting for all covariates. CONCLUSIONS: While patients using bupropion gained slightly less weight compared to those using varenicline, type of smoking cessation medication was not a significant predictor of weight change in the multivariate linear regression model.

Comparative Performance of Diagnosis-based and Prescription-based Comorbidity Scores to Predict Health-related Quality of Life.

OBJECTIVES: To compare the performance of the health-related quality of life-comorbidity index (HRQoL-CI) with the diagnosis-based Charlson, Elixhauser, and combined comorbidity scores and the prescription-based chronic disease score (CDS) in predicting HRQoL in Agency of Healthcare Research and Quality priority conditions (asthma, breast cancer, diabetes, and heart failure). METHODS: The Medical Expenditure Panel Survey (2005 and 2007-2011) data was used for this retrospective study. Four disease-specific cohorts were developed that included adult patients (age 18 y and above) with the particular disease condition. The outcome HRQoL [physical component score (PCS) and mental component score (MCS)] was measured using the Short Form Health Survey, Version 2 (SF-12v2). Multiple linear regression analyses were conducted with the PCS and MCS as dependent variables. Comorbidity scores were compared using adjusted R. RESULTS: Of 140,046 adult participants, the study cohort included 7436 asthma (5.3%), 1054 breast cancer (0.8%), 13,829 diabetes (9.9%), and 937 heart failure (0.7%) patients. Among individual scores, HRQoL-CI was best at predicting PCS and MCS. Adding prescription-based comorbidity scores to HRQoL-CI in the same model improved prediction of PCS and MCS. HRQoL-CI+CDS performed the best in predicting PCS (adjusted R): asthma (43.7%), breast cancer (31.7%), diabetes (32.7%), and heart failure (20.0%). HRQoL-CI+CDS and Elixhauser+CDS had superior and comparable performance in predicting MCS (adjusted R): asthma (HRQoL-CI+CDS=20.1%; Elixhauser+CDS=19.6%), breast cancer (HRQoL-CI+CDS=12.9%; Elixhauser+CDS=14.1%), diabetes (HRQoL-CI+CDS=17.7%; Elixhauser+CDS=17.7%), and heart failure (HRQoL-CI+CDS=18.1%; Elixhauser+CDS=17.7%). CONCLUSIONS: HRQoL-CI performed best in predicting HRQoL. Combining prescription-based scores to diagnosis-based scores improved the prediction of HRQoL.

Comparison of Diabetes Risk Following Smoking Cessation Treatment Using Varenicline Versus Bupropion Among Obese Smokers.

BACKGROUND: Recent literature suggests an initial increased risk of diabetes following smoking cessation. OBJECTIVES: To compare the risk of developing diabetes among obese smokers who tried to quit smoking using bupropion versus varenicline. METHODS: A population-based retrospective cohort study was conducted using the General Electric (GE) electronic medical record database (2006-2011). The cohort consisted of obese adult smokers without a diabetes diagnosis at baseline and newly initiating use of either bupropion or varenicline. This cohort was then followed for 1 year to observe the risk of developing diabetes. The relative risk of bupropion versus varenicline on developing diabetes was assessed using Cox Proportional Hazards regression model after controlling for covariates. RESULTS: The sample comprised of 78,002 obese smokers of which 1,937 (2.36%) developed diabetes during 1 year follow-up. Diabetes incidence rate was relatively comparable who used varenicline and bupropion (23.50 versus 25.80 per 1,000 person-years). Obese smokers who were prescribed bupropion had a statistically significant higher risk of developing diabetes during 1 year following cessation treatment than those who were prescribed varenicline. ([HR]: 1.58, 95% CI: 1.09-2.27) in the multivariate model. CONCLUSIONS/IMPORTANCE: Obese smokers who were prescribed bupropion might have a higher risk of developing diabetes during 1 year follow up compared to those who were prescribed varenicline. The clinical significance of the finding that bupropion had a higher risk of developing diabetes may need further investigation.

Potentially inappropriate anticholinergic medication use in older adults with dementia.

OBJECTIVE: To examine the prevalence and predictors of potentially inappropriate anticholinergic medication use in older adults with dementia. DESIGN: A cross-sectional study. SETTING: United States, 2009-2010. PARTICIPANTS: Medical Expenditure Panel Survey household component participants aged 65 years or older identified as having dementia and using potentially inappropriate anticholinergic medication. MAIN OUTCOME MEASURES: Prevalence and predictors of potentially inappropriate anticholinergic medication use as per the updated 2012 American Geriatrics Society Beers criteria. RESULTS: A total of 3.78 million older adult patients (95% confidence interval [CI] 3.17 million to 4.38 million) were identified as having dementia, for an overall prevalence of 4.81%. Of those patients, an estimated 1.02 million (95% CI 0.70 million to 1.30 million) were reported to use potentially inappropriate anticholinergic medications, for an overall prevalence of 26.95% (95% CI 20.10% to 33.79%). The most frequently prescribed drugs were oxybutynin, solifenacin, paroxetine, tolterodine, promethazine, and cyclobenzaprine. Multivariable logistic analysis revealed that those patients with the need characteristics of self-reported anxiety, mood disorders, and "fair/poor" general health status had increased odds of potentially inappropriate anticholinergic use, while patients with the predisposing characteristic of being aged 75-84 years had decreased odds of potentially inappropriate anticholinergic use. CONCLUSION: More than one in four older adults with dementia were found to use potentially inappropriate anticholinergics. Given the adverse cognitive effects of these medications, there is a strong need to monitor and optimize their use in older adult patients with dementia.

CMF-regimen preferred as first-course chemotherapy for older and sicker women with breast cancer: Findings from a SEER-Medicare-based population study.

OBJECTIVE: The objective of this study was to determine the sociodemographic and clinical characteristics associated with Cyclophosphamide, Methotrexate, and 5-Fluorouracil (CMF) utilization as a first-course chemotherapy regimen among female Medicare patients with early-stage breast cancer. METHODS: A longitudinal study was conducted with women 66 years and older, diagnosed with stage I to III breast cancer from 1993 to 2004, and receiving chemotherapy using the Surveillance, Epidemiology, and End Result-Medicare data. First-course CMF chemotherapy was defined as chemotherapy initiation within 6 months of breast cancer diagnosis, with at least 1 claim of CMF each within 1 year of diagnosis. Logistic regression was used to perform the analysis. RESULTS: Older and sicker women, living in census tracts with lower average education, and diagnosed with advanced stage, hormone receptor-negative tumors have a higher probability of CMF administration. Receipt of lymph node dissection and nonreceipt of radiation therapy were also associated with CMF administration. CMF administration has declined over the years and has significant regional variation. CONCLUSIONS: Reduction in CMF use overtime indicates the increased use of newer and more effective systemic therapies among breast cancer patients. In spite of the reduction in CMF use over time, CMF is more frequently administered to older and sicker women, possibly because of higher risk of anthracycline-induced toxicities in these patients. Clinical guidelines have no recommendations for CMF administration in breast cancer patients with certain clinical characteristics. Hence, it is important to understand if the associations observed in this study can be clinically justified in order to reduce unjustified use of less-effective regimens.