Publications

OBJECTIVE: The potential for beta blocker use to reduce joint pain and analgesic use in osteoarthritis (OA) patients has not been well established. The objective of this study was to estimate the association between beta blocker use and knee pain, areas of joint pain, and analgesic use among participants with symptomatic knee OA.

DESIGN: We selected participants with symptomatic knee OA from the Osteoarthritis Initiative. Outcome measures included knee pain (e.g., WOMAC pain subscale), areas of joint pain (e.g., widespread joint pain), and analgesic use (e.g., use of strong pain prescriptions including opioids). We decomposed time-varying beta blocker use into within-person and between-person variation, and included these components in linear mixed effects models for repeated outcome measures of knee pain, joint pain, and analgesic use over 8 years.

RESULTS: Among 1,168 participants, 15% reported beta blocker use at baseline. Beta blocker users (5.2, 95% CI [4.7, 5.8]) had similar estimated mean WOMAC pain scores as other anti-hypertensive users (4.9, 95% CI [4.6, 5.2]), with an estimated within-person difference of 0.1 (95% CI [-0.3, 0.4]). Proportion of participants reporting widespread joint pain was similar between beta blocker users and other anti-hypertensive users (40.1% vs 40.3%; within-person effect, odds ratio [OR] = 0.87, 95% CI [0.63, 1.22]). Reported use of strong prescription pain medication was also similar between beta blocker users and other anti-hypertensive users (7.7% vs 8.2%; within-person effect, OR = 1.39, 95% CI [0.75, 2.55]).

CONCLUSIONS: We found no evidence that beta blockers confer a clinically meaningful reduction in knee pain severity, areas of joint pain, or analgesic use among participants with symptomatic knee OA.

PURPOSE: Little is known about adherence to antidepressant treatment during acute and continuation phase of depression among older adults with dementia and newly diagnosed major depressive disorders (MDD). This study estimated the extent of and factors associated with adherence to acute and continuation phase antidepressant treatment among older adults with dementia and newly diagnosed MDD.

METHODS: We conducted a retrospective cohort study using the Medicare 5% sample claims data (2012-2013) among older adults (age≥65 years) with dementia who were newly diagnosed with MDD. Intake period of our study was from 01-May-2012 through 30-April-2013. The dependent variables of this study were acute and continuation phase depression treatment adherence. Factors associated with acute and continuation phase antidepressant treatment adherence were identified using multiple logistic regression analyses.

RESULTS: The final study sample consisted of 6239 [adherent: N=4644 (74.44%)] and 5617 [adherent: N=3584 (63.81%)] older adults with dementia and MDD during the acute and continuation phase treatment, respectively. During the acute phase, only race/ethnicity was significantly associated with adherence to depression treatment, whereas race/ethnicity and baseline antipsychotic use were significantly associated with adherence to depression treatment during the continuation phase.

CONCLUSION: Approximately, 74% and 64% older adults with dementia and MDD were adherent to acute and continuation phase antidepressant treatment in this nationally representative sample of Medicare beneficiaries, and we identified several modifiable and non-modifiable factors associated with adherence.

IMPORTANCE: Since 2011, immune checkpoint inhibitors (ICIs) have been effective treatment options for advanced melanoma. Little is known about how risks of immune-related adverse events (irAEs) vary by ICIs.

OBJECTIVE: To compare the risk of irAEs across different treatment regimens for advanced melanoma using network meta-analysis.

DATA SOURCES: PubMed/MEDLINE, Embase, Web of Science, and Scopus were searched for all randomized clinical trial (RCT) articles published from January 1, 2010, through June 30, 2019.

STUDY SELECTION: Studies included phases 2 and 3 RCTs in the treatment of advanced melanoma that compared ICIs (ipilimumab, nivolumab, and pembrolizumab) with chemotherapy drugs (eg, dacarbazine, carboplatin, and paclitaxel) or different ICI regimens.

DATA EXTRACTION AND SYNTHESIS: Different treatment regimens were compared using bayesian network meta-analysis with Markov chain Monte Carlo simulation with noninformative prior distribution and random-effects generalized linear models.

MAIN OUTCOMES AND MEASURES: Primary outcomes were the cumulative incidence of any irAEs (regardless of severity) and severe irAEs (grades 3-5). Based on the pooled odds ratios (ORs) and 95% credible intervals (95% CrI), the probability of being associated with the lowest irAE risks was estimated for each treatment regimen.

RESULTS: Nine RCTs with 8 different treatment regimens for advanced melanoma and involving a total of 5051 patients were included. Overall, the 3 ICI treatment regimens associated with the lowest risk of any or severe irAEs were pembrolizumab, 2 mg/kg, every 3 weeks; nivolumab, 3 mg/kg, every 2 weeks; and pembrolizumab, 10 mg/kg, every 3 weeks. Compared with ipilimumab, 10 mg/kg, every 3 weeks, only nivolumab, 3 mg/kg, every 2 weeks, was associated with a decreased risk for any irAEs (OR, 0.34; 95% CrI, 0.13-0.94). A decreased risk for severe irAEs was observed for ipilimumab, 3 mg/kg, every 3 weeks (OR, 0.35; 95% CrI, 0.14-0.74); pembrolizumab, 10 mg/kg, every 2 weeks (OR, 0.22; 95% CrI, 0.05-0.95) and 10 mg/kg every 3 weeks (OR, 0.20; 95% CrI, 0.06-0.68); and nivolumab, 3 mg/kg, every 2 weeks (OR, 0.20; 95% CrI, 0.07-0.48) compared with ipilimumab, 10 mg/kg, every 3 weeks. An increased risk for severe irAEs was associated with nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks compared with other ICI regimens (ORs ranging from 4.09 [95% CrI, 1.73-10.99] to 7.40 [95% CrI, 1.12-49.29]) except ipilimumab, 10 mg/kg, every 3 weeks.

CONCLUSIONS AND RELEVANCE: These findings suggest that for patients with advanced melanoma at high risk of irAEs, pembrolizumab, 2 mg/kg, every 3 weeks, nivolumab, 3 mg/kg, every 2 weeks, and pembrolizumab, 10 mg/kg, every 3 weeks may be the preferred treatment regimens (with respect to irAE risks) among the ICI regimens reported, whereas ipilimumab, 10 mg/kg, every 3 weeks alone and nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks should be used with caution. A network analysis may be valuable for clinical decision-making when evidence from head-to-head comparisons is lacking.

Tamoxifen or aromatase inhibitor (AI) therapy may prevent breast cancer recurrence, however, adverse effects may lead to treatment discontinuation. Evidence regarding the occurrence of AI-associated musculoskeletal problems among Asians is scarce. We identified women with breast cancer-initiating tamoxifen or AIs from the Taiwan National Health Insurance Research Database (2007-2012). Using multivariable cause-specific hazard models, we examined the association between endocrine therapy and the risk of any arthritis and carpal tunnel syndrome, adjusting for age, prior cancer treatment, and other health status factors. Among 32,055 eligible women with breast cancer (mean age = 52.6 ± 11.5 years), 87.4% initiated tamoxifen, 3.9% initiated anastrozole, 8.0% initiated letrozole, and 0.7% initiated exemestane. AI users had a higher 1-year cumulative incidence for any arthritis (13.0% vs. 8.2%, p < 0.0001) and carpal tunnel syndrome (1.4% vs. 0.8%, p = 0.008). Compared to tamoxifen users, AI users had a higher risk of any arthritis [adjusted hazard ratio (aHR) = 1.21, 95%CI = 1.09-1.34] and carpal tunnel syndrome (aHR = 1.68, 95%CI = 1.22-2.32). No significant difference was observed in the risks of any arthritis and carpal tunnel syndrome across different AIs. Taxane use was not associated with any arthritis (aHR = 0.92, 95%CI = 0.81-1.05) or carpal tunnel syndrome (aHR = 0.97, 95%CI = 0.67-1.40) compared to other chemotherapies. Taiwanese women with breast cancer-initiating AIs had an increased risk of arthritis and carpal tunnel syndrome compared to those who initiated tamoxifen.

This study uses national pharmacy claims data to describes trends in prescriptions for HIV preexposure prophylaxis (PrEP) overall and by specialty between 2012 and 2018.

Short Physical Performance Battery (SPPB) assessment is a widely used measure of lower extremity function, strength, and balance. In the Lifestyles Interventions and Independence for Elders (LIFE) Study, baseline SPPB and changes throughout the trial were strongly associated with major mobility disability (MMD). This study further investigated this association by identifying trajectories of SPPB and evaluating the predictive validity of SPPB trajectories for future MMD. Participants (n = 1635) aged 70-89 years were randomized to a physical activity or health education intervention and assessed every 6 months for MMD. We used group-based trajectory models (GBTMs) to identify trajectories of a binary outcome for a decrease from baseline SPPB of ≥1. Multinomial logistic regression explored baseline factors associated with group membership. Survival analyses evaluated the association between trajectories with MMD. The GBTM identified a 3-group model which included a "No Decline" group (46.0%), "Late Decline" group (27.7%), and an "Early Decline" group (26.3%). Adjusting for all other baseline characteristics, group assignment during the previous follow-up visit was strongly associated with MMD at the subsequent period. Comparisons between groups showed a 2-to-3-fold increase in MMD comparing the "Late" to "No" decline group and a 4-to-5-fold increase in MMD comparing the "Early" to "No" decline group. Group membership and impact on MMD was not different between intervention arms. Group-based trajectories of SPPB scores identified distinct subgroups in LIFE Study participants. Using these group assignments in outcome models were highly associated with MMD. GBTMs have potential to identify and improve prediction of aging-related decline to better design and identify patients for interventions.

OBJECTIVE: To develop and validate a machine-learning algorithm to improve prediction of incident OUD diagnosis among Medicare beneficiaries with ≥1 opioid prescriptions.

METHODS: This prognostic study included 361,527 fee-for-service Medicare beneficiaries, without cancer, filling ≥1 opioid prescriptions from 2011-2016. We randomly divided beneficiaries into training, testing, and validation samples. We measured 269 potential predictors including socio-demographics, health status, patterns of opioid use, and provider-level and regional-level factors in 3-month periods, starting from three months before initiating opioids until development of OUD, loss of follow-up or end of 2016. The primary outcome was a recorded OUD diagnosis or initiating methadone or buprenorphine for OUD as proxy of incident OUD. We applied elastic net, random forests, gradient boosting machine, and deep neural network to predict OUD in the subsequent three months. We assessed prediction performance using C-statistics and other metrics (e.g., number needed to evaluate to identify an individual with OUD [NNE]). Beneficiaries were stratified into subgroups by risk-score decile.

RESULTS: The training (n = 120,474), testing (n = 120,556), and validation (n = 120,497) samples had similar characteristics (age ≥65 years = 81.1%; female = 61.3%; white = 83.5%; with disability eligibility = 25.5%; 1.5% had incident OUD). In the validation sample, the four approaches had similar prediction performances (C-statistic ranged from 0.874 to 0.882); elastic net required the fewest predictors (n = 48). Using the elastic net algorithm, individuals in the top decile of risk (15.8% [n = 19,047] of validation cohort) had a positive predictive value of 0.96%, negative predictive value of 99.7%, and NNE of 104. Nearly 70% of individuals with incident OUD were in the top two deciles (n = 37,078), having highest incident OUD (36 to 301 per 10,000 beneficiaries). Individuals in the bottom eight deciles (n = 83,419) had minimal incident OUD (3 to 28 per 10,000).

CONCLUSIONS: Machine-learning algorithms improve risk prediction and risk stratification of incident OUD in Medicare beneficiaries.

BACKGROUND: Understanding geographic patterns of high-risk medication (HRM) prescribed and dispensed among older adults may help the Centers for Medicare & Medicaid Services and their partners develop and tailor prevention strategies.

OBJECTIVE: To compare the geographic variation in the prevalence of HRM use among Medicare Part D beneficiaries from 2011 to 2013, for Medicare Advantage Prescription Drug (MA-PD) plans and stand-alone Prescription Drug Plans (PDPs).

METHODS: This retrospective study used the data of a 5% national Medicare sample (2011-2013). Beneficiaries were included in the study if they were aged ≥ 65 years, continuously enrolled in MA-PDs or PDPs ( 1.3 million each year), and had ≥ 2 prescriptions for the same HRM (e.g., amitriptyline) prescribed and dispensed during the year based on the Pharmacy Quality Alliance's (PQA) quality measures for HRM use. Multivariable logistic regression was used to estimate adjusted annual HRM use rates (i.e., adjusted predictions, average marginal predictions, or model-adjusted risk) across 306 Dartmouth Atlas of Health Care hospital referral regions (HRRs), controlling for sociodemographic, health-status, and access-to-care factors.

RESULTS: Among eligible beneficiaries each year (1,161,076 in 2011, 1,237,653 in 2012, and 1,402,861 in 2013), nearly 40% were enrolled in MA-PD plans, whereas the remaining 60% were in PDP plans. The adjusted prevalence of HRM use significantly decreased among Medicare beneficiaries enrolled in MA-PD (13.1%-8.4%, P < 0.001) and PDP (16.2%-12.2%, P < 0.001) plans from 2011 to 2013. For MA-PD and PDP beneficiaries, HRM users were more likely to be (all P < 0.001) the following: female (MA-PD: 70.4% vs. 59.9%; PDP: 72.8% vs. 62.5%); White (MA-PD: 84.6% vs. 81.4%; PDP: 86.6% vs. 85.3%); with low-income subsidy or dual eligibility for Medicaid (MA-PD: 22.3% vs. 16.6%; PDP: 29.2% vs. 23.3%); and disabled (MA-PD: 15.6% vs. 8.7%; PDP: 15.4% vs. 8.5%) compared with non-HRM users in 2013. In 2013, significant geographic variation existed, with the ratios of 75th-25th percentiles of HRM use rates across HRRs as 1.42 for MA-PDs and 1.31 for PDPs. For MA-PDs, the top 5 HRRs with the highest HRM use rates in 2013 were Casper, WY (20.4%), Waco, TX (16.7%), Lubbock, TX (15.7%), Santa Barbara, CA (15.2%), and Temple, TX (15.1%); for PDPs, they were Lawton, OK (18.8%), Alexandria, LA (18.8%), Lake Charles, LA (18.6%), Oklahoma City, OK (18.0%), and Slidell, LA (18.0%).

CONCLUSIONS: Substantial geographic variation exists in the prevalence of HRM use among older adults in Medicare, regardless of prescription drug plan. Areas with high prevalence of HRM use may benefit from targeted interventions (e.g., medication therapy management monitoring or alternative medication substitutions) to prevent potential adverse consequences.

DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. This study was presented as a poster at the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Asia Pacific Meeting; September 8-11, 2018; Tokyo, Japan.

OBJECTIVE: To examine associations between opioid prescriber specialty and patient likelihood of opioid use disorder (OUD), opioid misuse, and opioid overdose.

DESIGN: Longitudinal retrospective study using Pennsylvania Medicaid data (2007-2015).

METHODS: We constructed an incident cohort of 432,110 enrollees initiating prescription opioid use without a history of OUD or overdose six months before opioid initiation. We attributed patients to one of 10 specialties using the first opioid prescriber's specialty or, alternatively, the specialty of the dominant prescriber writing the majority of the patient's opioid prescriptions. We estimated adjusted rates for OUD, misuse, and overdose, adjusting for demographic variables and medical (including pain) and psychiatric comorbidities.

RESULTS: The unadjusted incidence rates of OUD, misuse, and overdose were 7.13, 4.73, and 0.69 per 100,000 person-days, respectively. Patients initiating a new episode of opioid treatment with Pain Medicine/Anesthesiology (6.7 events, 95% confidence interval [CI] = 5.5 to 8.2) or Physical Medicine and Rehabilitation (PM&R; 6.1 events, 95% CI = 5.1 to 7.2) had higher adjusted rates for OUD per 100,000 person-days compared with Primary Care practitioners (PCPs; 4.4 events, 95% CI = 4.1 to 4.7). Patients with index prescriptions from Pain Medicine/Anesthesiology (15.9 events, 95% CI = 13.2 to 19.3) or PM&R (15.8 events, 95% CI = 13.5 to 18.4) had higher adjusted rates for misuse per 100,000 person-days compared with PCPs (9.6 events, 95% CI = 8.8 to 10.6). Findings were largely similar when patients were attributed to specialty based on dominant prescriber.

CONCLUSIONS: Differences in opioid-related risks by specialty of opioid prescriber may arise from differences in patient risk factors, provider behavior, or both. Our findings inform targeting of opioid risk mitigation strategies to specific practitioner specialties.